U.S. patent application number 13/080583 was filed with the patent office on 2012-01-05 for amide derivatives bearing a cyclopropylaminoacarbonyl substituent useful as cytokine inhibitors.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Dearg Sutherland Brown, John Graham Cumming, Ian Alun Nash.
Application Number | 20120004243 13/080583 |
Document ID | / |
Family ID | 30776197 |
Filed Date | 2012-01-05 |
United States Patent
Application |
20120004243 |
Kind Code |
A1 |
Brown; Dearg Sutherland ; et
al. |
January 5, 2012 |
AMIDE DERIVATIVES BEARING A CYCLOPROPYLAMINOACARBONYL SUBSTITUENT
USEFUL AS CYTOKINE INHIBITORS
Abstract
The invention concerns a compound of the Formula (I), wherein Qa
is heteroaryl and is substituted with halogeno; R1 and R2 are
hydrogen; and Qb is phenyl or heteroaryl, and Qb may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno and
(1-6C)alkyl, or a pharmaceutically-acceptable salt thereof;
processes for their preparation, pharmaceutical compositions
containing them and their use in the treatment of diseases or
medical conditions mediated by cytokines.
Inventors: |
Brown; Dearg Sutherland;
(Macclesfield, GB) ; Cumming; John Graham;
(Macclesfield, GB) ; Nash; Ian Alun; (Mcclesfield,
GB) |
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
30776197 |
Appl. No.: |
13/080583 |
Filed: |
April 5, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10581305 |
Oct 12, 2006 |
7943776 |
|
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PCT/GB04/05241 |
Dec 15, 2004 |
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13080583 |
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Current U.S.
Class: |
514/255.05 ;
514/256; 514/300; 514/357; 514/361; 514/362; 514/365; 514/378;
514/616; 544/316; 544/335; 546/121; 546/337; 548/127; 548/134;
548/204; 548/247; 564/158 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 31/04 20180101; C07D 277/24 20130101; A61P 31/14 20180101;
A61P 9/04 20180101; A61P 43/00 20180101; A61P 11/06 20180101; A61P
9/00 20180101; C07D 285/06 20130101; A61P 25/00 20180101; A61P
31/18 20180101; A61P 1/00 20180101; A61P 17/06 20180101; A61P 37/04
20180101; C07D 239/34 20130101; C07D 213/30 20130101; A61P 19/00
20180101; A61P 19/02 20180101; A61P 29/00 20180101; A61P 1/04
20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/255.05 ;
564/158; 546/337; 548/204; 548/247; 548/127; 546/121; 548/134;
544/335; 544/316; 514/616; 514/357; 514/365; 514/378; 514/361;
514/300; 514/362; 514/256 |
International
Class: |
A61K 31/167 20060101
A61K031/167; C07D 213/56 20060101 C07D213/56; C07D 277/30 20060101
C07D277/30; C07D 261/08 20060101 C07D261/08; C07D 285/06 20060101
C07D285/06; C07D 471/04 20060101 C07D471/04; C07D 285/10 20060101
C07D285/10; C07D 239/26 20060101 C07D239/26; A61K 31/4402 20060101
A61K031/4402; A61K 31/426 20060101 A61K031/426; A61K 31/42 20060101
A61K031/42; A61K 31/433 20060101 A61K031/433; A61K 31/437 20060101
A61K031/437; A61K 31/505 20060101 A61K031/505; A61K 31/497 20060101
A61K031/497; A61P 19/02 20060101 A61P019/02; A61P 11/06 20060101
A61P011/06; A61P 11/00 20060101 A61P011/00; A61P 1/00 20060101
A61P001/00; A61P 25/00 20060101 A61P025/00; A61P 9/04 20060101
A61P009/04; A61P 9/10 20060101 A61P009/10; A61P 17/06 20060101
A61P017/06; C07C 237/48 20060101 C07C237/48 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2003 |
GB |
0329572.2 |
Claims
1. A compound of the Formula I ##STR00011## wherein Q.sub.a is
phenyl or heteroaryl, and Q.sub.a may optionally bear 1 or 2
substituents selected from hydroxy, halogeno, trifluoromethyl,
cyano, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and
(1-6C)alkoxycarbonyl; R.sub.1 and R.sub.2 are each independently
selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and
(2-6C)alkynyl; and Q.sub.b is phenyl, heteroaryl or heterocyclyl,
and Q.sub.b may optionally bear 1 or 2 substituents selected from
hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and
(3-6C)cycloalkylsulphonyl; and wherein any of the substituents on
Q.sub.a or Q.sub.b defined hereinbefore which comprise a CH.sub.2
group which is attached to 2 carbon atoms or a CH.sub.3 group which
is attached to a carbon atom may optionally bear on each said
CH.sub.2 or CH.sub.3 group one or more substituents selected from
hydroxy, cyano, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino
and di-[(1-6C)alkyl]amino; or a pharmaceutically-acceptable salt
thereof.
2. A compound of the Formula I according to claim 1 wherein Q.sub.a
is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and
Q.sub.a may optionally bear 1 or 2 substituents selected from
halogeno, (1-6C)alkyl and (1-6C)alkoxy; R.sub.1 and R.sub.2 are
each independently selected from hydrogen, (1-6C)alkyl,
(2-6C)alkenyl and (2-6C)alkynyl; and Q.sub.b is phenyl, heteroaryl
or heterocyclyl, and Q.sub.b may optionally bear 1 or 2
substituents selected from hydroxy, halogeno, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
aminosulphonyl, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl; and
wherein any of the substituents on Q.sub.a or Q.sub.b defined
hereinbefore which comprise a CH.sub.2 group which is attached to 2
carbon atoms or a CH.sub.3 group which is attached to a carbon atom
may optionally bear on each said CH.sub.2 or CH.sub.3 group one or
more substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; or a
pharmaceutically-acceptable salt thereof.
3. A compound of the Formula I according to claim 1 or claim 2
wherein Q.sub.a is phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, and Q.sub.a may optionally bear 1 or 2 substituents
selected from hydroxy, halogeno, (1-6C)alkyl and (1-6C)alkoxy; or a
pharmaceutically-acceptable salt thereof.
4. A compound of the Formula I according to claim 1 or claim 2
wherein Q.sub.b is phenyl or heteroaryl, and Q.sub.b may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno,
(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
aminosulphonyl, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl; and
wherein any of the substituents on Q.sub.b which comprise a
CH.sub.2 group which is attached to 2 carbon atoms or a CH.sub.3
group which is attached to a carbon atom may optionally bear on
each said CH.sub.2 or CH.sub.3 group one or more substituents
selected from hydroxy, cyano, amino, (1-6C)alkyl, (1-6C)alkoxy,
(1-6C)alkylamino and di-[(1-6C)alkyl]amino; or a
pharmaceutically-acceptable salt thereof.
5. A compound of the Formula I according to claim 1 or claim 2
wherein Q.sub.b is phenyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, thiazolyl, thiadiazolyl, imidazolyl, isoxazolyl,
oxazolyl, furanyl, thienyl, benzimidazolyl, isoquinolinyl,
quinolinyl, benzothiazolyl or pyrido[1,2-a]imidazolyl, and Q.sub.b
may optionally bear 1 or 2 substituents selected from hydroxy,
halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and
(3-6C)cycloalkylsulphonyl; and wherein any of the substituents on
Q.sub.b which comprise a CH.sub.2 group which is attached to 2
carbon atoms or a CH.sub.3 group which is attached to a carbon atom
may optionally bear on each said CH.sub.2 or CH.sub.3 group one or
more substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; or a
pharmaceutically-acceptable salt thereof.
6. A compound of the Formula I according to claim 1 or claim 2
wherein R.sub.1 and R.sub.2 are each independently selected from
hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl; or a
pharmaceutically-acceptable salt thereof.
7. A compound of the Formula I according to claim 1 or claim 2
wherein R.sub.1 and R.sub.2 are each independently selected from
hydrogen and (1-6C)alkyl; or a pharmaceutically-acceptable salt
thereof.
8. A compound of the Formula I according to Claim 1 wherein Q.sub.a
is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and
Q.sub.a may optionally bear 1 or 2 substituents selected from
halogeno, (1-6C)alkyl and (1-6C)alkoxy; R.sub.1 and R.sub.2 are
each independently selected from hydrogen and (1-6C)alkyl; and
Q.sub.b is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
thiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, oxazolyl, furanyl,
thienyl, benzimidazolyl, isoquinolinyl, quinolinyl, benzothiazolyl
or pyrido[1,2-a]imidazolyl, and Q.sub.b may optionally bear 1 or 2
substituents selected from hydroxy, halogeno, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
aminosulphonyl, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl; and
wherein any of the substituents on Q.sub.b which comprise a
CH.sub.2 group which is attached to 2 carbon atoms or a CH.sub.3
group which is attached to a carbon atom may optionally bear on
each said CH.sub.2 or CH.sub.3 group one or more substituents
selected from hydroxy, cyano, amino, (1-6C)alkyl, (1-6C)alkoxy,
(1-6C)alkylamino and di-[(1-6C)alkyl]amino; or a
pharmaceutically-acceptable salt thereof.
9. A compound of the Formula I according to claim 1 or claim 2
selected from:--
3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide;
3-{[3-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide;
4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methylb-
enzamide;
4-(benzyloxy)-3-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methy-
lphenyl}benzamide;
4-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}b-
enzamide;
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}-
benzamide;
N-cyclopropyl-4-methyl-3-{[4-(1,3-thiazol-4-ylmethoxy)benzoyl]a-
mino}benzamide;
N-cyclopropyl-4-methyl-3-{[4-(pyridin-3-ylmethoxy)benzoyl]amino}benzamide-
;
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}ami-
no)benzamide;
3-({4-[(5-chloro-1,2,3-thiadiazol-4-yl)methoxy]benzoyl}amino)-N-cycloprop-
yl-4-methylbenzamide;
N-cyclopropyl-3-{[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)benzoyl]amino}-4-m-
ethylbenzamide;
N-cyclopropyl-4-methyl-3-({4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzoyl}-
amino)benzamide;
N-cyclopropyl-3-({4-[(3,5-dimethylisoxazol-4-yl)methoxy]benzoyl}amino)-4--
methylbenzamide;
N-cyclopropyl-4-methyl-3-{[4-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}-
benzamide; methyl
5-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)-2-furoate;
3-({4-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4--
methylbenzamide;
4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-
benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-4-(-
pyridin-2-ylmethoxy)benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-4-(1,3-thiazo-
l-4-ylmethoxy)benzamide;
N-cyclopropyl-4-methyl-3-{[3-methyl-4-(pyridin-2-ylmethoxy)benzoyl]amino}-
benzamide;
N-cyclopropyl-4-methyl-3-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)-
benzoyl]amino}benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-y-
lmethoxy)benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-[(2-methyl-1-
,3-thiazol-4-yl) methoxy]benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-[(3,5-dimethylisoxazo-
l-4-yl)methoxy]-3-fluorobenzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(1,2,5-thiad-
iazol-3-ylmethoxy)benzamide;
N-cyclopropyl-4-methyl-3-{[3-(1,3-thiazol-4-ylmethoxy)benzoyl]amino}benza-
mide;
N-cyclopropyl-4-methyl-3-({3-[(2-methyl-1,3-thiazol-4-yl)methoxy]ben-
zoyl}amino)benzamide;
N-cyclopropyl-4-methyl-3-{[3-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide-
;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(1,3-thiazo-
l-4-ylmethoxy)benzamide;
N-cyclopropyl-4-methyl-3-({3-methyl-4-[(2-methyl-1,3-thiazol-4-yl)methoxy-
]benzoyl}amino)benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-[(3,5-dimethylisoxazo-
l-4-yl)methoxy]-3-methylbenzamide;
N-cyclopropyl-4-methyl-3-{[3-methyl-4-(1,2,5-thiadiazol-3-ylmethoxy)benzo-
yl]amino}benzamide; methyl
5-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-2--
methylphenoxy}methyl)-2-furoate;
3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(pyridin-2-y-
lmethoxy)benzamide;
3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(1,3-thiazol-
-4-ylmethoxy)benzamide;
N-cyclopropyl-3-({3-[(3,5-dimethylisoxazol-4-yl)methoxy]benzoyl}amino)-4--
methylbenzamide;
N-cyclopropyl-4-methyl-3-{[3-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}-
benzamide;
3-({3-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzoyl}amino)-N-cycl-
opropyl-4-methylbenzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(imidazo[1,2-
-a]pyridin-2-ylmethoxy)benzamide;
N-cyclopropyl-3-({4-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-meth-
ylbenzamide;
N-cyclopropyl-4-methyl-3-{[4-(1-pyridin-2-ylethoxy)benzoyl]amino}benzamid-
e;
N-cyclopropyl-3-({3-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-me-
thylbenzamide;
N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino-
]-4-methylbenzamide;
N-cyclopropyl-3-[(4-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}ben-
zoyl)amino]-4-methylbenzamide;
N-cyclopropyl-3-{[4-({5-[(isopropylamino)methyl]pyridin-2-yl}methoxy)benz-
oyl]amino}-4-methylbenzamide;
N-cyclopropyl-3-{[4-({5-[(dimethylamino)methyl]pyridin-2-yl}methoxy)benzo-
yl]amino}-4-methylbenzamide; methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)nicotinate;
N-cyclopropyl-3-{[4-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}methoxy)ben-
zoyl]amino}-4-methylbenzamide;
N-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}be-
nzoyl)amino]-4-methylbenzamide;
N-cyclopropyl-3-({4-[(5-hydroxypyridin-2-yl)methoxy]benzoyl}amino)-4-meth-
ylbenzamide methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)pyridine-2-carboxylate;
N-cyclopropyl-3-[(4-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino-
]-4-methylbenzamide;
N-cyclopropyl-3-[(4-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}ben-
zoyl)amino]-4-methylbenzamide;
N-cyclopropyl-3-({4-[(6-{[2-(diethylamino)ethoxy]methyl}pyridin-2-yl)meth-
oxy]benzoyl}amino)-4-methylbenzamide;
N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethoxy]methyl}pyridin-2-yl)met-
hoxy]benzoyl}amino)-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-({4-[(1-oxidopyridin-2-yl)methoxy]benzoyl}amino)-
benzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(imidazo[1,-
2-a]pyridin-2-ylmethoxy)pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-2-ylmeth-
oxy)pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyrimidin-2-ylmethox-
y)pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1-methyl-1H-imidazo-
l-2-yl)methoxy]pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1,5-dimethyl-1H-pyr-
azol-3-yl)methoxy]pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1,3-dimethyl-1H-pyr-
azol-5-yl)methoxy]pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(3-methylpyridin-2-y-
l)methoxy]pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1-methyl-1H-benzimi-
dazol-2-yl)methoxy]pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(isoquinolin-1-ylmeth-
oxy)pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(quinolin-2-ylmethoxy-
)pyrimidine-5-carboxamide;
2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-meth-
ylphenyl}pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1-pyridin-2-ylethoxy-
)pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-4-ylmeth-
oxy)pyrimidine-5-carboxamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyridin-2-ylmethoxy)-
pyrimidine-5-carboxamide;
N-cyclopropyl-3-({4-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy]benzoyl-
}amino)-4-methylbenzamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-6-(pyridin-2-ylmethoxy)-
nicotinamide;
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)-
pyrazine-2-carboxamide;
3-({4-[(6-bromopyridin-2-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4-methyl-
benzamide
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,5-difluoro-4-
-(pyridin-2-ylmethoxy)benzamide;
N-cyclopropyl-4-methyl-3-({4-[(6-methylpyridin-2-yl)methoxy]benzoyl}amino-
)benzamide;
N-cyclopropyl-4-methyl-3-({4-[(3-methylpyridin-2-yl)methoxy]benzoyl}amino-
)benzamide;
N-cyclopropyl-4-methyl-3-{[4-(pyrimidin-2-ylmethoxy)benzoyl]amino}benzami-
de;
N-cyclopropyl-4-methyl-3-{[4-(pyridazin-3-ylmethoxy)benzoyl]amino}benz-
amide;
N-cyclopropyl-3-{[4-({6-[(2-methoxyethyl)amino]pyridin-2-yl}methoxy-
)benzoyl]amino}-4-methylbenzamide;
N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethyl]amino}pyridin-2-yl)metho-
xy]benzoyl}amino)-4-methylbenzamide;
5-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2-
-carboxamide
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)-
pyridine-2-carboxamide; and
N-cyclopropyl-4-methyl-3-[(4-{[4-(methylsulfonyl)benzyl]oxy}benzoyl)amino-
]benzamide; or a pharmaceutically-acceptable salt thereof.
10. A process for preparing a compound of the Formula I, or
pharmaceutically-acceptable salt thereof which comprises:-- (a)
reacting a benzoic acid of the Formula II, or a activated
derivative thereof, ##STR00012## with an amine of the Formula III
##STR00013## under standard amide bond forming conditions, wherein
Q.sub.a, Q.sub.b, R.sub.1 and R.sub.2 are as defined in claim 1 or
claim 2 and wherein any functional group is optionally protected,
and: (i) removing any protecting groups; and (ii) optionally
forming a pharmaceutically-acceptable salt; (b) reacting an acid of
the Formula IV, or an activated derivative thereof, ##STR00014##
with an aniline of the Formula VI ##STR00015## under standard amide
bond forming, wherein Q.sub.a, Q.sub.b, R.sub.1 and R.sub.2 are as
defined in claim 1 or claim 2 and wherein any functional group is
optionally protected, and: (i) removing any protecting groups; (ii)
optionally forming a pharmaceutically-acceptable salt; (c) for the
preparation of a compound of the Formula I wherein a substituent on
Q.sub.a or Q.sub.b is (1-6C)alkoxy or substituted (1-6C)alkoxy,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted
(1-6C)alkylamino, the alkylation of an amide derivative of the
Formula I wherein a substituent on Q.sub.a or Q.sub.b is hydroxy or
amino.
11. A pharmaceutical composition for use in the treatment of
diseases mediated by cytokines which comprises compound of the
Formula I as claimed in any one of claims 1 to 9, or a
pharmaceutically-acceptable salt thereof, in association with a
pharmaceutically-acceptable diluent or carrier.
12. A compound of the Formula I claimed in any one of claims 1 to
9, or a pharmaceutically-acceptable salt thereof, for use in a
method of treatment of the human or animal body by therapy.
13. A compound of the Formula I claimed in any one of claims 1 to
9, or a pharmaceutically-acceptable salt thereof, in the
manufacture of a medicament.
14. A compound of the Formula I claimed in any one of claims 1 to
9, or a pharmaceutically-acceptable salt thereof, in the
manufacture of a medicament for use in the treatment of medical
conditions mediated by cytokines.
15. The use of a compound of the Formula I claimed in any one of
claims 1 to 9, or a pharmaceutically-acceptable thereof, in the
manufacture of a medicament for use in the treatment of rheumatoid
arthritis, asthma, chronic obstructive pulmonary disease,
inflammatory bowel disease, multiple sclerosis, AIDS, septic shock,
congestive heart failure, ischaemic heart disease or psoriasis.
Description
[0001] This invention relates to amide derivatives, or
pharmaceutically-acceptable salts thereof, which are useful as
inhibitors of cytokine mediated disease. The invention also relates
to processes for the manufacture of said amide derivatives, to
pharmaceutical compositions containing said amide derivatives and
to their use in therapeutic methods, for example by virtue of
inhibition of cytokine mediated disease.
[0002] The amide derivatives disclosed in the present invention are
inhibitors of the production of cytokines such as Tumour Necrosis
Factor (hereinafter TNF), for example TNF.alpha., and various
members of the interleukin (hereinafter IL) family, for example
IL-1, IL-6 and IL-8. Accordingly the amide derivatives of the
invention will be useful in the treatment of diseases or medical
conditions in which excessive production of cytokines occurs, for
example excessive production of TNF.alpha. or IL-1. It is known
that cytokines are produced by a wide variety of cells such as
monocytes and macrophages and that they give rise to a variety of
physiological effects which are believed to be important in disease
or medical conditions such as inflammation and immunoregulation.
For example, TNF.alpha. and IL-1 have been implicated in the cell
signalling cascade which is believed to contribute to the pathology
of disease states such as inflammatory and allergic diseases and
cytokine-induced toxicity. It is also known that, in certain
cellular systems, TNF.alpha. production precedes and mediates the
production of other cytokines such as IL-1.
[0003] Abnormal levels of cytokines have also been implicated in,
for example, the production of physiologically-active eicosanoids
such as the prostaglandins and leukotrienes, the stimulation of the
release of proteolytic enzymes such as collagenase, the activation
of the immune system, for example by stimulation of T-helper cells,
the activation of osteoclast activity leading to the resorption of
calcium, the stimulation of the release of proteoglycans from, for
example, cartilage, the stimulation of cell proliferation and to
angiogenesis.
[0004] Cytokines are also believed to be implicated in the
production and development of disease states such as inflammatory
and allergic diseases, for example inflammation of the joints
(especially rheumatoid arthritis, osteoarthritis and gout),
inflammation of the gastrointestinal tract (especially inflammatory
bowel disease, ulcerative colitis, Crohn's disease and gastritis),
skin disease (especially psoriasis, eczema and dermatitis) and
respiratory disease (especially asthma, bronchitis, allergic
rhinitis, chronic obstructive pulmonary disease and adult
respiratory distress syndrome), and in the production and
development of various cardiovascular and cerebrovascular disorders
such as congestive heart failure, acute heart failure, myocardial
infarction, the formation of atherosclerotic plaques, hypertension,
platelet aggregation, angina, stroke, reperfusion injury, vascular
injury including restenosis and peripheral vascular disease, and,
for example, various disorders of bone metabolism such as
osteoporosis (including senile and postmenopausal osteoporosis),
Paget's disease, bone metastases, hypercalcaemia,
hyperparathyroidism, osteosclerosis, osteoperosis and
periodontitis, and the abnormal changes in bone metabolism which
may accompany rheumatoid arthritis and osteoarthritis. Excessive
cytokine production has also been implicated in mediating certain
complications of bacterial, fungal and/or viral infections such as
endotoxic shock, septic shock and toxic shock syndrome and in
mediating certain complications of CNS surgery or injury such as
neurotrauma and ischaemic stroke. Excessive cytokine production has
also been implicated in mediating or exacerbating the development
of diseases involving cartilage or muscle resorption, pulmonary
fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain
chronic diseases such as malignant disease and acquired immune
deficiency syndrome (AIDS), chronic obstructive pulmonary disease,
tumour invasiveness and tumour metastasis and multiple sclerosis.
Excessive cytokine production has also been implicated in pain.
[0005] Evidence of the central role played by TNF.alpha. in the
cell signalling cascade which gives rise to rheumatoid arthritis is
provided by the efficacy in clinical studies of antibodies of
TNF.alpha. (The Lancet, 1994, 344, 1125 and British Journal of
Rheumatology, 1995, 34, 334).
[0006] Thus cytokines such as TNF.alpha. and IL-1 are believed to
be important mediators of a considerable range of diseases and
medical conditions. Accordingly it is expected that inhibition of
the production of and/or effects of these cytokines will be of
benefit in the prophylaxis, control or treatment of such diseases
and medical conditions.
