U.S. patent application number 09/860492 was filed with the patent office on 2002-02-07 for benzophenones as inhibitors of il-1beta and tnf-alpha.
Invention is credited to Horneman, Anne Marie.
Application Number | 20020016347 09/860492 |
Document ID | / |
Family ID | 22762771 |
Filed Date | 2002-02-07 |
United States Patent
Application |
20020016347 |
Kind Code |
A1 |
Horneman, Anne Marie |
February 7, 2002 |
Benzophenones as inhibitors of IL-1beta and TNF-alpha
Abstract
Heteroaryl aminobenzophenones of general formula I inhibit
interleukin-1.beta. and TNF-.alpha. and may therefore be useful in
the therapy of inflammatory diseases and conditions.
Inventors: |
Horneman, Anne Marie;
(Humlebaek, DK) |
Correspondence
Address: |
PILLSBURY WINTHROP LLP
1600 TYSONS BOULEVARD
MCLEAN
VA
22102
US
|
Family ID: |
22762771 |
Appl. No.: |
09/860492 |
Filed: |
May 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60205579 |
May 22, 2000 |
|
|
|
Current U.S.
Class: |
514/351 ;
514/429; 514/524; 514/646; 546/329; 546/330; 548/577; 558/415 |
Current CPC
Class: |
A61P 19/10 20180101;
C07D 473/34 20130101; C07D 277/82 20130101; A61P 27/02 20180101;
A61K 31/47 20130101; A61P 19/02 20180101; C07D 209/08 20130101;
C07D 277/58 20130101; A61P 19/06 20180101; C07D 215/40 20130101;
A61P 11/06 20180101; A61P 31/04 20180101; A61K 45/06 20130101; A61P
29/00 20180101; C07D 213/79 20130101; A61P 17/06 20180101; A61P
1/00 20180101; A61K 31/403 20130101; A61P 37/08 20180101; A61P 9/10
20180101; C07D 235/30 20130101; A61K 31/136 20130101; C07D 215/38
20130101; C07D 277/64 20130101; A61P 7/00 20180101; C07D 249/10
20130101; A61P 37/02 20180101; C07D 213/85 20130101; A61K 31/15
20130101; C07D 263/58 20130101; A61P 17/00 20180101; C07D 239/42
20130101; C07D 213/89 20130101; A61P 31/18 20180101; C07D 213/74
20130101; C07D 241/20 20130101; C07D 213/80 20130101; C07D 217/22
20130101 |
Class at
Publication: |
514/351 ;
514/524; 514/429; 514/646; 546/329; 546/330; 548/577; 558/415 |
International
Class: |
A61K 031/44; A61K
031/40; A61K 031/277; C07D 207/04; C07D 211/70 |
Claims
We claim:
1. A compound of the general formula I 37wherein R.sub.1 is
selected from the group consisting of halogen, haloalkyl, hydroxy,
hydroxyalkyl, hydroxyalkyloxy, mercapto, cyano, carboxy, nitro,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, aryl, heteroaryl, aralkyl, alkylaryl, alkoxy,
aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyloxy,
alkoxycarbonyloxy, alkylsulfonyloxy, alkyloxysulfonyl,
alkylcarbonylamino, aminocarboaminoalkyl, aminosulfonyl,
alkylsulfonylamino, alkanoyl, alkylcarbonyl, --NRgR.sub.10 or
--CONRgR.sub.10 wherein R.sub.9 and R.sub.10 are the same or
different and individually represent hydrogen, alkyl or aryl;
R.sub.2 represents one or more, same or different substituents
selected from the group consisting of hydrogen, halogen, haloalkyl,
hydroxy, hydroxyalkyl, hydroxyalkyloxy, mercapto, cyano, carboxy,
nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, aryl, heteroaryl, aralkyl, alkylaryl, alkoxy,
aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyloxy,
alkoxycarbonyloxy, alkylsulfonyloxy, alkyloxysulfonyl,
alkylcarbonylamino, aminocarboaminoalkyl, aminosulfonyl,
alkylsulfonylamino, alkanoyl, alkylcarbonyl, --NRgR.sub.10 or
--CONR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10 are the same or
different and individually represent hydrogen, alkyl or aryl;
