U.S. patent application number 11/642977 was filed with the patent office on 2007-09-13 for substituted 3-cyanoquinolines as mek inhibitors.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Kevin Michael Foote, Keith Hopkinson Gibson, Laurent Francois Andre Hennequin.
Application Number | 20070213367 11/642977 |
Document ID | / |
Family ID | 9940078 |
Filed Date | 2007-09-13 |
United States Patent
Application |
20070213367 |
Kind Code |
A1 |
Hennequin; Laurent Francois Andre ;
et al. |
September 13, 2007 |
Substituted 3-cyanoquinolines as MEK inhibitors
Abstract
The invention concerns quinoline derivatives of Formula (I)
wherein each of Z.sup.1, m, R.sup.1, n, R.sup.3, Z.sup.2 and
R.sup.14 have any of the meanings defined hereinbefore in the
description; processes for their preparation, pharmaceutical
compositions containing them and their use in the manufacture of a
medicament for use as an anti-invasive or anti-proliferative agent
in the containment and/or treatment of solid tumour disease.
##STR1##
Inventors: |
Hennequin; Laurent Francois
Andre; (Macclesfield, GB) ; Gibson; Keith
Hopkinson; (Macclesfield, GB) ; Foote; Kevin
Michael; (Macclesfield, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
AstraZeneca AB
|
Family ID: |
9940078 |
Appl. No.: |
11/642977 |
Filed: |
December 21, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10520468 |
Jan 7, 2005 |
7173135 |
|
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PCT/GB03/02882 |
Jul 4, 2003 |
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11642977 |
Dec 21, 2006 |
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Current U.S.
Class: |
514/314 |
Current CPC
Class: |
C07D 405/12 20130101;
C07D 405/14 20130101; A61P 35/00 20180101; C07D 417/14
20130101 |
Class at
Publication: |
514/314 |
International
Class: |
A61K 31/47 20060101
A61K031/47; C07D 405/12 20060101 C07D405/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 9, 2002 |
GB |
0215823.6 |
Claims
1. (canceled)
2. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.3,
Z.sup.1, Z.sup.2, m and n have any of the meanings defined in claim
16 or claim 17 and R.sup.14 is selected from cyano, formyl,
carboxy, carbamoyl, methoxycarbonyl, vinyl, ethoxycarbonyl,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, acetyl, propionyl,
chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,
3-methoxypropyl or from a group of the formula: --X.sup.7-Q.sup.5
wherein X.sup.7 is a direct bond or CO and Q.sup.5 is pyridin-2-yl,
1-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1-homopiperidinylmethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or
3-morpholinopropyl, and wherein any CH.sub.2 or CH.sub.3 group
within a R.sup.14 substituent optionally bears on each said
CH.sub.2 or CH.sub.3 group one or more fluoro, chloro or methyl
groups or a substituent selected from hydroxy, amino, methoxy,
methylamino, dimethylamino, acetoxy, acetamido and
N-methylacetamido, and wherein any heteroaryl or heterocyclyl group
within a substituent on R.sup.14 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl,
methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl
and acetyl, or optionally bears 1 substituent selected from a group
of the formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a direct
bond and R.sup.17 is 2-fluoroethyl, 2-hydroxyethyl,
3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl,
aminomethyl, methylaminomethyl, dimethylaminomethyl,
acetamidomethyl, methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and
wherein any heterocyclyl group within a substituent on R.sup.14
optionally bears 1 or 2 oxo substituents.
3. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I wherein:
Z.sup.1 is O or NH; m is 1 and the R.sup.1 group is located at the
5-, 6- or 7-position or m is 2 and each R.sup.1 group, which may be
the same or different, is located at the 5- and 7-positions or at
the 6- and 7-positions and R.sup.1 is selected from hydroxy, amino,
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy,
butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino,
dimethylamino, diethylamino, acetamido, propionamido,
2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,
2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,
4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy,
pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
4-morpholinobutoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy,
piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy,
piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,
3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,
3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,
3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,
3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,
2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and
wherein adjacent carbon atoms in any (2-6C)alkylene chain within a
R.sup.1 substituent are optionally separated by the insertion into
the chain of a group selected from O, NH, N(Me), CH.dbd.CH and
C.ident.C, and wherein any CH.sub.2 or CH.sub.3 group within a
R.sup.1 substituent optionally bears on each said CH.sub.2 or
CH.sub.3 group one or more fluoro or chloro groups or a substituent
selected from hydroxy, amino, methoxy, methylsulphonyl,
methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino,
N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy, and
wherein any heteroaryl or heterocyclyl group within a substituent
on R.sup.1 optionally bears 1 or 2 substituents, which may be the
same or different, selected from fluoro, chloro, trifluoromethyl,
hydroxy, amino, carbamoyl, methyl, ethyl, methoxy,
N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl,
piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or
homopiperazin-1-yl group within a R.sup.1 substituent is optionally
N-substituted with allyl, methylsulphonyl, acetyl, 2-fluoroethyl,
3-fluoropropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl,
2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,
3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of
which substituents each optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro, methyl
and methoxy, and wherein any heterocyclyl group within a
substituent on R.sup.1 optionally bears 1 or 2 oxo substituents; n
is 0 or 1 and the R.sup.3 group, if present, is located at the 5-
or 6-position of the 1,3-benzodioxol-4-yl group and is selected
from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,
methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; Z.sup.2
is a C.ident.C or CH.dbd.CH group; and R.sup.14 is selected from
cyano, formyl, carboxy, carbamoyl, methoxycarbonyl, vinyl,
ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,
2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, methylaminomethyl,
ethylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,
2-acetamidoethyl and 3-acetamidopropyl, or from a group of the
formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or CO
and Q.sup.5 is pyridin-2-yl, 1-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1-homopiperidinylmethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or
3-morpholinopropyl, and wherein any CH.sub.2 or CH.sub.3 group
within a R.sup.14 substituent optionally bears on each said
CH.sub.2 or CH.sub.3 group one or more fluoro, chloro or methyl
groups or a substituent selected from hydroxy, amino, methoxy,
methylamino, dimethylamino, acetoxy, acetamido and
N-methylacetamido, and wherein any heteroaryl or heterocyclyl group
within a substituent on R.sup.14 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl,
methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl
and acetyl, or optionally bears 1 substituent selected from a group
of the formula: --X.sup.9--R.sup.7 wherein X.sup.9 is a direct bond
and R.sup.17 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,
3-methoxypropyl, cyanomethyl, aminomethyl, methylaminomethyl,
dimethylaminomethyl, acetamidomethyl, methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and
wherein any heterocyclyl group within a substituent on R.sup.14
optionally bears 1 or 2 oxo substituents; or a
pharmaceutically-acceptable acid-addition salt thereof.
4. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.3,
R.sup.14, Z.sup.2, m and n have any of the meanings defined in
claim 1 and Z.sup.1 is NH.
5. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.3,
R.sup.14, Z.sup.1, m and n have any of the meanings defined in
claim 1 and Z.sup.2 is a C.ident.C group.
6. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.3,
R.sup.14, Z.sup.1, Z.sup.2, m and n have any of the meanings
defined in claim 1 and the Z.sup.2-R.sup.14 group is located at the
7-position on the 1,3-benzodioxol-4-yl group.
7. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I wherein:
Z.sup.1 is NH; m is 2 and the first R.sup.1 group is a 6-methoxy
group and the second R.sup.1 group is located at the 7-position and
is selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,
2-(2-pyrrolidin-1-ylethoxy)ethoxy and
2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy; n is 0 or n is 1 and
R.sup.3 is a fluoro or chloro group located at the 5-position of
the 1,3-benzodioxol-4-yl group; the -Z.sup.2-R.sup.14 group is
located at the 7-position on the 1,3-benzodioxol-4-yl group,
Z.sup.2 is a C.ident.C group; and R.sup.14 is selected from vinyl,
hydroxymethyl, methoxymethyl, dimethylaminomethyl, pyridin-2-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and
piperazin-1-ylmethyl; or a pharmaceutically-acceptable
acid-addition salt thereof.
8. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I wherein
Z.sup.1 is NH; m is 2 and the first R.sup.1 group is located at the
5-position and is selected from N-methylpiperidin-4-yloxy and
tetrahydro-2H-pyran-4-yloxy and the second R.sup.1 group is located
at the 7-position and is selected from methoxy and
3-morpholinopropoxy, n is 0 or n is 1 and R.sup.3 is located at the
5-position of the 1,3-benzodioxol-4-yl group and is a chloro group;
the -Z.sup.2-R.sup.14 group is located at the 7-position on the
1,3-benzodioxol-4-yl group, Z.sup.2 is a C.ident.C group; and
R.sup.14 is selected from methoxymethyl and 2-methoxyethyl; or a
pharmaceutically-acceptable acid-addition salt thereof.
9. The method of claim 16 or claim 17 which comprises the
administration of a quinoline derivative of the Formula I and
selected from
7-[3-(4-acetylpiperazin-1-yl)propoxy]-3-cyano-6-methoxy-4-[4-(3-methoxypr-
op-1-ynl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-6,7-dimethoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanili-
no]quinoline;
3-cyano-6,7-dimethoxy-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylened-
ioxy anilino]quinoline;
3-cyano-7-ethoxy-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxy-
anilino]quinoline;
3-cyano-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[4-(3--
methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[4-(3-methoxypr-
op-1ynyl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]--
7-[3-morpholinopropoxy]quinoline;
4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-3-cyano-6-
-methoxy-7-[3-morpholinopropoxy]quinoline;
3-cyano-7-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)propoxy]-6-methoxy-4-[4-
-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-7-(2-fluoroethoxy)-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-meth-
ylenedioxyanilino]quinoline;
3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]--
7-[3-(3-oxopiperazin-1-yl)propoxy]quinoline;
3-cyano-6-methoxy-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxy-
anilino]-7-[3-(3-oxopiperazin-1-yl)propoxy]quinoline;
3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]--
7-[2-(2-pyrrolidin-1-ylethoxy)ethoxy]quinoline;
3-cyano-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-4-[4-(3-methoxyprop-1-yny-
l)-2,3-methylenedioxyanilino]quinoline;
3-cyano-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-
-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline;
3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]-4-[4-(3-methoxyprop-1-y-
nyl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)-4-[4--
(3-methoxyprop-1-ynyl)-2,3 -methylenedioxyanilino]quinoline;
3-cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-
-[(1-methylpiperidin-4-yl)oxy]quinoline;
4-[(4-but-3-en-1-ynyl-2,3-methylendioxy)anilino]-3-cyano-7-methoxy-5-[(1--
methylpiperidin-4-yl)oxy]quinoline;
3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[6-fluoro-4-(3--
methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-6-methoxy-7-[2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy]-4-[4-(3-
-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;
3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[4-(3-methoxypr-
op-1-ynyl)-2,3-methylenedioxyanilino]quinoline; and
3-cyano-6,7-dimethoxy-4-[4-(pyridin-2-ylethynyl)-2,3-methylenedioxyanilin-
o]quinoline, or a pharmaceutically acceptable acid addition salt
thereof.
10-15. (canceled)
16. A method for inhibiting a MEK enzyme in a warm-blooded animal
in need thereof which comprises administering to said animal an
effective amount of a quinoline derivative of the Formula I
##STR11## wherein Z.sup.1 is an O, S, SO, SO.sub.2, N(R.sup.2) or
C(R.sup.2).sub.2 group, wherein each R.sup.2 group, which may be
the same or different, is hydrogen or (1-6C)alkyl; m is 0, 1, 2, 3
or 4; each R.sup.1 group, which may be the same or different, is
selected from halogeno, trifluoromethyl, cyano, isocyano, nitro,
hydroxy, mercapto, amino, formyl, 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)alkylsulphinyl,
(1-6C)alkylsulphonyl, (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,
(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: Q.sup.1-X.sup.1-- wherein X.sup.1 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.4), CO, CH(OR.sup.4),
CON(R.sup.4), N(R.sup.4)CO, SO.sub.2N(R.sup.4), N(R.sup.4)SO.sub.2,
OC(R.sup.4).sub.2, SC(R.sup.4).sub.2 and
N(R.sup.4)C(R.sup.4).sub.2, wherein R.sup.4 is hydrogen or
(1-6C)alkyl, and Q.sup.1 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R.sup.1).sub.m is
(1-3C)alkylenedioxy, and wherein adjacent carbon atoms in any
(2-6C)alkylene chain within a R.sup.1 substituent are optionally
separated by the insertion into the chain of a group selected from
O, S, SO, SO.sub.2, N(R.sup.5), CO, CH(OR.sup.5), CON(R.sup.5),
N(R.sup.5)CO, SO.sub.2N(R.sup.5), N(R.sup.5)SO.sub.2, CH.dbd.CH and
C.ident.C wherein R.sup.5 is hydrogen or (1-6C)alkyl or, when the
inserted group is N(R.sup.5), R.sup.5 may also be (2-6C)alkanoyl,
and wherein any CH.sub.2.dbd.CH-- or HC.ident.C-- group within a
R.sup.1 substituent optionally bears at the terminal CH.sub.2.dbd.
or HC.ident. position a substituent selected from halogeno,
carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or
from a group of the formula: Q.sup.2-X.sup.2-- wherein X.sup.2 is a
direct bond or is selected from CO and N(R.sup.6)CO, wherein
R.sup.6 is hydrogen or (1-6C)alkyl, and Q.sup.2 is aryl,
aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl
or heterocyclyl-(1-6C)alkyl, and wherein any CH, CH.sub.2 or
CH.sub.3 group within a R.sup.1 substituent optionally bears on
each said CH, CH.sub.2 or CH.sub.3 group one or more halogeno or
(1-6C)alkyl substituents or a substituent selected from hydroxy,
cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.3-Q.sup.3 wherein X.sup.3 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.7), CO, CH(OR.sup.7),
CON(R.sup.7), N(R.sup.7)CO, SO.sub.2N(R.sup.7), N(R.sup.7)SO.sub.2,
C(R.sup.7).sub.2O, C(R.sup.7).sub.2S and
N(R.sup.7)C(R.sup.7).sub.2, wherein R.sup.7 is hydrogen or
(1-6C)alkyl, and Q.sup.3 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,
heteroaryl or heterocyclyl group within a substituent on R.sup.1
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl,
(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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.4--R.sup.8 wherein X.sup.4 is a direct bond or is
selected from O and N(R.sup.9), wherein R.sup.9 is hydrogen or
(1-6C)alkyl, and R.sup.8 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(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, (2-6C)alkanoylamino-(1-6C)alkyl
or (1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.5-Q.sup.4 wherein X.sup.5 is a direct bond or is
selected from O, N(R.sup.10) and CO, wherein R.sup.10 is hydrogen
or (1-6C)alkyl, and Q.sup.4 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl
which optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl and (1-6C)alkoxy, and wherein any heterocyclyl group
within a substituent on R.sup.1 optionally bears 1 or 2 oxo or
thioxo substituents; n is 0, 1, 2 or 3; each R.sup.3 group is
halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, (3-6C)alkenoylamino,
N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,
N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.6--R.sup.11 wherein X.sup.6 is a direct bond or is
selected from O and N(R.sup.12), wherein R.sup.12 is hydrogen or
(1-6C)alkyl, and R.sup.11 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or
di-[(1-6C)alkyl]amino-(1-6C)alkyl; Z.sup.2 is a C.ident.C or
C(R.sup.13).dbd.C(R.sup.13) group, wherein each R.sup.13 group,
which may be the same or different, is hydrogen or (1-6C)alkyl; and
R.sup.14 is selected from halogeno, cyano, isocyano, formyl,
carboxy, carbamoyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,
(1-6C)alkoxy-(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,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or is
selected from CO, CH(OR.sup.15), CON(R.sup.15) or
SO.sub.2N(R.sup.15), wherein R.sup.15 is hydrogen or (1-6C)alkyl,
and Q.sup.5 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH,
CH.sub.2 or CH.sub.3 group within a R.sup.14 substituent optionally
bears on each said CH, CH.sub.2 or CH.sub.3 group one or more
halogeno or (1-6C)alkyl substituents or a substituent selected from
hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]-sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.8-Q.sup.6 wherein X.sup.8 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.16), CO, CH(OR.sup.16),
CON(R.sup.16), N(R.sup.16)CO, SO.sub.2N(R.sup.16),
N(R.sup.16)SO.sub.2, C(R.sup.16).sub.2O, C(R.sup.16).sub.2S and
N(R.sup.16).sub.2, wherein R.sup.16 is hydrogen or (1-6C)alkyl, and
Q.sup.6 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,
heteroaryl or heterocyclyl group within a substituent on R.sup.14
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl,
(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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]-sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond or is
selected from O and N(R.sup.18), wherein R.sup.18 is hydrogen or
(1-6C)alkyl, and R.sup.17 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(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, (2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the
formula: --X.sup.10-Q.sup.7 wherein X.sup.10 is a direct bond or is
selected from O, N(R.sup.19) and CO, wherein R.sup.19 is hydrogen
or (1-6C)alkyl, and Q.sup.7 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl
which optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl and (1-6C)alkoxy, and wherein any heterocyclyl group
within a substituent on R.sup.14 optionally bears 1 or 2 oxo or
thioxo substituents; or a pharmaceutically-acceptable salt
thereof.
17. A method for the treatment and/or containment of a solid tumour
disease in a warm-blooded animal in need thereof which comprises
administering to said animal an effective amount of a quinoline
derivative of the Formula I ##STR12## wherein Z.sup.1 is an O, S,
SO, SO.sub.2, N(R.sup.2) or C(R.sup.2).sub.2 group, wherein each
R.sup.2 group, which may be the same or different, is hydrogen or
(1-6C)alkyl; m is 0, 1, 2, 3 or 4; each R.sup.1 group, which may be
the same or different, is selected from halogeno, trifluoromethyl,
cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, (3-6C)alkenoylamino,
N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,
N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: Q.sup.1-X.sup.1-- wherein X.sup.1 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.4), CO, CH(OR.sup.4),
CON(R.sup.4), N(R.sup.4)CO, SO.sub.2N(R.sup.4), N(R.sup.4)SO.sub.2,
OC(R.sup.4).sub.2, SC(R.sup.4).sub.2 and
N(R.sup.4)C(R.sup.4).sub.2, wherein R.sup.4 is hydrogen or
(1-6C)alkyl, and Q.sup.1 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R.sup.1).sub.m is
(1-3C)alkylenedioxy, and wherein adjacent carbon atoms in any
(2-6C)alkylene chain within a R.sup.1 substituent are optionally
separated by the insertion into the chain of a group selected from
O, S, SO, SO.sub.2, N(R.sup.5), CO, CH(OR.sup.5), CON(R.sup.5),
N(R.sup.5)CO, SO.sub.2N(R.sup.5), N(R.sup.5)SO.sub.2, CH.dbd.CH and
C.ident.C wherein R.sup.5 is hydrogen or (1-6C)alkyl or, when the
inserted group is N(R.sup.5), R.sup.5 may also be (2-6C)alkanoyl,
and wherein any CH.sub.2.dbd.CH-- or HC.ident.C-- group within a
R.sup.1 substituent optionally bears at the terminal CH.sub.2.dbd.
or HC.ident. position a substituent selected from halogeno,
carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1 -6C)alkyl]carbamoyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or
from a group of the formula: Q.sup.2-X.sup.2-- wherein X.sup.2 is a
direct bond or is selected from CO and N(R.sup.6)CO, wherein
R.sup.6 is hydrogen or (1-6C)alkyl, and Q.sup.2 is aryl,
aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl
or heterocyclyl-(1-6C)alkyl, and wherein any CH, CH.sub.2 or
CH.sub.3 group within a R.sup.1 substituent optionally bears on
each said CH, CH.sub.2 or CH.sub.3 group one or more halogeno or
(1-6C)alkyl substituents or a substituent selected from hydroxy,
cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.3-Q.sup.3 wherein X.sup.3 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.7), CO, CH(OR.sup.7),
CON(R.sup.7), N(R.sup.7)CO, SO.sub.2N(R.sup.7), N(R.sup.7)SO.sub.2,
C(R.sup.7).sub.2O, C(R.sup.7).sub.2S and
N(R.sup.7)C(R.sup.7).sub.2, wherein R.sup.7 is hydrogen or
(1-6C)alkyl, and Q.sup.3 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,
heteroaryl or heterocyclyl group within a substituent on R.sup.1
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl,
(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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.4--R.sup.8 wherein X.sup.4 is a direct bond or is
selected from O and N(R.sup.9), wherein R.sup.9 is hydrogen or
(1-6C)alkyl, and R.sup.8 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(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, (2-6C)alkanoylamino-(1-6C)alkyl
or (1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.5-Q.sup.4 wherein X.sup.5 is a direct bond or is
selected from O, N(R.sup.10) and CO, wherein R.sup.10 is hydrogen
or (1-6C)alkyl, and Q.sup.4 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl
which optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl and (1-6C)alkoxy, and wherein any heterocyclyl group
within a substituent on R.sup.1 optionally bears 1 or 2 oxo or
thioxo substituents; n is 0, 1, 2 or 3; each R.sup.3 group is
halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, (3-6C)alkenoylamino,
N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,
N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.6--R.sup.11 wherein X.sup.6 is a direct bond or is
selected from O and N(R.sup.12), wherein R.sup.12 is hydrogen or
(1-6C)alkyl, and R.sup.11 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or
di-[(1-6C)alkyl]amino-(1-6C)alkyl; Z.sup.2 is a C.ident.C or
C(R.sup.13).dbd.C(R.sup.13) group, wherein each R.sup.13 group,
which may be the same or different, is hydrogen or (1-6C)alkyl; and
R.sup.14 is selected from halogeno, cyano, isocyano, formyl,
carboxy, carbamoyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,
(1-6C)alkoxy-(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,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or is
selected from CO, CH(OR.sup.15), CON(R.sup.15) or
SO.sub.2N(R.sup.15), wherein R.sup.15 is hydrogen or (1-6C)alkyl,
and Q.sup.5 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH,
CH.sub.2 or CH.sub.3 group within a R.sup.14 substituent optionally
bears on each said CH, CH.sub.2 or CH.sub.3 group one or more
halogeno or (1-6C)alkyl substituents or a substituent selected from
hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]-sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.8-Q.sup.6 wherein X.sup.8 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.16), CO, CH(OR.sup.16),
CON(R.sup.16), N(R.sup.16)CO, SO.sub.2N(R.sup.16),
N(R.sup.16)SO.sub.2, C(R.sup.16).sub.2O, C(R.sup.16).sub.2S and
N(R.sup.16)C(R.sup.16).sub.2, wherein R.sup.16 is hydrogen or
(1-6C)alkyl, and Q.sup.6 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,
heteroaryl or heterocyclyl group within a substituent on R.sup.14
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl,
(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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]-sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond or is
selected from O and N(R.sup.18), wherein R.sup.18 is hydrogen or
(1-6C)alkyl, and R.sup.17 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(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, (2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the
formula: --X.sup.10-Q.sup.7 wherein X.sup.10 is a direct bond or is
selected from O, N(R.sup.19) and CO, wherein R.sup.19 is hydrogen
or (1-6C)alkyl, and Q.sup.7 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl
which optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl and (1-6C)alkoxy, and wherein any heterocyclyl group
within a substituent on R.sup.14 optionally bears 1 or 2 oxo or
thioxo substituents; or a pharmaceutically-acceptable salt
thereof.
18. The method of claim 17 wherein said treatment and/or
containment comprises producing an anti-invasive effect by
administering to said animal said effective amount of a quinoline
derivative of the Formula I, or a pharmaceutically-acceptable salt
thereof.
Description
[0001] The invention concerns certain novel quinoline 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 quinoline derivatives,
pharmaceutical compositions containing them and 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 cell proliferation
diseases such as psoriasis and cancer utilise compounds which
inhibit DNA synthesis. Such compounds are toxic to cells generally
but their toxic effect on rapidly dividing cells such as tumour
cells can be beneficial. Alternative approaches to anti-tumour
agents which act by mechanisms other than the inhibition of DNA
synthesis have the potential to display enhanced selectivity of
action.
[0003] In recent years it has been discovered that a cell may
become cancerous by virtue of the transformation of a portion of
its DNA into an oncogene i.e. a gene which, on activation, leads to
the formation of malignant tumour cells (Bradshaw, Mutagenesis,
1986, 1, 91). Oncogenes give rise to the production of peptides
which are receptors for growth factors. Activation of the growth
factor receptor complex subsequently leads to an increase in cell
proliferation. Oncogenes often encode abnormal versions of signal
pathway components, such as receptor tyrosine kinases,
serine-threonine kinases, or downstream signaling molecules such as
the ras genes. The ras genes code for closely related small guanine
nucleotide binding proteins which hydrolyse bound guanosine
triphosphate (GTP) to guanosine diphosphate (GDP). Ras proteins are
active in promoting cell growth and transformation when they are
bound to GTP and inactive when they are bound to GDP. Transforming
mutants of p21ras are defective in their GTPase activity and hence
remain in the active GTP bound state. The ras oncogene is known to
play an integral role in certain cancers and has been found to
contribute to the formation of over 20% of all cases of human
cancer.
[0004] When activated by ligand such as a growth factor, cell
surface receptors which are coupled to the mitogenic response can
initiate a chain of reactions which leads to the activation of
guanine nucleotide exchange activity on ras proteins. When ras
protein is in its active GTP-bound state, a number of other
proteins interact directly with ras at the plasma membrane
resulting in signal transmission through several distinct pathways.
The best characterised effector protein is the product of the raf
proto-oncogene. The interaction of raf and ras is a key regulatory
step in the control of cell proliferation. Ras-mediated activation
of the raf serine-threonine kinase in turn activates the
dual-specificity MEK (MEK1 and MEK2), which is the immediate
upstream activator of mitogen activated protein kinase (MAPKs known
as extracellular signal regulated protein kinases or ERK1 and
ERK2). To date, no substrates of MEK other than MAPK have been
identified, though recent reports indicate that MEK may also be
activated by other upstream signal proteins such as MEKK1 and
Cot/Tp1-2. Activated MAPK translocates and accumulates in the
nucleus, where it can phosphorylate and activate transcription
factors such as Elk-1 and Sap1a, leading to the enhanced expression
of genes such as c-fos.