[0007] Without wishing to imply that the amide derivatives
disclosed in the present invention possesses pharmacological
activity only by virtue of an effect on a single biological
process, it is believed that the amide derivatives inhibit the
effects of cytokines by virtue of inhibition of the enzyme p38
kinase. p38 kinase, otherwise known as cytokine suppressive binding
protein (hereinafter CSBP) and reactivating kinase (hereinafter
RK), is a member of the mitogen-activated protein (hereinafter MAP)
kinase family of enzymes which is known to be activated by
physiological stress such as that induced by ionising radiation,
cytotoxic agents, and toxins, for example endotoxins such as
bacterial lipopolysaccharide, and by a variety of agents such as
the cytokines, for example TNF.alpha. and IL-1. It is known that
p38 kinase phosphorylates certain intracellular proteins which are
involved in the cascade of enzymatic steps which leads to the
biosynthesis and excretion of cytokines such as TNF.alpha. and
IL-1. Known inhibitors of p38 kinase have been reviewed in Exp.
Opin. Ther. Patents, 2000, 10(1), 25-37. p38 kinase is known to
exist in isoforms identified as p38.alpha. and p38.beta..
[0008] The amide derivatives disclosed in the present invention are
inhibitors of the production of cytokines such as TNF, in
particular of TNF.alpha., and various interleukins, in particular
IL-1.
[0009] It is known from the International Patent Application WO
00/07980 that certain amide derivatives are inhibitors of the
production of cytokines such as TNF, and various interleukins. One
of the disclosed compounds is
N-cyclobutyl-3-(3,4-dimethoxybenzamido)-4-methylbenzamide
(Comparator Compound X).
[0010] There is no disclosure in this document of an amide
derivative which bears a cyclopropylaminocarbonyl substituent at
the 3-position of the central 6-methylphenyl core. We have now
found that such compounds possess potent cytokine inhibitory
activity and have desirable activity profiles.
[0011] Subsequently, International Patent Application WO
2004/071440 has disclosed amide derivatives that bear a
cycloalkylaminocarbonyl substituent at the 3-position of the
central 6-methylphenyl core. However, this application discloses
thiazolyl-based compounds, wherein the thiazole ring is mainly
substituted with a substituted amino group.
[0012] According to the present invention there is provided a
compound of the Formula I
##STR00001##
wherein Q.sub.a is phenyl or heteroaryl, and Q.sub.a may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno,
trifluoromethyl, cyano, amino, (1-6C)alkyl, (2-6C)alkenyl,
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; R.sub.1 and R.sub.2
are each independently selected from hydrogen, (1-6C)alkyl,
(2-6C)alkenyl and (2-6C)alkynyl; and Q.sub.b is phenyl, heteroaryl
or heterocyclyl, and Q.sub.b may optionally bear 1 or 2
substituents selected from hydroxy, halogen, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
aminosulphonyl, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl; and
wherein any of the substituents on Q.sub.a or Q.sub.b defined
hereinbefore which comprise a CH.sub.2 group which is attached to 2
carbon atoms or a CH.sub.3 group which is attached to a carbon atom
may optionally bear on each said CH.sub.2 or CH.sub.3 group one or
more substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; or a
pharmaceutically-acceptable salt thereof. According to a further
aspect of present invention there is provided a compound of the
Formula I wherein Q.sub.a is phenyl, pyridyl, pyrimidinyl,
pyrazinyl or pyridazinyl, and Q.sub.a may optionally bear 1 or 2
substituents selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy;
R.sub.1 and R.sub.2 are each independently selected from hydrogen,
(1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl; and Q.sub.b is
phenyl, heteroaryl or heterocyclyl, and Q.sub.b may optionally bear
1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
aminosulphonyl, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl; and
wherein any of the substituents on Q.sub.a or Q.sub.b defined
hereinbefore which comprise a CH.sub.2 group which is attached to 2
carbon atoms or a CH.sub.3 group which is attached to a carbon atom
may optionally bear on each said CH.sub.2 or CH.sub.3 group one or
more substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; or a
pharmaceutically-acceptable salt thereof.
[0013] In this specification, the term (1-6C)alkyl includes
straight-chain and branched-chain alkyl groups such as propyl,
isopropyl and tert-butyl. 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. In
this specification, the term (3-6C)cycloalkoxy includes
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
References to individual cycloalkyl groups such as "cyclopentyl"
are specific for that 5-membered ring only.
[0014] 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 property of inhibiting
cytokines, in particular TNF. 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, inhibitory properties against TNF may be evaluated
using the standard laboratory techniques referred to
hereinafter.
[0015] Suitable values for the generic radicals referred to above
include those set out below.
[0016] A suitable value for Q.sub.a or Q.sub.b when it is
heteroaryl is, for example, an aromatic 5- or 6-membered monocyclic
ring, a 9- or 10-membered bicyclic ring or a 13- or 14-membered
tricyclic ring each 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, naphthyridinyl, carbazolyl,
dibenzofuranyl, dibenzothiophenyl, S,S-dioxodibenzothiophenyl,
xanthenyl, dibenzo-1,4-dioxinyl, phenoxathiinyl, phenoxazinyl,
dibenzothiinyl, phenothiazinyl, thianthrenyl, benzofuropyridyl,
pyridoindolyl, acridinyl or phenanthridinyl, preferably furyl,
thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrido[1,2-a]imidazolyl,
pyrazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl,
pyrimidinyl or pyrazinyl, more preferably furyl, isoxazolyl,
thiazolyl, pyrido[1,2-a]imidazolyl, thiadiazolyl or pyridyl,
pyridazinyl, pyrimidinyl or pyrazinyl.
[0017] A suitable value for Q.sub.b when it is heterocyclyl is, for
example, a non-aromatic saturated or partially saturated 3- to
10-membered monocyclic or bicyclic ring or a 5- to 7-membered
monocyclic ring each with up to five heteroatoms selected from
oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl,
azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl,
pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl,
pyrazolidinyl, 1,1-dioxidoisothiazolidinyl, morpholinyl,
thiomorpholinyl, tetrahydro-1,4-thiazinyl,
1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl or
benzo derivatives thereof such as 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, indolinyl, isoindolinyl, chromanyl and
isochromanyl, preferably azetidin-1-yl, 3-pyrrolin-1-yl,
pyrrolidin-1-yl, pyrrolidin-2-yl, 1,1-dioxidoisothiazolidin-2-yl,
morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl,
piperidin-3-yl, piperidin-4-yl, homopiperidin-1-yl, piperidino,
piperazin-1-yl or homopiperazin-1-yl. 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. Suitable values for various substituents on
Q.sub.a or Q.sub.b or for R.sub.1 and R.sub.2 include:-- [0018] for
halogeno: fluoro, chloro, bromo and iodo; [0019] for (1-6C)alkyl:
methyl, ethyl, propyl, isopropyl and tert-butyl; [0020] for
(2-6C)alkenyl: vinyl and allyl; [0021] for (2-6C)alkynyl: ethynyl
and 2-propynyl; [0022] for (1-6C)alkoxy: methoxy, ethoxy, propoxy,
isopropoxy and butoxy; [0023] for (1-6C)alkoxycarbonyl:
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and
tert-butoxycarbonyl; [0024] for N-(1-6C)alkylcarbamoyl: N-methyl
carbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; [0025] for
N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,
N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; [0026] for
(2-6C)alkanoyl: acetyl and propionyl; [0027] for (1-6C)alkylamino:
methylamino, ethylamino and propylamino; [0028] for
di-[(1-6C)alkyl]amino: dimethylamino, diethylamino and
N-ethyl-N-methylamino; [0029] for halogeno-(1-6C)alkyl:
fluoromethyl, chloromethyl, bromomethyl, difluoromethyl,
dichloromethyl, dibromomethyl, 2-fluoroethyl, 2-chloroethyl and
2-bromoethyl; [0030] for hydroxy-(1-6C)alkyl: hydroxymethyl,
2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; [0031] for
(1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,
1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
[0032] for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl,
1-cyanoethyl and 3-cyanopropyl; [0033] for amino-(1-6C)alkyl:
aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl; [0034]
for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl,
ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,
2-ethylaminoethyl and 3-methylaminopropyl; [0035] for
di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,
diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and
3-dimethylaminopropyl. [0036] for (2-6C)alkanoyloxy: acetoxy and
propionyloxy: [0037] for (1-6C)alkanoylamino: formamido, acetamido
and propionamido; [0038] for carboxy-(1-6C)alkyl: carboxymethyl,
1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl;
[0039] for (1-6C)alkoxycarbonyl-(1-6C)alkyl: methoxycarbonylmethyl,
ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,
1-methoxycarbonylethyl, 1-ethoxycarbonylethyl,
2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,
3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; [0040] for
(1-6C)alkylthio: methylthio, ethylthio and propylthio; [0041] for
(1-6C)alkylsulphinyl: methylsulphinyl, ethylsulphinyl and
propylsulphinyl; [0042] for (1-6C)alkylsulphonyl: methylsulphonyl,
ethylsulphonyl and propylsulphonyl; [0043] for
N-(1-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl;
[0044] for N,N-di-[(1-6C)alkyl]sulphamoyl:
N,N-dimethylsulphamoyl;
[0045] A suitable value for a substituent on Q.sub.b when it is
(3-6C)cycloalkyl is, for example, a saturated monocyclic 3- to
6-membered carbon ring such as cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl,
more preferably cyclopropyl.
[0046] A suitable value for a substituent on Q.sub.b when it is
(3-6C)cycloalkyl-(1-6C)alkyl is, for example, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
cyclopropylethyl, preferably cyclopropylmethyl or cyclopropylethyl,
more preferably cyclopropylmethyl.
[0047] A suitable pharmaceutically-acceptable salt of a compound of
the Formula I, for example, an acid-addition salt of a compound of
the Formula I which is sufficiently basic, for example, an
acid-addition salt with an inorganic or organic acid such as
hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,
citric, maleic, tartaric, fumaric, hemifumaric, succinic,
hemisuccinic, mandelic, methanesulphonic, dimethanesulphonic,
ethane-1,2-sulphonic, benzenesulphonic, salicylic or
4-toluenesulphonic acid.
[0048] Further values of Q.sub.a, Q.sub.b, R.sub.1 and R.sub.2 are
as follows. Such values may be used where appropriate with any of
the definitions, claims or embodiments defined hereinbefore or
hereinafter.
[0049] Q.sub.a is phenyl or heteroaryl, and Q.sub.a may optionally
bear 1 or 2 substituents selected from hydroxy, halogen,
trifluoromethyl, cyano, amino, (1-6C)alkyl, (2-6C)alkenyl,
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl.
[0050] Q.sub.a is heteroaryl, and Q.sub.a may optionally bear 1 or
2 substituents selected from hydroxy, halogeno, trifluoromethyl,
cyano, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and
(1-6C)alkoxycarbonyl.
[0051] Q.sub.a is phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, and Q.sub.a may optionally bear 1 or 2 substituents
selected from hydroxy, halogeno, trifluoromethyl, cyano, amino,
(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino and
(1-6C)alkoxycarbonyl.
[0052] Q.sub.a is phenyl or heteroaryl, and Q.sub.a may optionally
bear 1 or 2 substituents selected from, halogeno, (1-6C)alkyl and
(1-6C)alkoxy.
[0053] Q.sub.a is phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, and Q.sub.a may optionally bear 1 or 2 substituents
selected from hydroxy, halogeno, (1-6C)alkyl and (1-6C)alkoxy.
[0054] Q.sub.a is phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, and Q.sub.a may optionally bear 1 or 2 substituents
selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy.
[0055] Q.sub.a is phenyl, pyridyl or pyrimidinyl, and Q.sub.a may
optionally bear 1 or 2 substituents selected from halogeno,
(1-6C)alkyl and (1-6C)alkoxy.
[0056] Q.sub.a is phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, and Q.sub.a may optionally bear 1 or 2 substituents
selected from hydroxy and halogeno.
[0057] Q.sub.a is phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, and Q.sub.a may optionally bear 1 or 2 substituents
selected from hydroxy, chloro and fluoro.
[0058] Q.sub.a is phenyl, and Q.sub.a may optionally bear 1 or 2
substituents selected from hydroxy, chloro and fluoro.
[0059] Q.sub.a is phenyl, and Q.sub.a may optionally bear 1 or 2
fluoro substituents.
[0060] Q.sub.a is phenyl which optionally bears 1 or 2 substituents
selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy.
[0061] Q.sub.a is heteroaryl, which optionally bears 1 or 2
substituents selected from halogeno, (1-6C)alkyl and
(1-6C)alkoxy.
[0062] Q.sub.a is phenyl or heteroaryl, and Q.sub.a may optionally
bear 1 or 2 substituents selected from fluoro, chloro, methyl and
methoxy.
[0063] Q.sub.a is phenyl, which optionally bears 1 or 2
substituents selected from fluoro, chloro, methyl and methoxy.
[0064] Q.sub.a is heteroaryl, which optionally bears 1 or 2
substituents selected from fluoro, chloro, methyl and methoxy.
[0065] Q.sub.a is phenyl, pyridyl or pyrimidinyl, which bears 1 or
2 substituents selected from fluoro, chloro, methyl and
methoxy.
[0066] Q.sub.a is phenyl or heteroaryl, which bears 1 or 2
substituents selected from fluoro, chloro, methyl and methoxy.
[0067] Q.sub.b is phenyl, heteroaryl or heterocyclyl, and Q.sub.b
may optionally bear 1 or 2 substituents selected from hydroxy,
halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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 and
di-[(1-6C)alkyl]amino-(1-6C)alkyl.
[0068] Q.sub.b is phenyl or heteroaryl, and Q.sub.b may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno,
(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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,
(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
aminosulphonyl, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl;
[0069] and wherein any of the substituents on Q.sub.b which
comprise a CH.sub.2 group which is attached to 2 carbon atoms or a
CH.sub.3 group which is attached to a carbon atom may optionally
bear on each said CH.sub.2 or CH.sub.3 group one or more
substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.
[0070] Q.sub.b is phenyl or heteroaryl, and Q.sub.b may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno,
(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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 and
di-[(1-6C)alkyl]amino-(1-6C)alkyl.
[0071] Q.sub.b is phenyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, thiazolyl, thiadiazolyl, imidazolyl, isoxazolyl,
oxazolyl, furanyl, thienyl, benzimidazolyl, isoquinolinyl,
quinolinyl, benzothiazolyl or pyrido[1,2-a]imidazolyl, and Q.sub.b
may optionally bear 1 or 2 substituents selected from hydroxy,
halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, aminosulphonyl,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl and
(3-6C)cycloalkylsulphonyl;
[0072] and wherein any of the substituents on Q.sub.b which
comprise a CH.sub.2 group which is attached to 2 carbon atoms or a
CH.sub.3 group which is attached to a carbon atom may optionally
bear on each said CH.sub.2 or CH.sub.3 group one or more
substituents selected from hydroxy, cyano, amino, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.
[0073] Q.sub.b is phenyl, pyridyl, thiazolyl, furanyl,
pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl, isoxazolyl,
piperidinyl, piperizinyl or pyrroldinyl, and Q.sub.b may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno,
(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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 and
di-[(1-6C)alkyl]amino-(1-6C)alkyl.
[0074] Q.sub.b is phenyl, pyridyl, thiazolyl, furanyl,
pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl or isoxazolyl, and
Q.sub.b may optionally bear 1 or 2 substituents selected from
hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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 and
di-[(1-6C)alkyl]amino-(1-6C)alkyl.
[0075] Q.sub.b is phenyl, pyridyl, thiazolyl, furanyl,
pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl or isoxazolyl, and
Q.sub.b may optionally bear 1 or 2 substituents selected from
hydroxy, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy,
methoxycarbonyl and ethoxycarboyl.
[0076] R.sub.1 and R.sub.2 are each independently selected from
hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl;
[0077] R.sub.1 and R.sub.2 are each independently selected from
hydrogen and (1-6C)alkyl.
[0078] R.sub.1 and R.sub.2 are hydrogen.
[0079] Particular novel compounds of the invention include, for
example, amide derivatives of the Formula I, or
pharmaceutically-acceptable salts thereof, wherein:--
(a) Q.sub.a is phenyl or heteroaryl, and Q.sub.a may optionally
bear 1 or 2 substituents selected from hydroxy, halogeno,
trifluoromethyl, cyano, amino, (1-6C)alkyl, (2-6C)alkenyl,
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; Q.sub.b is phenyl,
heteroaryl or heterocyclyl, and Q.sub.b may optionally bear 1 or 2
substituents selected from hydroxy, halogeno, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,
(3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkoxy,
(3-6C)cycloalkyl-(1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
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 and di-[(1-6C)alkyl]amino-(1-6C)alkyl
and R.sub.1 and R.sub.2 are hydrogen. (b) Q.sub.a is phenyl,
pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and Q.sub.a may
optionally bear 1 or 2 substituents selected from hydroxy,
halogeno, trifluoromethyl, cyano, amino, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; Q.sub.b is phenyl,
pyridyl, thiazolyl, furanyl, pyrido[1,2-a]imidazolyl, thiadiazolyl,
oxazolyl, isoxazolyl, piperidinyl, piperizinyl or pyrroldinyl, and
Q.sub.b may optionally bear 1 or 2 substituents selected from
hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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 and
di-[(1-6C)alkyl]amino-(1-6C)alkyl and R.sub.1 and R.sub.2 are
hydrogen. (c) Q.sub.a is phenyl which optionally bears 1 or 2
substituents selected from, halogeno, (1-6C)alkyl and (1-6C)alkoxy;
Q.sub.b is phenyl, pyridyl, thiazolyl, furanyl,
pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl or isoxazolyl, and
Q.sub.b may optionally bear 1 or 2 substituents selected from
hydroxy, halogeno, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
(3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxy,
(3-6C)cycloalkoxy, (3-6C)cycloalkyl-(1-6C)alkoxy, carboxy,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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 and
di-[(1-6C)alkyl]amino-(1-6C)alkyl and R.sub.1 and R.sub.2 are
hydrogen. (d) Q.sub.a is phenyl, which optionally bears 1 or 2
substituents selected from, fluoro, chloro, methyl and methoxy;
Q.sub.b is phenyl, pyridyl, thiazolyl, furanyl,
pyrido[1,2-a]imidazolyl, thiadiazolyl, oxazolyl or isoxazolyl, and
Q.sub.b may optionally bear 1 or 2 substituents selected from
hydroxy, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy,
methoxycarbonyl and ethoxycarbonyl and R.sub.1 and R.sub.2 are
hydrogen.
[0080] A particular preferred compound of the invention is, for
example:-- [0081]
3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide;
[0082]
3-{[3-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide;
[0083]
4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3--
methylbenzamide; [0084]
4-(benzyloxy)-3-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}b-
enzamide; [0085]
4-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}b-
enzamide; [0086]
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide-
; [0087]
N-cyclopropyl-4-methyl-3-{[4-(1,3-thiazol-4-methoxy)benzoyl]amino-
}benzamide; [0088]
N-cyclopropyl-4-methyl-3-{[4-(pyridin-3-ylmethoxy)benzoyl]amino}benzamide-
; [0089]
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benz-
oyl}amino)benzamide; [0090]
3-({4-[(5-chloro-1,2,3-thiadiazol-4-yl)methoxy]benzoyl}amino)-N-cycloprop-
yl-4-methylbenzamide; [0091]
N-cyclopropyl-3-{[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)benzoyl]amino}-4-m-
ethylbenzamide; [0092]
N-cyclopropyl-4-methyl-3-({4-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzoyl}-
amino)benzamide; [0093]
N-cyclopropyl-3-({4-[(3,5-dimethylisoxazol-4-yl)methoxy]benzoyl}amino)-4--
methylbenzamide; [0094]
N-cyclopropyl-4-methyl-3-{[4-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}-
benzamide; [0095] methyl
5-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)-2-furoate; [0096]
3-({4-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4--
methylbenzamide; [0097]
4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-
benzamide; [0098]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-4-(pyridin-2--
ylmethoxy)benzamide; [0099]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-4-(1,3-thiazo-
l-4-ylmethoxy)benzamide; [0100]
N-cyclopropyl-4-methyl-3-{[3-methyl-4-(pyridin-2-ylmethoxy)benzoyl]amino}-
benzamide; [0101]
N-cyclopropyl-4-methyl-3-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)benzoyl]am-
ino}benzamide; [0102]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-y-
lmethoxy)benzamide; [0103]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-[(2-methyl-1-
,3-thiazol-4-yl)methoxy]benzamide; [0104]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-[(3,5-dimethylisoxazo-
l-4-yl)methoxy]-3-fluorobenzamide; [0105]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(1,2,5-thiad-
iazol-3-ylmethoxy)benzamide; [0106]
N-cyclopropyl-4-methyl-3-{[3-(1,3-thiazol-4-ylmethoxy)benzoyl]amino}benza-
mide; [0107]
N-cyclopropyl-4-methyl-3-({3-[(2-methyl-1,3-thiazol-4-yl)methoxy]benzoyl}-
amino)benzamide; [0108]
N-cyclopropyl-4-methyl-3-{[3-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide-
; [0109]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(1,3-
-thiazol-4-ylmethoxy)benzamide; [0110]
N-cyclopropyl-4-methyl-3-({3-methyl-4-[(2-methyl-1,3-thiazol-4-yl)methoxy-
]benzoyl}amino)benzamide; [0111]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-[(3,5-dimethylisoxazo-
l-4-yl)methoxy]-3-methylbenzamide; [0112]
N-cyclopropyl-4-methyl-3-{[3-methyl-4-(1,2,5-thiadiazol-3-ylmethoxy)benzo-
yl]amino}benzamide; [0113] methyl
5-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-2--
methylphenoxy}methyl)-2-furoate; [0114]
3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(pyridin-2-y-
lmethoxy)benzamide; [0115]
3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(1,3-thiazol-
-4-ylmethoxy)benzamide; [0116]
N-cyclopropyl-3-({3-[(3,5-dimethylisoxazol-4-yl)methoxy]benzoyl}amino)-4--
methylbenzamide; [0117]
N-cyclopropyl-4-methyl-3-{[3-(1,2,5-thiadiazol-3-ylmethoxy)benzoyl]amino}-
benzamide; [0118]
3-({3-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4--
methylbenzamide; [0119]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(imidazo[1,2-
-a]pyridin-2-ylmethoxy)benzamide; [0120]
N-cyclopropyl-3-({4-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-meth-
ylbenzamide; [0121]
N-cyclopropyl-4-methyl-3-{[4-(1-pyridin-2-ylethoxy)benzoyl]amino}benzamid-
e; [0122]
N-cyclopropyl-3-({3-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amin-
o)-4-methylbenzamide; [0123]
N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino-
]-4-methylbenzamide; [0124]
N-cyclopropyl-3-[(4-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}ben-
zoyl)amino]-4-methylbenzamide; [0125]
N-cyclopropyl-3-{[4-({5-[(isopropylamino)methyl]pyridin-2-yl}methoxy)benz-
oyl]amino}-4-methylbenzamide; [0126]
N-cyclopropyl-3-{[4-({5-[(dimethylamino)methyl]pyridin-2-yl}methoxy)benzo-
yl]amino}-4-methylbenzamide; [0127] methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)nicotinate; [0128]
N-cyclopropyl-3-{[4-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}methoxy)ben-
zoyl]amino}-4-methylbenzamide; [0129]
N-cyclopropyl-3-[(4-({[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}b-
enzoyl)amino]-4-methylbenzamide; [0130]
N-cyclopropyl-3-({4-[(5-hydroxypyridin-2-yl)methoxy]benzoyl}amino)-4-meth-
ylbenzamide methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)pyridine-2-carboxylate; [0131]
N-cyclopropyl-3-[(4-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino-
]-4-methylbenzamide; [0132]
N-cyclopropyl-3-[(4-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}ben-
zoyl)amino]-4-methylbenzamide; [0133]
N-cyclopropyl-3-({4-[(6-{[2-(diethylamino)ethoxy]methyl}pyridin-2-yl)meth-
oxy]benzoyl}amino)-4-methylbenzamide; [0134]
N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethoxy]methyl}pyridin-2-yl)met-
hoxy]benzoyl}amino)-4-methylbenzamide; [0135]
N-cyclopropyl-4-methyl-3-({4-[(1-oxidopyridin-2-yl)methoxy]benzoyl}amino)-
benzamide; [0136]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(imidazo[1,2-a]pyridi-
n-2-ylmethoxy)pyrimidine-5-carboxamide; [0137]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-2-ylmeth-
oxy)pyrimidine-5-carboxamide; [0138]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyrimidin-2-ylmethox-
y)pyrimidine-5-carboxamide; [0139]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1-methyl-1H-imidazo-
l-2-yl)methoxy]pyrimidine-5-carboxamide; [0140]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1,5-dimethyl-1H-pyr-
azol-3-yl)methoxy]pyrimidine-5-carboxamide; [0141]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1,3-dimethyl-1H-pyr-
azol-5-yl)methoxy]pyrimidine-5-carboxamide; [0142]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(3-methylpyridin-2-y-
l)methoxy]pyrimidine-5-carboxamide; [0143]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-[(1-methyl-1H-benzimi-
dazol-2-yl)methoxy]pyrimidine-5-carboxamide; [0144]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(isoquinolin-1-ylmeth-
oxy)pyrimidine-5-carboxamide; [0145]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(quinolin-2-ylmethoxy-
)pyrimidine-5-carboxamide; [0146]
2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-meth-
ylphenyl}pyrimidine-5-carboxamide; [0147]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1-pyridin-2-ylethoxy-
)pyrimidine-5-carboxamide; [0148]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-4-ylmeth-
oxy)pyrimidine-5-carboxamide; [0149]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyridin-2-ylmethoxy)-
pyrimidine-5-carboxamide; [0150]
N-cyclopropyl-3-({4-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy]benzoyl-
}amino)-4-methylbenzamide; [0151]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-6-(pyridin-2-ylmethoxy)-
nicotinamide; [0152]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)-
pyrazine-2-carboxamide; [0153]
3-({4-[(6-bromopyridin-2-yl)methoxy]benzoyl}amino)-N-cyclopropyl-4-methyl-
benzamide [0154]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,5-difluoro-4-(pyridin-
-2-ylmethoxy)benzamide; [0155]
N-cyclopropyl-4-methyl-3-({4-[(6-methylpyridin-2-yl)methoxy]benzoyl}amino-
)benzamide; [0156]
N-cyclopropyl-4-methyl-3-({4-[(3-methylpyridin-2-yl)methoxy]benzoyl}amino-
)benzamide; [0157]
N-cyclopropyl-4-methyl-3-{[4-(pyrimidin-2-ylmethoxy)benzoyl]amino}benzami-
de; [0158]
N-cyclopropyl-4-methyl-3-{[4-(pyridazin-3-ylmethoxy)benzoyl]ami-
no}benzamide; [0159]
N-cyclopropyl-3-{[4-({6-[(2-methoxyethyl)amino]pyridin-2-yl}methoxy)benzo-
yl]amino}-4-methylbenzamide; [0160]
N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethyl]amino}pyridin-2-yl)metho-
xy]benzoyl}amino)-4-methylbenzamide; [0161]
5-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2-
-carboxamide [0162]
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)-
pyridine-2-carboxamide; and [0163]
N-cyclopropyl-4-methyl-3-[(4-{[4-(methylsulfonyl)benzyl]oxy}benzoyl)amino-
]benzamide; or a pharmaceutically-acceptable salt thereof.