R.sub.3 represents one or more, same or different substituents
selected from the group consisting of hydrogen, halogen, haloalkyl,
hydroxy, hydroxyalkyl, mercapto, cyano, nitro, alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, alkylaryl, alkoxy, aralkoxy,
alkylthio, alkoxycarbonyl, alkylcarbonylamino, alkylcarbonyloxy,
alkoxycarbonyloxy, alkylcarbonyl--NR.sub.9R.sub.10 or
--CONR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10 are the same or
different and individually represent hydrogen, alkyl or aryl;
R.sub.4 represents hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl,
cycloalkenyl, carboxy or aryl; R.sub.5 represents a heteroaromatic
mono-or bicyclic ring system comprising 1-4heteroatoms, except for
triazine, the ring system being optionally substituted by hydrogen,
halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy,
mercapto, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl,
aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl,
alkylcarbonyloxy, alkoxycarbonyloxy, alkylsulfonyloxy,
alkyloxysulfonyl, alkylcarbonylamino, aminocarboaminoalkyl,
aminosulfonyl, alkylsulfonylamino, alkanoyl, alkylcarbonyl,
--NR.sub.9R.sub.10or --CONR.sub.9R.sub.10, wherein R.sub.9 and
R.sub.10 are the same or different and individually represent
hydrogen, alkyl or aryl; X represents oxygen, sulphur, N--OH or
NR.sub.11 wherein R.sub.11 is hydrogen or alkyl; and salts thereof
with pharmaceutically acceptable acids, hydrates and solvates, and
optionally the N-oxides thereof wherein a nitrogen atom of the
heterocyclic R.sub.5 substituent is oxidised.
2. A compound according to claim 1 wherein R.sub.1 represents a
substituent selected from the group consisting of halogen, hydroxy,
mercapto, trifluoromethyl, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl, cyano, -CONH.sub.2, phenyl, and
nitro; in particular fluoro, chloro, bromo, hydroxy,
trifluoromethyl, amino, (C.sub.1-C.sub.3)alkyl,
(C.sub.2-C.sub.3)alkenyl, (C.sub.1-C.sub.3)alkoxy- ,
(C1-C.sub.3)alkoxycarbonyl, cyano, and --CONH.sub.2.
3. A compound according to claim 1 wherein R.sub.2 represents one
or more, same or different substituents selected from the group
consisting of hydrogen, halogen, hydroxy, mercapto,
trifluoromethyl, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy- ,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl, cyano, --CONH.sub.2, phenyl, and
nitro; in particular hydrogen, fluoro, chloro, bromo, hydroxy,
trifluoromethyl, amino, (C.sub.1-C.sub.3)alkyl,
(C.sub.2-C.sub.3)alkenyl, (C.sub.1-C.sub.3)alkoxy,
(C.sub.1-C.sub.3)alkoxycarbonyl, cyano, and --CONH.sub.2.
4. A compound according to claim 1 wherein R.sub.3 represents one
or more, same or different substituents selected from the group
consisting of hydrogen, halogen, hydroxy, mercapto,
trifluoromethyl, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy- ,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl, cyano, --CONH.sub.2, phenyl, and
nitro; in particular hydrogen, fluoro, chloro, bromo, hydroxy,
trifluoromethyl, amino, (C.sub.1-C.sub.3)alkyl,
(C.sub.2-C.sub.3)alkenyl, and (C.sub.1-C.sub.3)alkoxy.
5. A compound according to claim 1 wherein R.sub.4 represents
hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.3-C.sub.6) cycloalkyl or-cycloalkenyl; in particular
hydrogen, (C.sub.1-C.sub.4)alkyl, or (C.sub.2-C.sub.4)alkenyl.