[0005] The ras-dependent raf-MEK-MAPK cascade is one of the key
signalling pathways responsible for transmitting and amplifying
mitogenic signals from cell surface to the nucleus resulting in
changes in gene expression and cell fate. This ubiquitous pathway
appears essential for normal-cell proliferation and constitutive
activation of this pathway is sufficient to induce cellular
transformation. Transforming mutants of p21ras are constitutively
active, resulting in raf, MEK and MAPK activity and cell
transformation. Inhibition of MEK activity using either antisense
raf, a dominant negative MEK mutant or the selective inhibitor
PD098059 has been shown to block the growth and morphological
transformation of ras-transformed fibroblasts.
[0006] The mechanism of activation of raf, MEK and MAPK is through
phosphorylation on specific serine, threonine or tyrosine residues.
Activated raf and other kinases phosphorylate MEK1 on S218 and S222
and MEK2 on S222 and S226. This results in MEK activation and
subsequent phosphorylation and activation of ERK1 on T190 and Y192
and ERK2 on T183 and Y185 by the dual specificity MEKs. Whilst MEK
can be activated by a number of protein kinases, and active MAPKs
phosphorylate and activate a number of substrate proteins including
transcription factors and other protein kinases, MEKs appear
specific and sole activators of MAPKs and could act as a focal
point for cross-cascade regulation. MEK1 and MEK2 isoforms show
unusual specificity and also contain a proline-rich insert between
catalytic subdomains IX and X which is not present in any of the
other known MEK family members. These differences between MEK and
other protein kinases, together with the known role of MEK (MEK 1,
MEK 2) and, more recently MEK 5, in proliferative signalling
suggest it may be possible to discover and employ selective MEK
inhibitors as therapeutic agents for use in proliferative
disease.
[0007] Accordingly, it has been recognised that an inhibitor of the
MAPK kinase pathway should be of value as an anti-proliferative
agent for use in the containment and/or treatment of solid tumour
disease.
[0008] It is also known that several oncogenes encode tyrosine
kinase enzymes and that certain growth factor receptors are also
tyrosine kinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988,
57, 443; Larsen et al., Ann. Reports in Med. Chem, 1989, Chpt. 13).
The first group of tyrosine kinases to be identified arose from
such viral oncogenes, for example pp60.sup.v-Src tyrosine kinase
(otherwise known as v-Src), and the corresponding tyrosine kinases
in normal cells, for example pp60.sup.c-Src tyrosine kinase
(otherwise known as c-Src).
[0009] Receptor tyrosine kinases are important in the transmission
of biochemical signals which initiate cell replication. Some of
them are large enzymes which span the cell membrane and possess an
extracellular binding domain for growth factors such as epidermal
growth factor (EGF) and an intracellular portion which functions as
a kinase to phosphorylate tyrosine amino acids in proteins and
hence to influence cell proliferation. Various classes of receptor
tyrosine kinases are known (Wilks, Advances in Cancer Research,
1993, 60, 43-73) based on families of growth factors which bind to
different receptor tyrosine kinases. The classification includes
Class I receptor tyrosine kinases comprising the EGF family of
receptor tyrosine kinases such as the EGF, TGF.alpha., Neu and erbB
receptors, Class II receptor tyrosine kinases comprising the
insulin family of receptor tyrosine kinases such as the insulin and
IGFI. receptors and insulin-related receptor (IRR) and Class III
receptor tyrosine kinases comprising the platelet-derived growth
factor (PDGF) family of receptor tyrosine kinases such as the
PDGF.alpha., PDGF.beta. and colony-stimulating factor 1 (CSF1)
receptors.
[0010] It is also known that certain tyrosine kinases belong to the
class of non-receptor tyrosine kinases which are located
intracellularly and are involved in the transmission of biochemical
signals such as those that influence tumour cell motility,
dissemination and invasiveness and subsequently metastatic tumour
growth (Ullrich et al., Cell, 1990, 61, 203-212, Bolen et al.,
FASEB J., 1992, 6, 3403-3409, Brickell et al., Critical Reviews in
Oncogenesis, 1992, 3, 401-406, Bohlen et al., Oncogene, 1993, 8,
2025-2031, Courtneidge et al., Semin. Cancer Biol., 1994, 5,
239-246, Lauffenburger et al., Cell, 1996, 84, 359-369, Hanks et
al., BioEssays, 1996, 19, 137-145, Parsons et al., Current Opinion
in Cell Biology, 1997, 9, 187-192, Brown et al., Biochimica et
Biophysica Acta; 1996, 1287, 121-149 and Schlaepfer et al.,
Progress in Biophysics and Molecular Biology, 1999, 71, 435-478).
Various classes of non-receptor tyrosine kinases are known
including the Src family such as the Src, Lyn and Yes tyrosine
kinases, the Abl family such as Abl and Arg and the Jak family such
as Jak 1 and Tyk 2.
[0011] It is known that the Src family of non-receptor tyrosine
kinases are highly regulated in normal cells and in the absence of
extracellular stimuli are maintained in an inactive conformation.
However, some Src family members, for example c-Src tyrosine
kinase, are frequently significantly activated (when compared to
normal cell levels) in common human cancers such as
gastrointestinal cancer, for example colon, rectal and stomach
cancer (Cartwright et al., Proc. Natl. Acad. Sci. USA, 1990, 87,
558-562 and Mao et al., Oncogene, 1997, 15, 3083-3090), and breast
cancer (Muthuswamy et al., Oncogene, 1995, 11, 1801-1810). The Src
family of non-receptor tyrosine kinases has also been located in
other common human cancers such as non-small cell lung cancers
(NSCLCs) including adenocarcinomas and squamous cell cancer of the
lung (Mazurenko et al., European Journal of Cancer, 1992, 28,
372-7), bladder cancer (Fanning et al., Cancer Research, 1992, 52,
1457-62), oesophageal cancer (Jankowski et al., Gut. 1992, 33,
1033-8), cancer of the prostate, ovarian cancer (Wiener et al.,
Clin. Cancer Research, 1999, 5, 2164-70) and pancreatic cancer
(Lutz et al., Biochem. and Biophys. Res. Comm., 1998, 243, 503-8).
As further human tumour tissues are tested for the Src family of
non-receptor tyrosine kinases it is expected that its widespread
prevalence will be established.
[0012] It is further known that the predominant role of c-Src
non-receptor tyrosine kinase is to regulate the assembly of focal
adhesion complexes through interaction with a number of cytoplasmic
proteins including, for example, focal adhesion kinase and
paxillin. In addition c-Src is coupled to signalling pathways that
regulate the actin cytoskeleton which facilitates cell motility.
Likewise, important roles are played by the c-Src, c-Yes and c-Fyn
non-receptor tyrosine kinases in integrin mediated signalling and
in disrupting cadherin-dependent cell-cell junctions (Owens et al.,
Molecular Biology of the Cell. 2000, 11, 51-64 and Klinghoffer et
al., EMBO Journal, 1999, 18, 2459-2471). Cellular motility is
necessarily required for a localised tumour to progress through the
stages of dissemination into the blood stream, invasion of other
tissues and initiation of metastatic tumour growth. For example,
colon tumour progression from localised to disseminated, invasive
metastatic disease has been correlated with c-Src non-receptor
tyrosine kinase activity (Brunton et al., Oncogene, 1997, 14,
283-293, Fincham et al., EMBO J, 1998, 17, 81-92 and Verbeek et
al., Exp. Cell Research, 1999, 248, 531-537).
[0013] Accordingly it has been recognised that an inhibitor of such
non-receptor tyrosine kinases should be of value as a selective
inhibitor of the motility of tumour cells and as a selective
inhibitor of the dissemination and invasiveness of mammalian cancer
cells leading to inhibition of metastatic tumour growth. In
particular an inhibitor of such non-receptor tyrosine kinases
should be of value as an anti-invasive agent for use in the
containment and/or treatment of solid tumour disease.
[0014] We have now found that surprisingly certain quinoline
derivatives possess potent anti-tumour activity. It is believed
that the compounds disclosed in the present invention provide an
anti-tumour effect by way of inhibition of MEK enzymes that are
involved in the MAPK kinase pathway and/or by way of inhibition of
one or more of the non-receptor tyrosine-specific protein kinases
that are involved in the signal transduction steps which lead to
the invasiveness and migratory ability of metastasising tumour
cells. In particular, it is believed that the compounds of the
present invention provide an anti-tumour effect by inhibition of
one or more of the MEK enzymes and/or by way of inhibition of the
Src family of non-receptor tyrosine kinases, for example by
inhibition of one or more of c-Src, c-Yes and c-Fyn. It is also
known that c-Src non-receptor tyrosine kinase enzyme is involved in
the control of osteoclast-driven bone resorption (Soriano et al.,
Cell, 1991, 64, 693-702; Boyce et al., J. Clin. Invest., 1992, 90,
1622-1627; Yoneda et al., J. Clin. Invest., 1993, 91, 2791-2795 and
Missbach et al., Bone, 1999, 24, 437-49). An inhibitor of c-Src
non-receptor tyrosine kinase is therefore of value in the
prevention and treatment of bone diseases such as osteoporosis,
Paget's disease, metastatic disease in bone and tumour-induced
hypercalcaemia.
[0015] The compounds of the present invention are also useful in
inhibiting the uncontrolled cellular proliferation which arises
from various non-malignant diseases such as inflammatory diseases
(for example rheumatoid arthritis and inflammatory bowel disease),
fibrotic diseases (for example hepatic cirrhosis and lung
fibrosis), glomerulonephritis, multiple sclerosis, psoriasis,
hypersensitivity reactions of the skin, blood vessel diseases (for
example atherosclerosis and restenosis), allergic asthma,
insulin-dependent diabetes, diabetic retinopathy and diabetic
nephropathy.
[0016] The compounds of the invention may possess inhibitory
activity against the MEK enzymes that are involved in the MAPK
kinase pathway. They may also possess an inhibitory activity
against the Src family of non-receptor tyrosine kinases. Generally
the compounds of the present invention may also possess potent
inhibitory activity against the Src family of non-receptor tyrosine
kinases, for example by inhibition of c-Src and/or c-Yes, whilst
possessing less potent inhibitory activity against other tyrosine
kinase enzymes such as the receptor tyrosine kinases, for example
EGF receptor tyrosine kinase and/or VEGF receptor tyrosine
kinase.
[0017] It is stated in International Patent Application WO 98/43960
that a range of 3-cyanoquinoline derivatives are useful in the
treatment of cancer. Certain of the compounds are stated to be
inhibitors of the mitogen-activated protein kinase (MAPK) pathway,
others are stated to be inhibitors of EGF receptor tyrosine kinase,
and others are stated to be inhibitors of growth factors such as
vascular endothelial growth factor (VEGF). There is no disclosure
therein of any 1,3-benzodioxol-4-containing 3-cyanoquinoline
derivatives.
[0018] It is stated in International Patent Application WO 00/68201
that a range of 3-cyanoquinoline derivatives are also useful in the
treatment of cancer. Certain of the compounds are stated to be
inhibitors of MEK, a MAPK kinase. There is no disclosure therein of
any 1,3-benzodioxol-4-yl-containing 3-cyanoquinoline
derivatives.
[0019] It is disclosed in Journal Medicinal Chemistry, 2001, 44,
822-833 that certain 4-anilino-3-cyanoquinoline derivatives are
useful for the inhibition of Src-dependent cell proliferation.
There is no disclosure therein of any
1,3-benzodioxol-4-yl-containing 3-cyanoquinoline derivatives.
[0020] According to one aspect of the invention there is provided a
quinoline derivative of the Formula I ##STR2## wherein Z.sup.1 is
an O, S, SO, SO.sub.2, N(R.sup.2) or C(R.sup.2).sub.2 group,
wherein each R.sup.2 group, which may be the same or different, is
hydrogen or (1-6C)alkyl;
[0021] m is 0, 1, 2, 3 or 4;
[0022] each R.sup.1 group, which may be the same or different, is
selected from halogeno, trifluoromethyl, cyano, isocyano, nitro,
hydroxy, mercapto, amino, formyl, 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)alkylsulphinyl,
(1-6C)alkylsulphonyl, (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,
(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: Q.sup.1-X.sup.1-- wherein X.sup.1 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.4), CO, CH(OR.sup.4),
CON(R.sup.4), N(R.sup.4)CO, SO.sub.2N(R.sup.4), N(R.sup.4)SO.sub.2,
OC(R.sup.4).sub.2, SC(R.sup.4).sub.2 and
N(R.sup.4)C(R.sup.4).sub.2, wherein R.sup.4 is hydrogen or
(1-6C)alkyl, and Q.sup.1 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R.sup.1).sub.m is
(1-3C)alkylenedioxy,
[0023] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, S, SO,
SO.sub.2, N(R.sup.5), CO, CH(OR.sup.5), CON(R.sup.5), N(R.sup.5)CO,
SO.sub.2N(R.sup.5), N(R.sup.5)SO.sub.2, CH.dbd.CH and C.ident.C
wherein R.sup.5 is hydrogen or (1-6C)alkyl or, when the inserted
group is N(R.sup.5), R.sup.5 may also be (2-6C)alkanoyl,
[0024] and wherein any CH.sub.2.dbd.CH-- or HC.ident.C-- group
within a R.sup.1 substituent optionally bears at the terminal
CH.sub.2.dbd. or HC.ident. position a substituent selected from
halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,
di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q.sup.2-X.sup.2-- wherein X.sup.2 is a direct bond or is selected
from CO and N(R.sup.6)CO, wherein R.sup.6 is hydrogen or
(1-6C)alkyl, and Q.sup.2 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0025] and wherein any CH, CH.sub.2 or CH.sub.3 group within a
R.sup.1 substituent optionally bears on each said CH, CH.sub.2 or
CH.sub.3 group one or more halogeno or (1-6C)alkyl substituents or
a substituent selected from hydroxy, cyano, amino, carboxy,
carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,
(1-6C)alkylsulphonyl, (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,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.3-Q.sup.3 wherein X.sup.3 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.7), CO, CH(OR.sup.7),
CON(R.sup.7), N(R.sup.7)CO, SO.sub.2N(R.sup.7), N(R.sup.7)SO.sub.2,
C(R.sup.7).sub.2O, C(R.sup.7).sub.2S and
N(R.sup.7)C(R.sup.7).sub.2, wherein R.sup.7 is hydrogen or
(1-6C)alkyl, and Q.sup.3 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl,
[0026] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.1 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, N-(1-6C)alkylsulphamoyl, N,
N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.4--R.sup.8 wherein X.sup.4 is a direct bond or is
selected from O and (R.sup.9), wherein R.sup.9 is hydrogen or
(1-6C)alkyl, and R.sup.8 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(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, (2-6C)alkanoylamino-(1-6C)alkyl
or (1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.5-Q.sup.4 wherein X.sup.5 is a direct bond or is
selected from O, N(R.sup.10) and CO, wherein R.sup.10 is hydrogen
or (1-6C)alkyl, and Q.sup.4 is aryl, aryl-(1-6C)alkyl, heteroaryl
heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl
which optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl and (1-6C)alkoxy,
[0027] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo or thioxo substituents;
[0028] n is 0, 1, 2 or 3;
[0029] each R.sup.3 group is halogeno, trifluoromethyl, 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)alkylsulphinyl,
(1-6C)alkylsulphonyl, (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,
(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.6--R.sup.11 wherein X.sup.6 is a direct bond or is
selected from O and N(R.sup.12), wherein R.sup.12 is hydrogen or
(1-6C)alkyl, and R.sup.11 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or
di-[(1-6C)alkyl]amino-(1-6C)alkyl;
[0030] Z.sup.2 is a C.ident.C or C(R.sup.13).dbd.C(R.sup.13) group,
wherein each R.sup.13 group, which may be the same or different, is
hydrogen or (1-6C)alkyl; and
[0031] R.sup.14 is selected from halogeno, cyano, isocyano, formyl,
carboxy, carbamoyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,
(1-6C)alkoxy-(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,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or is
selected from CO, CH(OR.sup.15), CON(R.sup.15) or
SO.sub.2N(R.sup.15), wherein R.sup.15 is hydrogen or (1-6C)alkyl,
and Q.sup.5 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or eterocyclyl-(1-6C)alkyl,
[0032] and wherein any CH, CH.sub.2 or CH.sub.3 group within a
R.sup.14 substituent optionally bears on each said CH, CH.sub.2 or
CH.sub.3 group one or more halogeno or (1-6C)alkyl substituents or
a substituent selected from hydroxy, cyano, amino, carboxy,
carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,
(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbarnoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-2-6C)alkanoylamino,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.8-Q.sup.6 wherein X.sup.8 is a direct bond or is
selected from O, S, SO, SO.sub.2, N(R.sup.16), CO, CH(OR.sup.16),
CON(R.sup.16), N(R.sup.16)CO, SO.sub.2N(R.sup.16),
N(R.sup.16)SO.sub.2, C(R.sup.16).sub.2O, C(R.sup.16).sub.2S and
N(R.sup.16)C(R.sup.16).sub.2, wherein R.sup.16 is hydrogen or
(1-6C)alkyl, and Q.sup.6 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,
(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,
heterocyclyl or heterocyclyl-(1-6C)alkyl,
[0033] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.14 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl, 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)alkylsulphinyl, (1-6C)alkylsulphonyl, (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, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino or from a group of the
formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond or is
selected from O and N(R.sup.18), wherein R.sup.18 is hydrogen or
(1-6C)alkyl, and R.sup.17 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,
di-[(1-6C)alkyl]aminio-(1-6C)alkyl,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the
formula: --X.sup.10-Q.sup.7 wherein X.sup.10 is a direct bond or is
selected from O, N(R.sup.19) and CO, wherein R.sup.19 is hydrogen
or (1-6C)alkyl, and Q.sup.7 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl
which optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl and (1-6C)alkoxy,
[0034] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo or thioxo substituents;
or a pharmaceuticalIy-acceptable salt thereof.
[0035] In this specification the generic term "alkyl" includes both
straight-chain and branched-chain alkyl groups such as propyl,
isopropyl and tert-butyl, and also (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-[(1-6Calkyl]amino includes dimethylamino, diethylamino,
N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.
[0036] 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 asymmetric carbon atoms,
the invention includes in its definition any such optically active
or racemic form 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.
[0037] Suitable values for the generic radicals referred to above
include those set out below.
[0038] A suitable value for any one of the `Q` groups (Q.sup.1 to
Q.sup.7) when it is aryl or for the aryl group within a `Q` group
is, for example, phenyl or naphthyl, preferably phenyl.
[0039] A suitable value for any one of the `Q` groups (Q.sup.1,
Q.sup.3, Q.sup.5 or Q.sup.6) when it is (3-7C)cycloalkyl or for the
(3-7C)cycloalkyl group within a `Q` group is, for example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
bicyclo[2.2.1]heptyl and a suitable value for any one of the `Q`
groups (Q.sup.1, Q.sup.3 or Q.sup.6) when it is (3-7C)cycloalkenyl
or for the (3-7C)cycloalkenyl group within a `Q` group is, for
example, cyclobutenyl, cyclopentenyl, cyclohexenyl or
cycloheptenyl.
[0040] A suitable value for any one of the `Q` groups (Q.sup.1 to
Q.sup.7) when it is heteroaryl or for the heteroaryl group within a
`Q` group is, for example, an aromatic 5- or 6-membered monocyclic
ring or a 9- or 10-membered bicyclic ring with up to five ring
heteroatoms selected from oxygen, nitrogen and sulphur, for example
furyl, pyrrolyl, thienyl oxazolyl, isoxazolyl, imidazolyl,
pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,
triazolyl tetrazolyl pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl,
benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,
quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or
naphthyridinyl.
[0041] A suitable value for any one of the `Q` groups (Q.sup.1 to
Q.sup.7) when it is heterocyclyl or for the heterocyclyl group
within a `Q` group is, for example, a non-aromatic saturated or
partially saturated 3 to 10 membered monocyclic or bicyclic ring
with up to five heteroatoms selected from oxygen, nitrogen and
sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, oxepanyl, tetrahydrothienyl,
1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl,
1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl,
pyrrolidinyl morpholinyl, tetrahydro-1,4-thiazinyl,
1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl,
preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,
morpholinyl, 1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or
piperazinyl. A suitable value for such a group which bears 1 or 2
oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl,
2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl,
2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or
2,6-dioxopiperidinyl.
[0042] A suitable value for a `Q` group when it is
heteroaryl-(1-6C)alkyl is, for example, heteroarylmethyl,
2-heteroarylethyl and 3-heteroarylpropyl. The invention comprises
corresponding suitable values for `Q` groups when, for example,
rather than a heteroaryl-(1-6C)alkyl group, an aryl-(1-6C)alkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl-(1-6C)alkyl or
heterocyclyl-(1-6C)alkyl group is present.
[0043] A suitable value for a `Q` group when it is
heterocyclyl-(1-6C)alkyl is, for example, 3-piperazin-1-ylpropyl,
3-morpholinopropyl, 3-(1,1-dioxotetrahydro-4H-1,4-thiazinyl)propyl,
3-piperidin-4-ylpropyl, 3-piperidin-1-ylpropyl or
4-pyrrolidin-1ylbutyl.
[0044] In structural Formula I there is a hydrogen atom at the
2-position on the quinoline ring. It is to be understood thereby
that the R.sup.1 substituents may only be located at the 5-, 6-, 7-
or 8-positions on the quinoline ring i.e. that the 2-position
remains unsubstituted. It is further to be understood that the
R.sup.3 group that may be present on the 1,3-benzodioxol-4-yl group
within structural Formula I may be located on the phenyl ring or on
the methylene group within the dioxol group. Preferably, any
R.sup.3 group that is present on the 1,3-benzodioxol-4-yl group
within structural Formula I is located on the phenyl ring thereof.
It is further to be understood that the -Z.sup.2-R.sup.14 group
within structural Formula I may only be located on the phenyl ring
within the 1,3-benzodioxol-4-yl group.
[0045] For the avoidance of doubt, the positions on structural
Formula I are numbered as ##STR3## follows:
[0046] Suitable values for any of the `R` groups (R.sup.1 to
R.sup.19) or for various groups within an R.sup.1, R.sup.3 or
R.sup.14 group include: [0047] for halogeno fluoro, chloro, bromo
and iodo; [0048] for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl
and tert-butyl; [0049] for (2-8C)alkenyl: vinyl, isopropenyl, allyl
and but-2-enyl; [0050] for (2-8C)alkynyl: ethynyl, 2-propynyl and
but-2-ynyl; [0051] for (1-6C)alkoxy: methoxy, ethoxy, propoxy,
isopropoxy and butoxy; [0052] for (2-6C)alkenyloxy: vinyloxy and
allyloxy; [0053] for (2-6C)alkynyloxy: ethynyloxy and
2-propynyloxy; [0054] for (1-6C)alkylthio: methylthio, ethylthio
and propylthio; [0055] for (1-6C)alkylsulphinyl: methylsulphinyl
and ethylsulphinyl; [0056] for (1-6C)alkylsulphonyl:
methylsulphonyl and ethylsulphonyl; [0057] for (1-6C)alkylamino:
methylamino, ethylamino, propylamino, isopropylamino and
butylamino; [0058] for di-[(1-6C)alkyl]amino: dimethylamino,
diethylamino, N-ethyl-N-methylamino and diisopropylamino; [0059]
for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl and tert-butoxycarbonyl; [0060] for
N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl; [0061] for N,N-di-[(1-6C)alkyl]carbamoyl:
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and
N,N-diethylcarbamoyl; [0062] for (2-6C)alkanoyl: acetyl and
propionyl; [0063] for (2-6C)alkanoyloxy: acetoxy and propionyloxy;
[0064] for (2-6C)alkanoylamino: acetamido and propionamido; [0065]
forN-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and
N-methylpropionamido; [0066] for N-(1-6C)alkylsulphamoyl:
N-methylsulphamoyl and N-ethylsulphamoyl; [0067] for
N,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl; [0068] for
(1-6C)alkanesulphonylamino: methanesulphonylamino and
ethanesulphonylamino; [0069] for
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino:
N-methylmethanesulphonylamino and N-methylethanesulphonylamino;
[0070] for (3-6C)alkenoylamino: acrylamido, methacrylamido and
crotonamido; [0071] for N-(1-6C)alkyl-(3-6C)alkenoylamino:
N-methylacrylamido and N-methylcrotonamido; [0072] for
(3-6C)alkynoylamino: propiolamido; [0073] for
N-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; [0074] for
amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and
3aminopropyl; [0075] for (1-6C)alkylamino-(1-6C)alkyl:
methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl,
2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl;
[0076] for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,
diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and
3-dimethylaminopropyl; [0077] for halogeno-(1-6C)alkyl:
chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chloropropyl;
[0078] for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl,
1-hydroxyethyl and 3-hydroxypropyl; [0079] for
(1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,
1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
[0080] for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl,
1-cyanoethyl and 3-cyanopropyl; [0081] for
(2-6C)alkanoylamino-(1-6C)alkyl: acetamidomethyl,
propionamidomethyl and 2-acetamidoethyl; and [0082] for
(1-6C)alkoxycarbonylamino-1-6C)alkyl: methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and
2-methoxycarbonylaminoethyl.
[0083] A suitable value for (R.sup.1).sub.m when it is a
(1-3C)alkylenedioxy group is, for example, methylenedioxy or
ethylenedioxy and the oxygen atoms thereof occupy adjacent ring
positions.
[0084] When, as defined hereinbefore, an R.sup.1 group forms a
group of the formula Q.sup.1-X.sup.1-- and, for example, X.sup.1 is
a OC(R.sup.4).sub.2 linking group, it is the carbon atom, not the
oxygen atom, of the OC(R.sup.4).sub.2 linking group which is
attached to the quinoline ring and the oxygen atom is attached to
the Q.sup.1 group. Similarly, when, for example a CH.sub.3 group
within a R.sup.1 substituent bears a group of the formula
--X.sup.3-Q.sup.3 and, for example, X.sup.3 is a C(R.sup.7).sub.2O
linking group, it is the carbon atom, not the oxygen atom, of the
C(R.sup.7).sub.2O linking group which is attached to the CH.sub.3
group and the oxygen atom is linked to the Q.sup.3 group. A similar
convention applies to the attachment of the groups of the formulae
Q.sup.3-X.sup.3--, and --X.sup.8-Q.sup.6.
[0085] As defined hereinbefore, adjacent carbon atoms in any
(2-6C)alkylene chain within a R.sup.1 substituent may be optionally
separated by the insertion into the chain of a group such as O,
CON(R.sup.5) or C.ident.C. For example, insertion of a C.ident.C
group into the ethylene chain within a 2-morpholinoethoxy group
gives rise to a 4-morpholinobut-2-ynyloxy group and, for example,
insertion of a CONH group into the ethylene chain within a
3-methoxypropoxy group gives rise to, for example, a
2-(2-methoxyacetamido)ethoxy group.