[0164] Compounds of the Formula I, or a pharmaceutically-acceptable
salts thereof, may be prepared by any process known to be
applicable to the preparation of chemically-related compounds.
Suitable processes are illustrated by, for example, those in WO
00/07980. Such processes, when used to prepare a novel compound 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, Q.sub.a, Q.sub.b,
R.sub.1 and R.sub.2 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.
(a) A compound of the Formula I, or a pharmaceutically-acceptable
salt thereof, may be prepared by reacting a benzoic acid of the
Formula II, or a activated derivative thereof,
##STR00002##
with an amine of the Formula III
##STR00003##
under standard amide bond forming conditions, wherein Q.sub.a,
Q.sub.b, R.sub.1 and R.sub.2 are as defined hereinbefore and
wherein any functional group is optionally protected, and:
[0165] (i) removing any protecting groups; and
[0166] (ii) optionally forming a pharmaceutically-acceptable
salt.
[0167] A suitable activated derivative of an acid of the Formula II
is, for example, an acyl halide, for example an acyl chloride
formed by the reaction of the acid and an inorganic acid chloride,
for example thionyl chloride; a mixed anhydride, for example an
anhydride formed by the reaction of the acid and a chloroformate
such as isobutyl chloroformate; an active ester, for example an
ester formed by the reaction of the acid and a phenol such as
pentafluorophenol, an ester such as pentafluorophenyl
trifluoroacetate or an alcohol such as N-hydroxybenzotriazole; an
acyl azide, for example an azide formed by the reaction of the acid
and an azide such as diphenylphosphoryl azide; an acyl cyanide, for
example a cyanide formed by the reaction of an acid and a cyanide
such as diethylphosphoryl cyanide; or the product of the reaction
of the acid and a carbodiimide such as
dicyclohexylcarbodiimide.
[0168] The reaction is preferably carried out in the presence of a
suitable base such as, for example, an alkali or alkaline earth
metal carbonate, alkoxide, hydroxide or hydride, for example sodium
carbonate, potassium carbonate, sodium ethoxide, potassium
butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or
potassium hydride, or an organometallic base such as an
alkyl-lithium, for example n-butyl-lithium, or a
dialkylamino-lithium, for example lithium di-isopropylamide, or,
for example, an organic amine base such as, for example, pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is also
preferably carried out in a suitable inert solvent or diluent, for
example tetrahydrofuran, methylene chloride, 1,2-dimethoxyethane,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a
temperature in the range, for example, -78 to 150.degree. C.,
conveniently at or near ambient temperature.
[0169] Typically a carbodiimide coupling reagent is used in the
presence of an organic solvent (preferably an anhydrous polar
aprotic organic solvent) at a non-extreme temperature, for example
in the region -10 to 40.degree. C., typically at ambient
temperature of about 20.degree. C.
[0170] 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.
[0171] 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 is of course within the
scope of the invention.
[0172] 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, tert-butyl); lower alkoxy lower alkyl groups
(for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower
aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl,
propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower
alkoxycarbonyloxy lower alkyl groups (for example
1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower
alkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl,
p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl
groups (for example trimethylsilyl and tert-butyldimethylsilyl);
tri(lower alkyl)silyl lower alkyl groups (for example
trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl
and vinylethyl). Methods particularly appropriate for the removal
of carboxyl protecting groups include for example acid-, base-,
metal- or enzymically-catalysed hydrolysis.
[0173] 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 benzoyloxycarbonyl,
p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (for example
trimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl (for
example benzyl) groups.
[0174] Examples of amino protecting groups include formyl, aralkyl
groups (for example benzyl and substituted benzyl, p-methoxybenzyl,
nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);
di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for
example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example
allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl
(for example trimethylsilyl and tert-butyldimethylsilyl);
alkylidene (for example methylidene); benzylidene and substituted
benzylidene groups.
[0175] Methods appropriate for removal of hydroxy and amino
protecting groups include, for example, acid-, base-, metal- or
enzymically-catalysed hydrolysis for groups such as
p-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl
and photolytically for groups such as o-nitrobenzyloxycarbonyl.
[0176] The reader is referred to Advanced Organic Chemistry, 4th
Edition, by Jerry March, published by John Wiley & Sons 1992,
for general guidance on reaction conditions and reagents. The
reader is referred to Protective Groups in Organic Synthesis, 3rd
Edition, by Green and Wuts, published by John Wiley & Sons for
general guidance on protecting groups.
[0177] The benzoic acid of Formula II may be prepared by the
cleavage of the corresponding ester thereof which, in turn, may be
prepared by reaction of an acid of Formula IV wherein Q.sub.a,
Q.sub.b, R.sub.1 and R.sub.2 are as defined hereinbefore, or an
activated derivative thereof as defined hereinbefore,
##STR00004##
with an aniline of Formula V
##STR00005##
wherein R is, for example, lower alkyl or benzyl, under suitable
amide bond forming conditions as defined hereinbefore.
[0178] Typical conditions include activating the carboxy group of
the compound of Formula IV, for example by treatment with a halo
reagent (for example oxalyl chloride) to form an acyl halide in an
organic solvent at ambient temperature and then reacting the
activated compound with the aniline of Formula V. Any functional
groups are protected and deprotected as necessary.
(b) A compound of the Formula I, or a pharmaceutically-acceptable
salt thereof, may be prepared by reacting an acid of the Formula
IV, or an activated derivative thereof as defined hereinbefore,
##STR00006##
with an aniline of the Formula VI
##STR00007##
under standard amide bond forming conditions as defined
hereinbefore, wherein Q.sub.a, Q.sub.b, R.sub.1 and R.sub.2 are as
defined hereinbefore and wherein any functional group is optionally
protected, and:
[0179] (i) removing any protecting groups;
[0180] (ii) optionally forming a pharmaceutically-acceptable
salt.
[0181] The aniline of Formula VI may be prepared by reduction of
the corresponding nitro compound using convention procedures such
as those illustrated in the Examples. Typical reaction conditions
include the use of ammonium formate or hydrogen gas in the presence
of a catalyst (for example palladium-on-carbon) in the presence of
an organic solvent (preferably a polar protic solvent), preferably
with heating, for example to about 60.degree. C. Any functional
groups are protected and deprotected as necessary.
(c) A compound of the Formula I wherein a substituent on Q.sub.a or
Q.sub.b is (1-6C)alkoxy or substituted (1-6C)alkoxy,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted
(1-6C)alkylamino, may be prepared by the alkylation, conveniently
in the presence of a suitable base as defined hereinbefore, of an
amide derivative of the Formula I wherein a substituent on Q.sub.a
or Q.sub.b is hydroxy or amino as appropriate.
[0182] The reaction is preferably 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, 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, 10 to 150.degree. C., preferably in the range 20 to
80.degree. C.
[0183] 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 mercapto to alkylthio, or for the
alkylation of amino to alkylamino or substituted alkylamino, or for
the alkylation of hydroxy to heterocyclyloxy, 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 or a heterocyclyl chloride, bromide or iodide, in the
presence of a suitable base as defined hereinbefore.
(d) A compound of the Formula I wherein a substituent on Q.sub.a or
Q.sub.b is (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino
may be prepared by the acylation of a compound of the Formula I
wherein a substituent on Q.sub.a or Q.sub.b is amino.
[0184] A suitable acylating agent is, for example, any agent known
in the art for the acylation of amino to acylamino, for example an
acyl halide, for example a (1-6C)alkanoyl chloride or bromide,
conveniently in the presence of a suitable base, as defined
hereinbefore, an alkanoic acid anhydride or mixed anhydride, for
example a (1-6C)alkanoic acid anhydride such as acetic anhydride or
the mixed anhydride formed by the reaction of an alkanoic acid and
a (1-6C)alkoxycarbonyl halide, for example a (1-6C)alkoxycarbonyl
chloride, in the presence of a suitable base as defined
hereinbefore. In general the acylation is carried out in a suitable
inert solvent or diluent as defined hereinbefore and at a
temperature, in the range, for example, -30 to 120.degree. C.,
conveniently at or near ambient temperature.
(e) A compound of the Formula I wherein a substituent on Q.sub.b is
(1-6C)alkanesulphonylamino may be prepared by the reaction of a
compound of the Formula I wherein a substituent on Q.sub.b is amino
with a (1-6C)alkanesulphonic acid, or an activated derivative
thereof.
[0185] A suitable activated derivative of a (1-6C)alkanesulphonic
acid is, for example, an alkanesulphonyl halide, for example an
alkanesulphonyl chloride formed by the reaction of the sulphonic
acid and an inorganic acid chloride, for example thionyl chloride.
The reaction is preferably carried out in the presence of a
suitable base as defined hereinbefore, particularly pyridine, and
in a suitable inert solvent or diluent as defined hereinbefore,
particularly methylene chloride.
(f) A compound of the Formula I wherein a substituent on Q.sub.a or
Q.sub.b is amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,
di-[(1-6C)alkyl]amino-(1-6C)alkyl, may be prepared by the reaction
of a compound of the Formula I wherein a substituent on Q.sub.b is
a group of the formula -(1-6C)alkylene-Z wherein Z is a
displaceable group with an appropriate amine.
[0186] A suitable displaceable group Z is, for example, a halogeno
group such as fluoro, chloro or bromo, a (1-6C)alkanesulphonyloxy
group such as methanesulphonyloxy or an arylsulphonyloxy group such
as 4-toluenesulphonyloxy.
[0187] The reaction is conveniently carried out in the presence of
a suitable base as defined hereinbefore and in the presence of a
suitable inert diluent or carrier as defined hereinbefore. The
reaction is conveniently carried out at a temperature in the range
10 to 150.degree. C., preferably at or near 50.degree. C.
(g) A compound of the Formula I wherein a substituent on Q.sub.a or
Q.sub.b is an amino group may be prepared by the reduction of a
compound of the Formula I wherein a substituent on Q.sub.a or
Q.sub.b is a nitro group.
[0188] Typical reaction conditions include the use of ammonium
formate or hydrogen gas in the presence of a catalyst, for example
a metallic catalyst such as palladium-on-carbon. Alternatively a
dissolving metal reduction may be carried out, for example using
iron in the presence of an acid, for example an inorganic or
organic acid such as hydrochloric, hydrobromic, sulphuric or acetic
acid. The reaction is conveniently carried out in the presence of
an organic solvent (preferably a polar protic solvent) and
preferably with heating, for example to about 60.degree. C. Any
functional groups are protected and deprotected as necessary.
[0189] The following biological assays and Examples serve to
illustrate the present invention.
Biological Assays
[0190] The following assays can be used to measure the p38
kinase-inhibitory, the TNF-inhibitory and anti-arthritic effects of
compounds of the Formula I:
In Vitro Enzyme Assay
[0191] The ability test compounds to inhibit the enzyme p38 kinase
was assessed. Activity of the test compound against each of the
p38.alpha. and p38.beta. isoforms of the enzyme was determined.
[0192] Human recombinant MKK6 (GenBank Accession Number G1209672)
was isolated from Image clone 45578 (Genomics, 1996, 33, 151) and
utilised to produce protein in the form of a GST fusion protein in
a pGEX vector using analogous procedures to those disclosed by J.
Han et al., Journal of Biological Chemistry, 1996, 271, 2886-2891.
p38.alpha. (GenBank Accession Number G529039) and p38.beta.
(GenBank Accession Number G1469305) were isolated by PCR
amplification of human lymphoblastoid cDNA (GenBank Accession
Number GM1416) and human foetal brain cDNA [synthesised from mRNA
(Clontech, catalogue no. 6525-1) using a Gibco superscript cDNA
synthesis kit] respectively using oligonucleotides designed for the
5' and 3' ends of the human p38.alpha. and p38.beta. genes using
analogous procedures to those described by J. Han et al.,
Biochimica et Biophysica Acta, 1995, 1265, 224-227 and Y. Jiang et
al., Journal of Biological Chemistry, 1996, 271, 17920-17926.
[0193] Both p38 protein isoforms were expressed in E. coli in PET
vectors. Human recombinant p38.alpha. and p38.beta. isoforms were
produced as 5' c-myc, 6His tagged proteins. Both MKK6 and the p38
proteins were purified using standard protocols: the GST MKK6 was
purified using a glutathione sepharose column and the p38 proteins
were purified using nickel chelate columns.
[0194] The p38 enzymes were activated prior to use by incubation
with MKK6 for 3 hours at 30.degree. C. The unactivated E.
coli-expressed MKK6 retained sufficient activity to fully activate
both isoforms of p38. For p38.alpha., the activation incubate
comprised p38.alpha. (50 .mu.l of 10 mg/ml), MKK6 (5 .mu.l of 12
mg/ml), `Kinase buffer` [550 .mu.l; pH 7.4 buffer comprising Tris
HCl (50 mM), EGTA (0.1 mM), sodium orthovanadate (0.1 mM) and
.beta.-mercaptoethanol (0.1%)], Mg [75 .mu.l of 100 mM
Mg(OCOCH.sub.3).sub.2] and ATP (7511 of 1 mM). The activation
incubate for p38.beta. was similar to the above except containing
p38.beta. enzyme (82 .mu.l at 3.05 mg/ml) and 518 .mu.l "Kinase
buffer". p38.alpha. and p38.beta. activation incubates were either
used fresh or aliquoted and stored at -80.degree. C.
[0195] The test compound was solubilised in DMSO (10 mM) and 1:3
serial dilutions in DMSO carried out in polypropylene plates
(Costar 3365). Compound dilutions were then diluted 1:10 in "Kinase
buffer" and 10 .mu.l transferred to a microtiter assay plate
(Costar 3596). Control wells contained 10 .mu.l (1:10 dilution in
kinase buffer) DMSO. `Kinase Assay Mix` [30 .mu.l; comprising
Myelin Basic Protein (Sigma M-1891; 0.5 ml of a 6.66 mg/ml solution
in "Kinase buffer"), activated p38.alpha. enzyme (3.8 .mu.l) and
`Kinase Buffer` (2.55 ml)] was then added. Control wells on each
plate either contained the above "Kinase Assay Mix" (n=6
replicates) or contained "Kinase Assay Mix" in which the activated
p38 enzyme was replaced by Kinase buffer (n=6 replicates).
`Labelled ATP` was then added to all wells [10 .mu.l; comprising 50
.mu.M ATP, 5 .mu.Ci .sup.33P ATP (Amersham International cat. no.
AH9968) and 50 mM Mg(OCOCH.sub.3).sub.2]. For p38.beta., 23 .mu.l
activated p38.beta. enzyme and "Kinase buffer" (2.53 ml) were
included in the "Kinase Assay Mix". The final concentration of test
compound was 2.4 .mu.M-0.001 .mu.M (n=2 replicates). Microtiter
plates were incubated at ambient temperature (with gentle
agitation) for 60 minutes and the reaction stopped by addition of
20% trichloroacetic acid (TCA) (50 .mu.l). The precipitate protein
was captured onto filter plates (PerkinElmer 6005174) using a
Packard Filtermate harvester (2% TCA wash) which was then dried
overnight and 25 .mu.l MICROSCINT O (Packard O6013611) added to
each well. Plates were counted on a Top Count scintillation
counter. Dose response curves were generated using an in house
automated data analysis package and an Origin curve fitting
package.
In Vitro Cell-Based Assays
(i) PBMC
[0196] The ability of a test compound to inhibit TNF.alpha.
production was assessed by using human peripheral blood mononuclear
cells which synthesise and secrete TNF.alpha. when stimulated with
lipopolysaccharide (LPS).
[0197] Peripheral blood mononuclear cells (PBMC) were isolated from
heparinised (10 units/ml heparin) human blood by density
centrifugation (Lymphoprep.TM.; Nycomed). Mononuclear cells were
resuspended in "Culture Medium" [RPMI 1640 medium (Sigma R0883)
containing 50 units/ml penicillin, 50 .mu.g/ml streptomycin and 2
mM glutamine] supplemented with 1% heat-inactivated human AB serum
(Sigma H-1513)]. Compounds were solubilised in DMSO at a
concentration of 20 mM, diluted 1:100 in "culture medium" and
serial dilutions carried out in "Culture Medium" containing 1%
DMSO. PBMCs (2.2.times.10.sup.5 cells in 160 .mu.l culture medium)
were incubated with 20 .mu.l of varying concentrations of test
compound (duplicate cultures) or 20 .mu.l culture medium containing
1% DMSO (control wells) for 30 minutes at 37.degree. C. in a
humidified (5% CO.sub.2/95% air) incubator (Corning 3595; 96 well
flat-bottom tissue culture plates). 20 .mu.l lipopolysaccharide
[LPS E. Coli 0111:B4 (Sigma L-4130), final concentration 0.1
.mu.g/ml] solubilised in "Culture Medium" was added to appropriate
wells. 20 .mu.l Culture Medium was added to "medium alone" control
wells. Six "LPS alone" and six "medium alone" controls were
included on each 96 well plate.
[0198] The test compound was tested for TNF.alpha. inhibitory
activity over a final concentration dose range of 20 .mu.M-0.0001
.mu.M. Each test included a known TNF.alpha. inhibitor i.e. the p38
MAPK inhibitor, SB203580 (Lee, J. C., et al (1994) Nature 372 p
739-746). Plates were incubated for 24 hours at 37.degree. C.
(humidified incubator) after which 100 .mu.l of the supernatant was
removed from each well and stored at -80.degree. C. (96 well
round-bottom plates; Corning 3799). TNF.alpha. levels were
determined in each sample using a human TNF.alpha. ELISA (using
R&D Systems paired antibodies, MAB610 and BAF210.
% inhibition = ( LPS alone - medium alone ) - ( test concentration
- medium alone ) ( LPS alone - medium alone ) .times. 100
##EQU00001##
(ii) Human Whole Blood
[0199] The ability of a test compound to inhibit TNF.alpha.
production was also assessed in a human whole blood assay. Human
whole blood secretes TNF.alpha. when stimulated with LPS.
[0200] Heparinised (10 units/ml) human blood was obtained from
volunteers. 160 .mu.l whole blood was added to 96 well round-bottom
plates (Corning 3799). Compounds were solubilised in DMSO at a
concentration of 10 mM, diluted 1:100 in "culture medium" [RPMI
1640 medium (Sigma) containing 50 units/ml penicillin, 50 .mu.g/ml
streptomycin and 2 mM glutamine] and subsequently serial dilutions
were made in culture medium containing 1% DMSO. 20 .mu.l of each
test concentration was added to appropriate wells (triplicate
cultures)(final concentration dose range of 10 .mu.M-0.0001 .mu.M).
20 .mu.l of RPMI culture medium containing 1% DMSO was added to
control wells.
[0201] Plates were incubated for 30 minutes at 37.degree. C.