6. A compound according to claim 1 wherein R.sub.5 represents an
optionally substituted heteroaromatic ring system having one or 2
fused rings of 5 or 6 ring atoms and comprising 1 or 2 nitrogen
atoms.
7. A compound according to claim 6 wherein R.sub.5 is selected from
the group consisting of 38wherein R.sub.6 and R.sub.7 represent one
or more, same or different substituents selected from the group
consisting of hydrogen, halogen, hydroxy, mercapto,
trifluoromethyl, cyano, carboxy, carbamoyl, amino, nitro,
(C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alken- yl,
(C.sub.3-C.sub.8)cycloalkyl or --cycloalkenyl,
(C.sub.1-C.sub.10)alkox- y, (C.sub.1-C.sub.10)alkylthio,
(C.sub.1-C.sub.10)alkoxycarbonyl, and phenyl; and R.sub.8
represents hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.3-C.sub.6)cycloalkyl or
--cycloalkenyl; and wherein R.sub.5 is optionally oxidised to the
corresponding N-oxide as exemplified herein.
8. A compound according to claim 1 wherein X represents oxygen,
sulphur or NH, in particular oxygen or NH.
9. A compound according to claim 7, wherein R.sub.6 and R.sub.7
represent one or more, same or different substituents selected from
the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy,
trifluoromethyl, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, cyano, carboxy, and
--CONH.sub.2.
10. A compound according to claim 7 wherein R.sub.8 represents
hydrogen, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl, such as
allyl.
11. A compound according to claim 10 wherein R.sub.8 represents
hydrogen, methyl, ethyl, allyl, propyl, benzyl, or t-butyl.
12. A compound according to claim 2 wherein R.sub.1 represents a
substituent selected from the group consisting of fluoro, chloro,
bromo, hydroxy, methyl, and methoxy.
13. A compound according to claim 3 wherein R.sub.2 represents one
or more, same or different substituents selected from the group
consisting of hydrogen, fluoro, chloro, bromo, hydroxy,
trifluoromethyl, methyl, ethyl, and methoxy.
14. A compound according to claim 4 wherein R.sub.3 represents one
or more, same or different substituents selected from the group
consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methyl, and
methoxy.
15. A compound according to claim 5 wherein R.sub.4 represents
hydrogen, methyl, or ethyl.
16. A compound according to claim 6 wherein R.sub.5 is selected
from the group consisting of substituted or non-substituted
3-pyridyl, 2-pyridyl, 3-quinolyl, 4-isoquinolyl, 4-indolyl,
5-indolyl, 6-indolyl or 7-indolyl moieties, and the corresponding
N-oxides;
17. A compound according to claim 7 wherein R.sub.6 and R.sub.7
represents one or more, same or different substituents selected
from the group consisting of hydrogen, fluoro, chloro, bromo,
hydroxy, methyl, methoxy, cyano, and carboxy.
18. A compound according to claim 8 wherein X represents
oxygen.
19. A compound according to claim 7 wherein at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.6 and R.sub.7 represents a phenyl
group optionally substituted by hydroxy, amino, nitro, cyano,
halogen, methyl or methoxy.
20. A compound according to claim 1 wherein said halogen is
selected form the group consisting of fluoro, chloro, and
bromo.
21. A compound of the general formula Ic: 39wherein R.sub.1,
R.sub.2, R.sub.4, R.sub.5, R.sub.6 and X have the meaning specified
in formula I, and R.sub.3 represents (C.sub.1-C.sub.3)alkyl,
fluoro, chloro, bromo, methoxy, and hydroxy, and salts thereof with
pharmaceutically acceptable acids, hydrates and solvates.
22. A compound of the general formula Ic, in which R.sub.1
preferably represents methyl or halogen, and more preferably F or
Cl; R.sub.2 represents one or more substituents, preferably
hydrogen, (C.sub.1-C.sub.3)alkyl, methoxy or ethoxy, and R.sub.3
represents methyl, methoxy or chloro.