[0086] When, as defined hereinbefore, any CH, CH.sub.2 or CH.sub.3
group within a R.sup.1 or R.sup.14 substituent optionally bears on
each said CH, CH.sub.2 or CH.sub.3 group a substituent as defined
hereinbefore, suitable R.sup.1 or R.sup.14 substituents so formed
include, for example, hydroxy-substituted heterocyclyl-(1-6C)alkoxy
groups such as 2-hydroxy-3-piperidinopropoxy and
2-hydroxy-3-morpholinopropoxy.
[0087] 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,
sulphuric, 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.
[0088] Particular novel compounds of the invention include, for
example, quinoline derivatives of the Formula I, or
pharmaceutically-acceptable salts thereof, wherein, unless
otherwise stated, each of Z.sup.1, m, R.sup.1, n, R.sup.3, Z.sup.2
and R.sup.14 has any of the meanings defined hereinbefore or in
paragraphs (a) to (y) hereinafter:-- [0089] (a) Z.sup.1 is O, S,
SO, SO.sub.2, CH.sub.2 or NH; [0090] (b) Z.sup.1 is O; [0091] (c)
Z.sup.1 is NH; [0092] (d) R.sup.1 substituents may only be located
at the 5-, 6- and/or 7-positions on the quinoline ring i.e. the 2-
and 8-positions remain unsubstituted; [0093] (e) R.sup.1
substituents may only be located at the 6- and/or 7-positions on
the quinoline ring i.e. the 2-, 5- and 8-positions remain
unsubstituted; [0094] (f) R.sup.1 substituents may only be located
at the 5- and/or 7-positions on the quinoline ring i.e. the 2-, 6-
and 8-positions remain unsubstituted; [0095] (g) m is 1 or 2, and
each R.sup.1 group, which may be the same or different, is selected
from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl,
(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylamino,
di-[(1-6C)alkyl)amino, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,
N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino and
N-(1-6C)alkyl-(3-6C)alkynoylamino or from a group of the formula:
Q.sup.1-X.sup.1-- wherein X.sup.1 is a direct bond or is selected
from O, N(R.sup.4), CON(R.sup.4), N(R.sup.4)CO and
OC(R.sup.4).sub.2 wherein R.sup.4 is hydrogen or (1-6C)alkyl, and
Q.sup.1 is aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0096] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, N(R.sup.5),
CON(R.sup.5), N(R.sup.5)CO, CH.dbd.CH and C.ident.C wherein R.sup.5
is hydrogen or (1-6C)alkyl, or, when the inserted group is
N(R.sup.5), R.sup.5 may also be (2-6C)alkanoyl,
[0097] and wherein any CH.sub.2.dbd.CH-- or HC.ident.C-- group
within a R.sup.1 substituent optionally bears at the terminal
CH.sub.2.dbd. or HC.ident. position a substituent selected from
carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and
di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q.sup.2-X.sup.2-- wherein X.sup.2 is a direct bond or is CO or
N(R.sup.6)CO, wherein R.sup.6 is hydrogen or (1-6C)alkyl, and
Q.sup.2 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0098] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more halogeno groups or a substituent selected from
hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino or from a
group of the formula: --X.sup.3-Q.sup.3 wherein X.sup.3 is a direct
bond or is selected from O, N(R.sup.6), CON(R.sup.7), N(R.sup.7)CO
and C(R.sup.7).sub.2O, wherein R.sup.7 is hydrogen or (1-6C)alkyl,
and Q.sup.3 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0099] and wherein any aryl heteroaryl or heterocyclyl group within
a substituent on R.sup.1 optionally bears 1, 2 or 3 substituents,
which may be the same or different, selected from halogeno,
trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulphonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and
(2-6C)alkanoyl, or optionally bears 1 substituent selected from a
group of the formula: --X.sup.4--R.sup.8 wherein X.sup.4 is a
direct bond or is selected from O and N(R.sup.9), wherein R.sup.9
is hydrogen or (1-6C)alkyl, and R.sup.8 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(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, (2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.5-Q.sup.4 wherein X.sup.5 is a direct bond or is
selected from O, N(R.sup.10) and CO, wherein R.sup.10 is hydrogen
or (1-6C)alkyl, and Q.sup.4 is heterocyclyl or
heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2
substituents, which maybe the same or different, selected from
halogeno, (1-6C)alkyl and (1-6C)alkoxy,
[0100] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo substituents; [0101] (h) m is 1
or 2, and each R.sup.1 group, which may be the same or different,
is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino,
carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl,
pent-4-enyl, hex-5-enyl, ethynyl, 2-propynyl, but-3-ynyl,
pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy,
butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy,
ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy,
hex-5-ynyloxy, methylamino, ethylamino, propylamino, dimethylamino,
diethylamino, dipropylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and
propiolamido or from a group of the formula: Q.sup.1-X.sup.1--
wherein X.sup.1 is a direct bond or is selected from O, NH, CONH,
NHCO and OCH.sub.2 and Q.sup.1 is phenyl, benzyl,
cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-1-yl,
1,2,4-triazol-1-yl, 2-, 3- or 4-pyridyl, 2-imidazol-1-ylethyl,
3-imidazol-1-ylpropyl, 2-(1,2,3-triazolyl)ethyl,
3-(1,2,3-triazolyl)propyl, 2-(1,2,4-triazolyl)ethyl,
3-(1,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or
4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl,
tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 1-, 2- or
3-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
piperidin-3-yl, piperidinyl, 1-, 3- or 4-homopiperidinyl,
piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,
3- or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,
4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,
4-morpholinobutyl,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,
2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,
2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,
2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,
2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,
2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,
4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or
3-homopiperazin-1-ylpropyl,
[0102] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, NH, N(Me),
CONH, NHCO, CH.dbd.CH and C.ident.C,
[0103] and wherein any CH.sub.2.dbd.CH-- or HC.ident.C-- group
within a R.sup.1 substituent optionally bears at the terminal
CH.sub.2.dbd. or HC.ident. position a substituent selected from
carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,
N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl,
4-aminobutyl, methylaminomethyl, 2-methylaminoethyl,
3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl or
4-dimethylaminobutyl, or from a group of the formula:
Q.sup.2-X.sup.2-- wherein X.sup.2 is a direct bond or is CO, NHCO
or N(Me)CO and Q.sup.2 is pyridyl, pyridylmethyl, 2-pyridylethyl,
pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino,
piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,
pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl,
pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,
3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl,
3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl,
2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,
piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,
2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,
3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,
[0104] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro or chloro groups or a substituent selected
from hydroxy, amino, methoxy, methylsulphonyl, methylamino,
dimethylamino, diisopropylamino, N-ethyl-N-methylamino,
N-isopropyl-N-methylamino, N-methyl-N+EE,-propylamino, acetoxy,
acetamido and N-methylacetamido or from a group of the formula:
--X.sup.3-Q.sup.3 wherein X.sup.3 is a direct bond or is selected
from O, NH, CONH, NHCO and CH.sub.2O and Q.sup.3 is pyridyl,
pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino,
piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,
pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,
3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,
2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl,
2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,
[0105] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.1 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl,
ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl or optionally
bears 1 substituent selected from a group of the formula:
--X.sup.4--R.sup.8 wherein X.sup.4 is a direct bond or is selected
from O and NH and R.sup.8 is 2-fluoroethyl, 3-fluoropropyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl,
methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,
methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,
tert-butoxycarbonylaminomethyl or a group of the formula:
--X.sup.5-Q.sup.4 wherein X.sup.5 is a direct bond or is selected
from O, NH and CO and Q.sup.4 is pyrrolidin-1-ylmethyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, morpholinomethyl,
2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl,
2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, each of which
optionally bears 1 or 2 substituents, which may be the same or
different, selected from fluoro, chloro, methyl and methoxy, and
wherein any heterocyclyl group within a substituent on R.sup.1
optionally bears 1 or 2 oxo substituents; [0106] (i) m is 1 or 2,
and each R.sup.1 group, which may be the same or different, is
selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl,
(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino or from a
group of the formula: Q.sup.1-X.sup.1-- wherein X.sup.1 is selected
from O, N(R.sup.4), CON(R.sup.4), N(R.sup.4)CO and
OC(R.sup.4).sub.2 wherein R.sup.4 is hydrogen or (1-6C)alkyl, and
Q.sup.1 is aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl, or X.sup.1 is a direct bond and Q.sup.1
is aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl, heteroaryl-(1-6C)alkyl
or heterocyclyl-(1-6C)alkyl,
[0107] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, N(R.sup.5),
CON(R.sup.5), (R.sup.5)CO, CH.dbd.CH and C.ident.C wherein R.sup.5
is hydrogen or (1-6C)alkyl, or, when the inserted group is
N(R.sup.5), R.sup.5 may also be (2-6C)alkanoyl,
[0108] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent-optionally bears on each said CH.sub.2 or CH.sub.3
group one or more halogeno groups or a substituent selected from
hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino or a group
of the formula: --X.sup.3-Q.sup.3 wherein X.sup.3 is a direct bond
or is selected from O, N(R.sup.6), CON(R..sup.7), N(R.sup.7)CO and
C(R.sup.7).sub.2O, wherein R.sup.7 is hydrogen or (1-6C)alkyl, and
Q.sup.3 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0109] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.1 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl hydroxy, amino, carbamoyl, (1-6C)alkyl,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulphonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and
(2-6C)alkanoyl, or optionally bears 1 substituent selected from a
group of the formula: --X.sup.4--R.sup.8 wherein X.sup.4 is a
direct bond or is selected from O and N(R.sup.9), wherein R.sup.9
is hydrogen or (1-6C)alkyl, and R.sup.8 is hydroxy-(1-6C)alkyl,
(1-6C)alkoxy-(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,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl or from a group of the
formula: --X.sup.5-Q.sup.4 wherein X.sup.5 is a direct bond or is
selected from O, N(R.sup.10) and CO, wherein R.sup.10 is hydrogen
or (1-6C)alkyl, and Q.sup.4 is heterocyclyl or
heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2
substituents, which may be the same or different, selected-from
halogeno, (1-6C)alkyl and (1-6C)alkoxy,
[0110] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo substituents; [0111] (j) m is 1
or 2, and each R.sup.1 group, which may be the same or different,
is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino,
carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, methylamino, ethylamino, propylamino,
dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido,
propiolamido or from a group of the formula: Q.sup.1-X.sup.1--
wherein X.sup.1 is selected from O, NH, CONH, NHCO and OCH.sub.2
and Q.sup.1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl,
1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 2-, 3- or
4-pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl,
2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl,
2-(1,2,4-triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or
4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or
4-pyridyl)propyl, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl,
1-, 2- or 3-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4yl, piperidino, piperidin-3-yl,
piperidin-4yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,
homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,
3- or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,
4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,
4-morpholinobutyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4yl)ethyl,
3-(1,1-dioxotetrahydro-4H-1,4thiazin-4-yl)propyl,
2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,
2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,
2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,
2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,
2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, piperazin-1-ylbutyl,
2-homopiperazin-1-ylethyl or 3-homopiperazin-1-ylpropyl, or wherein
X.sup.1 is a direct bond and Q.sup.1 is benzyl, cyclopropylmethyl,
2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl,
2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl,
2-(1,2,4-triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or
4-pyridylmethyl, 2-(2-, 3- or 4pyridyl)ethyl, 3-(2-, 3- or
4-pyridyl)propyl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl,
piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or
4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,
4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,
4-morpholinobutyl,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,
3-(1,1-dioxotetrahydro-4H-1,4thiazin-4-yl)propyl,
2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,
2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,
2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,
2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,
2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,
4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or
3-homopiperazin-1-ylpropyl,
[0112] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, NH, N(Me),
CONH, NHCO, CH.dbd.CH and C.ident.C,
[0113] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro or chloro groups or a substituent selected
from hydroxy, amino, methoxy, methylsulphonyl, methylamino,
dimethylamino, diisopropylamino, N-ethyl-N-methylamino,
N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy,
acetamido, N-methylacetamido or from a group of the formula:
--X.sup.3-Q.sup.3 wherein X.sup.3 is a direct bond or is selected
from O, NH, CONH, NHCO and CH.sub.2O and Q.sup.3 is pyridyl,
pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino,
piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,
pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,
3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,
2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl,
2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,
[0114] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.1 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl,
ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally
bears 1 substituent selected from a group of the formula:
--X.sup.4--R.sup.8 wherein X.sup.4 is a direct bond or is selected
from O and NH and R.sup.8 is 2-hydroxyethyl, 3-hydroxypropyl,
2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl,
2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,
3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl,
dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
acetamidomethyl, methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl or from a
group of the formula: --X.sup.5-Q.sup.4 wherein X.sup.5 is a direct
bond or is selected from O, NH and CO and Q.sup.4 is
pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl,
3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,
3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or
3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2
substituents, which may be the same or different, selected from
fluoro, chloro, methyl and methoxy, [0115] and wherein any
heterocyclyl group within a substituent on R.sup.1 optionally bears
1 or 2 oxo substituents; [0116] (k) m is 2 and each R.sup.1 group,
which may be the same or different, is located at the 5- and
7-positions or at the 6- and 7-positions and R.sup.1 is selected
from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy,
propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino,
dimethylamino, diethylamino, acetamido, propionamido,
cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy,
3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy,
3-(1,2,3-triazol-1-yl)propoxy, 2-(1,2,4-triazol-1-yl)ethoxy,
3-(1,2,4-triazol-1-yl)propoxy, pyrid-2-ylmethoxy,
pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy,
2-pyrid-3-ylethoxy, 2-pyrid-4ylethoxy, 3-pyrid-2-ylpropoxy,
3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy,
pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,
2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy,
2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy,
piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy,
piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,
3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,
3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,
3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,
3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,
2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy,
2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1-ylpropylamino,
4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino,
pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino,
3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino,
3-morpholinopropylamino, 4-morpholinobutylamino,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4yl)ethylamino,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,
2-piperidinoethylamino, 3-piperidinopropylamino,
4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino,
piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino,
piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino,
2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino,
2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino,
4-piperazin-1-ylbutylamino, 2-homopiperazin-1-ylethylamino or
3-homopiperazin-1-ylpropylamino,
[0117] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, NH, N(Me),
CH.dbd.CH and C.ident.C,
[0118] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro or chloro groups or a substituent selected
from hydroxy, amino, methoxy, methylsulphonyl, methylamino,
dimethylamino, diisopropylamino, N-ethyl-N-methylamino,
N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy,
acetamido and N-methylacetamido,
[0119] and wherein any phenyl, imidazolyl, triazolyl, pyridyl or
heterocyclyl group within a substituent on R.sup.1 optionally bears
1 or 2 substituents, which may be the same or different, selected
from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl,
methyl, ethyl, N-methylcarbamoyl, N,N-dinethylcarbamoyl and
methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl,
piperazin-1-yl or homopiperazin-1-yl group within a R.sup.1
substituent is optionally N-substituted with allyl, 2-propynyl,
methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,
3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of
which substituents each optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro, methyl
and methoxy,
[0120] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo substituents; [0121] (l) n is
0; [0122] (m) n is 1 or 2 and the R.sup.3 groups, which may be the
same or different, are located at the 5- and/or 6-positions of the
1,3-benzodioxol-4-yl group and are selected from halogeno,
tifluoromethyl, cyano, hydroxy, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,
(1-6C)alkylsulphonyl or from a group of the formula:
--X.sup.6--R.sup.11 wherein X.sup.6 is a direct bond and R.sup.11
is hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl;
cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl
or di-[(1-6C)alkyl]amino-(1-6C)alkyl; [0123] (n) n is 1 or 2 and
the R.sup.3 groups, which may be the same or different, are located
at the 5- and/or 6-positions of the 1,3-benzodioxolyl-4-group and
are selected from halogeno, trifluoromethyl, cyano, hydroxy,
(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy; (o) n
is 1 or 2 and the R.sup.3 groups, which may be the same or
different, are located at the 5- and/or 6-positions of the
1,3-benzodioxol-4-yl group and are selected from fluoro, chloro,
bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl,
allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and
ethoxy; [0124] (p) n is 1 and the R.sup.3 group is located at the
5- or 6-position of the 1,3-benzodioxol-4-yl group, especially the
5-position, and is selected from chloro, bromo, trifluoromethyl,
cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; [0125] (q) n is
1 and the R.sup.3 group is located at the 5- or 6-position of the
1,3-benzodioxolyl-4-group, especially the 5-position, and is
selected from fluoro, chloro, bromo, trifluoromethyl, cyano,
hydroxy, methyl, ethyl, methoxy and ethoxy; [0126] (r) the
-Z.sup.2-R.sup.14 group is located at the 7- or 6-position on the
1,3-benzodioxol-4-yl group; [0127] (s) the -Z.sup.2-R.sup.14 group
is located at the 7-position on the 1,3-benzodioxol-4-yl group;
[0128] (t) Z.sup.2 is a C.ident.C group; [0129] (u) Z.sup.2 is a
CH.dbd.CH group; [0130] (v) R.sup.14 is selected from halogeno,
cyano, formyl, carboxy, carbamoyl, (2-8C)alkenyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,
(1-6C)alkoxy-(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,
(2-6C)alkanoylamino-(1-6C)alkyl or from a group of the formula:
--X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or CO and
Q.sup.5 is aryl, aryl-(1-6C)alkyl, heteroaryl,
heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0131] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.14
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more halogeno or (1-6C)alkyl substituents or a
substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,
(2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino or from a group of the formula:
--X.sup.8Q.sup.6 wherein X.sup.8 is a direct bond or is selected
from O, N(R.sup.16), CON(R.sup.16), N(R.sup.16)CO and
C(R.sup.16).sub.2O, wherein R.sup.16 is hydrogen or (1-6C)alkyl,
and Q.sup.6 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or
heterocyclyl-(1-6C)alkyl,
[0132] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.15 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulphonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and
(2-6C)alkanoyl, or optionally bears 1 substituent selected from a
group of the formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a
direct bond or is selected from O and N(R.sup.18), wherein R.sup.18
is hydrogen or (1-6C)alkyl, and R.sup.17 is hydroxy-(1-6C)alkyl,
(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-16C)alkyl]amino-(1-6C)alkyl,
(2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and from a group of the
formula: --X.sup.10-Q.sup.7 wherein X.sup.10 is a direct bond or is
selected from O, N(R.sup.19) and CO, wherein R.sup.19 is hydrogen
or (1-6C)alkyl, and Q.sup.7 is heterocyclyl or
heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2
substituents, which may be the same or different, selected from
halogeno, (1-6C)alkyl and (1-6C)alkoxy,
[0133] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo substituents; [0134] (w)
R.sup.14 is selected from chloro, cyano, formyl carboxy, carbamoyl
methoxycarbonyl, vinyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,
2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxymethyl 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, aminomethyl,
2-aminoethyl, 3-aminopropyl, methylaminomethyl, ethylaminomethyl,
2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,
3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, acetamidomethyl, 2-acetamidoethyl
3-acetamidopropyl or from a group of the formula: --X.sup.7-Q.sup.5
wherein X.sup.7 is a direct bond or CO and Q.sup.5 is phenyl,
benzyl, 1-, 2- or 3-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl,
piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,
3- or 4-homopiperidinylmethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl, homopiperazin-1-ylmethyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-(1,1-dioxotetrahydro-4H-4-thiazin-4-yl)ethyl,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,
2-piperidinoethyl, 3-piperidinopropyl, 2-piperidin-3-ylethyl,
3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl,
3-piperidin-4-propyl, 2-homopiperidin-1-ylethyl,
3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl,
3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethyl or
3-homopiperazin-1-ylpropyl,
[0135] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.14
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro, chloro or methyl groups or a substituent
selected from hydroxy, amino, methoxy, methylsulphonyl,
methylamino, dimethylamino, diisopropylamino,
N-ethyl-N-methylamino, N-isopropyl-N-methylamino,
N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido,
or from a group of the formula: --X.sup.8-Q.sup.6 wherein X.sup.8
is a direct bond or is selected from O, NH, CONH, NHCO and
CH.sub.2O and Q.sup.6 is pyridyl, pyridylmethyl, pyrrolidin-1-yl,
pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl,
piperidin-4yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,
2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or
3-piperazin-1-ylpropyl,
[0136] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.14 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl methyl,
ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally
bears 1 substituent selected from a group of the formula:
--X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond or is selected
from O and NH and R.sup.17 is 2-fluoroethyl, 3-fluoropropyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl,
methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,
methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,
tert-butoxycarbonylaminomethyl and from a group of the formula:
--X.sup.10-Q.sup.7 wherein X.sup.10 is a direct bond or is selected
from O, NH and CO and Q.sup.7 is pyrrolidin-1-ylmethyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, morpholinomethyl,
2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl,
2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, each of which
optionally bears 1 or 2 substituents, which may be the same or
different, selected from fluoro, chloro, methyl and methoxy,
[0137] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo substituents; and [0138] (x)
R.sup.14 is selected from chloro, cyano, formyl carboxy, carbamoyl,
vinyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N,N-diethylcarbamoyl, acetyl propionyl, chloromethyl,
2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, aminomethyl,
2-aminoethyl, 3-aminopropyl, methylaminomethyl, ethylaminomethyl,
2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,
3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, acetamidomethyl, 2-acetamidoethyl,
3-acetamidopropyl or from a group of the formula: --X.sup.7-Q.sup.5
wherein X.sup.7 is a direct bond or CO and Q.sup.5 is phenyl,
benzyl, 1-, 2- or 3-pyrrolidinyl morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, pyridin-2-yl, piperidino,
piperidin-3-yl, piperidin-4yl, 1-, 3- or 4-homopiperidinyl,
piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,
3- or 4-homopiperidinylmethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl, homopiperazin-1-ylmethyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl-2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,
2-piperidinoethyl, 3-piperidinopropyl, 2-piperidin-3-ylethyl,
3-piperidin-3-ylpropyl, 2-piperidin-4ylethyl,
3-piperidin-4-ylpropyl, 2-homopiperidin-1-ylethyl,
3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl,
3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethyl or
3-homopiperazin-1-ylpropyl,
[0139] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.14
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro, chloro or methyl groups or a substituent
selected from hydroxy, amino, methoxy, methylsulphonyl,
methylamino, dimethylamino, diisopropylamino,
N-ethyl-N-methylamino, N-isopropyl-N-methylamino,
N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido,
or from a group of the formula: --X.sup.8-Q.sup.6 wherein X.sup.8
is a direct bond or is selected from O, NH, CONH, NHCO and
CH.sub.2O and Q.sup.6 is pyridyl, pyridylmethyl, pyrrolidin-1-yl,
pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl,
piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl,
3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl,
2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,
2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or
3-piperazin-1-ylpropyl,
[0140] and wherein any aryl, heteroaryl or heterocyclyl group
within a substituent on R.sup.14 optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from
fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl,
ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally
bears 1 substituent selected from a group of the formula:
--X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond or is selected
from O and NH and R.sup.17 is 2-fluoroethyl, 3-fluoropropyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl 3-methoxypropyl,
cyanomethyl aminomethyl, 2-aminoethyl, 3-aminopropyl,
methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,
methoxycarbonylaminomethyl ethoxycarbonylaminomethyl,
tert-butoxycarbonylaminomethyl and from a group of the formula:
--X.sup.10-Q.sup.7 wherein X.sup.10 is a direct bond or is selected
from O, NH and CO and Q.sup.7 is pyrrolidin-1-ylmethyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, morpholinomethyl,
2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl,
2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, each of which
optionally bears 1 or 2 substituents, which may be the same or
different, selected from fluoro, chloro, methyl and methoxy,
[0141] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo substituents; and [0142] (y)
R.sup.14 is selected from cyano, formyl, carboxy, carbamoyl, vinyl,
methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,
2chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl or
from a group of the formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a
direct bond or CO and Q.sup.5 is pyridin-2-yl, 1-pyrrolidinyl
morpholino, 1,1-dioxotetrahydro-4H-1,4thiazin-4yl, piperidino,
1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1-homopiperidinylmethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or
3-morpholinopropyl,
[0143] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.14
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro, chloro or methyl groups or a substituent
selected from hydroxy, amino, methoxy, methylamino, dimethylamino,
acetoxy, acetamido and N-methylacetamido,
[0144] and wherein any heteroaryl or heterocyclyl group within a
substituent on R.sup.14 optionally bears 1, 2 or 3 substituents,
which may be the same or different, selected from hydroxy, amino,
carbamoyl, methyl, ethyl, allyl; 2-propynyl, methoxy,
methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and
acetyl, or optionally bears 1 substituent selected from a group of
the formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond
and R.sup.17 is 2-fluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl,
methylaminomethyl, dimethylaminomethyl, acetamidomethyl
methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or
tert-butoxycarbonylaminomethyl,
[0145] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo substituents.