(humidified incubator), prior to addition of 20 .mu.l LPS (final
concentration 10 .mu.g/ml). Culture medium was added to control
wells. Six "LPS alone" and six "medium alone" controls were
included on each plate. A known TNF.alpha. synthesis/secretion
inhibitor was included in each test. Plates were incubated for 6
hours at 37.degree. C. (humidified incubator). Plates were
centrifuged (2000 rpm for 10 minutes) and 80 .mu.l plasma removed
and stored at -80.degree. C. (Corning 3799 plates). TNF.alpha.
levels were measured by ELISA using paired antibodies from R&D
Systems (catalogue nos. MAB610 and BAF210).
In Vivo Assessment
[0202] The ability of a test compound to inhibit TNF.alpha.
synthesis in vivo was assessed in a rat lipopolysaccharide
(LPS)-challenge model. Briefly, compound was dosed orally (100-0.3
mg/kg in 20% DMSO (Sigma D-2650)/60% PEG 400 (Fisher Scientific
P/3676/08)/20% sterile de-ionised water; 5 animals per group) to
female Wistar Alderley Park (AP) rats (80-100 g) at appropriate
timepoints prior to challenge with LPS. Control animals (10 per
group) were dosed vehicle alone. LPS (LPS E. Coli 0111:B4; Sigma
L-4130) was administered intravenously (30 .mu.g in 0.2 ml sterile
physiological saline (Phoenix Pharma Ltd). A control group were
challenged with 0.2 ml sterile physiological saline. Blood was
obtained 60 minutes later from anaesthetised animals and serum
isolated after 2 hours incubation at ambient temperature (Sarstedt
serum separator 1 ml microtubes, ref 41.1500.005) and
centrifugation. Serum samples were stored at -80.degree. C. prior
to determination of TNF.alpha. content by ELISA (R&D Systems
rat TNF.alpha. Quantikine kit, catalogue no. SRTA00). % inhibition
TNF.alpha. calculated as
100-[(compound treated-saline control)/LPS control-saline
control).times.100]
Test as Anti-Arthritic Agent
[0203] Compound was tested for activity in a rat streptococcal
cell-wall-induced arthritis model (SCW) [for further information
see Carlson, R. P. and Jacobsen, P. B. (1999) Comparison of
adjuvant and streptococcal cell-wall-induced arthritis in the rat.
In In Vivo Models of Inflammation, eds Morgan, D. W. and Marshall,
L. A., Birkhauser Verlag, Basel, Switzerland].
[0204] Briefly, female Lewis rats (160-180 g) were sensitised by
intra-articular injection of 5 .mu.g streptococcal cell wall (Lee
Labs, PG-PS 100P) in 20 .mu.l sterile physiological saline into the
left ankle. Responsiveness was assessed 3 days later and animals
randomised. Arthritis was induced 21 days after sensitisation
(designated day 0) by intravenous injection of 100 .mu.g scw (in
500 .mu.l sterile physiological saline). Compound was dosed orally
(50- 1 mg/kg once daily) (4 ml/kg) either before (day-1) or after
disease onset (day+1) (10 animals per test group; vehicle 0.5%
(w/v) HPMC and 0.1% (w/v) polysorbate 80). Control animals (n=10)
received vehicle alone. "Non-induced" control animals which were
dosed with vehicle were also included (5 animals per group).
Animals were weighed on a daily basis from day-1 and ankle
diameters measured with Vernier callipers on a daily basis from
day-1. At termination on day 6, left hind limbs were removed and
fixed in 10% formalin for histological assessment.
[0205] Although the pharmacological properties of the compounds of
the Formula I vary with structural change as expected, in general a
compound of the Formula a gives over 50% inhibition of p38.alpha.
and/or p38.beta. at concentrations less than 1 .mu.M. No
physiologically unacceptable toxicity was observed at the effective
dose for compounds tested of the present invention.
[0206] The following table shows IC.sub.50 figures for a
representative selection of compounds according to the invention,
as well as for the Comparator Compound X disclosed in WO 00/07980
when tested in the above assays:
TABLE-US-00001 Example p38.alpha. (.mu.M) Human Whole Blood (.mu.M)
Comparator Compound X 4.4 >10 5[ac] 0.007 0.07 5[e] 0.01 0.52
5[y] 0.006 0.14 5[z] 0.007 0.30 8 0.059 1.8 23[a] 0.17 1.7
[0207] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises compound of
the Formula I, or a pharmaceutically-acceptable salt thereof, in
association with a pharmaceutically-acceptable diluent or
carrier.
[0208] According to a further aspect of the invention there is
provided a pharmaceutical composition for use in the treatment of
diseases mediated by cytokines which comprises compound of the
Formula I, or a pharmaceutically-acceptable salt thereof, in
association with a pharmaceutically-acceptable diluent or
carrier.
[0209] 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).
[0210] 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.
[0211] 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 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.
[0212] The size of the dose for therapeutic or prophylactic
purposes of a compound of the Formula I of the invention 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.
[0213] 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, 0.5 mg to 75 mg per 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, 0.5 mg to 30 mg per kg body weight will
generally be used. Similarly, for administration by inhalation, a
dose in the range, for example, 0.5 mg to 25 mg per kg body weight
will be used. Oral administration is however preferred,
particularly in tablet form. Typically, unit dosage forms will
contain about 1 mg to 500 mg of a compound of this invention.
[0214] According to a further aspect of the invention there is
provided a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof, for use in a method of
treatment of the human or animal body by therapy.
[0215] According to a further aspect of the invention there is
provided the use of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof, in the manufacture of a
medicament.
[0216] According to a further aspect of the invention there is
provided the use of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof, in the manufacture of a
medicament for use in the treatment of medical conditions mediated
by cytokines.
[0217] In a further aspect the present invention provides a method
of treating diseases or medical conditions mediated by cytokines
which comprises administering to a warm-blooded animal an effective
amount of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof.
[0218] In a further aspect the present invention provides a method
of treating a disease or medical condition mediated by cytokines
which comprises administering to a warm-blooded animal in need
thereof a cytokine inhibiting amount of a compound of the Formula
I, or a pharmaceutically-acceptable salt thereof.
[0219] In a further aspect the present invention provides a method
of treating a disease or medical condition mediated by the
production or effect of cytokines which comprises administering to
a warm-blooded animal in need thereof a cytokine inhibiting amount
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof.
[0220] In a further aspect on the invention there is provided a
method for inhibiting the production or effect of a cytokine in a
warm-blooded animal in need thereof a p38 kinase inhibiting amount
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof
[0221] In a further aspect the present invention provides the use
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof, in the manufacture of a medicament for use in the
treatment of diseases or medical conditions mediated by TNF, IL-1,
IL-6 or IL-8.
[0222] In a further aspect the present invention provides a method
of treating diseases or medical conditions mediated by TNF, IL-1,
IL-6 or IL-8 which comprises administering to a warm-blooded animal
an effective amount of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof.
[0223] In a further aspect the present invention provides the use
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof in the manufacture of a medicament for use in the
treatment of diseases or medical conditions mediated by TNF.
[0224] In a further aspect the present invention provides a method
of treating diseases or medical conditions mediated by TNF which
comprises administering to a warm-blooded animal an effective
amount of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof.
[0225] In a further aspect the present invention provides the use
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof, in the manufacture of a medicament for use in
inhibiting TNF, IL-1, IL-6 or IL-8.
[0226] In a further aspect the present invention provides a method
of inhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering
to a warm-blooded animal an effective amount of a compound of the
Formula I, or a pharmaceutically-acceptable salt thereof.
[0227] In a further aspect the present invention provides the use
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof, in the manufacture of a medicament for use in
inhibiting TNF.
[0228] In a further aspect the present invention provides a method
of inhibiting TNF which comprises administering to a warm-blooded
animal an effective amount of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof.
[0229] In a further aspect the present invention provides a
compound of the Formula I, or a pharmaceutically-acceptable salt
thereof, in the manufacture of a medicament for use in the
treatment of diseases or medical conditions mediated by p38
kinase.
[0230] In a further aspect the present invention provides a method
of treating diseases or medical conditions mediated by p38 kinase
which comprises administering to a warm-blooded animal an effective
amount of a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof.
[0231] In a further aspect the present invention provides the use
of a compound of the Formula I, or a pharmaceutically-acceptable
salt thereof, in the manufacture of a medicament for use in the
production of a p38 kinase inhibitory effect.
[0232] In a further aspect the present invention provides a method
of providing a p38 kinase inhibitory effect which comprises
administering to a warm-blooded animal an effective amount of a
compound of the Formula I, or a pharmaceutically-acceptable salt
thereof.
[0233] In a further aspect the present invention provides the use
of a compound of the Formula I, or a pharmaceutically-acceptable
thereof, in the manufacture of a medicament for use in the
treatment of rheumatoid arthritis, asthma, chronic obstructive
pulmonary disease, inflammatory bowel disease, multiple sclerosis,
AIDS, septic shock, congestive heart failure, ischaemic heart
disease or psoriasis.
[0234] In a further aspect the present invention provides a method
of treating rheumatoid arthritis, asthma, chronic obstructive
pulmonary disease, inflammatory bowel disease, multiple sclerosis,
AIDS, septic shock, congestive heart failure, ischaemic heart
disease or psoriasis which comprises administering to a
warm-blooded animal an effective amount of a compound of the
Formula I, or a pharmaceutically-acceptable salt thereof.
[0235] A compound of the Formula I may be used in combination with
other drugs and therapies used in the treatment of disease states
which would benefit from the inhibition of cytokines, in particular
TNF and IL-1. For example, a compound of the Formula I could be
used in combination with drugs and therapies used in the treatment
of rheumatoid arthritis, asthma, chronic obstructive pulmonary
disease, inflammatory bowel disease, multiple sclerosis, AIDS,
septic shock, congestive heart failure, ischaemic heart disease,
psoriasis and the other disease states mentioned earlier in this
specification.
[0236] For example, by virtue of its ability to inhibit cytokines,
a compound of the Formula I is of value in the treatment of certain
inflammatory and non-inflammatory diseases which are currently
treated with a cyclooxygenase-inhibitory non-steroidal
anti-inflammatory drug (NSAID) such as indomethacin, ketorolac,
acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam.
Co-administration of a compound of the Formula I of the present
invention with a NSAID can result in a reduction of the quantity of
the latter agent needed to produce a therapeutic effect. Thereby
the likelihood of adverse side-effects from the NSAID such as
gastrointestinal effects are reduced. Thus according to a further
feature of the invention there is provided a pharmaceutical
composition which comprises a compound of the Formula I, or a
pharmaceutically-acceptable salt thereof, in conjunction or
admixture with a cyclooxygenase inhibitory non-steroidal
anti-inflammatory agent, and a pharmaceutically-acceptable diluent
or carrier.
[0237] A compound of the Formula I may also be used with
anti-inflammatory agents such as an inhibitor of the enzyme
5-lipoxygenase.
[0238] A compound of the Formula I may also be used in the
treatment of conditions such as rheumatoid arthritis in combination
with antiarthritic agents such as gold, methotrexate, steroids and
pencillinamine, and in conditions such as osteoarthritis in
combination with steroids.
[0239] A compound of the Formula I may also be administered in
degradative diseases, for example osteoarthritis, with
chondroprotective, anti-degradative and/or reparative agents such
as Diacerhein, hyaluronic acid formulations such as Hyalan,
Rumalon, Arteparon and glucosamine salts such as Antril.
[0240] A compound of the Formula I may be used in the treatment of
asthma in combination with antiasthmatic agents such as steroids,
bronchodilators and leukotriene antagonists.
[0241] In particular, for the treatment of the inflammatory
diseases rheumatoid arthritis, psoriasis, inflammatory bowel
disease, chronic obstructive pulmonary disease, asthma and allergic
rhinitis a compound of the present invention may be combined with
agents such as TNF-.alpha. inhibitors such as anti-TNF monoclonal
antibodies (such as Remicade, CDP-870 and D.sub2.E.sub7.) and TNF
receptor immunoglobulin molecules (such as Enbrel.reg.),
non-selective COX-1/COX-2 inhibitors (such as piroxicam,
diclofenac, propionic acids such as naproxen, flubiprofen,
fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic
acid, indomethacin, sulindac, apazone, pyrazolones such as
phenylbutazone, salicylates such as aspirin), COX-2 inhibitors
(such as meloxicam, celecoxib, rofecoxib, valdecoxib and
etoricoxib) low dose methotrexate, lefunomide; ciclesonide;
hydroxychloroquine, d-penicillamine, auranofin or parenteral or
oral gold.
[0242] The present invention still further relates to the
combination of a compound of the Formula I together with a
leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor
or 5-lipoxygenase activating protein (FLAP) antagonist such as
zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175;
Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides;
2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyrans such as
Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted
2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline
compounds such as L-746,530; indole and quinoline compounds such as
MK-591, MK-886, and BAY.times.1005.
[0243] The present invention still further relates to the
combination of a compound of the Formula I together with a receptor
antagonist for leukotrienes LTB.sub4., LTC.sub4., LTD.sub4., and
LTE.sub4. selected from the group consisting of the
phenothiazin-3-ones such as L-651,392; amidino compounds such as
CGS-25019c; benzoxalamines such as ontazolast;
benzenecarboximidamides such as BIIL 284/260; and compounds such as
zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),
RG-12525, Ro-245913, iralukast (CGP 45715A), and
BAY.times.7195.
[0244] The present invention still further relates to the
combination of a compound of the Formula I together with a PDE4
inhibitor including inhibitors of the isoform PDE4D.
[0245] The present invention still further relates to the
combination of a compound of the Formula I together with a
antihistaminic H.sub 1 receptor antagonists such as cetirizine,
loratadine, desloratadine, fexofenadine, astemizole, azelastine,
and chlorpheniramine.
[0246] The present invention still further relates to the
combination of a compound of the Formula I together with a
gastroprotective H.sub2. receptor antagonist.
[0247] The present invention still further relates to the
combination of a compound of the Formula I together with an
.alpha..sub1.- and .alpha..sub2.-adrenoceptor agonist
vasoconstrictor sympathomimetic agent, such as propylhexedrine,
phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline
hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline
hydrochloride, xylometazoline hydrochloride, and
ethylnorepinephrine hydrochloride.
[0248] The present invention still further relates to the
combination of a compound of the Formula I together with
anticholinergic agents such as ipratropium bromide; tiotropium
bromide; oxitropium bromide; pirenzepine; and telenzepine.
[0249] The present invention still further relates to the
combination of a compound of the Formula I together with a
.beta..sub1.- to .beta..sub4.-adrenoceptor agonists such as
metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol,
formoterol, salmeterol, terbutaline, orciprenaline, bitolterol
mesylate, and pirbuterol; or methylxanthanines including
theophylline and aminophylline; sodium cromoglycate; or muscarinic
receptor (M1, M2, and M3) antagonist.
[0250] The present invention still further relates to the
combination of a compound of the Formula I together with an
insulin-like growth factor type I (IGF-1) mimetic.
[0251] The present invention still further relates to the
combination of a compound of the Formula I together with an inhaled
glucocorticoid with reduced systemic side effects, such as
prednisone, prednisolone, flunisolide, triamcinolone acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
and mometasone furoate.
[0252] The present invention still further relates to the
combination of a compound of the Formula I together with an
inhibitor of matrix metalloproteases (MMPs), i.e., the
stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; especially collagenase-1 (MMP-1), collagenase-2
(MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3),
stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1) and MMP-12.
[0253] The present invention still further relates to the
combination of a compound of the Formula I together with other
modulators of chemokine receptor function such as CCR1, CCR2,
CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and
CCR11 (for the C--C family); CXCR1, CXCR3, CXCR4 and CXCR5 (for the
C--X.sub.3--C family) and CX.sub.3CR1 for the C--X.sub.3--C
family.
[0254] The present invention still further relates to the
combination of a compound of the Formula I together with antiviral
agents such as Viracept, AZT, aciclovir and famciclovir, and
antisepsis compounds such as Valant.
[0255] The present invention still further relates to the
combination of a compound of the Formula I together with
cardiovascular agents such as calcium channel blockers, lipid
lowering agents such as statins, fibrates, beta-blockers, Ace
inhibitors, Angiotensin-2 receptor antagonists and platelet
aggregation inhibitors.
[0256] The present invention still further relates to the
combination of a compound of the Formula I together with CNS agents
such as antidepressants (such as sertraline), anti-Parkinsonian
drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors
such as selegine and rasagiline, comP inhibitors such as Tasmar,
A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,
Nicotine agonists, Dopamine agonists and inhibitors of neuronal
nitric oxide synthase), and anti-Alzheimer's drugs such as
donepezil, tacrine, COX-2 inhibitors, propentofylline or
metrifonate.
[0257] The present invention still further relates to the
combination of a compound of the Formula I together with (i)
tryptase inhibitors; (ii) platelet activating factor (PAF)
antagonists; (iii) interleukin converting enzyme (ICE) inhibitors;
(iv) IMPDH inhibitors; (v) adhesion molecule inhibitors including
VLA-4 antagonists; (vi) cathepsins; (vii) MAP kinase inhibitors;
(viii) glucose-6 phosphate dehydrogenase inhibitors; (ix)
kinin-B.sub1.- and B.sub2.-receptor antagonists; (x) anti-gout
agents, e.g., colchicine; (xi) xanthine oxidase inhibitors, e.g.,
allopurinol; (xii) uricosuric agents, e.g., probenecid,
sulfinpyrazone, and benzbromarone; (xiii) growth hormone
secretagogues; (xiv) transforming growth factor (TGF.beta.); (xv)
platelet-derived growth factor (PDGF); (xvi) fibroblast growth
factor, e.g., basic fibroblast growth factor (bFGF); (xvii)
granulocyte macrophage colony stimulating factor (GM-CSF); (xviii)
capsaicin cream; (xix) Tachykinin NK.sub1. and NK.sub3. receptor
antagonists selected from the group consisting of NKP-608C;
SB-233412 (talnetant); and D-441S; (xx) elastase inhibitors
selected from the group consisting of UT-77 and ZD-0892; (xxi) TNF?
converting enzyme inhibitors (TACE); (xxii) induced nitric oxide
synthase inhibitors (iNOS) or (xxiii) chemoattractant
receptor-homologous molecule expressed on TH2 cells, (CRTH2
antagonists).
[0258] A compound of the Formula I may also be used in combination
with osteoporosis agents such as roloxifene, droloxifene,
lasofoxifene or fosomax and immunosuppressant agents such as
FK-506, rapamycin, cyclosporine, azathioprine, and
methotrexate.
[0259] A compound of the Formula I may also be used in combination
with existing therapeutic agents for the treatment of
osteoarthritis. Suitable agents to be used in combination include
standard non-steroidal anti-inflammatory agents (hereinafter
NSAID's) such as piroxicam, diclofenac, propionic acids such as
naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen,
fenamates such as mefenamic acid, indomethacin, sulindac, apazone,
pyrazolones such as phenylbutazone, salicylates such as aspirin,
COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and
etoricoxib, analgesics and intraarticular therapies such as
corticosteroids and hyaluronic acids such as hyalgan and synvisc
and P2X7 receptor antagonists.
[0260] A compound of the Formula I can also be used in combination
with existing therapeutic agents for the treatment of cancer.
Suitable agents to be used in combination include:
(i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside, hydroxyurea, gemcitabine and paclitaxel
(Taxol.RTM.); antitumour antibiotics (for example anthracyclines
like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,
idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic
agents (for example vinca alkaloids like vincristine, vinblastine,
vindesine and vinorelbine and taxoids like taxol and taxotere); and
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example
tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),
oestrogen receptor down regulators (for example fulvestrant),
antiandrogens (for example bicalutamide, flutamide, nilutamide and
cyproterone acetate), LHRH antagonists or LHRH agonists (for
example goserelin, leuprorelin and buserelin), progestogens (for
example megestrol acetate), aromatase inhibitors (for example as
anastrozole, letrozole, vorazole and exemestane) and inhibitors of
5.alpha.-reductase such as finasteride; (iii) Agents which inhibit
cancer cell invasion (for example metalloproteinase inhibitors like
marimastat and inhibitors of urokinase plasminogen activator
receptor function); (iv) inhibitors of growth factor function, for
example such inhibitors include growth factor antibodies, growth
factor receptor antibodies (for example the anti-erbb2 antibody
trastuzumab [Herceptin.TM.] and the anti-erbb1 antibody cetuximab
[C225]), farnesyl transferase inhibitors, tyrosine kinase
inhibitors and serine/threonine kinase inhibitors, for example
inhibitors of the epidermal growth factor family (for example EGFR
family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, ZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), for example inhibitors of the
platelet-derived growth factor family and for example inhibitors of
the hepatocyte growth factor family; (v) antiangiogenic agents such
as those which inhibit the effects of vascular endothelial growth
factor, (for example the anti-vascular endothelial cell growth
factor antibody bevacizumab [Avastin.TM.], compounds such as those
disclosed in International Patent Applications WO97/22596, WO
97/30035, WO 97/32856 and WO 98/13354) and compounds that work by
other mechanisms (for example linomide, inhibitors of integrin
.alpha.v.beta.3 function and angiostatin); (vi) vascular damaging
agents such as Combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO00/40529, WO
00/41669, WO01/92224, WO02/04434 and WO02/08213; (vii) antisense
therapies, for example those which are directed to the targets
listed above, such as ISIS 2503, an anti-ms antisense; (viii) gene
therapy approaches, including for example approaches to replace
aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,
GDEPT (gene-directed enzyme pro-drug therapy) approaches such as
those using cytosine deaminase, thymidine kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance
to chemotherapy or radiotherapy such as multi-drug resistance gene
therapy; and (ix) immunotherapy approaches, including for example
ex-vivo and in-vivo approaches to increase the immunogenicity of
patient tumour cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell anergy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0261] If formulated as a fixed dose such combination products
employ a compound of the Formula I within the dosage range
described herein and the other pharmaceutically-active agent within
its approved dosage range. Sequential use is contemplated when a
combination formulation is inappropriate.
[0262] Although a compound of the Formula I is primarily of value
as a therapeutic agent for use in warm-blooded animals (including
man), it is also useful whenever it is required to inhibit the
effects of cytokines. Thus, it is useful as pharmacological
standard for use in the development of new biological tests and in
the search for new pharmacological agents.