23. A compound according to claim 22 wherein R.sub.3 represents a
halogen atom.
24. A compound according to claim 23 wherein R.sub.3 represents
chlorine.
25. A compound according to formula I selected from the group
consisting of: 2-Chloro-2'-methyl-4-(4-pyridylamino)benzophenone
(Compound 101), 2-Chloro-2'-methyl-4-(2-pyridylamino)benzophenone
(Compound 102),
2-Chloro-2'-methyl-4-(5-nitro-2-pyridylamino)benzophenone (Compound
103),
4-(6-Amino-5-nitro-2-pyridylamino)-2-chloro-2'-methylbenzophenone
(Compound 104),
6-Chloro-2-(3-chloro-4-(2-methylbenzoyl)phenylamino) isonicotinic
acid (Compound 105), 4-(6-carbonitrile-2-pyridylamino)-2-chl-
oro-2'-methylbenzophenone (Compound 106),
2-Chloro-2'-methyl-4-(3-pyridyla- mino)benzophenone (Compound 107),
2-Chloro-4-(5,6-diamino-2-pyridylamino) -2'-methylbenzophenone
(Compound 108), 2-Chloro-2'-methyl-4-(3-nitro-2-py- ridyl
amino)benzophenone (Compound 109),
4-(3-Amino-2-pyridylamino)-2-chlo- ro-2'-methylbenzophenone
(Compound 110), 4-(5-Amino-2-pyridylamino)-2-chlo-
ro-2'-methylbenzophenone (Compound 111), 2-Chloro-4-(4-isoquinolyl
amino)- 2'-methylbenzophenone (Compound 114), t-Butyl
5-(3-chloro-4-(2-methylbenz- oyl)phenylamino) nicotinoate (Compound
115), 2-Chloro-2'-methyl-4-(4-methy- l-3-pyridylamino)benzophenone
(Compound 116), 2-Chloro-2'-methyl-4-(6-meth-
yl-3-pyridylamino)benzophenone (Compound 117),
4-(5-Bromo-3-pyridylamino)-- 2-chloro-2'-methylbenzophenone
(Compound 118), 4-(5-Carbonitrile-3-pyridyl-
amino)-2-chloro-2'-methylbenzophenone (Compound 119),
4-(3-Bromo-2-pyridylamino)-2-chloro-2'-methylbenzophenone (Compound
120), 2-Chloro-2'-methyl-4-(8-quinolylamino) benzophenone (Compound
121), 2-Chloro -4-(6-ethoxy-3-pyridylamino)-2'-methylbenzophenone
(Compound 122),
4(4-Bromo-3-isoquinolylamino)-2-chloro-2'-methylbenzophenone
(Compound 123),
2-Chloro-2'-methyl-4-(2-methyl-5-trifluoromethyl-3-pyridy-
lamino)benzophenone (Compound 124),
2-Chloro-2'-methyl-4-(3-quinolylamino)- benzophenone (Compound
125), 2-Chloro-4-(4-ethoxy-3-pyridylamino)-2'-methy- lbenzophenone
(Compound 126), 2-Chloro-4-(2-ethoxy-3-pyridylamino)-2'-meth-
ylbenzophenone (Compound 127),
2-Chloro-2'-methyl-4-(2-methyl-6-quinolylam- ino)benzophenone
(Compound 129), 2-Chloro-2'-methyl-4-(2-quinolylamino)ben-
zophenone (Compound 131),
2-Chloro-4-(7-chloro-4-quinolylamino)-2'-methylb- enzophenone
(Compound 130), 2-Chloro-2'-methyl-4-(4-quinolylamino)benzophe-
none(Compound 132),
2-Chloro-2'-methyl-4-(1-methyl-7-indolylamino)benzophe- none
(Compound 133),
2-Chloro-2'-methyl-4(1-methyl-5-indolylamino)benzophe- none
(Compound 134),