[0146] A particular compound of the invention is a quinoline
derivative of the Formula I wherein:
[0147] Z.sup.1 is O or NH;
[0148] m is 1 and the R.sup.1 group is located at the 5-, 6- or
7-position or m is 2 and each R.sup.1 group, which may be the same
or different, is located at the 5- and 7-positions or at the 6- and
7-positions and R.sup.1 is selected from hydroxy, amino, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,
pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino,
dimethylamino, diethylamino, acetamido, propionamido,
2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,
2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,
4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy,
pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
4-morpholinobutoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy,
piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy,
piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,
3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,
3-piperidin-4ylpropoxy, 2-homopiperidin-1-ylethoxy,
3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,
3-piperazin-1-ylpropoxy, 4piperazin-1-ylbutoxy,
2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy,
[0149] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, NH, N(Me),
CH.dbd.CH and C.ident.C,
[0150] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro or chloro groups or a substituent selected
from hydroxy, amino, methoxy, methylsulphonyl, methylamino,
dimethylamino, diethylamino, N-ethyl-N-methylamino,
N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy;
[0151] and wherein any heteroaryl or heterocyclyl group within a
substituent on R.sup.1 optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro,
trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy,
N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl,
piperidin-3-yl, piperidin-4yl, piperazin-1-yl or homopiperazin-1-yl
group within a R.sup.1 substituent is optionally N-substituted with
allyl, methylsulphonyl, acetyl, 2-fluoroethyl, 3-fluoropropyl,
2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl,
3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of
which substituents each optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro, methyl
and methoxy,
[0152] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo substituents;
[0153] n is 0 or 1 and the R.sup.3 group, if present, is located at
the 5- or 6-position of the 1,3-benzodioxol-4-yl group and is
selected from fluoro, chloro, bromo, trifluoromethyl cyano,
hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and
ethoxy;
[0154] Z.sup.2 is a C.ident.C or CH.dbd.CH group; and
[0155] R.sup.14 is selected from cyano, formyl, carboxy, carbamoyl,
methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,
2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl 2-cyanoethyl, 3-cyanopropyl, methylaminomethyl,
ethylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,
2dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,
2-acetamidoethyl and 3-acetamidopropyl, or from a group of the
formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or CO
and Q.sup.5 is 1-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1-homopiperidinylmethyl,
1,1dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl,
homopiperazin-1-ylmethyl or 3-morpholinopropyl,
[0156] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.4
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro, chloro or methyl groups or a substituent
selected from hydroxy, amino, methoxy, methylamino, dimethylamino,
acetoxy, acetamido and N-methylacetamido,
[0157] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1, 2 or 3 substituents, which may be the
same or different, selected from hydroxy, amino, carbamoyl, methyl
ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally
bears 1 substituent selected from a group of the formula:
--X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond and R.sup.17
is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,
3-methoxypropyl, cyanomethyl, aminomethyl, methylaminomethyl,
dimethylaminomethyl, acetamidomethyl, methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl,
[0158] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo substituents;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0159] A particular compound of the invention is a quinoline
derivative of the Formula I wherein:
[0160] Z.sup.1 is O or NH;
[0161] m is 1 and the R.sup.1 group is located at the 5-, 6- or
7-position or m is 2 and each R.sup.1 group, which may be the same
or different, is located at the 5- and 7-positions or at the 6- and
7-positions and R.sup.1 is selected from hydroxy, amino, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,
pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino,
dimethylamino, diethylamino, acetamido, propionamido,
2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,
2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,
4pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,
2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy,
2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy,
piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy,
piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,
3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,
3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,
3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,
3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,
2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy,
[0162] and wherein adjacent carbon atoms in any (2-6C)alkylene
chain within a R.sup.1 substituent are optionally separated by the
insertion into the chain of a group selected from O, NH, N(Me),
CH.dbd.CH and C.ident.C,
[0163] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.1
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro or chloro groups or a substituent selected
from hydroxy, amino, methoxy, methylsulphonyl methylamino,
dimethylamino, diethylamino, N-ethyl-N-methylamino,
N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy,
[0164] and wherein any heteroaryl or heterocyclyl group within a
substituent on R.sup.1 optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro,
trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy,
N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl,
piperidin-3-yl, piperidin-4yl, piperazin-1-yl or homopiperazin-1-yl
group within a R.sup.1 substituent is optionally N-substituted with
allyl, methylsulphonyl, acetyl, 2-fluoroethyl, 3-fluoropropyl,
2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl,
3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl,
2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of
which substituents each optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro, methyl
and methoxy,
[0165] and wherein any heterocyclyl group within a substituent on
R.sup.1 optionally bears 1 or 2 oxo substituents;
[0166] n is 0 or 1 and the R.sup.3 group, if present, is located at
the 5- or 6-position of the 1,3-benzodioxol-4-yl group and is
selected from fluoro, chloro, bromo, trifluoromethyl, cyano,
hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and
ethoxy;
[0167] Z.sup.2 is a C.ident.C or CH.dbd.CH group; and
[0168] R.sup.14 is selected from cyano, formyl, carboxy, carbamoyl,
vinyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,
2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, methylaminomethyl,
ethylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,
2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,
2-acetamidoethyl and 3-acetamidopropyl, or from a group of the
formula: --X.sup.7-Q.sup.5 wherein X.sup.7 is a direct bond or CO
and Q.sup.5 is pyridin-2-yl, 1-pyrrolidinyl, morpholino,
1,1-dioxotetrahydro-4H-1,4thiazin-4-yl, piperidino,
1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1-homopiperidinylmethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or
3-morpholinopropyl,
[0169] and wherein any CH.sub.2 or CH.sub.3 group within a R.sup.14
substituent optionally bears on each said CH.sub.2 or CH.sub.3
group one or more fluoro, chloro or methyl groups or a substituent
selected from hydroxy, amino, methoxy, methylamino, dimethylamino,
acetoxy, acetamido and N-methylacetamido,
[0170] and wherein any heteroaryl or heterocyclyl group within a
substituent on R.sup.14 optionally bears 1, 2 or 3 substituents,
which may be the same or different, selected from hydroxy, amino,
carbamoyl, methyl ethyl, allyl, 2-propynyl, methoxy,
methylsulphonyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl and
acetyl, or optionally bears 1 substituent selected from a group of
the formula: --X.sup.9--R.sup.17 wherein X.sup.9 is a direct bond
and R.sup.17 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,
3-methoxypropyl, cyanomethyl, aminomethyl, methylaminomethyl,
dimethylaminomethyl, acetamidomethyl, methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl,
[0171] and wherein any heterocyclyl group within a substituent on
R.sup.14 optionally bears 1 or 2 oxo substituents;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0172] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0173] Z.sup.1 is NH;
[0174] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-methylsulphonylethoxy,
3-methylsulphonylpropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4ylmethoxy,
N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,
2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,
3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,
2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,
2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,
2-(2-piperidinoethoxy)ethoxy,
2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy and
2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy;
[0175] n is 0 or n is 1 and the R.sup.3 group, if present, is
located at the 5-position of the 1,3-benzodioxol-4-yl group and is
selected from fluoro, chloro and bromo;
[0176] the Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0177] Z.sup.2 is a C.ident.C or CH.dbd.CH group; and
[0178] R.sup.14 is selected from cyano, formyl carboxy, carbamoyl,
methoxycarbonyl vinyl, ethoxycarbonyl, Nmethylcarbamoyl,
N-ethylcarbamoyl, N-(2-methoxyethyl)carbamoyl,
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl, propionyl,
chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,
3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, pyridin-2-yl, 1-pyrrolidinylcarbonyl,
morpholinocarbonyl 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl, 1-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl
and 3-morpholinopropyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0179] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0180] Z.sup.1 is NH;
[0181] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-methylsulphonylethoxy,
3-methylsulphonylpropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,
N-methylpiperidin-4ylmethoxy, 2-piperidin-3-ylethoxy,
2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,
3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,
2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4-yl)propoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-3-oxopiperazin-1-yl)propoxy,
2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,
2-(2-piperidinoethoxy)ethoxy and
2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy;
[0182] n is 0 or n is 1 and the R.sup.3 group, if present, is
located at the 5-position of the 1,3-benzodioxolyl group and is
selected from chloro and bromo;
[0183] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0184] Z.sup.2 is a C.ident.C or CH.dbd.CH group; and
[0185] R.sup.14 is selected from cyano, formyl, carboxy, carbamoyl,
methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N-(2-methoxyethyl)carbamoyl,
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl, propionyl,
chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,
3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3
dimethylaminopropyl, 1-pyrrolidinylcarbonyl, morpholinocarbonyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl, 1l-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl
and 3-morpholinopropyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0186] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0187] Z.sup.1 is NH;
[0188] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-methylsulphonylethoxy,
3-methylsulphonylpropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,
N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,
2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,
3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,
2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4-yl)propoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,
2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,
2-(2-piperidinoethoxy)ethoxy,
2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy and
2-fluoro-3-(4-hydroxypiperidin-1-yl-propoxy;
[0189] n is 0 or n is 1 and the R.sup.3 group, if present, is
located at the 5-position of the 1,3-benziodioxol-4-yl group and is
selected from fluoro, chloro and bromo;
[0190] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0191] Z.sup.2 is a C.ident.C group; and
[0192] R.sup.14 is selected from chloromethyl, 2-chloroethyl,
3-chloropropyl, hydroxymethyl, vinyl
[0193] 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl,
2-methoxyethyl, 3-methoxypropyl, dimethylaminomethyl,
2-dimethylaminoethyl, 3-dimethylaminopropyl, pyridin-2-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl
and 3-morpholinopropyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0194] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0195] Z.sup.1 is NH;
[0196] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-methylsulphonylethoxy,
3-methylsulphonylpropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4ylmethoxy,
N-methylpiperidin-4ylmethoxy, 2-piperidin-3-ylethoxy,
2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,
3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,
2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4-yl)propoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,
2-2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,
2-(2-piperidinoethoxy)ethoxy and
2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy;
[0197] n is 0 or n is 1 and the R.sup.3 group, if present, is
located at the 5-position of the 1,3-benzodioxol-4-yl group and is
selected from chloro and bromo;
[0198] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0199] Z.sup.2 is a CH.dbd.CH group; and
[0200] R.sup.14 is selected from cyano, formyl, carboxy, carbamoyl,
methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N-(2-methoxyethyl)carbamoyl,
N,N-dinethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl, propionyl,
chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,
3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, 1-pyrrolidinylcarbonyl, morpholinocarbonyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl, 1-pyrrolidinylmethyl,
morpholinomethyl, piperidinomethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and
piperazin-1-ylmethyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0201] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0202] Z.sup.1 is NH;
[0203] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,
2-(2-pyrrolidin-1-ylethoxy)ethoxy and
2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy;
[0204] n is 0 or n is 1 and R.sup.3 is a fluoro or chloro group
located at the 5-position of the 1,3-benzodioxol-4-yl group;
[0205] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0206] Z.sup.2 is a C.ident.C group; and
[0207] R.sup.14 is selected from vinyl, hydroxymethyl,
methoxymethyl, dimethylaminomethyl, pyridin-2-yl,
1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and
piperazin-1-ylmethyl;
[0208] or a pharmaceutically-acceptable acid-addition salt
thereof.
[0209] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0210] Z.sup.1 is NH;
[0211] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy and
2-(2-pyrrolidin-1-ylethoxy)ethoxy;
[0212] n is 0 or n is 1 and R.sup.3 is a chloro group located at
the 5-position of the 1,3-benzodioxol-4-yl group;
[0213] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0214] Z.sup.2 is a C.ident.C group; and
[0215] R.sup.14 is selected from hydroxymethyl, methoxymethyl,
dimethylaminomethyl, 1-pyrrolidinylmethyl, morpholinomethyl,
piperidinomethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and
piperazin-1-ylmethyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0216] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0217] Z.sup.1 is NH;
[0218] m is 2 and the first R.sup.1 group is a 6-methoxy group and
the second R.sup.1 group is located at the 7-position and is
selected from methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy,
3-fluoropropoxy, 3-chloropropoxy, 2-(2-chloroethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy and
2-(2-pyrrolidin-1-ylethoxy)ethoxy;
[0219] n is 0 or n is 1 and R.sup.3 is a chloro group located at
the 5-position of the 1,3-benziodioxol-4-yl group;
[0220] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0221] Z.sup.2 is a CH.dbd.CH group; and
[0222] R.sup.14 is selected from cyano, carboxy, carbamoyl,
methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N-(2-methoxyethyl)carbamoyl,
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl, propionyl,
1-pyrrolidinylcarbonyl, morpholinocarbonyl,
1,1-dioxotetrahydro-4H-1,4thiazin-4-ylcarbonyl, piperidinocarbonyl
and piperazin-1-ylcarbonyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0223] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0224] Z.sup.1 is NH;
[0225] m is 2 and the first R.sup.1 group is located at the
5-position and is selected from N-methylpiperidin-4-yloxy and
tetrahydro-2H-pyran-4-yloxy and the second R.sup.1 group is located
at the 7-position and is selected from methoxy, ethoxy,
2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,
2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,
2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,
2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,
2-morpholinoethoxy, 3-morpholinopropoxy,
2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,
N-methylpiperidin-4ylmethoxy, 2-piperidin-3-ylethoxy,
2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,
3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4ylethoxy,
2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy,
3-(4-allylpiperazin-1-yl)propoxy,
3-(4-methylsulphonylpiperazin-1-yl)propoxy,
3-(4-acetylpiperazin-1-yl)propoxy,
2-(4-cyanomethylpiperazin-1-yl)ethoxy,
3-(4-cyanomethylpiperazin-1-yl)propoxy,
2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,
2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,
2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,
2-(2-piperidinoethoxy)ethoxy,
2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy and
2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy;
[0226] n is 0 or n is 1 and R.sup.3 is located at the 5-position of
the 1,3-benzodioxol-4-yl group and is selected from a fluoro,
chloro or bromo group;
[0227] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxolyl group,
[0228] Z.sup.2is a C.ident.C group; and
[0229] R.sup.14 is selected from cyano, formyl, carboxy, carbamoyl,
vinyl, methoxycarbonyl, ethoxycarbonyl N-methylcarbamoyl,
N-ethylcarbamoyl, N-(2-methoxyethyl)carbamoyl,
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
N-(2-methoxyethyl)-N-methylcarbamoyl acetyl, propionyl,
chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,
3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, 1-pyrrolidinylcarbonyl, morpholinocarbonyl,
1,1-dioxotetrahydro-4H-1,4thiazin-4-ylcarbonyl, piperidinocarbonyl,
piperazin-1-ylcarbonyl, 1-pyrrolidinylmethyl,
morpholinomethyl,piperidinomethyl
1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl
and 3-morpholinopropyl;
or a pharmaceutically-acceptable acid-addition salt thereof
[0230] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0231] Z.sup.1 is NH;
[0232] m is 2 and the first R.sup.1 group is located at the
5-position and is selected from N-methylpiperidin-4-yloxy and
tetrahydro-2H-pyran-4yloxy and the second R.sup.1 group is located
at the 7-position and is selected from methoxy and
3-morpholinopropoxy,
[0233] n is 0 or n is 1 and R.sup.3 is located at the 5-position of
the 1,3-benzodioxol-4-yl group and is selected from a fluoro,
chloro or bromo group;
[0234] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0235] Z.sup.2 is a C.ident.C group; and
[0236] R.sup.14 is selected from chloromethyl, 2-chloroethyl,
3-chloropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,
dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
pyridin-2-yl, 1-pyrrolidinylmethyl, morpholinomethyl,
piperidinomethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,
piperazin-1-ylmethyl and 3-morpholinopropyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0237] A further particular compound of the invention is a
quinoline derivative of the Formula I wherein:
[0238] Z.sup.1 is NH;
[0239] m is 2 and the first R.sup.1 group is located at the
5-position and is selected from N-methylpiperidin-4-yloxy and
tetrahydro-2H-pyran-4-yloxy and the second R.sup.1 group is located
at the 7-position and is selected from methoxy and
3-morpholinopropoxy,
[0240] n is 0 or n is 1 and the R.sup.3 group, if present, is
located at the 5-position of the 1,3-benziodioxol-4-yl group and is
chloro;
[0241] the -Z.sup.2-R.sup.14 group is located at the 7-position on
the 1,3-benzodioxol-4-yl group,
[0242] Z.sup.2 is a C.ident.C group; and
[0243] R.sup.14 is selected from methoxymethyl and
2-methoxyethyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
[0244] Particular compounds of the invention include, for example,
the quinoline derivatives of the Formula I described hereinafter in
Examples 1, 2, 3, 9(1) to 9(7), 10 and 11. Particular compounds
also include
3-cyano-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-
-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline,
3-cyano-7-methoxy-5-[(1-methylpiperidin-4yl)oxy]-4-[4-(3-methoxyprop-1-yn-
yl)-2,3-methylenedioxyanilino]quinoline,
3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4yloxy)-4-[4-(-
3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino)quinoline,
3-cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-
-[(1-methylpiperidin-4-yl)oxy]quinoline,
3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[4-(3-methoxypr-
op-1-ynyl)-2,3-methylenedioxyanilino]quinoline,
3-cyano-6,7-dinethoxy-4-[4-(pyridin-2-ylethynyl)-2,3-methylenedioxyanilin-
o]quinoline,
3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]--
7-[2-(2-pyrrolidin-1-ylethoxy)ethoxy]-quinoline,
4-[(4-but-3-en-1-ynyl-2,3-methylendioxy)anilino]-3-cyano-7-methoxy-5-[(1--
methylpiperidin-4-yl)oxy]quinoline,
3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[6-fluoro-4-(3--
methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline,
3-cyano-6-methoxy-7-[2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy]-4-[4-(3-
-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline and
3-cyano-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-4-[4(3-methoxyprop-1-ynyl-
)-2,3-methylenedioxyanilino]quinoline.
[0245] A quinoline 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 quinoline derivative of the Formula I are provided as a further
feature of the invention and are illustrated by the following
representative process variants in which, unless otherwise stated,
m, R.sup.1, Z.sup.1, n, R.sup.3, Z.sup.2 and R.sup.14 have any of
the meanings defined hereinbefore. Necessary starting materials may
be obtained by standard procedures of organic chemistry. The
preparation of such starting materials is described in conjunction
with the following representative process variants and within the
accompanying Examples. Alternatively necessary starting materials
are obtainable by analogous procedures to those illustrated which
are within the ordinary skill of an organic chemist.
[0246] (a) For the production of those compounds of the Formula I
wherein Z.sup.1 is an O, S or N(R.sup.2) group, the reaction of a
quinoline of the Formula II ##STR4## wherein L is a displaceable
group and m and R.sup.1 have any of the meanings defined
hereinbefore except that any functional group is protected if
necessary, with a compound of the Formula III ##STR5## wherein
Z.sup.1 is O, S, or N(R.sup.2) and n, R.sup.3, R.sup.2, Z.sup.2 and
R.sup.14 have any of the meanings defined hereinbefore except that
any functional group is protected if necessary, whereafter any
protecting group that is present is removed by conventional
means.
[0247] The reaction may conveniently be carried out in the presence
of a suitable acid or in the presence of a suitable base. A
suitable acid is, for example, an inorganic acid such as, for
example, hydrogen chloride or hydrogen bromide. A suitable base is,
for example, an organic amine base such as, for example, pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene,
or, for example, an alkali or alkaline earth metal carbonate or
hydroxide, for example sodium carbonate, potassium carbonate,
calcium carbonate, sodium hydroxide or potassium hydroxide, or, for
example, an alkali metal amide, for example sodium
hexamethyldisilazane, or, for example, an alkali metal hydride, for
example sodium hydride.
[0248] A suitable displaceable group L is, for example, a halogeno,
alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo,
methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or
toluene-4-sulphonyloxy group. 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-dioxan, an aromatic solvent such as toluene,
or a dipolar aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one or
dimethylsulphoxide. The reaction is conveniently carried out at a
temperature in the range, for example, 0 to 250.degree. C.,
preferably in the range 0 to 120.degree. C.
[0249] Typically, the quinoline of the Formula II may be reacted
with a compound of the Formula III in the presence of an aprotic
solvent such as N,N-dimethylformamide, conveniently in the presence
of a base, for example potassium carbonate or sodium
hexamethyldisilazane, and at a temperature in the range, for
example, 0 to 150.degree. C., preferably in the range, for example,
0 to 70.degree. C.
[0250] The quinoline derivative of the Formula I may be obtained
from this process in the form of the free base or alternatively it
may be obtained in the form of a salt with the acid of the formula
H-L wherein L has the meaning defined hereinbefore. When it is
desired to obtain the free base from the salt, the salt may be
treated with a suitable base, for example, an organic amine base
such as, for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, morpholine,
N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for
example, an alkali or alkaline earth metal carbonate or hydroxide,
for example sodium carbonate, potassium carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide.
[0251] Protecting groups may in general be chosen from any of the
groups described in the literature or known to the skilled chemist
as appropriate for the protection of the group in question and may
be introduced by conventional methods. 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.
[0252] Specific examples of protecting groups are given below for
the sake of convenience, in which "lower", as in, for example,
lower-alkyl, signifies that the group to which it is applied
preferably has 1-4 carbon atoms. It will be understood that these
examples are not exhaustive. Where specific examples of methods for
the removal of protecting groups are given below these are
similarly not exhaustive. The use of protecting groups and methods
of deprotection not specifically mentioned are, of course, within
the scope of the invention.
[0253] A carboxy protecting group may be the residue of an
ester-forming aliphatic or arylaliphatic alcohol or of an
ester-forming silanol (the said alcohol or silanol preferably
containing 1-20 carbon atoms). Examples of carboxy protecting
groups include straight or branched chain (1-12C)alkyl groups (for
example isopropyl, and tert-butyl); lower alkoxy-lower alkyl groups
(for example methoxymethyl, ethoxymethyl and isobutoxymethyl);
lower acyloxy-lower alkyl groups, (for example acetoxymethyl,
propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower
alkoxycarbonyloxy-lower alkyl groups (for example
1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower
alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl,
4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl
groups (for example trimethylsilyl and tert-butyldimnethylsilyl);
tri(lower alkyl)silyl-lower alkyl groups (for example
trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl).
Methods particularly appropriate for the removal of carboxyl
protecting groups include for example acid-, base-, metal- or
enzymically-catalysed cleavage.
[0254] Examples of hydroxy protecting groups include lower alkyl
groups (for example tert-butyl), lower alkenyl groups (for example
allyl); lower alkanoyl groups (for example acetyl); lower
alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower
alkenyloxycarbonyl groups (for example allyloxycarbonyl).;
aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and
4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example
trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl
(for example benzyl) groups.
[0255] Examples of amino protecting groups include formyl,
aryl-lower alkyl groups (for example benzyl and substituted benzyl,
4-methoxybenzyl 2-nitrobenzyl and 2,4-dimethoxybenzyl, and
triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower
alkoxycarbonyl (for example tert-butoxycarbonyl); lower
alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower
alkoxycarbonyl groups (for example benzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and
4-nitrobenzyloxycarbonyl); trialkylsilyl (for example
trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for
example methylidene) and benzylidene and substituted benzylidene
groups.
[0256] Methods appropriate for removal of hydroxy and amino
protecting groups include, for example, acid-, base-, metal- or
enzymically-catalysed hydrolysis for groups such as
2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl
and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
[0257] The reader is referred to Advanced Organic Chemistry, 4th
Edition, by J. March published by John Wiley & Sons 1992, for
general guidance on reaction conditions and reagents and to
Protective Groups in Organic Synthesis, 2.sup.nd Edition, by T.
Green et al., also published by John Wiley & Son, for general
guidance on protecting groups.
[0258] Quinoline starting materials of the Formula II may be
obtained by conventional procedures such as those disclosed in
International Patent Applications WO 98/43960 and WO 00/68201. For
example, a 1,4-dihydroquinolin-4-one of Formula IV ##STR6## wherein
m and R.sup.1 have any of the meanings defined hereinbefore except
that any functional group is protected if necessary, may be reacted
with a halogenating agent such as thionyl chloride, phosphoryl
chloride or a mixture of carbon tetrachloride and
triphenylphosphine whereafter any protecting group that is present
is removed by conventional means.
[0259] The 4-chloroquinoline so obtained may be converted, if
required, into a 4-pentafluorophenoxyquinoline by reaction with
pentafluorophenol in the presence of a suitable base such as
potassium carbonate and in the presence of a suitable solvent such
as N,N-dimethylformamide.
[0260] 2,3-Methylenedioxyanilino starting materials (Formula III,
for example when Z is NH) may be obtained by conventional
procedures as illustrated in the Examples. Corresponding
2,3-methylenedioxyphenol and 2,3-methylenedioxythiophenol starting
materials (Formula III, when Z is O or S) may be obtained by
conventional procedures.
[0261] (b) For the production of those compounds of the Formula I
wherein at least one R.sup.1 group is a group of the formula
Q.sup.1-X.sup.1-- wherein Q.sup.1 is an aryl-(1-6C)alkyl,
(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl-(1-6C)alkyl or heterocyclyl-(1-6C)alkyl group or an
optionally substituted alkyl group and X.sup.1 is an oxygen atom,
the coupling, conveniently in the presence of a suitable
dehydrating agent, of a quinoline of the Formula V ##STR7## wherein
m, R.sup.1, Z.sup.1, n, R.sup.3, Z.sup.2 and R.sup.14 have any of
the meanings defined hereinbefore except that any functional group
is protected if necessary, with an appropriate alcohol of the
formula Q.sup.1-OH wherein any functional group is protected if
necessary, whereafter any protecting group that is present is
removed by conventional means.
[0262] A suitable dehydrating agent is, for example, a carbodiimide
reagent such as dicyclohexylcarbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an
azo compound such as diethyl or di-tert-butyl azodicarboxylate and
a phosphine such as triphenylphosphine. The reaction is
conveniently carried out in the presence of a suitable inert
solvent or diluent, for example a halogenated solvent such as
methylene chloride, chloroform or carbon tetrachloride and at a
temperature in the range, for example, 10 to 1 50.degree. C.,
preferably at or near ambient temperature.
[0263] The reaction is conveniently carried out in the presence of
a suitable inert solvent or diluent, for example a halogenated
solvent such as methylene chloride, chloroform or carbon
tetrachloride and at a temperature in the range, for example, 10 to
150.degree. C., preferably at or near ambient temperature.
[0264] (c) For the production of those compounds of the Formula I
wherein R.sup.1 is an amino-substituted (1-6C)alkoxy group (such as
2-homopiperidin-1-ylethoxy or 3-dimethylaminopropoxy), the reaction
of a compound of the Formula I wherein R.sup.1 is a
halogeno-substituted (1-6C)alkoxy group with a heterocyclyl
compound or an appropriate amine. The reaction is conveniently
carried out in the presence of a suitable inert diluent or carrier
as defined hereinbefore and at a temperature in the range 10 to
150.degree. C., preferably at or near ambient temperature.
[0265] (d) For the production of those compounds of the Formula I
wherein an R.sup.1 group 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, of a quinoline
derivative of the Formula I wherein the R.sup.1 group contains a
hydroxy group or a primary or secondary amino group as
appropriate.
[0266] 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.
[0267] Conveniently for the production of those compounds of the
Formula I wherein R.sup.1 contains a (1-6C)alkylamino or
substituted (1-6C)alkylamino group, a reductive amination reaction
may be employed. For example, for the production of those compounds
of the Formula I wherein R.sup.1 contains a 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 an alkali metal aluminium hydride such as lithium
aluminium hydride or, preferably, 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. The reaction is performed at a temperature in the
range, for example, 10 to 80.degree. C., conveniently at or near
ambient temperature.
[0268] (e) For the production of those compounds of the Formula I
wherein Z.sup.1 is a SO or SO.sub.2 group, wherein an R.sup.1 or
R.sup.3 substituent is a (1-6C)alkylsulphinyl or
(1-6C)alkylsulphonyl group or wherein an R.sup.1, R.sup.3 or
R.sup.14 substituent contains a SO or SO.sub.2 group, the oxidation
of a compound of Formula I wherein Z.sup.1 is a S group or wherein
an R.sup.1 or R.sup.3 substituent is a (1-6C)alkylthio group or
wherein an R.sup.1 R.sup.3 or R.sup.14 substituent contains a S
group as appropriate.