[0263] The invention will now be illustrated in the following
non-limiting Example in which, unless otherwise stated:--
[0264] (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;
[0265] (ii) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids by filtration;
[0266] (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;
[0267] (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
[0268] (v) the structure of a compound of the Formula I of the
invention was confirmed by nuclear magnetic resonance (NMR) and
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
Varian Gemini 2000 spectrometer operating at a field strength of
300 MHz or a Bruker AM250 spectrometer operating at a field
strength of 250 MHz]; the following abbreviations have been used:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad;
[0269] (vi) melting points are uncorrected and were determined
using a Mettler SP62 automatic melting point apparatus or an
oil-bath apparatus; and
[0270] (vii) the following abbreviations have been used:-- [0271]
DMA N,N-dimethylacetamide [0272] DMF N,N-dimethylformamide [0273]
DCM dichloromethane [0274] DMSO dimethylsulphoxide [0275] THF
tetrahydrofuran [0276] HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0277] DIPEA N,N'-diisopropylethylamine [0278]
HOBT 1-hydroxybenzotriazole hydrate [0279] EDAC
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
EXAMPLE 1
3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide
[0280] To a solution of 4-benzyloxybenzoic acid (11.0 g, 48 mmol)
in DCM (100 mL) at 0.degree. C. was added oxalyl chloride (8.4 mL,
96 mmol) followed by DMF (two drops). The resulting mixture was
stirred at room temperature for 2 hours. The mixture was evaporated
giving a white solid which was dissolved in DCM (50 mL). The
resulting solution was added portionwise to a stirred solution of
3-amino-N-cyclopropyl-4-methylbenzamide (7.61 g, 40 mmol) and
pyridine (7.76 mL, 96 mmol) in DCM (100 mL) at 0.degree. C. The
resulting mixture was stirred at room temperature for 2 hours. The
solid was collected by filtration and washed three times with DCM
to give the title compound as a white solid (13.9 g, 87%); NMR
Spectrum: (DMSOd.sub.6) 0.60 (m, 4H), 2.25 (s, 3H), 2.84 (m, 1H),
5.20 (s, 2H), 7.14 (d, 2H), 7.39 (m, 6H), 7.63 (d, 1H), 7.79 (s,
1H), 7.97 (d, 2H), 8.37 (s, 1H), 9.82 (s, 1H); Mass Spectrum:
M+H.sup.+ 399.
[0281] The 3-amino-N-cyclopropyl-4-methylbenzamide used as starting
material was prepared as follows:--
A) To a stirred solution of 4-methyl-3 nitrobenzoyl chloride (20 g)
in methylene chloride (200 mL) at 0.degree. C. was added a mixture
of cyclopropylamine (7.62 mL) and triethylamine (28 mL). The
mixture was allowed to warm to room temperature and stirred for a
further 16 hours. The reaction mixture was evaporated in vacuo and
a saturated aqueous solution of sodium bicarbonate was added. The
precipitated solid was filtered off and washed with iso-hexane and
dried (magnesium sulphate) to give
N-cyclopropyl-4-methyl-3-nitrobenzamide as a colourless solid (22.9
g); NMR Spectrum: (DMSOd.sub.6) 0.60 (m, 2H), 0.72 (m, 2H), 2.56
(s, 3H), 2.87 (m, 1H), 7.60 (d, 1H), 8.06 (m, 1H), 8.41 (d, 1H),
8.67 (d, 1H); Mass Spectrum: M+H.sup.+ 221. B) A suspension of
N-cyclopropyl-4-methyl-3-nitrobenzamide (22.92 g) and 10% palladium
on carbon (2 g) in absolute alcohol (500 mL) was agitated under a
hydrogen atmosphere for 16 hours. The reaction mixture was filtered
through diatomaceous earth (Celite.RTM.) and the filtrate
evaporated to dryness to give the title compound as a colourless
solid (17.1 g); NMR Spectrum: (DMSOd.sub.6) 0.53 (m, 2H), 0.65 (m,
2H), 2.07 (s, 3H), 2.80 (m, 1H), 6.92 (m, 2H), 7.06 (d, 1H), 8.09
(d, 1H); Mass Spectrum: M+H.sup.+ 191.
EXAMPLE 2
[0282] Using an analogous procedure to that described in Example 1,
the appropriate starting material was reacted with oxalyl chloride
followed by 3-amino-N-cyclopropyl-4-methylbenzamide to give the
compounds described in Table 1.
TABLE-US-00002 TABLE 1 ##STR00008## R.sup.3 R.sup.4 Method Note
Benzyloxy H Ex 1 a Methoxy Benzyloxy Ex 1 b Methyl Benzyloxy Ex 1 c
Fluoro Benzyloxy Ex 1 d
Notes
[0283] a) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.86 (m,
1H), 5.22 (s, 2H), 7.25 (m, 1H), 7.42 (m, 7H), 7.62 (m, 2H), 7.83
(s, 1H), 8.41 (s, 1H), 9.99 (s, 1H); Mass Spectrum: M-H.sup.- 399.
b) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 3.86 (m,
3H), 5.22 (s, 2H), 7.17 (m, 1H), 7.41 (m, 6H), 7.63 (m, 3H), 7.79
(m, 1H), 8.37 (m, 1H), 9.86 (s, 1H); Mass Spectrum: M-H.sup.-
429.
[0284] The 4-(benzyloxy)-3-methoxybenzoic acid used as starting
material was prepared as follows:--
[0285] To a stirred solution of 4-hydroxy-3-methoxybenzoic acid (5
g, 30 mmol) in THF (15 mL) was added a solution of sodium hydroxide
(3 g) in water (37.5 mL). The resulting mixture was cooled to
0.degree. C. and a solution of benzyl chloride (4.1 mL, 34.8 mmol)
in THF (15 mL) was added. The resulting mixture was allowed to warm
to room temperature then heated to 70.degree. C. for 18 hours then
to 90.degree. C. for 4 hours. The mixture was cooled and
evaporated. The residual aqueous mixture was washed with isohexane
then acidified with 2M hydrochloric acid solution. The resulting
precipitate was collected by filtration, washed with isohexane and
dried giving the title compound (5.76 g, 74%); NMR Spectrum:
(DMSOd.sub.6) 3.83 (s, 3H), 5.19 (s, 2H), 7.14 (m, 1H), 7.40 (m,
6H), 7.55 (dd, 1H), 12.69 (m, 1H); Mass Spectrum: M-H.sup.-
257.
c) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.68 (m, 2H), 2.26 (m, 6H), 2.85 (m, 1H), 5.27 (s,
2H), 7.15 (m, 1H), 7.34 (m, 2H), 7.42 (m, 2H), 7.50 (m, 2H), 7.63
(m, 1H), 7.78 (m, 1H), 7.85 (m, 2H), 8.40 (m, 1H), 9.84 (s, 1H);
Mass Spectrum: M+H.sup.+ 415. d) The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.25
(s, 3H), 2.85 (m, 1H), 5.32 (s, 2H), 7.42 (m, 7H), 7.65 (dd, 1H),
7.83 (m, 3H), 8.41 (d, 1H), 9.97 (s, 1H)); Mass Spectrum: M+H.sup.+
419.
[0286] The 4-(benzyloxy)-3-fluorobenzoic acid used as starting
material was prepared from 4-hydroxy-3-fluorobenzoic acid using an
analogous procedure to that used to prepare
4-(benzyloxy)-3-methoxybenzoic acid; NMR Spectrum: (DMSOd.sub.6)
5.24 (s, 2H), 7.21 (m, 1H), 7.45 (m, 5H), 7.71 (m, 2H); Mass
Spectrum: M-H.sup.- 245.
EXAMPLE 3
4-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}be-
nzamide
[0287] To a solution of 4-(benzyloxy)-3-chlorobenzoic acid (1.5 g,
5.73 mmol) in DMF (11.5 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g,
11.5 mmol), hydroxybenztriazole (1.55 g, 11.5 mmol) and
N-methyl-morpholine (2.28 mL) followed by
3-amino-N-cyclopropyl-4-methylbenzamide (1.09 g, 5.73 mmol). The
resulting mixture was stirred at room temperature for 48 hours. The
mixture was evaporated. A saturated aqueous solution of potassium
carbonate was added, the resulting precipitate was collected by
filtration, washed with dilute hydrochloric acid then saturated
aqueous potassium carbonate solution, then triturated with diethyl
ether giving the title compound as a solid (2.0 g, 81%); NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.27 (s, 3H),
2.85 (m, 1H), 5.35 (s, 2H), 7.39 (m, 5H), 7.51 (m, 2H), 7.65 (m,
1H), 7.78 (m, 1H), 7.97 (m, 1H), 8.10 (m, 1H), 8.40 (m, 1H), 10.01
(s, 1H); Mass Spectrum: M+H.sup.+ 435.
[0288] The 4-(benzyloxy)-3-chlorobenzoic acid used as starting
material was prepared from 4-hydroxy-3-chlorobenzoic acid using an
analogous procedure to that used to prepare
4-(benzyloxy)-3-methoxybenzoic acid (paragraph (b) in the Notes
section of Example 2). NMR Spectrum: (DMSOd.sub.6) 5.21 (s, 2H),
7.14 (d, 1H), 7.34 (m, 1H), 7.41 (m, 2H), 7.48 (m, 2H), 7.80 (dd,
1H), 7.92 (d, 1H); Mass Spectrum: M-H.sup.- 261.
EXAMPLE 4
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide
[0289] To a stirred solution of
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (500
mg, 1.61 mmol) in DMF (2.5 mL) was added potassium carbonate (446
mg, 3.22 mmol). The resulting mixture was stirred at room
temperature for 15 minutes. 2-Chloromethyl-pyridine hydrochloride
(291 mg, 1.78 mmol) was added and the resulting mixture stirred and
heated to 50.degree. C. for 18 h. The mixture was cooled to room
temperature and saturated aqueous potassium carbonate solution (15
mL) and ethyl acetate (5 mL) were added. The resulting mixture was
stirred for 20 minutes. The solid was collected by filtration,
washed with saturated aqueous potassium carbonate solution, ethyl
acetate and isohexane and dried giving the title compound as a
solid (425 mg, 60%); NMR Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68
(m, 2H), 2.29 (s, 3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.16 (m, 2H),
7.34 (m, 2H), 7.55 (m, 1H), 7.62 (m, 1H), 7.81 (s, 1H), 7.86 (m,
1H), 7.98 (m, 2H), 8.36 (s, 1H), 8.60 (m, 1H), 10.00 (s, 1H); Mass
Spectrum: M+H.sup.+ 401.
[0290] The
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide used as
starting material was prepared as follows:--
[0291] To a stirred solution of
3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide
(11.5 g, 28.8 mmol) in methanol (250 mL) was added 10% palladium on
carbon (1.1 g) under argon. The argon atmosphere was replaced with
hydrogen (balloon) and the resulting mixture stirred at room
temperature for 18 h. The mixture was filtered through diatomaceous
earth (Celite.RTM.) and the filtrate evaporated to dryness to give
the title compound as a colourless solid (8.26 g, 92%); NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H),
2.86 (m, 1H), 6.87 (m, 2H), 7.32 (m, 1H), 7.62 (m, 1H), 7.81 (s,
1H), 7.88 (m, 2H), 8.36 (m, 1H), 9.74 (s, 1H), 10.31 (s, 1H); Mass
Spectrum: M-H.sup.- 309.
EXAMPLE 5
[0292] Using an analogous procedure to that described in Example 4,
the appropriate starting materials were reacted to give the
compounds described in Table 2.
TABLE-US-00003 TABLE 2 ##STR00009## R.sup.3 R.sup.4 Method Note H
1,3-thiazol-4-ylmethoxy Ex 4 a H pyridin-3-ylmethoxy Ex 4 b H
(5-methylisoxazol-3- Ex 4 c yl)methoxy H
(5-chloro-1,2,3-thiadiazol-4- Ex 4 d yl)methoxy H
imidazo[1,2-a]pyridin-2- Ex 4 e ylmethoxy H
(2-methyl-1,3-thiazol-4- Ex 4 f yl)methoxy H
(3,5-dimethylisoxazol-4- Ex 4 g yl)methoxy H
1,2,5-thiadiazol-3-ylmethoxy Ex 4 h H (2-carbomethoxy-furan-5- Ex 4
i yl)methoxy H (2-chloro-1,3-thiazol-5- Ex 4 j yl)methoxy
1,3-thiazol-4-ylmethoxy H Ex 4 k (2-methyl-1,3-thiazol-4- H Ex 4 1
yl)methoxy pyridin-2-ylmethoxy H Ex 4 m (3,5-dimethylisoxazol-4- H
Ex 4 n yl)methoxy 1,2,5-thiadiazol-3- H Ex 4 o ylmethoxy
(2-chloro-1,3-thiazol-5- H Ex 4 p yl)methoxy Methoxy
pyridin-2-ylmethoxy Ex 4 q Methoxy 1,3-thiazol-4-ylmethoxy Ex 4 r
Methyl pyridin-2-ylmethoxy Ex 4 s Methyl 1,3-thiazol-4-ylmethoxy Ex
4 t Methyl (2-methyl-1,3-thiazol-4- Ex 4 u yl)methoxy Methyl
(3,5-dimethylisoxazol-4- Ex 4 v yl)methoxy Methyl
1,2,5-thiadiazol-3-ylmethoxy Ex 4 w Methyl (2-carbomethoxy-furan-5-
Ex 4 x yl)methoxy Fluoro pyridin-2-ylmethoxy Ex 4 y Fluoro
(2-methyl-1,3-thiazol-4- Ex 4 z yl)methoxy Fluoro
(3,5-dimethylisoxazol-4- Ex 4 aa yl)methoxy Fluoro
1,2,5-thiadiazol-3-ylmethoxy Ex 4 ab Fluoro 1,3-thiazol-4-ylmethoxy
Ex 4 ac Fluoro imidazo[1,2-a]pyridin-2- Ex 4 ad ylmethoxy Chloro
pyridin-2-ylmethoxy Ex 4 ae Chloro 1,3-thiazol-4-ylmethoxy Ex 4 af
H 5-cyclopropyl-1,3,4- Ex 4 ag thiadiazol-2-ylmethoxy H
6-bromopyridin-2-ylmethoxy Ex 4 ah H 6-methylpyridin-2-ylmethoxy Ex
4 ai H 4-methanesulfonylbenzyloxy Ex 4 aj H
6-methoxycarbonylpyridin-2- Ex 4 ak ylmethoxy
Notes
[0293] a) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.58 (m, 2H), 0.68 (m, 2H), 2.30 (s, 3H), 2.85 (m,
1H), 5.37 (s, 2H), 7.18 (m, 2H), 7.33 (m, 1H), 7.64 (m, 1H), 7.83
(m, 2H), 7.99 (m, 2H), 8.39 (m, 1H), 9.17 (s, 1H), 9.90 (s, 1H);
Mass Spectrum: M-H.sup.- 406. b) The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m, 2H), 2.30
(s, 3H), 2.86 (m, 1H), 5.31 (s, 2H), 7.17 (m, 2H), 7.33 (m, 1H),
7.45 (m, 1H), 7.63 (m, 1H), 7.83 (s, 1H), 7.91 (m, 1H), 8.00 (min,
2H), 8.36 (m, 1H), 8.57 (m, 1H), 8.71 (m, 1H), 9.85 (s, 1H); Mass
Spectrum: M+H.sup.+ 402. c) The product gave the following data;
NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s,
3H), 2.44 (s, 3H), 2.85 (m, 1H), 5.28 (s, 2H), 6.37 (s, 1H), 7.15
(m, 2H), 7.31 (m, 1H), 7.60 (m, 1H), 7.82 (s, 1H), 7.99 (m, 2H),
8.41 (s, 1H), 10.40 (s, 1H); Mass Spectrum: M-H.sup.- 404. d) The
product gave the following data; NMR Spectrum: (DMSOd.sub.6) 0.58
(m, 2H), 0.68 (m, 2H), 2.29 (s, 3H), 2.86 (m, 1H), 5.62 (s, 2H),
7.24 (m, 2H), 7.34 (m, 1H), 7.64 (m, 1H), 7.83 (s, 1H), 8.01 (m,
2H), 8.37 (m, 1H), 9.95 (s, 1H); Mass Spectrum: M-H.sup.- 441. e)
The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.56 (m, 2H), 0.66 (m, 2H), 2.27 (s, 3H), 2.84 (m, 1H), 5.32 (s,
2H), 6.89 (m, 1H), 7.24 (m, 4H), 7.56 (m, 2H), 7.81 (s, 1H), 7.98
(m, 3H), 8.38 (m, 1H), 8.53 (m, 1H), 9.94 (s, 1H); Mass Spectrum:
M+H.sup.+ 441. f) The product gave the following data; NMR
Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.67 (m, 2H), 2.28 (s, 3H),
2.68 (s, 3H), 2.84 (m, 1H), 5.21 (s, 2H), 7.15 (m, 2H), 7.32 (m,
1H), 7.61 (m, 2H), 7.81 (s, 1H), 7.97 (d, 2H), 8.37 (m, 1H), 9.88
(s, 1H); Mass Spectrum: M+H.sup.+ 422. g) The product gave the
following data; NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m,
2H), 2.25 (s, 3H), 2.26 (m, 3H), 2.45 (s, 3H), 2.85 (m, 1H), 5.04
(s, 2H), 7.15 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.82 (s, 1H),
8.00 (d, 2H), 8.37 (m, 1H), 9.85 (s, 1H); Mass Spectrum: M+H.sup.+
420. h) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.86 (m,
1H), 5.58 (s, 2H), 7.20 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.82
(s, 1H), 8.00 (d, 2H), 8.37 (d, 1H), 9.01 (s, 1H), 9.87 (s, 1H);
Mass Spectrum: M-H.sup.- 407. i) The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m, 2H), 2.29
(s, 3H), 2.86 (m, 1H), 3.85 (s, 3H), 5.30 (s, 2H), 6.84 (d, 1H),
7.18 (d, 2H), 7.33 (m, 2H), 7.64 (m, 1H), 7.82 (s, 1H), 7.99 (d,
2H), 8.37 (m, 1H), 9.88 (s, 1); Mass Spectrum: M-H.sup.- 447. j)
The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 5.47 (s,
2H), 7.17 (d, 2H), 7.34 (d, 1H), 7.64 (d, 1H), 7.80 (m, 1H), 7.85
(m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.87 (s, 1H); Mass Spectrum:
M-H.sup.- 440. k) The product gave the following data; NMR
Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H),
2.86 (m, 1H), 5.34 (s, 2H), 7.29 (m, 1H), 7.35 (m, 1H), 7.47 (m,
1H), 7.60 (m, 1H), 7.66 (m, 2H), 7.82 (m, 2H), 8.38 (m, 1H), 9.15
(m, 1H), 9.99 (s, 1H); Mass Spectrum: M+H.sup.+ 408.
[0294] The
N-cyclopropyl-3-[(3-hydroxybenzoyl)amino]-4-methylbenzamide used as
starting material was prepared from
3-{[3-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide
using an analogous procedure to that used to prepare
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (Method
section of Example 4). The product gave the following data; NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H),
2.86 (m, 1H), 6.99 (dd, 1H), 7.37 (dd, 4H), 7.64 (dd, 1H), 7.80 (d,
1H), 8.37 (d, 1H), 9.80 (d, 2H); Mass Spectrum: M-H.sup.- 309.
l) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.58 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.67 (m, 3H), 2.86 (m,
1H), 5.22 (s, 2H), 7.27 (m, 1H), 7.35 (m, 1H), 7.46 (m, 1H), 7.58
(m, 2H), 7.65 (m, 2H), 7.81 (m, 1H), 8.38 (m, 1H), 9.99 (s, 1H);
Mass Spectrum: M+H.sup.+ 422. m) The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.29
(s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.27 (m, 1H), 7.36 (m, 2H),
7.47 (m, 1H), 7.61 (m, 4H), 7.81 (m, 1H), 7.86 (m, 1H), 8.38 (m,
1H), 8.60 (m, 1H), 9.98 (m, 1H); Mass Spectrum: M+H.sup.+ 402. n)
The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.27 (s, 3H), 2.44 (s,
3H), 2.86 (m, 1H), 5.02 (s, 2H), 6.90 (s, 1H), 7.24 (m, 1H), 7.35
(d, 1H), 7.47 (t, 1H), 7.63 (m, 2H), 7.80 (d, 1H), 8.38 (d, 1H),
9.97 (s, 1H); Mass Spectrum: M+H.sup.+ 442. o) The product gave the
following data; Mass Spectrum: M-H.sup.- 407. p) The product gave
the following data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69
(m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 5.46 (s, 2H), 7.27 (dd, 1H),
7.35 (d, 1H), 7.48 (m, 1H), 7.64 (m, 3H), 7.82 (m, 2H), 8.38 (d,
1H), 9.98 (s, 1H); Mass Spectrum: M+H.sup.+ 409. q) The product
gave the following data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H),
0.68 (m, 2H), 2.27 (s, 3H), 2.86 (m, 1H), 3.90 (s, 3H), 5.29 (s,
2H), 7.17 (d, 1H), 7.36 (m, 2H), 7.59 (m, 4H), 7.79 (m, 1H), 7.87
(m, 1H), 8.42 (m, 1H), 8.60 (m, 1H), 9.98 (s, 1H); Mass Spectrum:
M+H.sup.+ 432.
[0295] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-hydroxy-3-m-
ethoxybenzamide used as starting material was prepared from
4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methoxy-
benzamide using an analogous procedure to that used to prepare
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide
(Methods section of Example 4). The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28
(s, 3H), 2.86 (m, 1H), 3.85 (s, 3H), 6.88 (d, 1H), 7.33 (d, 1H),
7.52 (dd, 1H), 7.57 (d, 1H), 7.64 (dd, 1H), 7.79 (d, 1H), 8.36 (d,
1H), 9.63 (s, 1H), 9.74 (s, 1H); Mass Spectrum: M+H.sup.+ 341.
r) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 3.87 (s,
3H), 5.32 (s, 2H), 7.25 (d, 1H), 7.33 (m, 1H), 7.62 (m, 3H), 7.81
(m, 2H), 8.42 (m, 1H), 9.16 (m, 1H), 10.04 (s, 1H); Mass Spectrum:
M+H.sup.+ 438. s) The product gave the following data; NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H),
2.35 (s, 3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.14 (m, 1H), 7.35 (m,
2H), 7.56 (m, 2H), 7.64 (m, 2H), 7.83 (m, 4H), 8.36 (m, 1H), 8.61
(m, 1H), 9.81 (s, 1H); Mass Spectrum: M+H.sup.+ 416.