2-Chloro-2',5'-dimethyl-4-(4-methyl-3-pyridylamino)be- nzophenone
(Compound 135), 2-Chloro-2',5'-dimethyl-4-(4-isoquinolylamino)b-
enzophenone (Compound 136),
2-Chloro-4-(4-isoquinolylamino)-2',4',5'-trime- thylbenzophenone
(Compound 137), 2,3'-Dichloro-2'-methyl-4-(4-methyl-3-pyr-
idylamino)benzophenone (Compound 138),
2-Fluoro-2'-methyl-4-(4-methyl-3-py- ridylamino)benzophenone
(Compound 139), 2,4'-Dichloro-2'-methyl-4-(4-methy-
l-3-pyridylamino)benzophenone (Compound 140),
2-Chloro-4'-fluoro-4-(4-isoq- uinolylamino)-2'-methylbenzophenone
(Compound 141),
4'-n-Butyl-2-chloro-4-(4-isoquinolylamino)-2'-methylbenzophenone
(Compound 142), 2-Chloro-4-(5-isoquinol
ylamino)-2'-methylbenzophenone (Compound 143),
2-Chloro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylbenzo- phenone
(Compound 144), 2Fluoro-4-(4-isoquinolylamino)-4'-methoxy-2'-methy-
lbenzophenone (Compound 145),
2,4'-Dichloro-2'-methyl-4-(1-methyl--7indoly- lamino)benzophenone
(Compound 146), 2-Chloro-4-(5-methyl-7-indoly)amino)-2-
',4',5'-trimethylbenzophenone (Compound 147),
2-Chloro-2',5'-dimethyl-4-(1- -methyl-7-indolylamino)benzophenone
(Compound 148), 2-Chloro-4-(3-ethoxy-4-isoquinolyyamino)
-2'-methylbenzophenone (Compound 149),
2-Chloro-4-(1-ethoxy-4-isoquinolylamino) -2'-methylbenzophenone
(Compound 150),
4-(2-Benzoxazolylamino)-2-chloro-2'-methylbenzophenone (Compound
151), 4-(2-Methyl-2-benzimidazolylamino)-2-chloro-2'-methylbenz-
ophenone (Compound 152),
4-(2-Benzothiazolylamino)-2-chloro-2'-methyl benzophenone (Compound
153), 2-Chloro-2'-methyl-4-(2-pyimidylamino)benzop- henone
(Compound 154),
2-Chloro-2'-methyl-4-(7-methyl-purin-6-ylamino)benz- ophenone
(Compound 155), 2-Chloro-2'-methyl-4-(2-methyl-5-benzothiazoryami-
no)benzophenone (Compound 156),
2-Chloro-2'-methyl-4-(pyrazin-2-ylamino)be- nzophenone (Compound
157), 2-Chloro-2'-methyl-4-(5-pyrimidylamino)benzophe- none
(Compound 158) and the N-oxides thereof wherein the nitrogen atom
of the heterocyclic R.sub.5 substituent is specifically oxidised,
including the N-oxides:
2-Chloro-2'-methyl-4((2-pyridyl-N-oxide)amino)benzophenone
(Compound 112),
2-Chloro-2'-methyl-4((3-pyridyl-N-oxide)amino)benzophenon- e
(Compound 113),
2-Chloro-4((4-isoquinolyl-N-oxide)amino)-2'-methylbenzop- henone
(Compound 128), and salts thereof with pharmaceutically acceptable
acids, hydrates and solvates.
26. A compound of the general formula Ia or Ib 40wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 have the meaning specified
for formula I, and salts thereof with pharmaceutically acceptable
acids, hydrates and solvates.