[0269] Conventional oxidation reagents and reaction conditions for
such partial or complete oxidation of a sulphur atom are well known
to the organic chemist.
[0270] (f) The reaction, conveniently in the presence of a suitable
base as defined hereinbefore and in the presence of a suitable
catalyst, of a compound of the Formula VI ##STR8## wherein L is a
displaceable group as defined hereinbefore and m, R.sup.1, Z.sup.1,
n and R.sup.3 have any of the meanings defined hereinbefore except
that any functional group is protected if necessary, with a
compound of the Formula VII HZ.sup.2-R.sup.14 VII wherein Z.sup.2
is a C.ident.C or C(R.sup.13).dbd.C(R.sup.13) group and R.sup.13
and R.sup.14 have any of the meanings defined hereinbefore except
that any functional group is protected if necessary, whereafter any
protecting group that is present is removed by conventional
means.
[0271] Conveniently the displaceable group is a halogeno group such
as iodo, bromo or chloro. A suitable catalyst is, for example, an
organometallic reagent, for example an organopalladium compound
such as tetrakis(triphenylphosphine)palladium(0) or
bis(triphenylphosphine)palladium(II) dichloride. The conversion
reaction is conveniently carried out in the presence of a suitable
inert diluent or carrier as defined hereinbefore and at a
temperature in the range 10 to 150.degree. C., preferably at or
near 60.degree. C.
[0272] (g) For the production of a compound of the Formula I
wherein R.sup.14 is a carboxy group, the cleavage of a compound of
the Formula I wherein R.sup.14 is a (1-6C)alkoxycarbonyl group.
[0273] The cleavage reaction is conveniently carried out by the
hydrolysis of the (1-6C)alkoxycarbonyl group in the presence of a
suitable base, for example an alkali or alkaline earth metal
carbonate or hydroxide such as sodium carbonate, potassium
carbonate, calcium carbonate, sodium hydroxide or potassium
hydroxide and in the presence of a suitable inert diluent or
carrier as defined hereinbefore such as methanol and at a
temperature in the range 10 to 150.degree. C., preferably at or
near 40.degree. C.
[0274] (h) The reaction, conveniently in the presence of a suitable
dehydrating agent as defined hereinbefore, of a compound of the
Formula I wherein R.sup.14 is a carboxy group with an appropriate
amine to form a further compound of the Formula I wherein R.sup.14
is a carbamoyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl or heterocyclylcarbonylamino
group.
[0275] The reaction is conveniently carried out in the presence of
a suitable inert diluent or carrier as defined hereinbefore and at
a temperature in the range, for example, 10 to 150.degree. C.,
preferably at or near ambient temperature.
[0276] When a pharmaceutically-acceptable salt of a quinoline
derivative of the Formula I is required, for example an
acid-addition salt, it may be obtained by, for example, reaction of
said quinoline derivative with a suitable acid using a conventional
procedure.
Biological Assays
[0277] The following assays can be used to measure the effects of
the compounds as inhibitors of the MAPK pathway.
[0278] (a) Assay to Detect MEK Inhibition
[0279] To evaluate inhibitors of the MAPK pathway, a coupled assay
was carried out which measures phosphorylation of serine/threonine
residues present in the substrate in the presence or absence of
inhibitor. Recombinant glutathione S-transferase fusion protein
containing human p45MEK1 (GST-MEK) was activated by c-raf (Sf9
insect cell lysate from triple baculoviral infection with
c-raf/ras/]ck) and used for the assay. Active GST-MEK was first
used to activate a recombinant glutathione S-transferase fusion
protein containing p44MAP kinase (GST-MAPK) in the presence of ATP
and Mg.sup.2+ for 60 minutes at room temperature in the presence or
absence of potential inhibitors. The activated GST-MAPK was then
incubated with myelin basic protein (MBP) as substrate for 10
minutes at room temperature in the presence of ATP, Mg.sup.2+ and
.sup.33P-ATP. The reaction was stopped by addition of 20% v/v
phosphoric acid Incorporation of .sup.33P into the myelin basic
protein was determined by capture of the substrate on a filter mat,
washing and counting using scintillation methods. The extent of
inhibition was determined by comparison with untreated
controls.
[0280] The final assay solution contained 10 mM Tris, pH 7.5, 0.05
mM EGTA, 8.33 .mu.M [.gamma..sup.33P]ATP, 8.33 mM Mg(OAc).sub.2,
0.5 mM sodium orthovanadate, 0.05% w/v BSA, 6.5 ng GST-MEK, 1 .mu.g
GST-MAPK and 16.5 .mu.g MBP in a reaction volume of 60 .mu.l.
(b) In Vitro MAP Kinase Assay
[0281] To determine whether compounds were inhibiting GST-MEK or
GST-MAPK, a direct assay of MAPK activity was employed. GST-MAPK
was activated by a constitutively active GST-MEK fusion protein
containing two point mutations (S217E, S221E) and used for the
assay in the presence and absence of potential inhibitors. The
activated GST-MAPK was incubated with substrate (MBP) for 60 min at
room temperature in the presence of ATP, Mg.sup.2+ and
.sup.33P-ATP. The reaction was stopped by addition of 20% v/v
phosphoric acid. Incorporation of .sup.33P into the myelin basic
protein was determined by capture of the substrate on a filter mat,
washing and counting using scintillation methods.
[0282] The final assay solution contained 12 mM Tris, pH 7.5, 0.06
mM EGTA, 30 .mu.M [.gamma.P]ATP, 10 mM Mg(OAc).sub.2, 0.6 mM sodium
orthovanadate, 0.06% w/v BSA, 28 ng GST-MAPK and 16.5 .mu.g MBP in
a reaction volume of 60 .mu.l.
(c) Cell Proliferation Assays
[0283] Cells were seeded into multi-well plates at 20,000-40,000
cells/ml in growth medium containing 5% FCS and incubated overnight
at 37.degree. C. The compounds were prepared in fresh medium at an
appropriate concentration and added to the wells containing the
cells. These were then incubated for a further 72 hours. Cells were
then either removed from the wells by incubating with trypsin/EDTA
and counted using a Coulter counter, or treated with XTT/PMS in
PBSA and optical densities read at 450 nm.
[0284] The following assays can be used to measure the effects of
the compounds of the present invention as c-Src tyrosine kinase
inhibitors, as inhibitors in vitro of the proliferation of c-Src
transfected fibroblast cells, as inhibitors in vitro of the
migration of A549 human lung tumour cells and as inhibitors in vivo
of the growth in nude mice of xenografts of A549 tissue.
(d) In Vitro Src Enzyme Assay
[0285] The ability of test compounds to inhibit the phosphorylation
of a tyrosine containing polypeptide substrate by-the enzyme c-Src
kinase-was assessed using a conventional Elisa assay.
[0286] A substrate solution [100 .mu.l of a 20 .mu.g/ml solution of
the polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275)
in phosphate buffered saline (PBS) containing 0.2 mg/ml of sodium
azide] was added to each well of a number of Nunc 96-well
immnunoplates (Catalogue No 439454) and the plates were sealed and
stored at 4.degree. C. for 16 hours. The excess of substrate
solution was discarded, and aliquots of Bovine Serum Albumin (BSA;
150 .mu.l of a 5% solution in PBS) were transferred into each
substrate-coated assay well and incubated for 1 hour at ambient
temperature to block non specific binding. The assay plate wells
were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST)
and with Hepes pH7.4 buffer (50 mM, 300 .mu.l/well) before being
blotted dry.
[0287] Each test compound was dissolved in dimethyl sulphoxide and
diluted with distilled water to give a series of dilutions (from
100 .mu.M to 0.001 .mu.M). Portions (25 .mu.l) of each dilution of
test compound were transferred to wells in the washed assay plates.
"Total" control wells contained diluted DMSO instead of compound.
Aliquots (25 .mu.l) of an aqueous magnesium chloride solution (80
mM) containing adenosine-5'-triphosphate (ATP; 40 .mu.M) was added
to all test wells except the "blank" control wells which contained
magnesium chloride without ATP.
[0288] Active human c-Src kinase (recombinant enzyme expressed in
Sf9 insect cells; obtained from Upstate Biotechnology Inc. product
14-117) was diluted immediately prior to use by a factor of
1:10,000 with an enzyme diluent which comprised 100 mM Hepes pH7.4
buffer, 0.2 mM sodium orthovanadate, 2 mM dithiothreitol and 0.02%
BSA. To start the reactions, aliquots (50 .mu.l) of freshly
diluted-enzyme were added to each well and the plates were
incubated at ambient temperature for 20 minutes. The supernatant
liquid in each well was discarded and the wells were washed twice
with PBST. Mouse IgG anti-phosphotyrosine antibody (Upstate
Biotechnology Inc. product 05-321; 100 .mu.l) was diluted by a
factor of 1:6000 with PBST containing 0.5% w/v BSA and added to
each well. The plates were incubated for 1 hour at ambient
temperature. The supernatant liquid was discarded and each well was
washed with PBST (.times.4). Horse radish peroxidase (HRP)-linked
sheep anti-mouse Ig antibody (Amersham Catalogue No. NXA 931; 100
.mu.l) was diluted by a factor of 1:500 with PBST containing 0.5%
wlv BSA and added to each well. The plates were incubated for 1
hour at ambient temperature. The supernatant liquid was discarded
and the wells were washed with PBST (.times.4).
[0289] A PCSB capsule (Sigma Catalogue No. P4922) was dissolved in
distilled water (100 ml) to provide phosphate-citrate pH5 buffer
(50 nM) containing 0.03% sodium perborate. An aliquot (50 ml) of
this buffer was mixed with a 50 mg tablet of
2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS;
Boehringer Catalogue No. 1204 521). Aliquots (100 .mu.l) of the
resultant solution were added to each well. The plates were
incubated for 20 to 60 minutes at ambient temperature until the
optical density value of the "total" control wells, measured at 405
nm using a plate reading spectrophotometer, was approximately 1.0.
"Blank" (no ATP) and "total" (no compound) control values were used
to determine the dilution range of test compound which gave 50%
inhibition of enzyme activity.
(e) In Vitro c-Src Transfected NIH 3T3 (c-src 3T3) Fibroblast
Proliferation Assay
[0290] This assay determined the ability of a test compound to
inhibit the proliferation of National Institute of Health (NIH
mouse 3T3 fibroblast cells that had been stably-transfected with an
activating mutant (Y530F) of human c-Src.
[0291] Using a similar procedure to that described by Shalloway et
al., Cell, 1987, 49, 65-73, NIH 3T3 cells were transfected with an
activating mutant (Y530F) of human c-Src. The resultant c-Src 3T3
cells were typically seeded at 1.5.times.10.sup.4 cells per well
into 96-well tissue-culture-treated clear assay plates (Costar)
each containing an assay medium comprising Dulbecco's modified
Eagle's medium (DMEM; Sigma) plus 0.5% foetal calf serum (FCS), 2
mM glutamine, 100 units/ml penicillin and 0.1 mg/ml streptomycin in
0.9% aqueous sodium chloride solution. The plates were incubated
overnight at 37.degree. C. in a humidified (7.5% CO.sub.2: 95% air)
incubator.
[0292] Test compounds were solubilised in DMSO to form a 10 mM
stock solution. Aliquots of the stock solution were diluted with
the DMEM medium described above and added to appropriate wells.
Serial dilutions were made to give a range of test concentrations.
Control wells to which test compound was not added were included on
each plate. The plates were incubated overnight at 37.degree. C. in
a humidified (7.5% CO.sub.2: 95% air) incubator.
[0293] BrdU labelling reagent (Boehringer Mannheim Catalogue No.
647 229) was diluted by a factor of 1:100 in DMEM medium containing
0.5% FCS and aliquots (20 .mu.l) were added to each well to give a
final concentration of 10 mM). The plates were incubated at
37.degree. C. for 2 hours. The medium was decanted. A denaturating
solution (FixDenat solution, Boehringer Mannheim Catalogue No. 647
229; 50 .mu.l) was added to each well and the plates were placed on
a plate shaker at ambient temperature for 45 minutes. The
supernatant was decanted and the wells were washed with PBS (200
.mu.l per well). Anti-BrdU-Peroxidase solution (Boehringer Mannheim
Catalogue No. 647 229) was diluted by a factor of 1:100 in PBS
containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered
trade mark), Premier Beverages, Stafford, GB) and an aliquot (100
.mu.l) of the resultant solution was added to each well. The plates
were placed on a plate shaker-at ambient temperature for 90
minutes. The wells were washed with PBS (.times.5) to ensure
removal of non-bound antibody conjugate. The plates were blotted
dry and tetramethylbenzidine substrate-solution (Boehringer
Mannheim Catalogue No. 647 229; 100 .mu.l) was added to each well.
The plates were gently agitated on a plate shaker while the colour
developed during a 10 to 20 minute period. The absorbance of the
wells was measured at 690 nm. The extent of inhibition of cellular
proliferation at a range of concentrations of each test compound
was determined and an anti-proliferative IC.sub.50 value was
derived.
(f) In Vitro Microdroplet Migration Assay
[0294] This assay determines the ability of a test compound to
inhibit the migration of adherent mammalian cell lines, for example
the human tumour cell line A549.
[0295] RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and
0.3% agarose (Difco Catalogue No. 0142-01) was warmed to 37.degree.
C. in a water bath. A stock 2% aqueous agar solution was autoclaved
and stored at 42.degree. C. An aliquot (1.5 ml) of the agar
solution was added to RPMI medium (10 ml) immediately prior to its
use. A549 cells (Accession No. ATCC CCL185) were suspended at a
concentration of 2.times.10.sup.7 cells/ml in the medium and
maintained at a temperature of 37.degree. C.
[0296] A droplet (2 .mu.l) of the cell/agarose mixture was
transferred by pipette into the centre of each well of a number of
96-well, flat bottomed non-tissue-culture-treated microtitre plate
(Bibby Sterilin Catalogue No. 642000). The plates were placed
briefly on ice to speed the gelling of the agarose-containing
droplets. Aliquots (90 .mu.l) of medium which had been cooled to
4.degree. C. were transferred into each well, taking care not to
disturb the microdroplets. Test compounds were diluted from a 10 mM
stock solution in DMSO using RPMI medium as described above.
Aliquots (10 .mu.l) of the diluted test compounds were transferred
to the wells, again taking care not to disturb the microdroplets.
The plates were incubated at 37.degree. C. in a humidified (7.5%
CO.sub.2: 95% air) incubator for about 48 hours.
[0297] Migration was assessed visually and the distance of
migration was measured back to the edge of the agar droplet. A
migratory inhibitory IC.sub.50 was derived by plotting the mean
migration measurement against test compound concentration.
(g) In Vivo A549 Xenograft Growth Assay
[0298] This test measures the ability of compounds to inhibit the
growth of the A549 human carcinoma grown as a tumour in athymic
nude mice (Alderley Park nu/nu strain). A total of about
5.times.10.sup.6 A549 cells in matrigel (Beckton Dickinson
Catalogue No. 40234) were injected subcutaneously into the left
flank of each test mouse and the resultant tumours were allowed to
grow for about 14 days. Tumour size was measured twice weekly using
callipers and a theoretical volume was calculated. Animals were
selected to provide control and treatment groups of approximately
equal average tumour volume. Test compounds were prepared as a
ball-milled suspension in 1% polysorbate vehicle and dosed orally
once daily for a period of about 28 days. The effect on tumour
growth was assessed.
[0299] 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) to (g):
[0300] Test (a):--IC.sub.50 in the range, for example, less than 4
.mu.M;
[0301] Test (b):--activity was observed in this screen;
[0302] Test (c):--IC.sub.50 in the range, for example, less than 30
.mu.M.
[0303] Test (d):--IC.sub.50 in the range, for example, 0.001-10
.mu.M;
[0304] Test (d):--IC.sub.50 in the range, for example, 0.01-20
.mu.M;
[0305] Test (f):--activity in the range, for example, 0.1-25
.mu.M;
[0306] Test (g):--activity in the range, for example, 1-200
mg/kg/day;
[0307] No physiologically-unacceptable toxicity was observed in
Test (g) 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.
[0308] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a quinoline
derivative of the Formula I, or a pharmaceutically-acceptable salt
thereof, as defined hereinbefore in association with a
pharmaceutically-acceptable diluent or carrier.
[0309] 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).
[0310] 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.
[0311] 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.
[0312] 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.
[0313] 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.
[0314] According to a further aspect of the invention there is
provided a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
for use in a method of treatment of the human or animal body by
therapy.
[0315] According to a further aspect of the invention there is
provided a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
for use in the treatment or cancer.
[0316] As stated above we have also found that the quinoline
derivatives of the present invention of Formula I possess potent
anti-tumour activity which it is believed is obtained by way of
inhibition of one or more of the MEK enzymes that are involved in
the MAPK pathway.
[0317] Accordingly, the quinoline derivatives of Formula I are of
value as anti-proliferative agents in the containment and/or
treatment of solid tumour disease. Particularly, the compounds of
Formula I are expected to be useful in the prevention or treatment
of those tumours which are sensitive to inhibition of one or more
of the MEK enzymes that are involved in the MAPK pathway. Further,
the compounds of Formula I are expected to be useful in the
prevention or treatment of those tumours which are mediated alone
or in part by inhibition of the MBK enzymes i.e. the compounds may
be used to produce a MEK enzyme inhibitory effect in a warm-blooded
animal in need of such treatment Specifically, the compounds of
Formula I are expected to be useful in the prevention or treatment
of solid tumour disease.
[0318] Thus, according to this aspect of the invention there is
provided of a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
for use as an anti-proliferative agent in the containment and/or
treatment of solid tumour disease.
[0319] According to a further aspect of the-invention there is
provided the use of a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use as an anti-proliferative
agent in the containment and/or treatment of solid tumour
disease.
[0320] According to a further feature of the invention there is
provided a method for producing an anti-proliferative effect by the
containment and/or treatment of solid tumour disease in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0321] According to a further aspect of the invention there is
provided the use of a quinoline 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 solid tumour disease in a warm-blooded animals such as
man.
[0322] According to a further feature of this aspect of the
invention there is provided a method for the prevention or
treatment of solid tumour disease in a warm-blooded animal, such as
man, in need of such treatment which comprises administering to
said animal an effective amount of a quinoline derivative of the
Formula 1, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore.
[0323] According to a further aspect of the invention there is
provided the use of a quinoline 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 MEK
enzymes that are involved in the MAPK pathway. Particular enzymes
that the tumours may be sensitive to are MEK 1, MEK 2 and MEK
5.
[0324] 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
MEK-enzymes that are involved in the MAPK pathway which comprises
administering to said animal an effective amount of a quinoline
derivative of the Formula I, or a pharmaceutically-acceptable salt
thereof, as defined hereinbefore.
[0325] According to a further aspect of the invention there is
provided the use of a quinoline 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 MEK
enzyme inhibitory effect.
[0326] According to a further feature of this aspect of the
invention there is provided a method for providing a MEK enzyme
inhibitory effect which comprises administering to said animal an
effective amount of a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0327] We have also found that the quinoline derivatives of the
present invention possess potent anti-tumour activity which it is
believed is obtained by way of inhibition of one or more of the
non-receptor tyrosine-specific protein kinases such as c-Src kinase
that are involved in the signal transduction steps which lead to
the invasiveness and migratory ability of metastasising tumour
cells.
[0328] Particularly, the quinoline derivatives of the present
invention are of value as anti-invasive agents in the containment
and/or treatment of solid tumour disease. Particularly, the
compounds of the present invention are expected to be useful in the
prevention or treatment of those tumours which are sensitive to
inhibition of one or more of the multiple non-receptor tyrosine
kinases such as c-Src kinase that are involved in the signal
transduction steps which lead to the invasiveness and migratory
ability of metastasising turnour cells. Further, the compounds of
the present invention are expected to be useful in the prevention
or treatment of those tumours which are mediated alone or in part
by inhibition of the enzyme c-Src, i.e. the compounds may be used
to produce a c-Src enzyme inhibitory effect in a warm-blooded
animal in need of such treatment. Specifically, the compounds of
the present invention are expected to be useful in the prevention
or treatment of solid tumour disease.
[0329] According to this aspect of the invention there is provided
a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
for use as an anti-invasive agent in the containment and/or
treatment of solid tumour disease.
[0330] According to a further feature of this aspect of the
invention there is provided the use of a quinoline derivative of
the Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore in the manufacture of a medicament for use as
an anti-invasive agent in the containment and/or treatment of solid
tumour disease.
[0331] According to a further feature of this aspect of the
invention there is provided a method for producing an anti-invasive
effect by the containment and/or treatment of solid tumour disease
in a warm-blooded animal, such as man, in need of such treatment
which comprises administering to said animal an effective amount of
a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0332] According to a further aspect of the invention there is
provided the use of a quinoline 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
non-receptor tyrosine kinases such as c-Src kinase that are
involved in the signal transduction steps which lead to the
invasiveness and migratory ability of metastasising tumour
cells.
[0333] 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
non-receptor tyrosine kinases such as c-Src kinase that are
involved in the signal transduction steps which lead to the
invasiveness and migratory ability of metastasising tumour cells
which comprises administering to said animal an effective amount of
a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0334] According to a further aspect of the invention there is
provided the use of a quinoline 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 c-Src
kinase inhibitory effect.
[0335] According to a further feature of this aspect of the
invention there is provided a method for providing a c-Src kinase
inhibitory effect which comprises administering to said animal an
effective amount of a quinoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0336] The anti-proliferative and anti-invasive treatment defined
hereinbefore may be applied as a sole therapy or may involve, in
addition to the quinoline 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:-- [0337] (i) other anti-invasion agents (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function); [0338] (ii)
other anti-proliferative or 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, or, for example, one of the
preferred antimetabolites disclosed in European Patent Application
No. 562734 such as
(2S)-2-{o-fluoro-p-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylme-
thyl)-N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyric
acid); 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, viriblastine,
vindesine and vinorelbine and taxoids like taxol and taxotere); and
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecin);
[0339] (iii) cytostatic agents such as antioestrogens (for example
tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),
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, letrazole, vorazole and exemestane) and inhibitors of
5 .alpha.-reductase such as finasteride; [0340] (iv) inhibitors of
growth factor function, for example such inhibitors include growth
factor antibodies, growth factor receptor antibodies, farnesyl
transferase inhibitors, tyrosine kinase inhibitors and
serine/threonine kinase inhibitors, for example inhibitors of the
epidermal growth factor family (for example the EGFR tyrosine
kinase inhibitors
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-3-morpholinopropoxy)quinazolin-4--
amine (ZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (CP
358774) 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; [0341] (v) antiangiogenic
agents such as those which inhibit vascular endothelial growth
factor such as the compounds disclosed in International-Patent
Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354
and those that work by other mechanisms (for example linomide,
inhibitors of integrin .alpha.v.beta.3 function and angiostatin);
[0342] (vi) antisense therapies, for example those which are
directed to the targets listed above, such as ISIS 2503, an
anti-ras antisense; [0343] (vii) gene therapy approaches, including
for example approaches to replace aberrant genes such as aberrant
p53 or aberrant BRCA1 GDEPT (gene-directed enzyme pro-drug therapy)
approaches such as those using cytosine deaminase, thynidine kinase
or a bacterial nitroreductase enzyme and approaches to increase
patient tolerance to chemotherapy or radiotherapy such as multidrug
resistance gene therapy; and [0344] (viii) immunotherapy
approaches, including for example ex-vivo and in-vivo approaches to
increase the immunogenicity of patient tumour cells, such as
transfection with cytokines such as interleukin 2, interleukin 4 or
granulocyte-macrophage colony stimulating factor, approaches to
decrease T-cell anergy, approaches using transfected immune cells
such as cytoline-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0345] 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.
[0346] According to this aspect of the invention there is provided
a pharmaceutical product comprising a quinoline derivative of the
formula I as defined hereinbefore and an additional anti-tumour
agent as defined hereinbefore for the conjoint treatment of
cancer.
[0347] 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 MEK enzymes that are involved in the
MAPK kinase pathway or the effects of c Src. Thus, they are useful
as pharmacological standards for use in the development of new
biological tests and in the search for new pharmacological
agents.
[0348] The invention will now be illustrated in the following
Examples in which, generally:
[0349] (i) operations were carried out at ambient temperature, i.e.
in the range 17 to 25.degree. C. and under an atmosphere of an
inert gas such as argon unless otherwise stated;
[0350] (ii) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids by filtration;
[0351] (iii) column chromatography (by the flash procedure) and
medium pressure liquid chromatography (MPLC) were performed on
Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art.
9303) reversed-phase silica obtained from E. Merck, Darmstadt,
Germany or high pressure liquid chromatography (HPLC) was performed
on C18 reverse phase silica, for example on a Dynamax C-18 60 .ANG.
preparative reversed-phase column;
[0352] (iv) yields, where present, are not necessarily the maximum
attainable;
[0353] (v) in general, the end-products of the Formula I have
satisfactory microanalyses and their structures were confirmed by
nuclear magnetic resonance (NMR) and/or mass spectral techniques;
fast-atom bombardment (FAB) mass spectral data were obtained using
a Platform spectrometer and, where appropriate, either positive ion
data or negative ion data were collected; NMR chemical shift values
were measured on the delta scale [proton magnetic resonance spectra
were determined using a Jeol JNM EX 400 spectrometer operating at a
field strength of 400 MHz, Varian Gemini 2000 spectrometer
operating at a field strength of 300 MHz or a Bruker AM300
spectrometer operating at a field strength of 300 MHz]; the
following abbreviations have been used: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad;
[0354] (vi) intermediates were not generally fully characterised
and purity was assessed by thin layer chromatographic, HPLC,
infra-red (IR) and/or NMR analysis;
[0355] (vii) melting points are uncorrected and were determined
using a Mettler SP62 automatic melting point apparatus or an
oil-bath apparatus; melting points for the end-products of the
Formula I were determined after crystallisation from a conventional
organic solvent such as ethanol, methanol, acetone, ether or
hexane, alone or in admixture;
[0356] (viii) the following abbreviations have been used: [0357]
DMF N,N-dimethylformamide [0358] DMSO dimethylsulphoxide [0359] THF
tetrahydrofuran
EXAMPLE 1
3-cyano-6,7-dimethoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilin-
o]quinoline monohydrochloride salt
[0360] A mixture of
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
(0.2 g), methyl 2-propynyl ether (0.071 ml),
tetrakis(triphenylphosphine)palladium(0) (0.05 g), cuprous iodide
(0.01 g) and N,N-diethylamine (4 ml) was stirred and heated to
60.degree. C. for 4 hours. The reaction mixture was evaporated and
the residue was partitioned between methylene chloride and a 2N
aqueous hydrochloric acid solution. The precipitate that was formed
was isolated by filtration, washed in turn with methylene chloride,
ethanol and diethyl ether and dried. There was thus obtained the
title compound (0.085 g); NMR Spectrum: (DMSOd.sub.6) 3.33 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 4.36 (s, 2H), 6.12 (s, 2H), 6.98 (d,
1H), 7.02 (d, 1H), 7.47 (s, 1H), 8.13 (s, 1H), 8.98 (s, 1H); Mass
Spectrum: M+H.sup.+ 418.