[0296] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-hydroxy-3-m-
ethylbenzamide used as starting material was prepared from
4-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-methylb-
enzamide using an analogous procedure to that used to prepare
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide
(Methods section of Example 4). The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.21
(s, 3H), 2.27 (s, 3H), 2.85 (d, 1H), 6.87 (m, 1H), 7.32 (m, 1H),
7.62 (m, 1H), 7.70 (m, 1H), 7.79 (s, 2H), 8.40 (m, 1H), 9.72 (s,
1H), 10.02 (s, 1H); Mass Spectrum: M+H.sup.+ 325.
t) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.69 (m, 2H), 2.26 (m, 6H), 2.86 (m, 1H), 5.38 (s,
2H), 7.24 (m, 1H), 7.33 (m, 1H), 7.63 (m, 1H), 7.83 (m, 4H), 8.37
(m, 1H), 9.15 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M+H.sup.+ 422.
u) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.68 (m, 2H), 2.24 (m, 6H), 2.68 (m, 3H), 2.86 (m,
1H), 5.25 (s, 2H), 7.22 (m, 1H), 7.33 (m, 1H), 7.59 (s, 1H), 7.64
(m, 1H), 7.79 (m, 1H), 7.85 (m, 2H), 8.40 (m, 1H), 9.85 (s, 1H);
Mass Spectrum: M+H.sup.+ 436. v) The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.70 (m, 2H), 2.22
(s, 3H), 2.28 (s, 6H), 2.46 (s, 3H), 2.85 (m, 1H), 5.06 (s, 2H),
7.19 (m, 1H), 7.34 (m, 1H), 7.64 (m, 1H), 7.85 (m, 3H), 8.43 (m,
1H), 9.84 (m, 1H); Mass Spectrum: M+H.sup.+ 434. w) The product
gave the following data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H),
0.68 (m, 2H), 2.27 (s, 3H), 2.31 (s, 3H), 2.85 (m, 1H), 5.60 (s,
2H), 7.20 (m, 1H), 7.33 (m, 1H), 7.63 (m, 1H), 7.79 (m, 1H), 7.86
(m, 2H), 8.41 (m, 1H), 9.03 (s, 1H), 9.87 (s, 1H); Mass Spectrum:
M+H.sup.+ 423 x) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.23 (s, 3H), 2.25 (m,
3H), 2.85 (m, 1H), 3.81 (m, 3H), 5.31 (s, 2H), 6.84 (m, 1H), 7.24
(m, 1H), 7.33 (m, 2H), 7.64 (m, 1H), 7.78 (m, 1H), 7.86 (m, 2H),
8.40 (m, 1H), 9.87 (s, 1H); Mass Spectrum: M+H.sup.+ 463. y) The
product gave the following data; NMR Spectrum: (DMSOd.sub.6) 0.57
(m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 5.41 (s, 2H),
7.38 (m, 3H), 7.56 (m, 1H), 7.64 (m, 1H), 7.84 (m, 4H), 8.40 (m,
1H), 8.61 (m, 1H), 10.04 (m, 1H); Mass Spectrum: M+H.sup.+ 420.
[0297] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-hy-
droxybenzamide used as starting material was prepared from
4-(benzyloxy)-3-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}b-
enzamide using an analogous procedure to that used to prepare
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide
(Methods section of Example 4). The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.28
(s, 3H), 2.85 (m, 1H), 7.08 (m, 1H), 7.33 (m, 1H), 7.64 (m, 1H),
7.72 (m, 1H), 7.80 (m, 2H), 8.37 (m, 1H), 9.84 (s, 1H), 10.60 (m,
1H); Mass Spectrum: M-H.sup.- 327.
z) The product gave the following data; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.67 (m, 4H), 2.85 (m,
1H), 5.31 (s, 2H), 7.35 (m, 1H), 7.48 (m, 1H), 7.65 (m, 2H), 7.80
(s, 1H), 7.86 (m, 2H), 9.99 (s, 1H); Mass Spectrum: M+H.sup.+ 440.
aa) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 6H), 2.46 (s,
3H), 2.86 (m, 1H), 5.15 (s, 2H), 7.34 (d, 1H), 7.44 (t, 1H), 7.64
(m, 1H), 7.80 (m, 1H), 7.87 (m, 2H), 8.37 (m, 1H), 9.95 (m, 1H);
Mass Spectrum: M+H.sup.+ 438. ab) The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28
(s, 3H), 2.85 (m, 1H), 5.68 (s, 2H), 7.35 (m, 1H), 7.47 (m, 1H),
7.65 (m, 1H), 7.81 (s, 1H), 7.87 (m, 2H), 8.37 (m, 1H), 9.01 (s,
1H), 9.97 (s, 1H); Mass Spectrum: M-H.sup.- 425. ac) The product
gave the following data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H),
0.69 (m, 2H), 2.28 (s, 3H), 2.86 (m, 1H), 5.44 (s, 2H), 7.34 (m,
1H), 7.50 (m, 1H), 7.65 (m, 1H), 7.79 (m, 1H), 7.86 (m, 3H), 8.37
(m, 1H), 9.16 (m, 1H), 9.94 (m, 1H); Mass Spectrum: M-H.sup.- 424.
ad) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H), 2.86 (m,
1H), 5.40 (s, 2H), 6.91 (td, 1H), 7.27 (ddd, 1H), 7.34 (m, 1H),
7.55 (t, 2H), 7.65 (dd, 1H), 7.79 (d, 1H), 7.85 (m, 2H), 8.08 (s,
1H), 8.37 (d, 1H), 8.55 (m, 1H), 9.91 (s, 1H); Mass Spectrum:
M+H.sup.+ 459 ae) The product gave the following data; NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.27 (s, 3H),
2.86 (m, 1H), 5.42 (s, 2H), 7.33 (m, 1H), 7.39 (m, 2H), 7.61 (m,
2H), 7.79 (m, 1H), 7.89 (m, 1H), 7.97 (m, 1H), 8.12 (m, 1H), 8.36
(m, 1H), 8.61 (m, 1H), 9.98 (m, 1H); Mass Spectrum: M+H.sup.+
436.
[0298] The
3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-hy-
droxybenzamide used as starting material was prepared from
4-(benzyloxy)-3-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}b-
enzamide using an analogous procedure to that used to prepare
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide
(Methods section of Example 4) except that ethyl acetate was used
as the solvent in place of methanol. The product gave the following
data; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28
(s, 3H), 2.86 (m, 1H), 7.08 (m, 1H), 7.33 (m, 1H), 7.64 (m, 1H),
7.80 (m, 2H), 8.03 (m, 1H), 8.36 (m, 1H), 9.87 (s, 1H), 10.79 (m,
1H); Mass Spectrum: M-H.sup.- 343.
af) The product gave the following data; NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.28 (s, 3H), 2.86 (m,
1H), 5.46 (s, 2H), 7.33 (d, 1H), 7.48 (d, 1H), 7.62 (dd, 1H), 7.79
(d, 1H), 7.86 (d, 1H), 7.98 (dd, 1H), 8.10 (d, 1H), 8.36 (d, 1H),
9.16 (d, 1H), 9.98 (s, 1H); Mass Spectrum: M-H.sup.- 424. ag) The
product gave the following data: NMR Spectrum: (DMSOd.sub.6) 0.57
(m, 2H), 0.68 (m, 2H), 1.04 (m, 2H), 1.23 (m, 2H), 2.33 (s, 3H),
2.85 (m, 1H), 5.68 (s, 1H), 5.77 (s, 1H), 7.20 (d, 2H), 7.34 (d,
1H), 7.64 (d, 1H), 7.80 (s, 1H), 7.98 (d, 2H), 8.41 (d, 1H), 8.42
(s, 1H), 9.90 (s, 1H); Mass Spectrum: M+H.sup.+ 449. ah) The
product gave the following data: NMR Spectrum: (DMSOd.sub.6) 0.57
(m, 2H), 0.69 (m, 2H), 2.26 (s, 3H), 2.86 (m, 1H), 5.29 (s, 2H),
7.18 (d, 2H), 7.33 (d, 1H), 7.59 (m, 1H), 7.64 (m, 2H), 7.82 (m,
2H), 8.00 (m, 2H), 8.37 (m, 1H), 9.86 (s, 1H); Mass Spectrum:
M+H.sup.+ 482. ai) The product gave the following data: NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H),
2.86 (m, 1H), 5.23 (s, 2H), 7.16 (d, 2H), 7.23 (d, 1H), 7.33 (m,
2H), 7.64 (m, 1H), 7.73 (m, 1H), 7.80 (d, 1H), 8.37 (m, 1H), 9.83
(s, 1H); Mass Spectrum: M+H.sup.+ 416. aj) The product gave the
following data: NMR Spectrum: (DMSOd.sub.6) 0.62 (m, 2H), 0.85 (m,
2H), 2.40 (s, 3H), 2.88 (m, 1H), 3.07 (s, 3H), 5.25 (s, 1H), 6.40
(s, 1H), 7.08 (d, 2H), 7.28 (m, 1H), 7.62 (d, 1H), 7.65 (d, 2H),
7.70 (s, 1H), 7.88 (d, 2H), 7.98 (d, 2H), 8.40 (s, 1H); Mass
Spectrum: M+Na.sup.+ 501. ak) The product gave the following data:
NMR Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s,
3H), 2.84 (m, 1H), 5.38 (s, 2H), 7.16 (d, 2H), 7.31 (d, 1H), 7.62
(dd, 1H), 7.69 (d, 1H), 7.98 (d, 2H), 8.35 (m, 2H), 9.09 (s, 1H),
9.82 (s, 1H); Mass spectrum: M+H.sup.+ 460.
[0299] The methyl 2-chloromethylnicotinate used as starting
material was prepared according to Chem. Ber. (1987) 120, 649.
EXAMPLE 6
N-cyclopropyl-3-({4-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-methy-
lbenzamide
[0300] To a stirred solution of
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (200
mg, 0.64 mmol) and 4-methoxy-2-hydroxymethylpyridine (500 mg, 3.6
mmol) in dry THF (25 mL) under an argon atmosphere was added
successively tributylphosphine (500 mg, 2.5 mmol) and di-isopropyl
azodicarboxylate (500 mg, 2.5 mmol). The mixture was stirred at
20.degree. C. for 16 hours, then the solvent was evaporated at
reduced pressure and the residue purified by silica column
chromatography, eluting with a gradient of 0 to 10% methanol in
ethyl acetate to give the title compound as a white solid (100 mg);
NMR Spectrum: (DMSOd.sub.6) 1.55 (m, 2H), 1.65 (m, 2H), 2.25 (s,
3H), 2.85 (m, 1H), 3.85 (s, 3H), 5.20 (s, 2H), 6.95 (dd, 1H), 7.05
(d, 1H), 7.15 (d, 2H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.80 (s, 1H),
7.95 (d, 2H), 8.35 (d, 1H), 8.40 (broad s, 1H), 9.80 (s, 1H); Mass
Spectrum: M+H.sup.+ 432.
[0301] The 4-methoxy-2-hydroxymethylpyridine used as starting
material was prepared according to J. Med. Chem. (1995) 38,
4910.
EXAMPLE 7
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,5-difluoro-4-(pyridin--
2-ylmethoxy)benzamide
[0302] A mixture of
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5-trifluorobenzamid-
e (100 mg, 0.29 mmol), 2-pyridinylmethanol (400 .mu.l) and
potassium t-butoxide (32 mg, 0.29 mmol) in NMP (600 .mu.l) was
heated in the microwave at 180.degree. C. for 1.5 hrs. The reaction
mixture was cooled and partitioned between saturated aqueous sodium
bicarbonate and ethyl acetate. The organic phase was washed with
dilute aqueous citric acid. Evaporation of the ethyl acetate gave
impure product which was purified on silica column chromatography
eluting with 0 to 100% ethyl acetate in isohexane. The solvents
were evaporated to give a residue which was dissolved in ethyl
acetate, then extracted with dilute hydrochloric acid. The aqueous
extracts were basified with saturated aqueous sodium bicarbonate
solution and then extracted with ethyl acetate to give the title
compound as a solid (29 mg, 23%); NMR Spectrum: (DMSOd.sub.6) 0.58
(m, 2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 5.36 (s, 2H),
7.37 (m, 2H), 7.64 (m, 2H), 7.84 (m, 4H), 8.40 (m, 1H), 8.56 (m,
1H), 10.14 (s, 1H); Mass Spectrum: M-H.sup.- 436.
[0303] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5-trifluo-
robenzamide used as starting material was prepared as follows:
--
To a solution of 3-amino-N-cyclopropyl-4-methylbenzamide (1.06 g,
5.58 mmol) in DMF (11 mL) was added trifluorobenzoic acid (0.983
mg, 5.58 mmol), HOBT (1.51 g, 11.2 mmol) and EDAC hydrochloride
(2.14 g, 11.2 mmol) and the resulting mixture was stirred for 16 h.
Saturated aqueous sodium bicarbonate was added and the title
compound filtered off (1.70 g, 88%).
EXAMPLE 8
N-cyclopropyl-4-methyl-3-({4-[(3-methylpyridin-2-yl)methoxy]benzoyl}amino)-
benzamide
[0304] To (3-methylpyridine-2-yl)methanol (157 mg, 1.272 mmol) in
DCM (5 mL) was added thionyl chloride (200 .mu.l) and the mixture
stirred and heated at reflux for 4 h. The mixture was evaporated to
dryness. To the residue was added
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197
mg, 0.636 mmol) and potassium carbonate (176 mg, 1.27 mmol) in
acetonitrile (5 mL) and the resulting mixture heated at 80.degree.
C. for 16 h. The reaction mixture was cooled and partitioned
between saturated aqueous sodium bicarbonate and ethyl acetate. The
organic phase was concentrated under reduced pressure.
Precipitation with DCM in diethyl ether gave the title compound as
a solid (270 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m,
2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.17
(d, 2H), 7.33 (m, 2H), 7.65 (m, 2H), 7.82 (s, 1H), 7.97 (d, 2H),
8.39 (m, 2H), 9.81 (s, 1H); Mass Spectrum: M+H.sup.+ 416.
EXAMPLE 9
N-cyclopropyl-4-methyl-3-{[4-(pyrimidin-2-ylmethoxy)benzoyl]amino}benzamid-
e
[0305] The title compound was prepared from 2-pyrimidinemethanol
and N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide
according to the method used to prepared Example 8, to give the
title compound as a solid (149 mg, 58%); NMR Spectrum: (DMSOd6)
0.56 (m, 2H), 0.67 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.37 (s,
2H), 7.09 (d, 2H), 7.31 (d, 1H), 7.47 (m, 1H), 7.61 (m, 1H), 7.78
(d, 1H), 7.93 (d, 2H), 8.35 (m, 1H), 8.83 (m, 2H), 9.80 (s, 1H);
Mass Spectrum: M+H.sup.+ 403.
EXAMPLE 10
N-cyclopropyl-4-methyl-3-{[4-(pyridazin-3-ylmethoxy)benzoyl]amino}benzamid-
e
[0306] To a solution of 3-pyridazinylmethanol (140 mg, 1.27 mmol)
in DCM (5 mL) was added thionyl chloride (103 .mu.l, 1.42 mmol) and
the resulting mixture stirred at room temperature for 4 h. The
solvent was evaporated under reduced pressure and then to the
residue in DMSO (4 mL) was added
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197
mg, 0.636 mmol), cesium carbonate (621 mg, 1.91 mmol) and
tetrabutylammonium iodide (235 mg, 0.636 mmol) and the resulting
mixture stirred at 60.degree. C. for 16 h. The reaction mixture was
added to a 20 g SCX column and product eluted with methanol.
Concentration under reduced pressure gave impure product which was
further purified on silica column chromatography eluting with 0-20%
methanol/1% ammonium hydroxide SG 0.88 in ethyl acetate.
Evaporation and trituration with DCM and diethyl ether and
filtration gave the title compound as a solid (15 mg, 5.9%); NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H),
2.86 (m, 1H), 5.54 (s, 2H), 7.21 (d, 2H), 7.34 (d, 1H), 7.64 (m,
1H), 7.79 (m, 2H), 7.86 (m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.24
(m, 1H), 9.86 (s, 1H); Mass Spectrum: M-H.sup.- 401.
EXAMPLE 11
N-cyclopropyl-3-({3-[(4-methoxypyridin-2-yl)methoxy]benzoyl}amino)-4-methy-
lbenzamide
[0307] To a stirred solution of
N-cyclopropyl-3-[(3-hydroxybenzoyl)amino]-4-methylbenzamide (200
mg, 0.65 mmol) in acetonitrile (50 mL) was added anhydrous
potassium carbonate (220 mg, 1.59 mmol) and
4-methoxy-2-chloromethyl-pyridine hydrochloride (150 mg, 0.75
mmol). The mixture was stirred at reflux for 16 hours, then
filtered and the solvent evaporated at reduced pressure to give a
gum, which was dissolved in ethyl acetate/methanol (19:1, 20 mL)
and purified by chromatography on silica, eluting with ethyl
acetate/methanol (9:1) to give the compound as a white solid (250
mg, 90%); NMR Spectrum: (CDCl.sub.3) 0.60 (m, 2H), 0.80 (m, 2H),
2.32 (s, 3H), 2.86 (m, 1H), 3.85 (s, 3H), 5.19 (s, 2H), 6.67 (s,
1H), 6.75 (dd, 1H), 7.04 (d, 1H), 7.17 (dd, 1H), 7.21 (d, 1H), 7.38
(dd, 1H), 7.48 (d, 1H), 7.54 (m, 2H), 8.02 (s, 1H), 8.14 (s, 1H),
8.40 (d, 1H); Mass spectrum: M+H.sup.+ 432.
[0308] The 4-methoxy-2-chloromethyl-pyridine hydrochloride used as
starting material was prepared according to J. Med. Chem. (1995)
38, 4913.
EXAMPLE 12
N-cyclopropyl-3-({4-[(5-hydroxypyridin-2-yl)methoxy]benzoyl}amino)-4-methy-
lbenzamide hydrobromide
[0309] To a stirred solution of
N-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)benzoyl]amin-
o}benzamide (1.0 g, 1.97 mmol) in glacial acetic acid (10 mL) was
added a solution of HBr (48% in acetic acid, 30 mL). After 6 hours
at 25.degree. C. the solution was diluted with ether (100 mL) and
the resultant precipitate filtered off and dried to give the title
compound as a pale yellow solid (610 mg, 62%); NMR Spectrum:
(DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.84 (m,
1H), 5.36 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.63 (dd, 1H),
7.78-7.84 (m, 3H), 8.00 (d, 2H), 8.36 (m, 2H), 9.86 (s, 1H); Mass
Spectrum: M+H.sup.+ 418.
[0310] The
N-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)be-
nzoyl]amino}benzamide used as starting material was prepared from
5-benzyloxypyrid-2-ylmethanol (prepared according to J. Med. Chem.
(1977), 20, 1261) and
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide
according to the procedure used to prepare
N-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}be-
nzoyl)amino]-4-methylbenzamide (Example 14).
EXAMPLE 13
N-cyclopropyl-4-methyl-3-({4-[(1-oxidopyridin-2-yl)methoxy]benzoyl}amino)b-
enzamide
[0311]
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}ben-
zamide (200 mg, 0.5 mmol) was dissolved in dichloromethane (50 mL)
and stirred while adding 3-chloroperbenzoic acid (85%, 200 mg). The
solution was stirred for one hour at 25.degree. C., then washed
twice with sodium bicarbonate solution and dried. The solvent was
evaporated to give the title compound as a white solid (120 mg);
NMR Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s,
3H), 2.84 (m, 1H), 5.35 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.42
(m, 2H), 7.60 (m, 2H), 7.78 (m, 1H), 7.99 (d, 2H), 8.36 (m, 2H),
9.84 (s, 1H); Mass Spectrum: M+H.sup.+ 418.
EXAMPLE 14
N-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}ben-
zoyl)amino]-4-methylbenzamide
[0312] To a stirred solution of
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (3.1 g,
10 mmol) in dry THF (200 mL) at 25.degree. C. was added
[5-(1,3-dioxolan-2-ylmethoxy)-pyridin-2-yl]methanol (2.4 g, 11
mmol), triphenylphosphine (2.9 g, 11 mmol) and di-tert-butyl
azodicarboxylate (2.6 g, 11 mmol). The solution was stirred for 16
hours, then the solvent was evaporated and the residue dissolved in
ethyl acetate/methanol (19:1, 50 mL) and purified by chromatography
on silica, eluting with a gradient of 5-20% methanol in ethyl
acetate, to give the title compound as a white solid (3.8 g, 76%).
NMR Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s,
3H), 2.84 (m, 1H), 3.85 (m, 2H), 3.92 (m, 2H), 4.10 (m, 2H), 5.20
(m, 3H), 7.12 (d, 2H), 7.30 (d, 1H), 7.45 (s, 2H), 7.62 (dd, 1H),
7.78 (s, 1H), 7.95 (d, 2H), 8.30 (s, 1H), 8.35 (d, 1H), 9.80 (s,
1H); Mass Spectrum: M+H.sup.+ 504.
[0313] The [5-(1,3-dioxolan-2-ylmethoxy)-pyridin-2-yl]methanol used
as starting material was prepared as follows:--
[0314] To a stirred solution of
[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methyl acetate (6.5 g,
25.7 mmol) in ethanol (100 mL) was added sodium hydroxide (1.2 g,
30 mmol) and the mixture refluxed for 1 hour. The solvent was
evaporated at reduced pressure and the residue was partitioned
between water (100 mL) and ethyl acetate (100 mL). The organic
layer was separated, dried and evaporated to give the title
compound as a solid (5.4 g, 99%); NMR Spectrum: (DMSOd.sub.6) 3.84
(m, 2H), 3.95 (m, 2H), 4.06 (m, 2H), 4.48 (d, 2H), 5.19 (t, 1H),
5.28 (broad t, 1H), 7.37 (m, 2H), 8.18 (s, 1H); Mass Spectrum:
M+H.sup.+ 212.
[0315] The [5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methyl acetate
used as starting material was prepared as follows:--
[0316] A solution of 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine
1-oxide (10 g, 47.4 mmol) in acetic anhydride (100 mL) was stirred
at reflux for 2 hours. The reaction was cooled and the solvent
evaporated at reduced pressure. The residue was purified by
chromatography on silica eluting with 50% hexane/ethyl acetate to
give an oil (6.8 g, 57%); NMR Spectrum: (CDCl.sub.3) 2.12 (s, 3H),
3.94-4.10 (m, 6H), 5.15 (s, 2H), 5.28 (t, 1H), 7.16 (m, 2H), 8.32
(d, 1H); Mass Spectrum: M+H.sup.+ 254.
[0317] The 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine 1-oxide
used as starting material was prepared as follows:--
[0318] To a stirred solution of
5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine (20 g, 0.1 mole) in
dichloromethane (200 mL) was added portionwise 3-chloroperbenzoic
acid (.about.80% peracid, 24 g, 0.11 mole) during 10 minutes. The
mixture was stirred for 1 hour, washed twice with 2N sodium
hydroxide (100 mL) and the organic layer was dried over anhydrous
magnesium sulphate. Evaporation of the solvent gave the title
compound as a white solid (15.4 g, 73%); NMR Spectrum:
(DMSOd.sub.6) 2.24 (s, 3H), 3.83 (m, 2H), 3.93 (m, 2H), 4.05 (m,
1H), 5.16 (t, 1H), 6.97 (dd, 1H), 7.34 (d, 1H), 8.08 (d, 1H); Mass
Spectrum: M+H.sup.+ 212.
[0319] The 5-(1,3-dioxolan-2-ylmethoxy)-2-methylpyridine used as
starting material was prepared as follows:--
[0320] To a stirred solution of 2-methyl-5-hydroxypyridine (16.0 g,
0.147 mole) in dry DMF (100 mL) at 25.degree. C. was added
portionwise sodium hydride (60% dispersion in oil, 6.0 g, 0.15
mole) during 10 minutes. To the mixture was added
2-bromomethyl-1,3-dioxolane (16.0 mL, 0.154 mole) and the resulting
mixture heated at 100.degree. C. for 12 hours, cooled to 25.degree.
C. and diluted with ice/water (400 g). The product was extracted
into diethyl ether (400 mL), dried over anhydrous magnesium
sulphate, and the solvent evaporated at reduced pressure to give
the title compound as an oil (25 g, 87%); NMR Spectrum:
(CDCl.sub.3) 2.50 (s, 3H), 3.94-4.04 (m, 6H), 5.27 (t, 1H), 7.05
(d, 1H), 7.15 (dd, 1H), 8.22 (d, 1H); Mass Spectrum: M+H.sup.+
196.