27. A compound of formula Ia selected from the group consisting of
2-Chloro-2'-methyl-4-(4-pyridylamino)thiobenzophenone
2-Chloro-2'-methyl-4-(2-pyridylamino)thiobenzophenone
2-Chloro-2'-methyl-4-(5-nitro-2-pyridylamino)thiobenzophenone
4-(6-Amino-5-nitro-2-pyridylamino)-2-chloro-2'-methyl((thiobenzophenone)
6-Chloro-2-(3-chloro-4-(2-methylthiobenzoyl)phenylamino)
isonicotinic acid
4-(6-carbonitrile-2-pyridylamino)-2-chloro-2'-methyl(thiobenzophenon-
e) 2-Chloro-2'-methyl-4-(3-pyridylamino)thiobenzophenone
2-Chloro-4-(5,6-diamino-2-pyridylamino)-2'-methyl(thiobenzophenone)
2-Chloro-2'-methyl-4-(3-nitro-2-pyridylamino)thiobenzophenone
4(3-Amino-2-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone)
4(5-Amino-2-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone)
2-Chloro-4-(4-isoquinolylamino)-2'-methyl(thiobenzophenone) t-Butyl
5-(3-chloro-4-(2-methylthiobenzoyl)phenylamino)nicotinoate
2-Chloro-2'-methyl-4-(4-methyl-3-pyridylamino)thiobenzophenone
2-Chloro-2'-methyl-4-(6-methyl-3-pyridylamino)thiobenzophenone
4-(5-Bromo-3-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone)
4-(5-Carbonitrile-3-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone)
4-(3-Bromo-2-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone)
2-Chloro-2'-methyl-4-(8-quinolylamino)thiobenzophenone
2-Chloro-4-(6-ethoxy-3-pyridylamino)-2'-methyl(thiobenzophenone)
4-(4-Bromo-1-isoquinolylamino) -2-chloro-2'-methyl (th
iobenzophenone)
2-Chloro-2'-methyl-4-(2-methyl-5-trifluoromethyl-3-pyridylamino)thiobenzo-
phenOne 2-Chloro-2'-methyl-4-(3-quinolylamino)thiobenzophenone
2-Chloro-4-(4-ethoxy-3-pyridylamino)-2'-methyl(thiobenzophenone)
2-Chloro-4-(2-ethoxy-3-pyridylamino)-2'-methyl(thiobenzophenone)
2-Chloro-2'-methyl-4-(2-methyl-6-quinolylamino)thiobenzophenone
2-Chloro-2'-methyl-4-(2-quinolylamino)thiobenzophenone
2-Chloro-4-(7-chloro-4-quinolylamino)-2'-methyl(thiobenzophenone)
2-Chloro-2'-methyl-4-(4-quinolylamino)thiobenzophenone
2-Chloro-2'-methyl-4-(1-methyl-7-indolylamino)thiobenzophenone
2-Chloro-2'-methyl-4-(1-methyl-5-indolylamino)thiobenzophenone
2-Chloro-2',5'-dimethyl-4-(4-methyl-3-pyridylamino)thiobenzophenone,
2-Chloro-2',5'-dimethyl-4-(4-isoquinolylamino)thiobenzophenone,
2-Chloro-4-(4-isoquinolylamino)-2',4',5'-trimethyl(thiobenzophenone),
2,3'-Dichloro-2'-methyl-4-(4methyl-3-pyridylamino)thiobenzophenone,
2Fluoro-2'-methyl-4-(4-methyl-3-pyridylamino) thiobenzophenone,
2,4'-Dichloro-2'-methyl-4-(4-methyl-3-pyridylamino)thiobenzophenone,
2-Chloro-4'-fluoro-4-(4-isoquinolylamino)-2'-methyl(thiobenzophenone),
4'-n-
Butyl-2-chloro-4-(4-isoquinolylamino)-2'-methyl(thiobenzophenone),
2-Chloro-4(5isoquinolylamino)-2'methyI(thiobenzophenone),
2-Chloro-4-(4-isoquinolylamino)-4'-methoxy-2'-methyl(thiobenzophenoe),
2-Fluoro-4-(4-isoquinolylamino)-4'-methoxy-2'-methyl(thiobenzophenone),
2,4'-Dichloro-2'-methyl-4-(1-methyI-7-indolylamino)thiobenzophenone,