[0361] The
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
used as a starting material was prepared as follows:
[0362] Sodium hexamethyldisilazane (1M solution in THF; 3.8 ml) was
added to a solution of 4-iodo-2,3-methylenedioxyaniline (0.5 g) in
DMF (12 ml) that was cooled to 0.degree. C. and the mixture was
stirred for 5 minutes. A solution of
4-chloro-3-cyano-6,7-dimethoxyquinoline (International Patent
Application WO 98/43960; 0.43 g) in DMF (3 ml) was added and the
resultant mixture was stirred at ambient temperature for 2 hours.
The reaction mixture was diluted with water and extracted with
ethyl acetate. The organic phase was washed with water and with a
saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica increasingly polar mixtures of ethylene chloride and ethyl
acetate as eluent. There was thus obtained
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
as a solid (0.8 g); NMR Spectrum: DMSOd.sub.6) 3.77 (s, 3H), 3.81
(s, 3H), 5.88 (s, 2H), 6.3 (d, 1H), 6.87 (d, 1H), 6.93 (s, 1H), 7.7
s, 1H), 7.83 (s, 1H); Mass Spectrum: M+H.sup.+ 476;.
[0363] The 4-iodo-2,3-methylenedioxyaniline used as a starting
material was prepared as follows:
[0364] A mixture of 2,3-dihydroxybenzoic acid (5 g), methanol (50
ml) and concentrated sulphuric acid (10 drops) was stirred and
heated to 60.degree. C. for 24 hours. The mixture was evaporated
and the residue was taken up in ethyl acetate. The organic solution
was washed with a saturated solution of sodium bicarbonate, dried
over magnesium sulphate and evaporated to give methyl
2,3-dihydroxybenzoate (2.19 g); NMR Spectrum: (CDCl.sub.3) 3.95 (s,
3H), 5.7 (s, 1H), 6.8 (t, 1H), 7.15 (d, H), 7.35 (d, H).
[0365] After repetition of the previous reaction, a mixture of
methyl 2,3-dihydroxybenzoate (2.8 g), potassium fluoride (4.8 g)
and DMF (45 ml) was stirred at ambient temperature for 30 minutes.
Dibromomethane (1.28 ml) was added and the mixture was heated to
120.degree. C. for 3 hours. The mixture was cooled to ambient
temperature, poured into water and extracted with diethyl ether.
The organic phase was washed with water and with a saturated brine
solution, dried over magnesium sulphate and evaporated. The residue
was purified by column chromatography using a 9:1 mixture of
petroleum ether (b.p. 40-60.degree. C.) and ethyl acetate as
eluent. There was thus obtained methyl 2,3-methylenedioxybenzoate
(2.3 g) as a solid; NMR Spectrum: (CDCl.sub.3) 3.95 (s, 3H), 6.1
(s, 2H), 6.85 (t, 1H), 7.0 (d, 1H), 7.45 (d, 1H).
[0366] A mixture of the material so obtained, a 2N aqueous
potassium hydroxide solution (15.5 ml) and methanol (40 ml) was
stirred at ambient temperature for 2 hours. The solution was
concentrated to about one quarter of the original volume and cooled
in an ice bath. The mixture was acidified to pH3.5 by the addition
of a 2N aqueous hydrochloric acid solution. The resultant
precipitate was collected by filtration and washed in turn with
water and diethyl ether. There was thus obtained
2,3-methylenedioxybenzoic acid (1.87 g); NMR Spectrum:
(DMSOd.sub.6) 6.1 (s, 1H), 6.9 (t, 1H), 7.15 (d, 1H), 7.3 (d, 1H),
13.0 (br s, 1H).
[0367] The material so obtained was suspended in anhydrous dioxane
(30 ml) and anhydrous diphenylphosphoryl azide (2.45 ml),
triethylamine (1.6 ml) and tert-butanol (9 ml) were added. The
mixture was heated to reflux for 5 hours. The mixture was cooled to
ambient temperature, concentrated by evaporation and diluted with
ethyl acetate. The organic phase was washed in turn with a 5%
aqueous citric acid solution, water, an aqueous sodium bicarbonate
solution and a saturated brine solution and dried over magnesium
sulphate. The solvent was evaporated and the residue was purified
by column chromatography on silica using a 19:1 mixture of
petroleum ether (b.p. 40-60.degree. C.) and ethyl acetate as
eluent. There was thus obtained tert-butyl
N-(2,3-methylenedioxyphenyl)carbamate (1.98 g) as a solid; NMR
Spectrum: (CDCl.sub.3) 1.55 (s, 9H), 5.95 (s, 2H), 6.4 (br s, 1H),
6.55 (d, 1H), 6.8 (t, 1H), 7.45 (d, 1H).
[0368] A 5N aqueous hydrochloric acid solution (30 ml) was added to
a solution of tert-butyl N-(2,3-methylenedioxyphenyl)carbamate (1.9
g) in ethanol (38 ml) and the reaction mixture was stirred at
ambient temperature for 20 hours. The ethanol was evaporated and
the residual aqueous phase was washed with diethyl ether and
neutralised to pH7 by the addition of solid potassium hydroxide.
The resultant mixture was filtered and the aqueous phase was
extracted with diethyl ether. The organic phase was washed with a
saturated brine solution, dried over magnesium sulphate and
evaporated. There was thus obtained 2,3-methylenedioxyaniline (1.0
g) as an oil; NMR Spectrum: (CDCl.sub.3) 3.0 (br s, 2H), 5.9 (s,
2H), 6.3 (m, 2H), 7.25 (t, 1H).
[0369] Benzyltrimethylammonium dichloroiodate (2.8 g) was added
portionwise during 10 minutes to a stirred mixture of
2,3-methylenedioxyaniline (1 g), calcium carbonate (0.95 g),
methanol (5 ml) and methylene chloride (10 ml). The reaction
mixture was stirred at ambient temperature for 1.5 hours.
The-resultant mixture was diluted with water and extracted with
methylene chloride. The organic phase was washed with water and
with a saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using increasingly polar mixtures of isohexane and methylene
chloride as eluent. There was thus obtained
4-iodo-2,3-methylenedioxyaniline as a solid (1.1 g); NMR Spectrum:
(DMSOd.sub.6) 5.04 (br s, 2H), 5.94 (s, 2H), 6.13 (d, 1H), 6.8 (d,
1H).
EXAMPLE 2
3-cyano-6,7-dimethoxy-4-[6chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylene
dioxyanilino]quinoline
[0370] A mixture of 4-(6-chloro-4-iodo-2,3-methylenedioxyan
ilino)-3-cyano-6,7-dimethoxyquinoline (0.25 g), methyl 2-propynyl
ether (0.09 ml), N,N-diisopropylamine (0.154 ml),
bis(triphenylphosphine)palladium(II) dichloride (0.069 g), cuprous
iodide (0.028 g) and ethyl acetate (10 ml) was stirred and heated
to reflux for 12 hours. The reaction mixture was cooled to ambient
temperature and partitioned between ethyl acetate and water. The
organic layer was dried over magnesium sulphate and evaporated and
the residue was purified by column chromatography on silica using
increasingly polar mixtures of hexane and ethyl acetate as eluent
There was thus obtained the title compound as an oil (0.138 g); NMR
Spectrum: (DMSOd.sub.6) 3.42 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H),
4.38 (s, 2H), 6.17 (s, 2H), 7.13 (s, 1H), 7.36 (s, 1H), 7.92 (s,
1H), 8.39 (s, 1H), 9.42 (br s, 1H); Mass Spectrum: M+H.sup.+
452.
[0371] The
4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7dimethoxyquinoli-
ne used as a starting material was prepared as follows:
[0372] Using an analogous procedure to that described in the
portion of Example 1 that is concerned with the preparation of
starting materials, 4-chloro-3-cyano-6,7-dimethoxyquinoline (1.74
g) was reacted with 6-chloro-4-iodo-2,3-methylenedioxyaniline (2.5
g) to give
4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinol-
ine as a solid (2.59 g) which gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 4.0 (s, 6H), 6.18 (s, 2H), 7.38
(s, 1H), 7.48 (s, 1H), 7.88 (s, 1H), 8.44 (s, 1H), 9.45 (s, 1H);
Mass Spectrum: M+H.sup.+ 510.
[0373] The 6-chloro-4-iodo-2,3-methylenedioxyaniline used as a
starting material was prepared as follows:
[0374] Sulphuryl chloride (72.5 ml) was added dropwise during 1.7
hours to a stirred mixture of benzodioxole (100 g), aluminium
trichloride (0.43 g) and diphenyl sulphide (0.55 ml). Once the
reaction started with the evolution of sulphur dioxide, the
reaction mixture was cooled in a water bath to a temperature of
approximately 22.degree. C. After completion of the addition, the
reaction mixture was stirred at-ambient temperature for 45 minutes.
The reaction mixture was degassed under vacuum and filtered and the
filtrate was distilled at atmospheric pressure using a Vigreux
distillation column. There was thus obtained
5-chloro-1,3-benzodioxole; b.p. 185-187.degree. C.; NMR Spectrum:
(CDCl.sub.3) 6.0 (s, 2H); 6.7 (d, 1H); 6.75-6.9 (m, 2H).
[0375] A mixture of diisopropylamine (4.92 ml) and THF (100 ml) was
cooled to -78.degree. C. and n-butyllithium (2.5 M in hexane, 14
ml) was added dropwise. The mixture was stirred at -78.degree. C.
for 15 minutes. 5-Chloro-1,3-benzodioxole (3.73 ml) was added
dropwise and the reaction mixture was stirred at -78.degree. C. for
30 minutes. Dry carbon dioxide gas was bubbled into the reaction
mixture for 30 minutes. The resultant reaction mixture was allowed
to warm to ambient temperature and was stirred for a further hour.
Water was added and the organic solvent was evaporated. The residue
was acidified to pH2 by the addition of 2N aqueous hydrochloric
acid solution. The resultant solid was isolated and washed in turn
with water and diethyl ether. There was thus obtained
5-chloro-1,3-benzodioxole-4-carboxylic acid (5.4 g); NMR Spectrum:
(DMSOd.sub.6) 6.15 (s, 2H), 7.0 (m, 2H), 13.7 (br s, 1H).
[0376] A portion (1 g) of the material so obtained was dissolved in
1,4-dioxane (15 ml) and anhydrous tert-butanol (4 ml),
diphenylphosphoryl azide (1.12 ml) and triethylamine (0.73 ml) were
added in turn. The resultant mixture was stirred and heated to
100.degree. C. for 4 hours. The mixture was evaporated and the
residue was partitioned between ethyl acetate and a 5% aqueous
citric acid solution. The organic phase was washed in turn with
water, a saturated aqueous sodium bicarbonate solution and a
saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using a 9:1 mixture of petroleum ether (b.p. 40-60.degree.
C.) and ethyl acetate as eluent. There was thus obtained tert-butyl
N-(5-chloro-1,3-benzodioxol-4-yl)carbamate (1.1 g); NMR Spectrum:
(DMSOd.sub.6) 1.45 (s, 9H), 6.1 (s, 2H), 6.85 (d, 1H), 6.95 (d,
1H), 8.75 (s, 1H).
[0377] A mixture of the material so obtained (1.1 g),
trifluoroacetic acid (6 ml) and methylene chloride (20 ml) was
stirred at ambient temperature for 3 hours. The solvent was
evaporated and the residue was partitioned between ethyl acetate
and a saturated aqueous sodium bicarbonate solution. The organic
phase was washed with a saturated brine solution, dried over
magnesium sulphate and evaporated. There was thus obtained
6-chloro-2,3-methylenedioxyaniline (0.642 g); NMR Spectrum:
(DMSOd.sub.6) 5.15 (s, 2H), 6.0 (s, 2H), 6.25 (d, 1H), 6.75 (d,
1H).
[0378] 6-Chloro-2,3-methylenedioxyaniline was reacted with
benzyltrimethylammonium dichloroiodate in an analogous manner to
that described in the last paragraph of the portion of Example 1
that is concerned with the preparation of starting materials. There
was thus obtained
4-6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimetho-
xyquinoline which gave the following characterising data; NMR
Spectrum: (DMSOd.sub.6) 6.04 (s, 2H), 7.0 (s, 1H).
EXAMPLE 3
3-cyano-7-ethoxy-6-methoxy-4-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyan-
ilino]quinoline monohydrochloride salt
[0379] Sodium hexamethyldisilazane (1M solution in THF; 1.17 ml)
was added to a stirred mixture of
4-(3-methokyprop-1-ynyl)-2,3-methylenedioxyaniline (0.12 g),
4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline (0.146 g) and DMF (8
ml) that had been cooled to 0.degree. C. and the resultant mixture
was allowed to warm to ambient temperature and was stirred for 2
hours. The reaction mixture was diluted with water and extracted
with ethyl acetate. The organic phase was washed with water and
with a saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica increasingly polar mixtures of methylene chloride and
methanol as eluent. The material so obtained was dissolved in the
minimum quantity of methylene chloride. The solution was diluted
with diethyl ether and a solution of hydrogen chloride in diethyl
ether (1M) was added. The resultant solid was isolated, washed with
diethyl ether and dried. Thereby, the product was obtained the
title compound (0.18 g); NMR Spectrum: (DMSOd.sub.6) 1.44 (t, 3H),
3.33 (s, 3H), 4.0 (s, 3H), 4.24 (q, 2H), 4.36 (s, 2H), 6.12 (s,
2H), 6.96 (d, 1H), 7.03 (d, 1H), 7.45 (s, 1H), 8.11 (s, 1H), 8.96
(s, 1H); Mass Spectrum: M+H.sup.+ 432.
[0380] The 4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline used as a
starting material was prepared as follows:
[0381] Diethyl azodicarboxylate (2.6 g) was added dropwise to a
suspension of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (1.5 g;
prepared as described in International Patent Application WO
00/68201, disclosed as compound (7) within Preparation 1 therein),
ethanol (0.441 g), triphenylphosphine (2.18 g) and methylene
chloride (15 ml) and the mixture was stirred at ambient temperature
for 16 hours. The resultant mixture was washed with water and with
a saturated brine solution. The organic phase was dried over
magnesium sulphate and evaporated. The residue was purified by
column chromatography on silica using increasingly polar mixtures
of methylene chloride and ethyl acetate. There was thus obtained
4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline as a solid (0.225 g);
NMR Spectrum: (DMSOd.sub.6 at 100.degree. C) 1.39-1.48 (m, 3H), 4.0
(s, 3H), 4.25-4.35 (m, 2H), 7.46 (s, 1H), 7.5 (s, 1H), 8.89 (s,
1H); Mass Spectrum: M+H.sup.+ 263.
[0382] The 4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline used
as a starting material was prepared as follows:
[0383] N,N-Diisopropylamine (0.231 g) was added to a stirred
mixture of 4-iodo-2,3-methylenedioxyaniline (0.3 g), methyl
2-propynyl ether (0.16 g), bis(triphenylphosphine)palladium(II)
dichloride (0.16 g), cuprous iodide (0.065 g) and ethyl acetate (10
ml) that had been cooled to -20.degree. C. The resultant mixture
was allowed to warm to ambient temperature and was stirred for 16
hours. The reaction mixture was partitioned between ethyl acetate
and a saturated aqueous sodium bicarbonate solution. The organic
layer was washed with water and with a saturated brine solution,
dried over magnesium sulphate and evaporated. The residue was
purified by column chromatography on silica using increasingly
polar mixtures of isohexane and methylene chloride as eluent. There
was thus obtained
4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline as a gum (0.2
g); NMR Spectrum: (DMSOd.sub.6) 3.28 (s, 3H), 4.25 (s, 2H), 5.29
(s, 2H), 5.94 (s, 2H), 6.2 (d, 1H), 6.64 (d, 1H).
EXAMPLE 4
3-cyano-6,7-dimethoxy-4-{-4-8
3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)prop-1-ynyl]-2,3-methylenedioxyani-
lino}quinoline
[0384] N,N-Diisopropylamine (0.043 g) was added to a stirred
mixture of
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
(0.2 g), 4-(2-propynyl)-1,1-dioxotetrahydro-4H-thiazine (0.145 g),
bis(triphenylphosphine)palladium(II) dichloride (0.071 g), cuprous
iodide (0.024 g) and ethyl acetate (10 ml) that had been cooled to
-20.degree. C. The resultant mixture was allowed to warm to ambient
temperature and was stirred for 16 hours. The reaction mixture was
partitioned between ethyl acetate and a saturated aqueous sodium
bicarbonate solution. The organic layer was washed with water and
with a saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was triturated under a mixture of
acetonitrile and water. The resultant solid was isolated and dried.
There was thus obtained the title compound as a solid (0.05 g); NMR
Spectrum: (DMSOd.sub.6) 2.97-3.04 (m, 4H), 3.12-3;18 (m, 4H), 3.72
(s, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 6.04 (s, 2H), 6.82 (d, 1H),
6.95 (d, 1H), 7.31 (s, 1H), 7.74 (s, 1), 8.48 (s, 1H), 9.6 (s, 1H);
Mass Spectrum: M+H.sup.+ 521.
EXAMPLE 5
3-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-(3-morpholinoprop-1-ynyl)ani-
lino]quinoline dihydrochloride salt
[0385] Using an analogous procedure to that described in Example 4,
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
was reacted with 4-(2-propynyl)morpholine. The reaction mixture was
partitioned between ethyl acetate and a saturated aqueous sodium
bicarbonate solution. The organic layer was washed with water and
with a saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using increasingly polar mixtures of methylene chloride and
methanol as eluent. The material so obtained was dissolved in the
minimum quantity of methylene chloride. The solution was diluted
with diethyl ether and a solution of hydrogen chloride in diethyl
ether (1M) was added. The resultant solid was isolated, washed with
diethyl ether and dried. There was thus obtained the title compound
as a solid (0.065 g); NMR Spectrum: (DMSOd.sub.6 and
CD.sub.3CO.sub.2D) 3.24-3.29 (m, 4H), 3.9-3.95 (m, 4H), 4.0 (s,
3H), 4.01 (s, 3H), 4.28 (s, 2H), 6.1 (s, 2H), 6.95 (d, 1H), 7.05
(d, 1H), 7.49 (s, 1H), 7.5-7.65 (m, 1H), 8.06 (s, 1H), 8.67 (s,
1H); Mass Spectrum: M-H.sup.- 471.
EXAMPLE 6
3-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-(3-piperazin-1-ylprop-1-ynyl-
)anilino]quinoline dihydrochloride salt
[0386] Using an analogous procedure to that described in Example 1,
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dinethoxyquinoline
was reacted with 1-(2-propynyl)piperazine (J. Med. Chem. 1993, 36
610-616). The reaction mixture was partitioned between methylene
chloride and a 2N aqueous hydrochloric acid solution. The organic
layer was dried over magnesium sulphate and evaporated and the
residue was purified by column chromatography on silica using
increasingly polar mixtures of methylene chloride and a saturated
methanolic ammonia solution as eluent. The material so obtained was
dissolved in the minimum quantity of methylene chloride. The
solution was diluted with diethyl ether and a solution of hydrogen
chloride in diethyl ether (1M) was added. The resultant solid was
isolated, washed with diethyl ether and dried. There was thus
obtained the title compound; NMR Spectrum: (DMSOd.sub.6 and
CD.sub.3CO.sub.2D) 3.28-3.44 (m, 8H), 3.99 (s, 3H), 4.0 (s, 3H),
4.27 (br s, 2H), 6.15 (s, 2H), 7.04 (d, 1H), 7.14 (d, 1H), 7.5 (s,
1H), 8.24 (s, 1H), 9.05 (s, 1H); Mass Spectrum: M-H.sup.- 470.
EXAMPLE 7
4-[4-(5-chloropent-1-ynyl)-2,3-methylenedioxyanilino]-3-cyano-6,7-dimethox-
yquinoline
[0387] Using an analogous procedure to that described in Example 4,
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
was reacted with 5-chloropent-1-yne. The reaction mixture was
partitioned between ethyl acetate and a saturated aqueous sodium
bicarbonate solution. The organic layer was washed with water and
with a saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using increasingly polar mixtures of methylene chloride and
ethyl acetate as eluent. There was thus obtained the title compound
as a gum in 69% yield; Mass Spectrum: M+H.sup.+ 450.
EXAMPLE 8
3-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-(5-morpholinopent-1-ynyl)ani-
lino]quinoline dihydrochloride salt
[0388] Morpholine (5 ml) was added to a mixture of
4-[4-(5-chloropent-1-ynyl)-2,3-methylenedioxyanilino]-3-cyano-6,7-dimetho-
xyquinoline (0.11 g) and sodium iodide (0.073 g) and the reaction
mixture was stirred at ambient temperature for 16 hours. The
resultant mixture was evaporated and the residue partitioned
between methylene chloride and water. The organic phase was washed
with water and with a saturated brine solution, dried over
magnesium sulphate and evaporated. The residue was purified by
column chromatography on silica using increasingly polar mixtures
of methylene chloride and a saturated methanolic ammonia solution
as eluent. The material so obtained was dissolved in the minimum
quantity of methylene chloride. The solution was diluted with
diethyl ether and a solution of hydrogen chloride in diethyl ether
(1M) was added. The resultant solid was isolated, washed with
diethyl ether and dried. There was thus obtained the title compound
as a solid (0.105 g); NMR Spectrum: (DMSOd.sub.6 and
CD.sub.3CO.sub.2D) 1.98-2.04 (m, 2H), 2.56-2.65 (m, 2H), 3.04-3.16
(m, 2H), 3.17-3.26 (m, 2H), 3.39-3.51 (m, 2H), 3.69-4.02 (m, 10H),
6.06 (s, 2H), 6.9 (d, 1H), 6.98 (d, 1H), 7.37 (s, 1H), 7.95 (s,
1H), 8.75 (s, 1H); Mass Spectrum: M+H.sup.+ 501.
EXAMPLE 9
[0389] Using an analogous procedure to that described in Example 3,
the appropriate 4-chloro-3-cyanoquinoline was reacted with the
appropriate 2,3-methylenedioxyaniline to give the compounds
described in Table I. Unless otherwise stated, each compound
described in Table I was obtained as a dihydrochloride salt
TABLE-US-00001 TABLE I ##STR9## Compound No. & Note R[HU 1
(R[HU 3[L )[HD n [1] 3-(4-methylpiperazin-1-yl)propoxy
4-(3-methoxyprop-1-ynyl) [2] 3-morpholinopropoxy
4-(3-methoxyprop-1-ynyl) [3] 3-morpholinopropoxy
6-chloro-4-(3-methoxyprop-1-ynyl) [4]
3-(1,1-dioxotetrahydro-4H-thiazin-4- 4-(3-methoxyprop-1-ynyl)
yl)propoxy [5] 2-fluoroethoxy 4-(3-methoxyprop-1-ynyl) [6]
3-(3-oxopiperazin-1-yl)propoxy 4-(3-methoxyprop-1-ynyl) [7]
3-(3-oxopiperazin-1-yl)propoxy 6-chloro-4-(3-methoxyprop-1-ynyl)
[8] 2-(2-methoxyethoxy)ethoxy 4-(3-methoxyprop-1-ynyl) [9]
3-chloropropoxy 4-(3-methoxyprop-1-ynyl) [10]
2-(2-chloroethoxy)ethoxy 4-(3-methoxyprop-1-ynyl) Notes [1] The
product was obtained as a trihydrochloride salt and gave the
following characterising data; NMR Spectrum (DMSOd.sub.6) 2.27-2.38
(m, 2H), 2.83 (s, 3H), 3.23-3.85 (m, 10H), 3.34 (s, 3H), 4.01 (s,
3H), 4.3 (t, 2H), 4.35 (s, 2H), 6.11 (s, 2H), 6.97 (d, 1H), 7.01
(d, 1H), 7.53 (s, 1H), 8.21 (s, 1H), 8.94 (s, 1H); Mass Spectrum: M
- H.sup.- 542.
[0390] The
4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quioline
used as a starting material was prepared as follows:
[0391] A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29
ml), potassium carbonate (83 g) and ethanol (200 ml) was stirred
and heated to reflux for 20 hours. The mixture was cooled to
ambient temperature and filtered. The filtrate was evaporated and
the residue was triturated under diethyl ether. The resultant
mixture was filtered and the filtrate was evaporated. The residue
was purified by distillation at about 60-70.degree. C. under about
0.2 mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g);
NMR Spectrum: (CDCl.sub.3) 1.72 (m, 2H), 2.3 (s, 3H), 2.2-2.8 (m,
8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, 1H).
[0392] A solution of diisopropyl azodicarboxylate (12.1 ml) in
methylene chloride (50 ml) was added dropwise during 30 minutes to
a stirred mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline
(12 g), 1-(3-hydroxypropyl)-4-methylpiperazine (9.7 g),
triphenylphosphine (16.1 g) and methylene chloride (200 ml) that
had been cooled to 5.degree. C. The resultant mixture was allowed
to warm to ambient temperature and was then stirred for 1 hour.
Further portions of diisopropyl azodicarboxylate (1.2 ml) and
triphenylphosphine (1.6 g) were added and the mixture was stirred
at ambient temperature for a further 1 hour. The mixture was poured
into water and the organic layer was separated, washed with a
saturated brine solution, dried over magnesium sulphate and
evaporated. The material so obtained was purified by column
chromatography on silica using increasingly polar mixtures of
methylene chloride and methanol as eluent. There was thus obtained
the required starting material as a solid (14.5 g); NMR Spectrum:
(DMSOd.sub.6) 1.95 (m, 2H), 2.13 (s, 3H), 2.24-2.5 (m, 10H), 4.0
(s, 3H), 4.25 (t, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 8.95 (s, 1H);
Mass Spectrum: M+H.sup.+ 375 and 377.