EXAMPLE 15
N-cyclopropyl-3-{[4-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}methoxy)benz-
oyl]amino}-4-methylbenzamide
[0321] To a stirred solution of
N-cyclopropyl-3-[(4-{[5-(1,3-dioxolan-2-ylmethoxy)pyridin-2-yl]methoxy}be-
nzoyl)amino]-4-methylbenzamide (1.0 g, 2 mmol) in methanol (20 mL)
was added hydrochloric acid (36% aqueous solution, 10 mL). After 2
hours the solution was basified by addition of 2N sodium hydroxide
(55 mL). The precipitate was filtered off and dissolved in THF (100
mL), then stirred while adding a solution of dimethylamine (2M in
THF, 2 mL, 4 mmol), titanium isopropoxide (3 mL, 10 mmol) and
sodium triacetoxyborohydride (2.2 g, 10 mmol). After 16 hours the
mixture was basified with 2N sodium hydroxide, stirred for 10
minutes and the top layer decanted. The lower layer was stirred
with THF (50 mL) and decanted again, the combined top layers were
dried over magnesium sulphate. The title compound was isolated by
chromatography on silica, eluting with a gradient of 0-30% methanol
in ethyl acetate to give a gum (120 mg); NMR Spectrum: (CDCl.sub.3)
0.60 (m, 2H), 0.83 (m, 2H), 2.32 (s, 3H), 2.40 (s, 6H), 2.82 (t,
2H), 2.90 (m, 1H), 4.17 (t, 2H), 5.20 (s, 2H), 6.60 (s, 1H), 7.06
(d, 2H), 7.26 (dd, 2H), 7.42 (d, 1H), 7.56 (d, 1H), 7.86 (d, 2H),
7.90 (s, 1H), 8.10 (s, 1H), 8.32 (s, 1H); Mass Spectrum: M+H.sup.+
489.
EXAMPLE 16
5-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2--
carboxamide
[0322] The title compound was prepared from
5-(benzyloxy)pyridine-2-carboxylic acid and
3-amino-N-cyclopropyl-4-methylbenzamide according to the method
described for Example 1; NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H),
0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.32 (s, 2H), 7.39 (m,
4H), 7.51 (m, 2H), 7.57 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.22
(m, 1H), 8.36 (m, 1H), 8.48 (s, 1H), 10.16 (s, 1H); Mass Spectrum:
M+Na.sup.+ 424.
EXAMPLE 17
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)p-
yridine-2-carboxamide
[0323] The title compound was prepared from
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-hydroxypyridine-2-car-
boxamide and 2-chloromethyl-pyridine hydrochloride according to the
method described for Example 4; NMR Spectrum: (DMSOd.sub.6) 0.58
(m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.40 (s, 2H),
7.33 (m, 1H), 7.39 (m, 1H), 7.58 (m, 2H), 7.72 (m, 1H), 7.88 (m,
1H), 8.13 (m, 1H), 8.21 (m, 1H), 8.36 (m, 1H), 8.51 (m, 1H), 8.61
(m, 1H), 10.14 (s, 1H); Mass Spectrum: M+H.sup.+ 403.
[0324] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-hydroxypyri-
dine-2-carboxamide used as starting material was prepared from
5-(benzyloxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}pyridine-2-
-carboxamide according to the method used to prepare
N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide from
3-{[4-(benzyloxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide
(methods section of Example 4).
EXAMPLE 18
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)p-
yrazine-2-carboxamide
[0325] To 2-pyridinylmethanol (300 .mu.L) was added sodium hydride
60% dispersion in oil (20 mg, 1.39 mmol) under inert atmosphere and
the mixture stirred at room temperature for 10 minutes. NMP (600
.mu.L) was then added followed by
5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-pyrazinecarb-
oxamide (100 mg, 0.303 mmol) and the resulting mixture stirred for
48 hrs. The solvent was evaporated under reduced pressure and the
residue partitioned between saturated aqueous sodium bicarbonate
and DCM. Evaporation of DCM, precipitation with diethyl ether and
isohexanes and filtration gave the title compound as a solid (25
mg, 20%); NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m, 2H),
2.31 (s, 3H), 2.86 (m, 1H), 5.59 (s, 2H), 7.36 (m, 2H), 7.55 (m,
1H), 7.62 (d, 1H), 7.86 (m, 1H), 8.08 (m, 1H), 8.37 (m, 1H), 8.58
(m, 2H), 8.89 (s, 1H), 9.76 (s, 1H); Mass Spectrum: M+H.sup.+
404.
[0326] The
5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-py-
razinecarboxamide used as starting material was prepared as
follows:--
[0327] To 5-hydroxypyrazine-2-carboxylic acid (1 g, 1.14 mmol) was
added phosphorous oxychloride (10 mL) and phosphorous pentachloride
(4.91 g). After the initial reaction had subsided the mixture was
heated to 100.degree. C. and stirred for 16 h. The mixture was
cooled and formic acid (347 mL, 9.19 mmol) was added to convert all
excess phosphorous pentachloride to phosphorous oxychloride then
the excess phosphorous oxychloride was carefully evaporated off to
give a residue which was dissolved in DCM (50 mL). Triethylamine
(10 mL) and 3-amino-N-cyclopropyl-4-methylbenzamide (1.307 g) were
added and the resulting mixture stirred at room temperature for 16
h. The solvent was evaporated under reduced pressure and the
residue purified on a 20 g silica chromatography column, eluting
with 20% methanol/1% ammonium hydroxide SG 0.88 in ethyl acetate.
The crude product was dissolved in DCM and washed with saturated
aqueous sodium bicarbonate and evaporated to dryness to give the
title compound as a solid (1.24 g, 52.6%); NMR Spectrum: (DMSOd6)
0.62 (m, 2H), 0.74 (m, 2H), 2.37 (s, 3H), 2.91 (m, 1H), 7.41 (m,
1H), 7.70 (m, 1H), 8.05 (m, 1H), 8.44 (m, 1H), 9.02 (m, 1H), 9.18
(m, 1H), 10.44 (s, 1H); Mass Spectrum: M-H- 329.
EXAMPLE 19
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-6-(pyridin-2-ylmethoxy)n-
icotinamide
[0328] To 2-pyridinylmethanol (1 mL) was added sodium hydride 60%
dispersion in oil (122 mg, 3.05 mmol) under inert atmosphere and
the resulting mixture was stirred for 10 minutes then added to a
mixture of
6-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}nicotinamide
(334 mg, 1.02 mmol) and copper (I) iodide in collidine (3 mL). The
resulting mixture was stirred at room temperature for 30 minutes
then at 100.degree. C. for 4 h. The mixture was cooled to room
temperature, ethyl acetate was added and the mixture filtered. The
filtrates were concentrated under reduced pressure and purified by
silica column chromatography eluting with 0 to 100% ethyl acetate
in isohexane. Trituration with diethyl ether gave the title
compound as a colourless solid (105.6 mg, 26%); NMR Spectrum:
(DMSOd.sub.6) 0.59 (m, 2H), 0.67-0.71 (m, 2H), 2.27 (s, 3H), 2.86
(m, 1H), 5.53 (s, 2H), 7.10 (d, 1H), 7.35 (m, 2H), 7.48 (m, 1H),
7.65 (m, 1H), 7.82 (m, 2H), 8.29 (m, 1H), 8.37 (m, 1H), 8.58 (m,
1H), 8.80 (d, 1H), 9.99 (s, 1H); Mass Spectrum: M+H.sup.+ 403.
[0329] The
6-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}nicot-
inamide used as starting material was prepared as follows:--
[0330] To a solution of 6-chloronicotinyl chloride (7.5 g, 42.61
mmol) in DCM (125 mL) cooled in ice was added a mixture of
3-amino-N-cyclopropyl-4-methylbenzamide (5 g, 26.31 mmol) and
triethylamine (11.30 mL, 81.07 mmol) in DCM (125 mL). The resulting
mixture was stirred for 16 h at room temperature. The mixture was
concentrated under reduced pressure and the residue partitioned
between DCM and saturated aqueous potassium carbonate solution. The
organic phase was concentrated under reduced pressure and the
residue triturated with diethyl ether and isohexane and filtered to
give the title compound as a solid (10.56 g); NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.85 (m,
1H), 7.36 (m, 1H), 7.70 (m, 2H), 7.83 (s, 1H), 8.38 (m, 2H), 8.98
(s, 1H), 10.24 (s, 1H); Mass Spectrum: M-H- 328.
EXAMPLE 20
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(pyridin-2-ylmethoxy)p-
yrimidine-5-carboxamide
[0331] To a solution of 2-pyridinylmethanol (258 .mu.l, 2.67 mmol)
in THF (50 mL) cooled in ice bath to 0.degree. C. was added
dropwise lithium hexamethyldisilazide (1M solution in THF, 2.67 mL,
2.67 mmol) and the resulting mixture stirred for 30 minutes at
0.degree. C.
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrim-
idine-5-carboxamide (1 g, 2.67 mmol) was added and the resulting
mixture stirred for 16 h at room temperature. The reaction mixture
was concentrated under reduced pressure and the residue partitioned
between water and DCM. Concentration of the organic phase under
reduced pressure and crystallisation from acetonitrile gave the
title compound as a colourless solid (132 mg, 12%); NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.30 (s, 3H), 2.86 (m,
1H), 5.61 (s, 2H), 7.36 (m, 2H), 7.49 (m, 1H), 7.66 (m, 1H), 7.85
(m, 2H), 8.38 (m, 1H), 8.58 (m, 1H), 9.16 (s, 2H), 10.16 (s, 1H);
Mass Spectrum: M+H.sup.+ 404.
[0332] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulf-
onyl)pyrimidine-5-carboxamide used as starting material was
prepared as follows:--
[0333] To a mixture of
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylthio)pyrimidin-
e-5-carboxamide (3.04 g, 8.82 mmol) in methanol (160 mL) cooled in
ice bath to 0.degree. C. was added slowly a solution of Oxone.RTM.
(11.93 g, 19.40 mmol) in water (57 mL) maintaining temperature
below 10.degree. C. and the resulting mixture stirred for 16 hrs at
room temperature. The methanol was evaporated and the residue
partitioned between water and ethyl acetate. The organic phase was
washed with brine and concentrated under reduced pressure to give
the title compound as a solid (2.385 g, 72%); NMR Spectrum:
(DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m, 2H), 2.33 (s, 3H), 2.86 (m,
1H), 3.49 (s, 3H), 7.38 (d, 1H), 7.69 (m, 1H), 7.92 (s, 1H), 8.42
(m, 1H), 9.54 (s, 2H), 10.56 (s, 1H); Mass Spectrum: M-H.sup.-
373.
[0334] The
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylthio-
)pyrimidine-5-carboxamide used as starting material was prepared as
follows:--
[0335] To a solution of 2-(methylthio)pyrimidine-5-carboxylic acid
(1.50 g, 8.82 mmol) and 3-amino-N-cyclopropyl-4-methylbenzamide
(1.68 g, 8.82 mmol) in DMF (7.5 mL) was added HATU (3.69 g, 9.70
mmol) and DIPEA (4.30 mL, 26.46 mmol) and the resulting mixture
stirred for 16 h at room temperature. Saturated aqueous sodium
bicarbonate was added and the mixture extracted with ethyl acetate,
washed with brine and concentrated under reduced pressure to give
the title compound as a solid (3.04 g, 100%); NMR Spectrum:
(DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.60 (s,
3H), 2.86 (m, 1H), 7.36 (m, 1H), 7.65 (m, 1H), 7.85 (m, 1H), 8.39
(m, 1H), 9.12 (s, 2H), 10.18 (m, 1H); Mass Spectrum: M-H.sup.-
341.
[0336] The 2-(methylthio)pyrimidine-5-carboxylic acid used as
starting material was prepared as follows:--
[0337] To a solution of ethyl
2-(methylthio)-5-pyrimidinecarboxylate (2.68 g, 13.53 mmol) in
ethanol (18.6 mL) was added potassium hydroxide (1.304 g, 23.28
mmol) and the resulting mixture stirred for 20 minutes at room
temperature. The solvent was evaporated under reduced pressure and
the residue partitioned between water and diethyl ether. The
aqueous phase was then acidified with dilute aqueous hydrochloric
acid and the resulting solid filtered off to give the title
compound as a solid (1.96 g, 85.2%); NMR Spectrum: (DMSOd.sub.6)
2.58 (m, 3H), 9.01 (s, 2H), 13.54 (m, 1H).
[0338] The ethyl 2-(methylthio)-5-pyrimidinecarboxylate used as
starting material was prepared as follows:--
[0339] To a solution of ethyl
4-chloro-2-methylthiopyrimidine-5-carboxylate (5 g, 21.49 mmol) in
THF (25 mL) was carefully added zinc powder (4.213 g, 64.46 mmol)
and the resulting mixture heated to reflux. Glacial acetic acid
(1.23 mL, 21.49 mmol) was added and the reaction mixture stirred
and heated for 6 h. The mixture was cooled and filtered through
diatomaceous earth (Celite.RTM.) and the filtrate evaporated to
dryness to give a solid residue which was triturated with DCM and
isohexane. The filtrate was evaporated to dryness to give the title
compound as a solid (2.68 g, 63%); NMR Spectrum: (DMSOd.sub.6) 1.33
(t, 3H), 2.59 (s, 3H), 4.35 (q, 2H), 9.03 (s, 2H).
EXAMPLE 21
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(imidazo[1,2-a]pyridin-
-2-ylmethoxy)pyrimidine-5-carboxamide
[0340] A mixture of
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrim-
idine-5-carboxamide (120 mg, 0.32 mmol),
imidazo[1,2-a]pyridine-2-methanol (48 mg, 0.32 mmol) and potassium
carbonate (44 mg, 0.32 mmol) in THF (5 mL) was heated to 67.degree.
C. for 3.5 h. The mixture was cooled to room temperature and
partitioned between DCM and water and the layers separated. The
aqueous layer was extracted with DCM and the combined organic
extracts dried (MgSO.sub.4), filtered and concentrated at reduced
pressure to give a yellow oil. This material was purified by silica
column chromatography, eluting with a gradient of 0 to 8% methanol
in DCM to give the title compound as a white solid (33 mg, 23%);
NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.67 (m, 2H), 2.27 (s,
3H), 2.83 (m, 1H), 5.70 (s, 2H), 7.26 (t, 1H), 7.35 (d, 1H), 7.66
(m, 2H), 7.78 (d, 1H), 7.83 (d, 1H), 8.30 (s, 1H), 8.38 (d, 1H),
8.75 (d, 1H), 9.17 (s, 2H), 10.16 (s, 1H); Mass Spectrum: M-H.sup.-
441, M+H.sup.+ 443.
[0341] The imidazo[1,2-a]pyridine-2-methanol used as starting
material was prepared as follows:--
[0342] To a mixture of imidazo[1,2-a]pyridine-2-carboxylic acid
ethyl ester (500 mg, 2.63 mmol) in THF (10 mL) at 5.degree. C. was
added 1M LiAlH.sub.4 in THF (2.63 mL, 2.63 mmol) dropwise under
argon. The mixture was stirred at 5.degree. C. for 1 h and then
quenched by the addition of ethyl acetate (5 mL) and stirred for a
further 15 min. The mixture was partitioned between DCM and water
and the layers separated. The organic layer was washed with brine,
dried (MgSO.sub.4), filtered and concentrated at reduced pressure
to give a yellow oil. This material was purified by silica column
chromatography, eluting with a gradient of 0 to 10% methanol in DCM
to give the title compound as a colourless oil (130 mg, 33%); NMR
Spectrum: (CDCl.sub.3); 3.30 (br s, 1H), 4.85 (s, 2H), 6.77 (t,
1H), 7.16 (1H, dt), 7.54 (1H, s), 7.57 (1H, s), 8.08 (d, 1H).
EXAMPLE 22
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(1,3-thiazol-4-ylmetho-
xy)pyrimidine-5-carboxamide
[0343] To a solution of thiazole-4-methanol (79 mg) in THF (1 mL)
at 0.degree. C. under argon was added 1M lithium
bis(trimethylsilyl)amide in THF (0.35 mL). After 30 minutes
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrim-
idine-5-carboxamide (127 mg, 0.34 mmol) in THF (3 mL) was added and
the reaction warmed to room temperature and stirred for 5 hours.
The reaction mixture was partitioned between ethyl acetate and
water, the organic phases washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified by
flash chromatography on a 12 g silica cartridge eluting with a
gradient of 0 to 5% Methanol/DCM to give the title compound as a
solid (31 mg, 23%); NMR Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.69
(m, 2H), 2.29 (s, 3H), 2.85 (m, 1H), 5.63 (s, 2H), 7.36, (d, 1H)
7.67 (dd, 1H), 7.83 (dd, 2H), 8.49 (d, 1H), 9.14 (m, 2H), 10.14 (s,
1H); Mass Spectrum: M+H.sup.+ 410.
[0344] The thiazole-4-methanol used as a starting material was
prepared as follows:--
[0345] Lithium aluminium hydride (1M solution THF, 1.5 mL) was
added slowly to a stirred solution of ethyl thiazole-4-carboxylate
(224 mg) in THF (4 mL) cooled to 0.degree. C. The reaction mixture
was stirred and allowed to warm to room temperature over 1 hour.
Ethyl acetate (20 mL) was added to the reaction mixture followed by
water (1 mL), 2M NaOH solution (2 mL) then water (3 mL). A
precipitate formed which was filtered off through Celite.RTM.. The
filtrate was concentrated to give the title compound (150 mg, 92%);
NMR Spectrum: (DMSOd.sub.6) 4.12 (s, 2H), 7.47 (s, 1H), 9.03 (s,
1H).
EXAMPLE 23
[0346] Using an analogous procedure to that described in Example
22, the appropriate starting material was reacted with
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrim-
idine-5-carboxamide to give the compounds described in Table 3.
TABLE-US-00004 TABLE 3 ##STR00010## R.sup.4 Method Note
thiazol-2-ylmethoxy Ex 22 a pyrimidin-2-ylmethoxy Ex 22 b
(1-methyl-1H-imidazol-2-yl)methoxy Ex 22 c
(1,5-dimethyl-1H-pyrazol-3-yl)methoxy Ex 22 d
(1,3-dimethyl-1H-pyrazol-5-yl)methoxy Ex 22 e
(3-methylpyridin-2-yl)methoxy Ex 22 f
(1-methyl-1H-benzimidazol-2-yl)methoxy Ex 22 g
isoquinolin-1-ylmethoxy Ex 22 h quinolin-2-ylmethoxy Ex 22 i
1,3-benzothiazol-2-ylmethoxy Ex 22 j 1-(2-pyridinyl)ethoxy Ex 22
k
Notes
[0347] a) The product gave the following data: Mass Spectrum:
M+H.sup.+ 410. b) The product gave the following data: NMR
Spectrum: (DMSOd.sub.6) 0.50 (m, 2H), 0.61 (m, 2H), 2.23 (s, 3H),
2.50 (s, 3H), 2.78 (m, 1H), 3.27 (s, 1H), 5.65 (s, 2H), 7.27 (d,
1H), 7.37 (t, 1H), 7.57 (d, 1H), 7.78 (s, 1H), 8.28 (d, 1H), 8.71
(d, 2H), 9.05 (s, 1H), 10.07 (s, 1H); Mass Spectrum: M+H.sup.+ 405.
c) The product gave the following data: Mass Spectrum: M+H.sup.+
407. d) The product gave the following data: Mass Spectrum:
M+H.sup.+ 421. e) The product gave the following data: Mass
Spectrum: M+H.sup.+ 421. f) The product gave the following data:
Mass Spectrum: M+H.sup.+ 418. g) The product gave the following
data: Mass Spectrum: M+H.sup.+ 457. h) The product gave the
following data: Mass Spectrum: M+H.sup.+ 454. i) The product gave
the following data: NMR Spectrum: (DMSOd.sub.6) 0.53 (m, 2H), 0.69
(m, 2H), 2.28 (s, 3H), 2.85 (m, 1H), 5.75 (s, 2H), 7.34, (d, 1H)
7.64 (m, 2H), 7.80 (m, 1H), 7.64 (s, 1H), 8.01 (d, 2H), 8.38 (s,
1H), 8.43 (d, 1H), 9.15 (s, 2H), 10.12 (s, 1H); Mass Spectrum:
M+H.sup.+ 421. j) The product gave the following data: NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.69 (m, 2H), 2.28 (s, 3H),
2.85 (m, 1H), 5.95 (s, 2H), 7.34, (d, 1H) 7.49 (m, 1H), 7.55 (m,
1H), 7.66 (m, 1H), 7.85 (s, 1H), 8.03 (d, 1H), 8.14 (d, 1H), 8.38
(s, 1H), 9.18 (s, 1H), 10.18 (s, 1H);
Mass Spectrum: M-H.sup.- 458.
[0348] k) The product gave the following data: Mass Spectrum:
M+H.sup.+ 418.
EXAMPLE 24
N-cyclopropyl-4-methyl-3-{[4-(1-pyridin-2-ylethoxy)benzoyl]amino}benzamide
[0349] To
3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (150
mg, 0.484 mmol) in DCM (20 mL) was added polymer supported
triphenyl phosphine (937 mg, 1.45 mmol) and the
1-pyridin-2-ylethanol (45 mg, 0.363 mmol). Diethyl azodicarboxylate
(126 mg, 0.726 mmol) was then added dropwise. The reaction was
stirred for 17 h at room temperature and was then filtered and the
filtrates were evaporated. The crude residue was purified by flash
silica chromatography using ethyl acetate in iso-hexane (5-100%) as
the eluent to give the title compound as a colourless oil (22 mg,
11%); NMR Spectrum: (DMSOd.sub.6) 0.55 (m, 2H), 0.68 (m, 2H), 1.64
(d, 3H), 2.22 (s, 3H), 2.83 (m, 1H), 5.60 (q, 1H), 7.02 (d, 2H),
7.31 (d, 2H), 7.43 (d, 1H), 7.62 (d, 1H), 7.80 (m, 2H), 7.90 (d,
2H), 8.35 (d, 1H), 8.58 (d, 1H), 9.75 (s, 1H); Mass Spectrum:
M+H.sup.+ 416.
[0350] The 1-pyridin-2-ylethanol used as starting material was
prepared as follows:--
To 1-pyridin-2-ylethanone (600 mg, 3.18 mmol) in methanol (10 mL)
was added polymer supported sodium borohydride (3.0 g, 9.92 mmol)
and the reaction was stirred at room temperature for 72 h. The
reaction was filtered and the filtrates were evaporated to give the
1-pyridin-2-ylethanol as colourless oil (630 mg, quantitative); NMR
Spectrum: (DMSOd.sub.6) 1.38 (d, 3H), 4.71 (q, 1H), 5.30 (br, 1H),
7.21 (m, 1H), 7.50 (d, 1H), 7.75 (m, 1H), 8.47 (1H, d); Mass
Spectrum: M+H.sup.+ 192.
EXAMPLE 25
N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-
-4-methylbenzamide
[0351] To a solution of methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)nicotinate (200 mg, 0.436) in THF (10 mL) was added
LiAlH.sub.4 (33 mg, 0.871 mmol). Extra THF (7 mL) was added and the
mixture was stirred for 16 h at room temperature. Glauber's salt
(Na.sub.2SO.sub.4.10H.sub.2O) (1.0 g, 3.11 mmol) was added and the
reaction was stirred for a further 16 h. The mixture was filtered
and the solid washed with methanol (40 mL). The filtrates were
evaporated and the resulting crude material was purified by SCX
cartridge to give the title compound as a white solid (150 mg,
80%); NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.67 (m, 2H), 2.25
(s, 3H), 2.85 (m, 1H), 4.56 (d, 2H), 5.28 (s, 2H), 5.59 (t, 1H),
7.15 (d, 2H), 7.34 (d, 1H), 7.51 (d, 1H), 7.64 (m, 1H), 7.79 (m,
2H), 7.97 (m, 2H), 8.37 (d, 1H), 8.55 (s, 1H), 9.83 (s, 1H); Mass
Spectrum: M+H.sup.+ 432.
EXAMPLE 26
N-cyclopropyl-3-[(4-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}benz-
oyl)amino]-4-methylbenzamide
[0352] To methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)nicotinate (300 mg, 0.654) in THF (10 mL) at 0.degree.
C. was added a 3M solution of methyl magnesium bromide in diethyl
ether (0.54 mL, 1.62 mmol) dropwise and the resulting mixture
stirred while allowing to warm to ambient temperature. After 3 h
the reaction was at room temperature and a 3M solution of methyl
magnesium bromide in diethyl ether (0.54 mL, 1.62 mmol) was added
dropwise. The reaction was stirred at room temperature for 2 h and
then a saturated aqueous solution of ammonium chloride (15 mL) was
carefully added. The mixture was extracted with DCM (3.times.20 mL)
and the organic layers were combined, filtered and the filtrates
evaporated. The resulting crude product was purified by silica
flash chromatography using ethyl acetate as the eluent to give a
mixture of the product and the corresponding methyl ketone. This
was dissolved in DCM (5 mL) and polymer supported tosyl hydrazine
(400 mg, 1.07 mmol) and acetic acid (1 drop) were added. After
stirring for 16 h at room temperature the reaction had MP carbonate
(275 mg, 0.751 mmol) added and was stirred for 30 minutes at room
temperature. The mixture was filtered and the solid washed with
methanol. The filtrates and washings were combined and evaporated
to give the title compound as a white solid (65 mg, 22%); NMR
Spectrum: (DMSOd.sub.6) 0.62 (m, 2H), 0.74 (m, 2H), 1.52 (s, 6H),
2.31 (s, 3H), 2.90 (m, 1H), 5.61 (s, 2H), 7.21 (d, 2H), 7.38 (d,
1H), 7.52 (d, 1H), 7.19 (d, 1H), 7.86 (s, 1H), 7.94 (m, 1H), 8.02
(d, 2H), 8.41 (d, 1H), 8.76 (d, 1H), 9.88 (s, 1H); Mass Spectrum:
M+H.sup.+ 460.
EXAMPLE 27
N-cyclopropyl-3-{[4-({5-[(dimethylamino)methyl]pyridin-2-yl}methoxy)benzoy-
l]amino}-4-methylbenzamide
[0353] To
N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benz-
oyl)amino]-4-methylbenzamide (100 mg, 0.232 mmol) in DCM (10 mL)
was added Dess-Martin periodinane (197 mg, 0.464 mmol) and the
reaction was stirred at room temperature for 3 h. The reaction was
diluted with DCM (40 mL), washed with 2N NaOH (3.times.15 mL) and
then a saturated brine solution (20 mL). The DCM solution of the
aldehyde was dried with magnesium sulphate and then concentrated
under reduced pressure to approximately 10 mL. To this solution was
added dimethylamine (2M in THF, 0.13 mL, 0.260 mmol), acetic acid
(2 drops) and titanium iso-propoxide (132 mg, 0.464 mmol). The
mixture was stirred at room temperature for 1 h and then sodium
triacetoxyborohydride (123 mg, 0.580 mmol) was added. The reaction
was stirred for 18 h at room temperature. Water (4 drops) was added
and the reaction was evaporated to dryness. The residue was
purified by basic preparative HPLC to give the title compound as a
white solid (30 mg, 28%); NMR Spectrum: (DMSOd.sub.6) 0.62 (m, 2H),
0.75 (m, 2H), 2.21 (s, 6H), 2.31 (s, 3H), 2.90 (m, 1H), 3.48 (s,
2H), 5.83 (s, 2H), 7.22 (d, 2H), 7.38 (d, 1H), 7.57 (d, 1H), 7.68
(dd, 1H), 7.81 (m, 1H), 7.85 (d, 1H), 8.04 (d, 2H), 8.42 (d, 1H),
8.57 (s, 1H), 9.88 (s, 1H); Mass Spectrum: M+H.sup.+ 459.
EXAMPLE 28
N-cyclopropyl-3-{[4-({5-[(isopropylamino)methyl]pyridin-2-yl}methoxy)benzo-
yl]amino}-4-methylbenzamide
[0354] Using an analogous procedure to that described in Example
27,
N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino-
]-4-methylbenzamide was oxidised and the resulting aldehyde reacted
with isopropylamine to give the title compound; NMR Spectrum:
(DMSOd.sub.6) 0.58 (m, 2H), 0.68 (m, 2H), 1.00 (d, 6H), 2.25 (s,
3H), 2.70 (m, 1H), 2.86 (m, 1H), 3.71 (s, 2H), 5.76 (s, 2H), 7.14
(d, 2H), 7.33 (d, 1H), 7.49 (d, 1H), 7.64 (m, 1H), 7.80 (m, 2H),
7.99 (d, 2H), 8.40 (d, 1H), 8.55 (s, 1H), 9.87 (s, 1H); Mass
Spectrum: M+H.sup.+ 473.
EXAMPLE 29
N-cyclopropyl-3-[(4-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-
-4-methylbenzamide
[0355]
3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (100
mg, 0.323 mmol), [6-(bromomethyl)pyridin-2-yl]methanol (71 mg,
0.355 mmol) and potassium carbonate (49 mg, 0.355 mmol) were mixed
in acetonitrile (3 mL) and the reaction was stirred at room
temperature for 16 h. The reaction was then heated at 100.degree.
C. in the microwave for 10 mins. Water (10 mL) was added and the
mixture was extracted with DCM (3.times.15 mL). The organic layers
were combined and evaporated to give a white solid which was
triturated with DCM to give the title compound as a white solid (80
mg, 58%); NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.68 (m, 2H),
2.25 (s, 3H), 2.85 (m, 1H), 4.59 (s, 2H), 5.24 (s, 2H), 7.16 (d,
2H), 7.32 (d, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.63 (m, 1H), 7.80
(m, 2H), 7.97 (d, 2H), 8.36 (d, 1H), 9.82 (s, 1H); Mass Spectrum:
M+H.sup.+ 432.
EXAMPLE 30
Methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbon-
yl]phenoxy}methyl)pyridine-2-carboxylate
[0356]
3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (200
mg, 0.626 mmol), pyridine (164 mg, 0.710 mmol) and potassium
carbonate (98 mg, 0.710 mmol) were mixed in acetonitrile (6 mL) and
the reaction was stirred at room temperature for 16 h. The reaction
was then heated at 100.degree. C. in the microwave for 20 mins.
Water (10 mL) was added and the mixture was extracted with DCM
(3.times.20 mL). The organic layers were combined and evaporated to
give a white solid which was triturated with DCM to give the title
compound as a white solid (220 mg, 74%); NMR Spectrum:
(DMSOd.sub.6) 0.58 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.85 (m,
1H), 3.92 (s, 3H), 5.37 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.63
(m, 1H), 7.80 (m, 2H), 8.05 (m, 4H), 8.38 (d, 1H), 9.85 (s, 1H);
Mass Spectrum: M+H.sup.+ 460.
EXAMPLE 31
N-cyclopropyl-3-[(4-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methoxy}benz-
oyl)amino]-4-methylbenzamide
[0357] To methyl
6-({4-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phe-
noxy}methyl)pyridine-2-carboxylate (139 mg, 0.303 mmol) in THF (5
mL) at 0.degree. C. was added a 3M solution of methyl magnesium
bromide in diethyl ether (0.44 mL, 1.32 mmol) dropwise. The mixture
was stirred in the melting ice bath. After 3 h the reaction was at
room temperature and a 3M solution of methyl magnesium bromide in
diethyl ether (0.50 mL, 1.50 mmol) was added dropwise. The reaction
was stirred at room temperature for 72 h and then a saturated
aqueous solution of ammonium chloride (15 mL) was carefully added.
The mixture was extracted with DCM (3.times.20 mL) and the organic
layers were combined, filtered and the filtrates were evaporated.
This crude solid was dissolved in DCM (5 mL) and polymer supported
tosyl hydrazine (100 mg, 0.268 mmol) and acetic acid (2 drops) were
added and the mixture was stirred for 1 h. The reaction was
filtered and the solid washed with methanol (10 mL) and the
filtrates and washings were combined and evaporated to dryness. The
resulting crude product was purified by silica flash chromatography
using ethyl acetate in iso-hexane (50 to 100%) as the eluent to
give the title compound as a white solid (47 mg, 34%); NMR
Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H), 1.46 (s, 6H),
2.25 (s, 3H), 2.85 (m, 1H), 5.27 (s, 2H), 7.17 (d, 2H), 7.32 (d,
1H), 7.38 (d, 1H), 7.62 (m, 2H), 7.81 (m, 2H), 7.97 (d, 2H), 8.35
(d, 1H), 9.81 (s, 1H); Mass Spectrum: M+H.sup.+ 460.
EXAMPLE 32
N-cyclopropyl-3-({4-[(6-{[2-(diethylamino)ethoxy]methyl}pyridin-2-yl)metho-
xy]benzoyl}amino)-4-methylbenzamide
[0358] To a 60% dispersion of NaH in mineral oil (25 mg, 0.625
mmol) in DMA (4 mL) was added N,N-diethylethanolamine (24 mg, 0.205
mmol). The reaction was stirred at room temperature for 20 minutes.
A solution of
3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl--
4-methylbenzamide (77 mg, 0.155 mmol) in DMA (2 mL) was added
dropwise to the reaction which was then stirred for 1 h at room
temperature. The reaction was quenched by the addition of water (1
mL) and was purified by preparative HPLC to give the title compound
as a white solid (29 mg, 35%); NMR Spectrum: (DMSOd.sub.6) 0.58 (m,
2H), 0.69 (m, 2H), 0.96 (t, 6H), 2.26 (s, 3H), 2.50 (m, 4H), 2.64
(t, 2H), 2.86 (m, 1H), 3.59 (t, 2H), 4.59 (s, 2H), 5.75 (s, 2H),
7.18 (d, 2H), 7.33 (d, 1H), 7.42 (m, 2H), 7.64 (dd, 1H), 7.80 (s,
1H), 7.87 (t, 1H), 7.96 (d, 2H), 8.36 (d, 1H), 9.83 (s, 1H); Mass
Spectrum: M+H.sup.+ 531.
[0359] The
3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cy-
clopropyl-4-methylbenzamide used as starting material was prepared
as follows:--
[0360] To
3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (1.50
g, 4.84 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in
refluxing acetonitrile (20 mL) was added a solution of
2,6-bis(bromomethyl)pyridine (5.13 g, 19.4 mmol) in acetonitrile
(10 mL) over 25 mins. The reaction was cooled to room temperature
and water (20 mL) was added. The mixture was extracted with DCM
(3.times.30 mL) and the organic layers were combine and evaporated
to leave a solid which was triturated with hot ethyl acetate to
give
3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl--
4-methylbenzamide as a white solid (1.449 g, 61%); NMR Spectrum:
(DMSOd.sub.6) 0.58 (m, 2H), 0.70 (m, 2H), 2.27 (s, 3H), 2.85 (m,
1H), 4.73 (s, 2H), 5.30 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.49
(d, 1H), 7.55 (d, 1H), 7.65 (d, 1H), 7.81 (s, 1H), 7.90 (t, 1H)
7.98 (d, 2H), 8.38 (d, 1H), 9.85 (s, 1H); Mass Spectrum: M+H.sup.+
494, 496 Br pattern.
EXAMPLE 33
N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethoxy]methyl}pyridin-2-yl)meth-
oxy]benzoyl}amino)-4-methylbenzamide
[0361] Using an analogous procedure to that described in Example
32, 2-dimethylaminoethanol was reacted with
3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl--
4-methylbenzamide to give the title compound; NMR Spectrum:
(DMSOd.sub.6) 0.58 (m, 2H), 0.69 (m, 2H), 2.19 (s, 6H), 2.26 (s,
3H), 2.50 (m, 2H), 2.86 (m, 1H), 3.62 (t, 2H), 4.60 (s, 2H), 5.28
(s, 2H), 7.18 (d, 2H), 7.34 (d, 1H), 7.41 (d, 1H), 7.46 (d, 1H),
7.63 (d, 1H), 7.80 (s, 1H), 7.89 (t, 1H), 7.98 (d, 2H), 8.37 (d,
1H), 9.83 (s, 1H); Mass Spectrum: M+H.sup.+ 503.
EXAMPLE 34
N-cyclopropyl-3-{[4-({6-[(2-methoxyethyl)amino]pyridin-2-yl}methoxy)benzoy-
l]amino}-4-methylbenzamide
[0362] A mixture of
N-cyclopropyl-4-methyl-3-({4-[(6-bromo-2-pyridinyl)methoxy]benzoyl}amino)-
benzamide (100 mg, 0.21 mmol), 2-methoxyethylamine (500 .mu.L) and
NMP (500 .mu.L) was heated to 190.degree. C. in the microwave for
90 min. The cooled reaction mixture was eluted through a silica
cartridge with isohexane then ethyl acetate to give the crude
product which was triturated with diethyl ether to give the title
compound as a solid (36 mg); NMR Spectrum: (DMSOd.sub.6) 0.57 (m,
2H), 0.68 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 3.28 (m, 2H), 3.31
(m, 3H), 5.08 (s, 2H), 6.47 (d, 1H), 6.61 (d, 2H), 7.14 (d, 2H),
7.32 (m, 2H), 7.40 (m, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (m,
2H), 8.37 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M+H.sup.+475.
EXAMPLE 35
N-cyclopropyl-3-({4-[(6-{[2-(dimethylamino)ethyl]amino}pyridin-2-yl)methox-
y]benzoyl}amino)-4-methylbenzamide
[0363] Using an analogous procedure to that described in Example
34, 2-dimethylaminoethylamine was reacted with
N-cyclopropyl-4-methyl-3-({4-[(6-bromo-2-pyridinyl)methoxy]benzoyl}amino)-
benzamide to give the title compound; NMR Spectrum: (DMSOd.sub.6)
0.57 (m, 2H), 0.69 (m, 2H), 2.16 (s, 2H), 2.22 (s, 6H), 2.27 (s,
3H), 2.43 (t, 2H), 2.86 (m, 1H), 5.07 (s, 2H), 6.38 (t, 1H), 6.44
(d, 1H), 6.60 (d, 1H), 7.13 (d, 2H), 7.63 (m, 1H), 7.82 (s, 1H),
7.97 (d, 2H), 8.36 (m, 1H), 9.83 (s, 1H); Mass Spectrum: M+H.sup.+
488.
EXAMPLE 36
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino-
)benzamide hydrochloride
[0364] To a solution of
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amin-
o)benzamide (20 mg, 0.05 mmol) in 1:1 DCM and methanol (2.0 mL) was
added hydrochloric acid (0.05 mmol). The solvent was evaporated to
give the title compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H),
0.68 (m, 2H), 2.26 (s, 3H), 2.44 (s, 3H), 2.85 (m, 1H), 5.25 (s,
2H), 6.37 (s, 1H), 7.15 (m, 2H), 7.31 (m, 1H), 7.61 (m, 1H), 7.78
(s, 1H), 7.98 (m, 2H), 8.37 (s, 1H), 9.82 (s, 1H); Mass Spectrum:
M-H.sup.- 404, M+Na.sup.+ 428.
EXAMPLE 37
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino-
)benzamide hydrobromide
[0365] Using an analogous procedure to that described in Example
36,
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amin-
o)benzamide was reacted with hydrobromic acid to give the title
compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H),
2.26 (s, 3H), 2.44 (s, 3H), 2.85 (m, 1H), 5.25 (s, 2H), 6.37 (s,
1H), 7.15 (m, 2H), 7.31 (m, 1H), 7.61 (m, 1H), 7.78 (s, 1H), 7.98
(m, 2H), 8.37 (s, 1H), 9.82 (s, 1H); Mass Spectrum: M-H.sup.- 404,
M+Na.sup.+ 428.
EXAMPLE 38
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amino-
)benzamide methanesulfonate
[0366] Using an analogous procedure to that described in Example
36,
N-cyclopropyl-4-methyl-3-({4-[(5-methylisoxazol-3-yl)methoxy]benzoyl}amin-
o)benzamide was reacted with methanesulfonic acid to give the title
compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m, 2H),
2.26 (s, 3H), 2.44 (s, 3H), 2.52 (s, 3H), 2.85 (m, 1H), 5.25 (s,
2H), 6.37 (s, 1H), 7.15 (m, 2H), 7.31 (m, 1H), 7.61 (m, 1H), 7.78
(s, 1H), 7.98 (m, 2H), 8.37 (s, 1H), 9.82 (s, 1H), 12.12 (br s,
1H); Mass Spectrum: M-H.sup.- 404, M+Na.sup.+ 428.
EXAMPLE 39
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide
hydrochloride
[0367] Using an analogous procedure to that described in Example
36,
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide
was reacted with hydrochloric acid to give the title compound; NMR
Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H),
2.86 (m, 1H), 5.44 (s, 2H), 7.18 (d, 2H), 7.32 (m, 1H), 7.65 (m,
2H), 7.81 (m, 2H), 7.98 (d, 2H), 8.19 (m, 1H), 8.36 (m, 1H), 8.73
(m, 1H), 9.85 (s, 1H); Mass Spectrum: M+H.sup.+ 401.
EXAMPLE 40
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide
sulfate
[0368] Using an analogous procedure to that described in Example
36,
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide
was reacted with sulfonic acid to give the title compound; NMR
Spectrum: (DMSOd.sub.6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H),
2.86 (m, 1H), 5.46 (s, 2H), 7.18 (d, 2H), 7.32 (m, 1H), 7.62 (m,
1H), 7.75 (m, 2H), 7.89 (m, 1H), 7.99 (d, 2H), 8.36 (m, 2H), 8.80
(m, 1H), 9.85 (s, 1H); Mass Spectrum: M+H.sup.+ 401.
EXAMPLE 41
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-yl-
methoxy)benzamide hydrochloride
[0369] Using an analogous procedure to that described in Example
36,
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-y-
lmethoxy)benzamide was reacted with hydrochloric acid to give the
title compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m,
2H), 2.28 (s, 3H), 2.86 (m, 1H), 5.60 (s, 2H), 7.32 (m, 1H), 7.43
(m, 1H), 7.66 (m, 1H), 7.84 (m, 5H), 8.40 (m, 2H), 8.83 (m, 1H),
10.07 (br s, 1H); Mass Spectrum: M+H.sup.+ 420.
EXAMPLE 42
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-yl-
methoxy)benzamide hydrobromide
[0370] Using an analogous procedure to that described in Example
36,
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-y-
lmethoxy)benzamide was reacted with hydrobromic acid to give the
title compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68 (m,
2H), 2.25 (s, 3H), 2.86 (m, 1H), 5.48 (s, 2H), 7.32 (m, 1H), 7.42
(m, 1H), 7.64 (m, 2H), 7.82 (m, 4H), 8.17 (m, 1H), 8.37 (m, 1H),
8.75 (m, 1H), 9.92 (s, 1H); Mass Spectrum: M+H.sup.+ 420.
EXAMPLE 43
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-yl-
methoxy)benzamide methanesulfonate
[0371] Using an analogous procedure to that described in Example
36,
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-fluoro-4-(pyridin-2-y-
lmethoxy)benzamide was reacted with methanesulfonic acid to give
the title compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m, 2H), 0.68
(m, 2H), 2.25 (s, 3H), 2.40 (s, 3H), 2.86 (m, 1H), 5.51 (s, 2H),
7.32 (m, 1H), 7.42 (m, 1H), 7.63 (m, 1H), 7.73 (m, 1H), 7.78 (s,
1H), 7.86 (m, 3H), 8.25 (m, 1H), 8.37 (m, 1H), 8.78 (m, 1H), 9.95
(s, 1H); Mass Spectrum: M+H.sup.+ 420.
EXAMPLE 44
2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methy-
lphenyl}pyrimidine-5-carboxamide hydrobromide
[0372] Using an analogous procedure to that described in Example
36,
2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-meth-
ylphenyl}pyrimidine-5-carboxamide was reacted with hydrobromic acid
to give the title compound; NMR Spectrum: (DMSOd.sub.6) 0.57 (m,
2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.85 (m, 1H), 5.10 (s, 2H), 7.34,
(d, 1H) 7.49 (m, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.76 (s, 1H),
7.99 (d, 1H), 8.10 (d, 1H), 8.38 (s, 1H), 9.11 (s, 2H), 9.19, (s,
1H), 10.09 (s, 1H); Mass Spectrum: M-H.sup.- 458.
EXAMPLE 45
2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-methy-
lphenyl}pyrimidine-5-carboxamide methanesulfonate
[0373] Using an analogous procedure to that described in Example
36,
2-(1,3-benzothiazol-2-ylmethoxy)-N-{5-[(cyclopropylamino)carbonyl]-2-meth-
ylphenyl}pyrimidine-5-carboxamide was reacted with methanesulfonic
acid to give the title compound; NMR Spectrum: (DMSOd.sub.6) 0.57
(m, 2H), 0.69 (m, 2H), 2.28 (s, 3H), 2.52 (s, 3H), 2.85 (m, 1H),
5.91 (s, 2H), 7.34, (d, 1H) 7.49 (m, 1H), 7.55 (m, 1H), 7.66 (m,
1H), 7.76 (s, 1H), 7.99 (d, 1H), 8.10 (d, 1H), 8.38 (s, 1H), 9.11
(s, 2H), 9.17, (s, 1H), 10.17 (s, 1H), 10.78 (br s, 1H); Mass
Spectrum: M-H.sup.- 458.
EXAMPLE 46
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)p-
yridine-2-carboxamide hydrobromide
[0374] Using an analogous procedure to that described in Example
36,
N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(pyridin-2-ylmethoxy)-
pyridine-2-carboxamide was reacted with hydrobromic acid to give
the title compound; NMR Spectrum: (DMSOd.sub.6) 0.58 (m, 2H), 0.69
(m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.49 (s, 2H), 7.33 (m, 1H),
7.58 (m, 1H), 7.76 (m, 2H), 7.95 (m, 1H), 8.15 (m, 2H), 8.34 (m,
2H), 8.53 (m, 1H), 8.82 (m, 1H), 10.13 (s, 1H); Mass Spectrum:
M+H.sup.+ 403.
* * * * *