[0393] [2]
4-Chloro-3-cyano-6-methoxy-7-(3-morpholinopropoxy)quinoline
(International Patent Application WO 00/68201, page 52) was used as
a starting material. The product gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 2.3-2.38 (m, 2H), 3.04-3.14 (m,
2H), 3.25-3.31 (m, 2H), 3.35 (s, 3H), 3.44-3.52 (m, 2H), 3.78-3.86
(m, 2H), 3.98 (d, 2H), 4.01, (s, 3H), 4.3 (t, 2H), 4.36 (s, 2H),
6.14 (s, 2H), 7.0 (d, 1H), 7.03 (d, 1H), 7.55 (s, 1H), 8.21 (s,
1H), 8.94 (s, 1H); Mass Spectrum: M+H.sup.+ 531.
[0394] [3] The product gave the following characterising data; NMR
Spectrum: (DMSOd.sub.6) 2.26-2.35 (m, 2H), 3.03-3.14 (m, 2H),
3.22-3.31 (m, 2H), 3.33 (s, 3H), 3.44-3.51 (m, 2H), 3.81 (t, 2H),
3.91-4.0 (m, 5H), 4.3 (t, 2H), 4.36 (s, 2H), 6.2 (d, 2H), 7.22 (s,
1H), 7.51 (s, 1H), 8.15 (s, 1H), 8.86 (s, 1H); Mass Spectrum:
M-H.sup.- 563 and 565.
[0395] The
6-chloro-4-(3-methoxyprop-1-ynyl)-2;3-methylenedioxyaniline used as
a starting material was prepared as follows:
[0396] N,N-Diisopropylamine (0.68 g) was added to a stirred mixture
of 6-chloro-4-iodo-2,3-methylenedioxyaniline (1 g), methyl
2-propynyl ether (0.471 g), bis(triphenylphosphine)palladium(II)
dichloride (0.472 g), cuprous iodide (0.192 g) and ethyl acetate
(20 ml) that had been cooled to -20.degree. C. The resultant
mixture was allowed to warm to ambient temperature and was stirred
for 16 hours. The reaction mixture was partitioned between ethyl
acetate and a saturated aqueous sodium bicarbonate solution. The
organic layer was washed with water and with a saturated brine
solution, dried over magnesium sulphate and evaporated. The residue
was purified by column chromatography on silica using increasingly
polar mixtures of isohexane and methylene chloride as eluent. There
was thus obtained
6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline as a
solid (0.2 g); NMR Spectrum: (DMSOd.sub.6) 3.28 (s, 3H), 4.26 (s,
2H), 5.52 (s, 2H), 6.05 (s, 2H), 6.93 (s, 1H).
[0397] [4] The product gave the following characterising data; NMR
Spectrum: (DMSOd.sub.6) 2.2-2.27 (m, 2H), 3.16-3.2 (m, 2H), 3.36
(s, 3H), 3.37-3.54 (m, 8H), 4.0 (s, 3H), 4.3-4.37 (m, 4H), 6.19 (s,
2H), 6.8 (d, 1H), 7.0 (d, 1H), 7.46 (s, 1H), 8.0 (s, 1H), 8.74 (s,
1H); Mass Spectrum: M-H.sup.- 577.
[0398] The
4-chloro-3-cyano-7-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)propoxy]-6-met-
hoxyquinoline used as a starting material was prepared as
follows:
[0399] A mixture of 3-aminopropan-1-ol (0.65 ml) and divinyl
sulphone (1 g) was heated to 110.degree. C. for 45 minutes. The
mixture was allowed to cool to ambient temperature and was purified
by column chromatography on silica using a 19:1 mixture of
methylene chloride and methanol as eluent. There was thus obtained
4-(3-hydroxypropyl)-1,1-dioxotetrahydro-4H-thiazine (0.8 g); NMR
Spectrum: (CDCl.sub.3) 1.7-1.8 (m, 2H), 2.73 (t, 2H), 3.06 (br s,
8H), 3.25 (s, 1H), 3.78 (t, 2H); Mass Spectrum: M+H.sup.+ 194.
[0400] Diethyl azodicarboxylate (1.72 g) was added dropwise to a
suspension of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (1 g),
4-(3-hydroxypropyl)-1,1-dioxotetrahydro-4H-thiazine (1.23 g),
triphenylphosphine (1.45 g) and methylene chloride (10 ml) and the
mixture was stirred at ambient temperature for 16 hours. The
resultant mixture was washed with water and with a saturated brine
solution. The organic phase was dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using increasingly polar mixtures of methylene chloride,
ethyl acetate and a saturated methanolic ammonia solution as
eluent. The material so obtained was triturated under diethyl
ether. There was thus obtained
4-chloro-3-cyano-7-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)propoxy]-6-met-
hoxyquinoline (0.15 g); NMR Spectrum: (DMSOd.sub.6) 1.96 (m, 2H),
2.64 (t, 2H), 2.88-2.93 (m, 4H), 3.07-3.12 (m, 4H), 4.0 (s, 3H),
4.29 (t, 2H), 7.44 (s, 1H), 7.55 (s, 1H), 8.96 (s, 1H); Mass
Spectrum: M+H.sup.+ 410.
[0401] [5] The product was obtained as a monohydrochloride salt and
gave the following characterising data; NMR Spectrum: (DMSOd.sub.6)
3.33 (s, 3H), 4.0 (s, 3H), 4.35 (s, 2H), 4.39-4.43 (m, 1H),
4.49-4.53 (m, 1H), 4.75-4.8 (m, 1H), 4.91-4.96 (m, 1H), 6.12 (s,
2H), 6.96 (d, 1H), 7.01 (d, 1H), 7:48 (s, 1H), 8.13 (s, 1H), 8.94
(s, 1H); Mass Spectrum: M+H.sup.+ 450.
[0402] The 4-chloro-3-cyano-7-(2-fluoroethoxy)-6-methoxyquinoline
used as a starting material was prepared by the reaction of
4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and 2-fluoroethanol
using an analogous procedure to that described in Note [4]
immediately above except that the residue was purified by column
chromatography on silica using increasingly polar mixtures of
methylene chloride and ethyl acetate as eluent. The material so
obtained gave the following characterising data; NMR Spectrum:
(DMSOd.sub.6) 4.01 (s, 3H), 4.43-4.48 (m, 1H), 4.53-4.58 (m, 1H),
4.74-4.78 (m, 1H), 4.9-4.94 (m, 1H), 7.42 (s, 1H), 7.56 (s, 1H),
8.96 (s, 1H); Mass Spectrum: M+H.sup.+ 281.
[0403] [6] The product was obtained as a free base after
chromatographic purification and was not converted into a
hydrochloride salt. The product gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6 and CD.sub.3CO.sub.2D) 1.96-2.02
(m, 2H), 2.6-2.68 (m, 4H), 3.03 (s, 2H), 3.21 (m, 2H), 3.34 (s,
3H), 3.94 (s, 3H), 4.21 (t, 2H), 4.3 (s, 2H), 6.01 (s, 2H), 6.76
(d, 1H), 6.91 (d, 1H), 7.34 (s, 1H), 7.71 (s, 1H), 8.41 (s, 1H);
Mass Spectrum: M-H.sup.- 542.
[0404] The
4-chloro-3-cyano-6-methoxy-7-[3-(3-oxopiperazin-1-yl)propoxy]quinoline
used as a starting material was prepared by the reaction of
4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and
4-(3-hydroxypropyl)piperazin-2-one (Tet. Letters, 1994, 35, 9545)
using an analogous procedure to that described in Note [4]
immediately above. The material so obtained gave the following
characterising data; NMR Spectrum: (DMSOd.sub.6) 1.92-2.03 (m, 2H),
2.49-2.59 (m, 4H), 2.94 (s, 2H), 3.1-3.17 (m, 2H), 4.0 (s, 3H),
4.27 (t, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 7.69 (s, 1H), 8.95 (s,
1H); Mass Spectrum: M+H.sup.+ 375.
[0405] [7] The product gave the following-characterising data; NMR
Spectrum: (DMSOd.sub.6) 2.29-2.36 (m, 2H), 3.21-3.41 (m, 5H),
3.55-3.9 (m, 4H), 3.99 (s, 3H), 4.28-4.32 (m, 2H), 4.35 (s, 2H),
5.99 (s, 1H), 6.01 (s, 1H), 6.01 (s, 2H), 7.21 (s, 1H), 7.48 (s,
1H), 8.11 (s, 1H), 8.81 (s, 1H); Mass Spectrum: M+H.sup.+ 578 and
580.
[0406] [8] The product was obtained as a monohydrochloride salt and
gave the following characterising data; NMR spectrum: (DMSOd.sub.6
and CD.sub.3CO.sub.2D) 3.26 (s, 3H), 3.36 (s, 3H), 3.49 (t, 2H),
3.54 (t, 2H), 3.86 (t, 2H), 4.0 (s, 3H), 4.32-4.36 (m, 4H), 6.09
(s, 2H), 6.91 (d, 1H), 7.0 (d, 1H), 7.48 (s, 1H), 8.01 (s, 1H),
8.75 (s, 1H); Mass Spectrum: M+H.sup.+ 506.
[0407] The
4-chloro-3-cyano-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]quinoline
used as a starting material was prepared by the reaction of
4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and
2-(2-methoxyethoxy)ethanol using an analogous procedure to that
described in Note [4] immediately above except that the residue was
purified by column chromatography on silica using increasingly
polar mixtures of methylene chloride and ethyl acetate as eluent.
The material so obtained gave the following characterising data;
NMR Spectrum: (DMSOd.sub.6) 3.23 (s, 3H), 3.46 (m, 2H), 3.61 (m,
2H), 3.82 (m, 2H), 4.0 (s, 3H), 4.34 (t, 2H), 7.42 (s, 1H), 7.55
(s, 1H), 8.95 (s, 1H).
[0408] [9] The product was obtained as a free base after
chromatographic purification and was not converted into a
hydrochloride salt. The product gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 2.25 (m, 2H), 3.32 (s, 3H), 3.8
(t, 2H), 3.92 (s, 3H), 4.27 (t, 2H), 4.34 (s, 2H), 6.05 (s, 2H),
6.82 (d, 1H), 6.96 (d, 1H), 7.35 (s, 1H), 7.74 (s, 1H), 8.47 (s,
1H), 9.60 (s, 1H); Mass Spectrum: M+H.sup.+ 480.
[0409] The 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline
used as a starting material was prepared as follows:
[0410] A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline
(0.2 g), potassium tert-butoxide (0.1 g) and DMF (8 ml) was stirred
at ambient temperature for 15 minutes. 1-Bromo-3-choropropane
(0.134 g) was added and the reaction mixture was stirred at ambient
temperature for 16 hours. The resultant mixture was evaporated and
the residue was partitioned between methylene chloride and an
aqueous sodium bicarbonate solution. The organic layer was dried
using magnesium sulphate and evaporated. The residue was purified
by column chromatography on silica using increasingly polar
mixtures of ethyl acetate and hexane. There was thus obtained the
required starting material (0.131 g); NMR Spectrum: (DMSOd.sub.6)
2.3 (m, 2H), 3.8 (m, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 7.42 (s, 1H),
7.68 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H.sup.+ 311.
[0411] [10] The product was obtained as a free base after
chromatographic purification and was not converted into a
hydrochloride salt. The product gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 3.32 (s, 3H), 3.72-3.78 (m, 4H),
3.85-3.89 (m, 2H), 3.91 (s, 3H), 4.28 (t, 2H), 4.34 (s, 2H), 6.05
(s, 2H), 6.82 (d, 1H), 6.95 (d, 1H), 7.35 (s, 1H), 7.74 (s, 1H),
8.47 (s, 1H), 9.60 (s, 1H); Mass Spectrum: M+H.sup.+ 510.
[0412] The
4-chloro-7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxyquinoline
used as a starting material was prepared by the reaction of
4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and
2-(2-chloroethoxy)ethanol using an analogous procedure to that
described in Note [4] immediately above except that the residue was
purified by column chromatography on silica using increasingly
polar mixtures of methylene chloride and ethyl acetate as eluent.
The material so obtained gave the following characterising data;
NMR Spectrum: (DMSOd.sub.6) 3.72-3.8 (m, 4H), 3.88-3.93 (m, 2H),
4.0 (s, 3H), 4.33-4.39 (m, 2H), 7.4 (s, 1H), 7.55 (s, 1H), 8.94 (s,
1H); Mass Spectrum: M+H.sup.+ 341.
EXAMPLE 10
3-cyano-7-{3-[4-(2-fuoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[4-(3-me-
thoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline
dihydrochloride salt
[0413] A mixture of
7-(3-chloropropoxy)-3-cyano-6-methoxy-4-[4-(3-methokyprop-1-ynyl)-2,3-met-
hylenedioxyanilino]quinoline (0.14 g), 1-(2-fluoroethyl)piperazine
trifluoroacetic acid salt (0.158 g), diisopropylethylamine (0.189
g), sodium iodide (0.02 g) and 2-methoxyethanol (20 ml) was stirred
and heated to 100.degree. C. for 30 hours. The cooled mixture was
evaporated and the resultant residue was partitioned between ethyl
acetate and water. The organic layer was dried over magnesium
sulphate and evaporated and the residue was purified by column
chromatography on silica using increasingly polar mixtures of
methylene chloride and methanol as eluent. The material so obtained
was dissolved in the minimum quantity of methylene chloride. The
solution was diluted with diethyl ether and a solution of hydrogen
chloride in diethyl ether (1M) was added. The resultant solid was
isolated, washed with diethyl ether and dried. There was thus
obtained the title compound (0.045 g); NMR Spectrum: (DMSOd.sub.6
and CF.sub.3CO.sub.2D at 100.degree. C.) 2.22-2.31 (m, 2H),
2.98-3.1 (m, 6H), 3.16-3.21 (m, 2H), 3.25-3.31 (m, 4H), 3.36 (s,
3H), 3.99 (s, 3H), 4.3-4.34 (m, 4H), 4.6 (t, 1H), 4.72 (t, 1H),
6.08 (s, 2H), 6.9 (d, 1H), 6.98 (d, 1H), 7.49 (s, 1H), 7.96 (s,
1H), 8.69 (s, 1H); Mass Spectrum: M+H.sup.+ 576.
[0414] The 1-(2-fluoroethyl)piperazine trifluoroacetic acid used as
a starting material was prepared as follows:
[0415] A mixture of 1-(tert-butoxycarbonyl)piperazine (5 g),
1-bromo-2-fluoroethane (5.11 g), potassium carbonate (9.26 g) and
acetonitrile (60 ml) was stirred and heated to 60.degree. C. for 4
hours. The reaction mixture was cooled to ambient temperature and
filtered and the filtrate was evaporated. The residue was purified
by column chomatography on silica using increasingly polar mixtures
of isohexane and ethyl acetate as eluent. There was thus obtained
4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine as a solid (3.7
g); NMR Spectrum: (DMSOd.sub.6 and CD.sub.3CO.sub.2D) 1.37 (s, 9H),
2.34-2.4 (m, 4H), 2.56 (t, 1H), 2.67 (t, 1H), 3.25-3.34 (m, 4H),
4.42 (t, 1H), 4.58 (t, 1H).
[0416] Trifluoroacetic acid (20 ml) was added to a mixture of
4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine (3.7 g),
triethylsilane (8 ml) and methylene chloride (100 ml) and the
resultant mixture was stirred at ambient temperature for 1.5 hours.
The mixture was evaporated and the residue was triturated under
diethyl ether. The solid so obtained was isolated, washed with
diethyl ether and dried. There was thus obtained
1-(2-fluoroethyl)piperazine trifluoroacetic acid salt as a solid
(6.0 g); NMR Spectrum: (DMSOd.sub.6 and CD.sub.3CO.sub.2D) 3.0-3.31
(m, 10H), 4.59 (m, 1H), 4.75 (m, 1H).
EXAMPLE 11
7-[3-4-acetylpiperazin-1-yl)propoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-
-1-ynyl)-2,3-methylenedioxyanilino]quinoline dihydrochloride
salt
[0417] Using an analogous procedure to that described in Example
10,
7-(3-chloropropoxy)-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-met-
hylenedioxyanilino]quinoline was reacted with 1-acetylpiperazine to
give the title compound in 58% yield; NMR Spectrum: (DMSOd.sub.6
and CF.sub.3CO.sub.2D at 100.degree. C.) 2.04 (s, 3H), 2.3-2.37 (m,
2H), 3.27-3.37 (m, 9H), 3.74-3.84 (m, 4H), 3.96 (s, 3H), 4.3-4.36
(m, 4H), 6.04 (s, 2H), 6.89 (d, 1H), 6.96 (d, 1H), 7.51 (s, 1H),
7.96 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H.sup.+ 572.
EXAMPLE 12
3cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7--
[2-(2-pyrrolidin-1-ylethoxy)ethoxy]quinoline dihydrochloride
salt
[0418] Pyrrolidine (10 ml) was added to a mixture of
7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl-
)-2,3-methylenedioxyanilino]quinoline (0.225 g) and sodium iodide
(0.133 g) and the reaction mixture was stirred at ambient
temperature for 24 hours. The reaction mixture was evaporated and
the residue was triturated under methylene chloride. The resultant
solid was washed with water and dried. The material so obtained was
dissolved in the minimum quantity of ethyl acetate and a solution
of hydrogen chloride in diethyl ether (1M) was added. The resultant
solid was isolated, washed with diethyl ether and dried. There was
thus obtained the title compound as a solid (0.145 g); NMR
Spectrum: (DMSOd.sub.6 and CD.sub.3CO.sub.2D at 100.degree. C.)
1.84-1.89 (m, 4H), 3.29-3.39 (m, 9H), 3.88 (m, 2H), 3.94 (m, 2H),
3.96 (s, 3H), 4.3 (s, 2H), 4.36 (m, 2H), 6.04 (s, 2H), 6.84 (d,
1H), 6.94 (d, 1H), 7.46 (s, 1H), 7.87 (s, 1H), 8.56 (s, 1H); Mass
Spectrum: M+H.sup.+ 545.
EXAMPLE 13
3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]ac-
rylonitrile
[0419] A mixture of
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
(0.2 g), acrylonitrile (0.2 ml), triethylamine (0.2 ml),
palladium(II) acetate (0.01 g) and DMF (2 ml) was stirred and
heated to 115.degree. C. for 3 hours. The reaction mixture was
evaporated and the residue was purified by column chromatography on
silica using increasingly polar mixtures of hexane and ethyl
acetate as eluent. The material so obtained was triturated under
diethyl ether. There was thus obtained the title compound, in the
form of a 4:1 mixture of trans and cis isomers and as a yellow
solid (0.095 g); NMR Spectrum: (DMSOd.sub.6, data relating to the
major trans isomer) 3.91 (s, 3H), 3.93 (s, 3H), 6.12 (s, 2H), 6.26
(d, 1H), 6.88 (d, 1H), 7.14 (d, 1H), 7.35 (s, 1H), 7.56 (d, 1H),
7.7 (s, 1H), 8.51 (s, 1H), 9.7 (s, 1H); Mass Spectrum: M+H.sup.+
401.
EXAMPLE 14
[0420] Using an analogous procedure to that described in Example
13, the appropriate
4-(4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline
was reacted with the appropriate olefin to give the compounds
described in Table II. TABLE-US-00002 TABLE II ##STR10## Compound
No. & Note R.sup.1 (R.sup.3).sub.n [1] methoxy
6-chloro-4-(2-cyanovinyl) [2] methoxy 4-(2-methoxycarbonylvinyl)
[3] methoxy 6-chloro-4-(2-methoxycarbonylvinyl) [4] methoxy
4-(2-propionylvinyl)
[0421] [1] The required olefin was acrylonitrile. The product was
obtained as the trans isomer and gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 3.94 (s, 3H), 3.98 (s, 3H), 6.17
(s, 2H), 6.32 (d, 1H), 7.33 (s, 1H), 7.36 (s, 1H), 7.49 (d, 1H),
7.84 (s, 1H), 8.39 (s, 1H), 9.6 (br s, 1H); Mass Spectrum:
M+H.sup.+ 435 and 437.
[0422] [2] The required olefin was methyl acrylate. The product was
obtained as the trans isomer and gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 3.72 (s, 3H), 3.91 (s, 3H), 3.93
(s, 3H), 6.12 (s, 2H), 6.29 (d, 1H), 6.88 (d, 1H), 7.22 (d, 1H),
7.35 (s, 1H), 7.59 (d, 1H), 7.74 (s, 1H), 8.51 (s, 1H), 9.68 (s,
1H); Mass Spectrum: M+H.sup.+ 434.
[0423] [3] The required olefin was methyl acrylate. The reaction
solvent was a 6:1 mixture of acetonitrile and DMF and the reaction
mixture was heated to 80.degree. C. for 5 hours. The product was
obtained as the trans isomer and gave the following characterising
data; NMR Spectrum: (DMSOd.sub.6) 3.74 (s, 3H), 3.95 (s, 6H), 6.22
(d, 2H), 6.7 (d, 1H), 7.33 (s, 1H), 7.53 (s, 1H), 7.59 (d, 1H),
7.86 (s, 1H), 8.44 (s, 1H), 9.45 (s, 1H); Mass Spectrum: M+H.sup.+
468 and 470.
[0424] [4] The required olefin was ethyl vinyl ketone. The product
was obtained as the trans isomer and gave the following
characterising data; NMR Spectrum: (DMSOd.sub.6) 1.03 (t, 3H), 2.70
(q, 2H), 3.91 (s, 3H), 3.93 (s, 3H), 6.12 (s, 2H), 6.83-6.93 (m,
2H), 7.22 (d, 1H), 7.35 (s, 1H), 7.52 (d, 1H), 7.74 (s, 1H), 8.51
(s, 1H), 9.65 (s, 1H); Mass Spectrum: M+H.sup.+ 432.
EXAMPLE 15
(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphen-
yl]acrylic acid
[0425] A mixture of methyl
(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphe-
nyl]acrylate (0.75 g), a 1N aqueous sodium hydroxide solution (12
ml) and methanol (45 ml) was stirred and warmed to 40.degree. C.
for 12 hours. The reaction mixture was evaporated. Water was added
and the mixture was acidified by the addition of 2N aqueous
hydrochloric acid solution. The resultant precipitate was isolated
and dried. There was thus obtained the title compound as a solid
(0.703 g); NMR Spectrum: (DMSOd.sub.6) 3.98 (s, 6H), 6.19 (s, 2H),
6.59 (d, 1H), 7.02 (d, 1H), 7.28 (d, 1H), 7.48 (s, 1H), 7.55 (d,
1H), 8.09 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H.sup.+ 420.
EXAMPLE 16
N-{(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylene
dioxyphenyl]acryloyl}morpholine
[0426] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.196 g) was added to a mixture of
(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin4-ylamino)-2,3-methylenedioxyphen-
yl]acrylic acid (0.35 g), morpholine (0.36 ml), N-methylmorpholine
(0.112 ml), 1-hydroxybenzotriazole (0.112 ml), DMF (2 ml) and
methylene chloride (10 ml) and the reaction mixture was stirred at
ambient temperature for 12 hours. The resultant mixture was
partitioned between methylene chloride and water. The organic layer
was dried over magnesium sulphate and evaporated and the residue
was purified by column chromatography on silica using increasingly
polar mixtures of methylene chloride and methanol as eluent. The
material so obtained was triturated under diethyl ether. There was
thus obtained the title compound as a solid (0.031 g); NMR
Spectrum: (DMSOd.sub.6) 3.66 (s, 8H), 3.96 (s, 6H), 6.09 (s, 2H),
6.87 (d, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.34 (s, 1H), 7.49 (d,
1H), 7.77 (s, 1H), 8.48 (s, 1H), 9.63 (s, 1H); Mass Spectrum:
M+H.sup.+ 489.
EXAMPLE 17
(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphen-
yl]-N-(2-methoxyethyl)acrylamide
[0427] Using an analogous procedure to that described in Example
16,
(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphe-
nyl]acrylic acid was reacted with 2-methoxyethylamine to give the
title compound in 64% yield; NMR Spectrum: (DMSOd.sub.6) 3.22-3.43
(m, 7H), 3.95 (s, 3H), 3.96 (s, 3H), 6.1 (s, 2H), 6.74 (d, 1H),
6.87 (d, 1H), 7.07 (d, 1H), 7.32 (s, 2H), 7.73 (s, 1H), 8.22 (t,
1H), 8.48 (s, 1H), 9.62 (s, 1H); Mass Spectrum: M+H.sup.+ 477.
EXAMPLE 18
(2E)-3-[4-3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxypheny-
l]-N-(2-methoxyethyl)-N-methylacrylamide
[0428] Using an analogous procedure to that described in Example
16,
(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4ylamino)-2,3-methylenedioxyphen-
yl]acrylic acid was reacted with N-(2-methoxyethyl)-N-methylamine
to give the title compound in 47% yield; NMR Spectrum:
(DMSOd.sub.6) 2.94 (s, 1.5H), 3.08 (s, 1.5H), 3.17 (s, 3H),
3.43-3.65 (m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 6.1 (s, 2H), 6.84
(d, 1H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33 (s, 1H), 7.43 (d, 1H),
7.76 (s, 1H), 8.48 (s, 1H), 9.62 (s, 1H); Mass Spectrum: M+H.sup.+
491.
EXAMPLE 19
3-cyano-6,7-dimethoxy-4-[5-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilin-
o]quinoline
[0429] A mixture of
4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline
(0.15 g), methyl 2-propynyl ether (0.049 g),
tetrakis(triphenylphosphine)palladium(0) (0.02 g) and pyrrolidine
(2 ml) was stirred and heated to 80.degree. C. for 8 hours. The
resultant mixture was cooled to ambient temperature, poured into a
dilute aqueous ammonium chloride solution and extracted with ethyl
acetate. The organic phase was washed with water and with a
saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using increasingly polar mixtures of methylene chloride and
methanol as eluent. There was thus obtained the title compound as a
solid (0.032 g); NMR Spectrum: (CDCl.sub.3) 3.4 (s, 3H), 3.77 (s,
3H), 4.04 (s, 3H), 4.24 (s, 2H), 5.97 (s, 2H), 6.65 (br s, 1H),
6.73 (d, 1H), 6.78 (d, 1H), 6.99 (s, 1H), 7.38 (s, 1H), 8.63 (s,
1H); Mass Spectrum: M+H.sup.+ 418.
[0430] The
4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline
used as a starting material was prepared as follows:--
[0431] A mixture of 6-bromo-1,3-benzodioxole-4-carboxylic acid
[Khin. Geterotsikl. Soedin 1979, 9, 1183-8 (Chemical Abstracts 92,
94280); 0.92 g], diphenylphosphoryl azide (1.08 g), tert-butanol (3
ml), triethylamine (0.34 g) and toluene (15 ml) were stirred and
heated at 100.degree. C. for 4 hours. The resultant mixture was
evaporated and the residue was partitioned between methyl
tert-butyl ether and a 5% aqueous citric acid solution. The organic
phase was washed with water and a saturated aqueous sodium
bicarbonate solution, dried over magnesium sulphate and evaporated.
The residual oil was purified by column chromatography on silica
using a 5:1 mixture of isohexane and ethyl acetate as eluent. There
was thus obtained tert-butyl
N-(6-bromo-1,3-benzodioxol-4-yl)carbamate (0.6 g); NMR Spectrum:
(CDCl.sub.3) 1.52 (s, 9H), 5.95 (s, 2H), 6.39 (br s, 1H), 6.7 (d,
1H), 7.73 (br s, 1H).
[0432] A mixture of the material so obtained, trifluoroacetic acid
(3 ml) and methylene chloride (8 ml) was stirred at ambient
temperature for 1 hour. The solvent was evaporated and the residue
was partitioned between methyl tert-butyl ether and a saturated
aqueous sodium bicarbonate solution. The organic phase was washed
with a saturated brine solution, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using a 4:1 mixture of isohexane and ethyl acetate as
eluent. There was thus obtained 5-bromo-2,3-methylenedioxyaniline
(0.318 g) as a colourless solid; NMR Spectrum: (CDCl.sub.3) 3.6 (br
s, 2H), 5.92 (s, 2H), 6.27 (m, 2H).
[0433] Using an analogous procedure to that described in Example 3,
4-chloro-3-cyano-6,7-dimethoxyquinoline (0.65 g) was reacted with
5-bromo-2,3-methylenedioxyaniline (0.587 g). The free base obtained
after chromatographic purification was not converted into the
dihydrochloride salt. There was thus obtained
4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline
as a solid (1.16 g); NMR Spectrum: (CDCl.sub.3) 3.83 (s, 3H), 4.05
(s, 3H), 5.98 (s, 2H), 6.76 (d, 1H), 6.84 (d, 1H), 6.9 (br s, 1H),
7.06 (s, 1H), 7.39 (s, 1H), 8.64 (s, 1H); Mass Spectrum: M+H.sup.+
428 and 430.
EXAMPLE 20
3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]-4-[4-(3-methoxyprop-1-yn-
yl)-2,3-methylenedioxyanilino]quinoline dihydrochloride salt
[0434] A mixture of
4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
(165 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (123
mg) in 1-propanol (10 ml) was treated with a 1.0M solution of
hydrogen chloride in diethyl ether (0.5 ml) then stirred and heated
at reflux for 2 hours. On cooling a solid precipitated from the
reaction mixture. The resulting suspension was basified with
aqueous ammonia and evaporated to a gum. This residue was purified
by multi-injection preparative RP HPLC [Kromasil C185 .mu.m silica
column, 100 mm.times.10 mm; eluted with a mixture of acetonitrile
(55%) and 0.1% aqeous ammonia solution (45%)]. After isolation, the
major product was converted to its dihydrochloride salt in
acetonitrile using two equivalents of a 1.0M solution of hydrogen
chloride in diethyl ether. The title compound was thus obtained as
a yellow solid (81 mg); NMR Spectrum: (DMSOd.sub.6 &
CD.sub.3COOD, 373K) 2.17 (m, 2H), 238 (m, 2H), 2.77 (s, 3H), 3.30
(m, 4H), 3.37 (s, 3H), 3.96 (s, 3H), 4.33 (s, 2H), 5.04 (m, 1H),
6.12 (s, 2H), 6.92 (d, 1H), 6.97 (m, 2H), 7.08 (s, 1H), 8.63 (s,
1H); Mass Spectrum: M+H.sup.+ 501.
[0435] The 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline used
as a starting material was prepared as described in example 3.
[0436] The
4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
used as a starting material was prepared as follows:
[0437] i) Preparation of ethyl
(2-E/Z)-2-cyano-3-[(3,5-difluorophenyl)amino]acrylate A mixture of
3,5-difluoroaniline (32.25 g) and ethyl 2-cyano-3-ethoxyacrylate
(42.25 g) dissolved in ethanol (200 ml) was refluxed for 2 hours
and then allowed to cool. The product was filtered off and washed
with a little ethanol to give the title compound as white needles
58.0 g; 92%); NMR spectrum: (DMSOd.sub.6) E/Z or Z/E mixture 64/36,
1.28 (m, 3H), 4.23 (m, 2H), 6.98-7.42 (m, 3H), 8.44 (m, 1H), 10.80
(m, 1H); Mass spectrum: M+H.sup.+ 253.
ii) Preparation of 3-cyano-5,7-difluoro-4hydroxyquinoline
[0438] Di(ethylene glycol) dibutyl ether (100 ml) was refluxed at
255.degree. C. under nitrogen in a 250 ml flask. To this was added
ethyl (2-E/Z)-2-cyano-3-[(3,5-difluorophenyl)amino]acrylate (12.5
g) in portions over 10 minutes. The mixture was heated for a
further 30 minutes and then allowed to cool. The precipitated solid
was collected and washed with ethyl acetate. The title compound was
thus obtained as a grey/brown solid (4.24 g, 41%); NMR spectrun:
(DMSOd.sub.6) 7.21 (m, 1H), 7.30 (m, 1H), 8.72 (s, 1H), 12.86
(broad, 1H); Mass spectrum: M+H.sup.+ 207.
iii) Preparation of
3-cyano-7-fluorohydroxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
[0439] A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (4.12
g), 1-methylpiperidin-4-ol (2.6 g) and potassium tert-butoxide
(6.72 g) in anhydrous tetrahydrofuran (250 ml) was stirred and
heated at 60.degree. C. for 2 hours. Acetic acid was added until
pH6 was reached and then the solution was evaporated to dryness.
The residue was dissolved in a mixture of dichloromethane and
methanol (2:1) and the solution added to powdered silica gel (15
g). The suspension was evaporated to dryness and powder was packed
into a preload cartridge. This was then chromatographed with an
Isco Combiflash system and a Biotage 40M silica cartridge using a
gradient elution of 0.6% to 30% ammonia (7.0M in methanol) in
dichloromethane. The fractions containing the product were combined
and evaporated. This gave the title compound as a white foam (3.55
g, 59%); NMR spectrum: DMSOd.sub.6) 1.77 (m, 2H), 1.92 (m, 2H),
2.30 (s, 3H), 2.43 (m, 2H), 2.81 (m, 2H), 4.55 (m, 1H), 6.81 (m,
2H), 8.40 (s, 1H); Mass spectrum: M+H.sup.+ 302.
iv) Preparation of
3-cyano-4-hydroxy-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
[0440] A mixture of
3-cyano-7-fluoro-4-hydroxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
(600 mg), methanol (0.40 ml) and potassium tert-butoxide (1.0M
solution in tetrahydrofuran; 10.0 ml) in anhydrous dimethyl
sulphoxide (20 ml) was heated at 70.degree. C. for 16 hours. The
solution was cooled and then diluted with water (100 ml). Dilute
hydrochloric acid was added until pH6 was reached and the
by-product precipitate (3-cyano-4-hydroxy-5,7-dimethoxyquinoline)
was filtered off. The filtrate was pumped onto a cation exchange
cartridge (Waters Oasis MCX 6.0 g) and washed on with water. The
column was flushed successively with water (200 ml), methanol/water
(1:1; 200 ml) and methanol (200 ml). The product was eluted off the
column with methanol containing triethylamine (1%). The fractions
containing the product were combined and evaporated. This gave the
title compound as an white solid (460 mg, 73%); NMR spectrum:
(DMSOd.sub.6) 1.67 (m, 2H), 1.83 (m, 2H), 2.12 (m, 2H), 2.15 (s,
3H), 2.64 (m, 2H), 4.31 (m, 1H), 6.31 (d, 1H), 6.56 (d, 1H), 8.16
(s, 1H); Mass spectrum: M+H.sup.+ 314.
v) Preparation of
4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
[0441] A mixture of
3-cyano-4-hydroxy-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
(313 mg) and phosphoryl chloride (1.8 ml) in acetonitrile (10 ml)
was refluxed and stirred for 20 hours. After cooling, the solution
was evaporated to dryness. The flask containing the residue was
filled with ice chips and excess concentrated aqueous ammonia (25
ml) was added. This mixture was allowed to warm up while stirring
overnight. The product was filtered off and dried under high vacuum
overnight. The title compound was obtained as a white solid (225
mg, 68%); NMR-spectrum: (DMSOd.sub.6) 1.80 (m, 2H), 1.98 (m, 2H),
2.18 (s, 3H), 2.27 (m, 2H), 2.58 (m, 2H), 3.94 (s, 3H), 4.72 (m,
1H), 6.92 (d, 1H), 7.09 (d, 1H), 8.93 (s, 1H); Mass spectrum:
M+H.sup.+ 332.
EXAMPLE 21
3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)-4-[4-(-
3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline
dihydrochloride salt
[0442] A mixture of
4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-ylo-
xy)quinoline (125 mg) and
4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (179 mg) in
1-propanol (8 ml) was treated with a 1.0M solution of hydrogen
chloride in diethyl ether (0.30 ml) then stirred and heated at
reflux for 1 hour. The mixture was allowed to cool and neutralised
by the addition of tetramethylguanidine (0.10 ml). The resulting
solution was evaporated to dryness and the residue was purified by
chromatography on a Biotage silica cartridge (20 g) eluting with a
gradient of methanol in dichloromethane (1-10%). The fractions
containing the product were combined and evaporated. The residue
was dissolved in ethanol (8 ml) and treated with 2 equivalents of
hydrogen chloride (1.0M in diethyl ether). The title compound was
thus obtained as a white solid (130 mg); NMR Spectrum:
(DMSOd.sub.6, 300K) 1.87 (m, 2H), 2.10 (m, 2H), 2.31 (m, 2H), 3.11
(n 2H), 3.30 (m, 2H), 3.36 (s, 3H), 3.50 (m, 4H), 3.87 (m, 4H),
3.97 (m, 2H), 4.32 (m, 2H), 4.37 (s, 2H), 5.10 (m, 1H), 6.18 (s,
2H), 7.05 (m, 3H), 7.13 (s, 1H), 8.87 (s, 1H), 10.43 (s, 1H), 11.34
(s, 1H); Mass Spectrum: M+H.sup.+ 601.
[0443] The 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline used
as a starting material was prepared as described in example 3.
[0444] The
4-chloro-3-cyano-7-3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-ylox-
y)quinoline used as a starting material was prepared as
follows:
i) 3-cyano-5,7-difluoro-4-hydroxyquinoline was Prepared as
Described in Example 20
ii) Preparation of
3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline
[0445] A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (2.06
g), tetrahydro-2H-pyran-4-ol (1.02 g) and potassium tert-butoxide
(1.0M solution in tetrahydrofuran; 30.0 ml) in anhydrous
tetrahydrofuran (100 ml) was stirred and heated under nitrogen at
60.degree. C. for 1.5 hours. Acetic acid was added until pH6 was
reached and then the solution was evaporated to dryness. The
residue was dissolved in aqueous sodium hydroxide solution (2.0M)
and the resulting solution was filtered through a GF/A glass fibre
pad. The filtrate was acidified to pH5 with acetic acid and the
resulting oily precipitate allowed to stand 3 days when it had
become solid. The solid was collected and washed with water then
air-dried. (1.8 g, 62%); NMR spectrum: (DMSOd.sub.6) 1.67 (m, 2H),
1.92 (m, 2H), 3.50 (m, 2H), 3.91 (m, 2H), 4.76 (m, 1H), 6.81 (m,
1H), 6.94 (m, 1H), 8.52 (s, 1H); Mass spectrum: M+H.sup.+ 289.
iii) Preparation of
3-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yl-
oxy)quinoline
[0446] A mixture of
3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline
(864 mg), 3-morpholin-4-ylpropan-1-ol (876 mg) and potassium
tert-butoxide (1:0M solution in tetrahydrofuran; 9.0 ml) in
anhydrous dimethyl sulphoxide (30 ml) was heated at 60.degree. C.
for 8 hours. The solution was cooled and then diluted with water
(120 ml). Acetic acid was added until pH5 was reached. The solution
was pumped onto a cation exchange cartridge (Waters Oasis MCX 6.0
g) and washed on with water. The column was flushed successively
with water (200 ml), methanol/water (1:1, 200 ml) and methanol (200
ml). The product was eluted off the column with methanol containing
triethylamine (1%). The fractions containing the product were
combined and evaporated. The residue was further purified by
chromatography on a Redisep silica cartridge (40 g) eluting with a
gradient of methanol in dichloromethane (5-20%). This gave the
title compound as an white solid (540 mg, 44%); NMR spectrum:
(DMSOd.sub.6; 373.degree. K.) 1.73 (mn, 2H), 1.91 (m, 4H), 2.39 (m,
4H), 2.45 (t, 2H), 3.49 (m, 2H), 3.58 (m, 4H), 3.95 (m, 2H), 4.10
(t, 2H), 4.64 (m, 1H), 6.46 (d, 1H), 6.60 (d, 1H), 8.24 (s, 1H);
Mass spectrum: M+H.sup.+ 414.
iv) Preparation of
4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-ylo-
xy)quinoline
[0447] A mixture of
3-cyano-4-hydroxy-7-(3-morpholin-4ylpropoxy)-5-(tetrahydro-2H-pyran-4-ylo-
xy)quinoline (500 mg) and phosphoryl chloride (2.5 ml) in
acetonitrile (15 ml) was refluxed and stirred for 4 hours. After
cooling, the solution was evaporated to dryness. The flask
containing the residue was filled with ice chips and excess
concentrated aqueous ammonia (25 ml) was added. This mixture was
allowed to warm up while stirring overnight. The product was
filtered off and air-dried. The title compound was obtained as a
white solid (480 mg, 92%); Mass spectrum: M+H.sup.+ 432.
EXAMPLE 22
3-Cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5--
[(1-methylpiperidin-4-yl)oxy]quinoline dihydrochloride salt
[0448] A mixture of
4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
(165 mg) and 4-(4-methoxybut-1-ynyl)-2,3-methylendioxyaniline (131
mg) in 1-propanol (10 ml) was treated with a 1.0M solution of
hydrogen chloride in diethyl ether (0.5 ml) then stirred and heated
at reflux for 2 hours. On cooling a solid precipitated from the
reaction mixture. This solid was collected and washed with
1-propanol. Analysis by LC/MS suggested the product was impure. The
solid hydrochloride salt and the liquors were combined and basified
with a solution of sodium bis(trimethylsilyl)amide (1.0M in THF;
1.0 ml) and the solution allowed to stand overnight. The mixture
was evaporated and separated by multi-injection preparative RP HPLC
[Kromasil C18 5 .mu.m silica column, 100 mm.times.10 mm;
eluted-with a mixture of acetonitrile (55%) and 0.1% aqeous ammonia
solution (45%)]. After isolation, the component bases were
converted to their dihydrochloride salts in acetonitrile using two
equivalents of a 1.0M solution of hydrogen chloride in diethyl
ether.
[0449] The main component,
3-cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-
-[(1-methylpiperidin-4-yl)oxy]quinoline dihydrochloride salt, was
thus obtained as a yellow solid (51 mg); NMR Spectrum: (DMSOd.sub.6
and CD.sub.3CO.sub.2D, 393K) 2.19 (m, 2H), 2.37 (m, 2H), 2.72 (m,
5H), 3.00 (m, 3H), 3.26 (m, 1H), 3.35 (s, 3H), 3.58 (t, 2H), 3.96
(s, 3H), 5.00 (m, 1H), 6.10 (s, 2H), 6.85 (m, 2H), 6.92 (s, 1H),
7.05 (s, 1H), 8.48 (s, 1H), 9.51 (br, 1H); Mass Spectrum: M+H.sup.+
515.
[0450] The second component,
4-[(4-but-3-en-1-ynyl-2,3-methylendioxy)anilino]-3-cyano-7-methoxy-5-[(1--
methylpiperidin-4-yl)oxy]quinoline dihydrochloride salt, was thus
obtained as a yellow solid (18 mg); NMR Spectrum: (DMSOd.sub.6,
393K). 2.18 (m, 2H), 2.35 (m, 2H), 2.70 (s, 3H), 3.09 (m, 4H), 3.95
(s, 3H), 5.00 (m, 1H), 5.62 (d, 1H), 5.73 (d, 1H), 6.11 (m. 3H),
6.90 (m, 3H), 7.07 (s, 1H), 8.51 (s, 1H), 9.55 (br, 1H); Mass
Spectrum: M+H.sup.+ 483.
[0451] The third component,
4-[4-(1-chloro-4-methoxybut-1-enyl)-2,3-methylenedioxyanlino]-3-cyano-7-m-
ethoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline dihydrochloride
salt, was thus obtained as a yellow solid (2.1 mg); Mass Spectrum:
M+H.sup.+ 551. (The stereochemistry of the double bond was not
established.)
[0452]
4-Chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinolin-
e used as a starting material was prepared as described in example
20.
[0453] 4-(4-methoxybut-1-yn-1-yl)-2,3-methylendioxyaniline used as
a starting material was prepared as follows:
[0454] A solution of 4-iodo-2,3-methylenedioxyaniline (1.32 g, 5.00
mmol) and 4-methoxybut-1-yne (0.84 g, 10.00 mmol) in ethyl acetate
(25 ml) was cooled in ice-methanol, under an atmosphere of
nitrogen, then treated with bis(triphenylphosphine)palladium(II)
dichloride (350 mg, 10 mol %) followed by copper(I) iodide (95 mg,
10 mol %) and diisopropylamine (1.40 ml, 10.0 mmol). The reaction
was stirred for 2 hours in the cooling bath and then allowed to
warm to room temperature over 4 hours. The mixture was filtered
through Celite and the filtrate was then purified by column
chromatography on silica using a gradient of methanol in
dichloromethane (0-2%) as eluent to give
4-(4-methoxybut-1-yn-1-yl)-2,3-methylendioxyaniline (524 mg, 82%)
as a dark oil; LCMS: M+H.sup.+ 220 (82%).
[0455] 4-Methoxybut-1-yne is described in Aust. J. Chem. 1988,
41(2), 251 261.
[0456] 4-iodo-2,3-methylenedioxyaniline was prepared as described
in example 1.
EXAMPLE 23
3-cyano-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7--
methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline dihydrochloride
salt
[0457] A mixture of
4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline
(203 mg) and
6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (139 mg)
in dry dimethylformamide (6 ml) was stirred at room temperature.
Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran;
1.35 ml) was added and then the mixture was allowed to warm to room
temperature over one hour. The reaction mixture was acidified with
acetic acid (2.0 ml) and the solvent was evaporated under high
vacuum. The residue was dissolved in a mixture of dichloromethane
and methanol (9:1) and the mixture preabsorbed onto silica gel
(kieselgel 60; 2.5 g). The solvent was evaporated and the solid
packed into a preload cartridge. This was then purified by
chromatography on a 40 g silica Redisep cartridge using gradient
elution [0.5% to 3% ammonia solution (7.0M in methanol) in
dichloromethane]. Fractions containing the required product were
combined and evaporated to give the free base (240 mg). This
material was dissolved in ethanol (10 ml) and treated with 2
equivalents of 1.0M hydrogen chloride in diethyl ether. The
solvents were evaporated and the residue was dissolved in
acetonitrile (10 ml). The title compound crystallised on standing
overnight as a pale yellow solid (158 mg); NMR Spectrum:
(DMSOd.sub.6, 373K) 2.21 (m, 2H), 2.41 (m, 2H), 2.76 (s, 3H), 3.15
(m, 2H), 3.47 (s, 3H), 3.49 (m, 2H), 3.97 (s, 3H), 4.36 (s, 2H),
5.04 (m, 1H), 6.16 (s, 2H), 6.97 (m, 1H), 7.07 (s, 1H), 7.13 (s,
1H), 8.56 (s, 1H), 9.73 (br. 1H), 10.75 (br, 1H); Mass Spectrum:
M+H.sup.+ 535.
[0458]
4-Chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinolin-
e used as a starting material was prepared as described in example
20.
[0459] 6-Chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline
used as a starting material was prepared as follows:
[0460] Sulphuryl chloride (72.5 ml) was added dropwise during 1.7
hours to a stirred mixture of benzodioxole (100 g), aluminum
trichloride (0.43 g) and diphenyl sulphide (0.55 ml). Once the
reaction started with the evolution of sulphur dioxide, the
reaction mixture was cooled in a water bath to a temperature of
approximately 22.degree. C. After completion of the addition, the
reaction mixture was stirred at ambient temperature for 45 minutes.
The reaction mixture was degassed under vacuum and filtered and the
filtrate was distilled at atmospheric pressure using a Vigreux
distillation column. There was thus obtained
5-chloro-1,3-benzodioxole; b.p. 185-187.degree. C.; NMR Spectrum:
(CDCl.sub.3) 6.0 (s, 2H); 6.7 (d, 1H); 6.75-6.9 (m, 2H).
[0461] A mixture of diisopropylamine (4.92 ml) and THF (100 ml) was
cooled to -78.degree. C. and n-butyllithium (2.5 M in hexane, 14
ml) was added dropwise. The mixture was stirred at -78.degree. C.
for 15 minutes. 5-Chloro-1,3-benzodioxole (3.73 ml) was added
dropwise and the reaction mixture was stirred at -78.degree. C. for
30 minutes. Dry carbon dioxide gas was bubbled into the reaction
mixture for 30 minutes. The resultant reaction mixture was allowed
to warm to ambient temperature and was stirred for a further hour.
Water was added and the organic solvent was evaporated. The residue
was acidified to pH2 by the addition of 2N aqueous hydrochloric
acid solution. The resultant solid was isolated and washed in turn
with water and diethyl ether. There was thus obtained
5-chloro-1,3-benzodioxole-4-carboxylic acid (5.4 g); NMR Spectrum
(DMSOd.sub.6) 6.15 (s, 2H), 7.0 (m, 2H), 13.7 (br s, 1H).
[0462] A portion (1 g) of the material so obtained was dissolved in
1,4-dioxane (15 ml) and anhydrous tert-butanol (4 ml),
diphenylphosphoryl azide (1.12 ml) and triethylamine (0.73 ml) were
added in turn. The resultant mixture was stirred and heated to
100.degree. C. for 4 hours. The mixture was evaporated and the
residue was partitioned between ethyl acetate and a 5% aqueous
citric acid solution. The organic phase was washed in turn with
water, a saturated aqueous sodium bicarbonate solution and brine,
dried over magnesium sulphate and evaporated. The residue was
purified by column chromatography on silica using a 9:1 mixture of
petroleum ether (b.p. 40-60.degree. C.) and ethyl acetate as
eluent. There was thus obtained tert-butyl
5-chloro-1,3-benzodioxol-4-ylcarbamate (1.1 g); NMR Spectrum:
(DMSOd.sub.6) 1.45 (s, 9H), 6.1 (s, 2H), 6.85 (d, 1H), 6.95 (d,
1H), 8.75 (s, 1H).
[0463] A mixture of the material so obtained (1.1 g),
trifluoroacetic acid (6 ml) and methylene chloride (20 ml) was
stirred at ambient temperature for 3 hours. The solvent was
evaporated and the residue was partitioned between ethyl acetate
and a saturated aqueous sodium bicarbonate solution. The organic
phase was washed with brine, dried over magnesium sulphate and
evaporated. There was thus obtained
6-chloro-2,3-methylenedioxyaniline (0.642 g); NMR Spectrum:
(DMSOd.sub.6) 5.15 (s, 2H), 6.0 (s, 2H), 6.25 (d, 1H), 6.75 (d,
1H),
[0464] Benzyltrimethylammonium dichloroiodate (6.7 g) was added
portionwise over 10 minutes to a stirred mixture of
6-chloro-2,3-methylenedioxyaniline (3 g), calcium carbonate (2.28
g) in methanol (15 ml) and dichloromethane (30 ml). The reaction
mixture was stirred at ambient temperature for 1.5 hours. The
reaction mixture was diluted with water and extracted with
dichloromethane. The organics were washed with water, saturated
brine and dried over magnesium sulfate. The residue was purified by
column chromatography on silica using a gradient of an 8:1 mixture
of dichloromethane/isohexane to dichloromethane as eluent. There
was thus obtained 6-chloro-4-iodo-2,3-methylendioxyaniline as a
black crystalline solid (4.82 g); NMR Spectrum: (DMSOd.sub.6) 6.04
(s, 2H), 7.00 (s, 1H).
[0465] Bis(Triphenyl-phosphine)palladium(II) chloride (472 mg),
copper iodide (192 mg) and diisopropylamine (680 mg) were added to
a stirred solution of 6-chloro-4-iodo-2,3-methylenedioxyaniline
(1000 mg) and methyl propargyl ether (471 mg) in ethyl acetate (10
mls) at -20.degree. C. The reaction was allowed to warm to ambient
temperature over 16 hours. The reaction mixture was partitioned
between ethyl acetate and saturated NaHCO3. The organics were
washed with water and saturated brine and dried over magnesium
sulfate. The product was purified by column chromatography on
silica using a gradient of 80-100% Dichloromethane/isohexane as
eluent 6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline
was thus obtained as a tan crystalline solid (200 mg); NMR
Spectrum: (DMSOd.sub.6) 3.28 (s, 3H), 4.26 (s, 2H), 5.52 (s, 2H),
6.05 (s, 2H), 6.93 (s, 1H),
EXAMPLE 24
3-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-pyridin-2-ylethynyl)anilino]-
quinoline dihydrochloride salt
[0466] Using an analogous procedure to that described in Example 1,
3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline
was reacted with 2-ethynylpyridine. The reaction mixture was
partitioned between methylene chloride and a 2N aqueous
hydrochloric acid solution. This resulted in the precipitation of
the product which was filtered, washed with dichloromethane,
ethanol and diethyl ether and dried to give the title compound as
as a yellow solid (53%); NMR Spectrum: (DMSOd.sub.6) 4.00 (s, 3H),
4.02 (s, 3H), 6.19 (s, 2H), 7.07 (d, 1H), 7.19 (d, 1H), 7.43-7.49
(m, 1H), 7.50 (s, 1H), 7.68 (d, 1H), 7.88 (t, 1H), 8.21 (s, 1H),
8.63 (d, 1H), 9.08 (s, 1H); Mass Spectrum: M+H.sup.+ 451.05.
* * * * *