2-Chloro-4-(1-methyl-7-indolylamino)-2', 4',
5'-trimethyl(thiobenzophenon- e),
2-Chloro-2',5'-dimethyl-4-(1-methyl-7-indoIylamino)thiobenzophenone,
2-Chloro-4-(3-ethoxy-4-isoquinolylamino)-2'-methyl(thiobenzophenone),
2-Chloro-4-(1-ethoxy-4-isoquinolylamino)-2'-methyl(thiobenzophenone),
4-(2-Benzoxazolylamino)-2-chloro-2'-methyl(thiobenzophenone),
4-(1-Methyl-2-benzimidazolylamino)-2-chloro-2'-methyl(thiobenzophenone),
4-(2-Benzothiazolylamino)-2-chloro-2'-methyl(thiobenzophenone),
2-Chloro-2'-methyl-4-(2-pyrimidylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(7-methyl-purin-6-ylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(2-methyl-5-benzothiazolylamino)thiobenzo
phenone, 2-Chloro-2'-methyl-4-(pyrazin-2-ylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(5-pyrimidylamino)thiobenzophenone and salts
thereof with pharmaceutically acceptable acids, hydrates and
solvates.
28. A compound of formula lb selected form the group consisting of:
2-Chloro-2'-methyl-4-(4-pyridylamino)benzophenone oxime
2-Chloro-2'-methyl-4-(2-pyridylamino)benzophenone oxime
2-Chloro-2'-methyl-4-(5-nitro-2-pyridylamino)benzophenone oxime
4-(6-Amino-5-nitro-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime
6-Chloro-2-((3-chloro-4-((hydroxyimino)(2-methylphenyl)methyl))phenylamin-
o) isonicotinic acid
4-(6-carbonitrile-2-pyridylamino)-2-chloro-2'-methylb- enzophenone
oxime 2-Chloro-2'-methyl-4-(3-pyridylamino)benzophenone oxime
2-Chloro-4-(5, 6-diamino-2-pyridylamino)-2'-methylbenzophenone
oxime 2-Chloro-2'-methyl-4-(3-nitro-2-pyridylamino)benzophenone
oxime 4-(3-Amino-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime 4-(5-Amino-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime 2-Chloro-4-(4-isoquinolylamino)-2'-methylbenzophenone oxime
t-Butyl
5-((3-chloro-4-((hydroxyimino)(2-methylphenyl)methyl))phenylamino)
nicotinoate
2-Chloro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone oxime
2-Chloro-2'-methyl-4-(6-methyl-3-pyridylamino)benzophenone oxime
4-(5-Bromo-3-pyridylamino)-2-chloro-2'-methylbenzophenone oxime
4-(5-Carbonitrile-3-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime 4-(3-Bromo-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime 2-Chloro-2'-methyl-4-(8-quinolylamino)benzophenone oxime
2-Chloro-4-(6-ethoxy-3-pyridylamino)-2'-methylbenzophenone oxime
4-(4-Bromo-1-isoquinolylamino)-2-chloro-2'-methylbenzophenone oxime
2-Chloro-2'-methyl-4-(2-methyl-5-trifluoromethyl-3-pyridylamino)benzophen-
one oxime 2-Chloro-2'-methyl-4-(3-quinolylamino)benzophenone oxime
2-Chloro-4-(4-ethoxy-3-pyridylamino)-2'-methylbenzophenone oxime
2-Chloro-4-(2-ethoxy-3-pyridylamino)-2'-methylbenzophenone oxime
2-Chloro-2'-methyl-4-(2-methyl-6-quinolylamino)benzophenone oxime
2-Chloro-2'-methyl-4-(2-quinolylamino)benzophenone oxime
2-Chloro-4-(7-chloro-4-quinolylamino)-2'-methylbenzophenone oxime
2-Chloro-2'-methyl-4-(4-quinolylamino)benzophenone oxime
2-Chloro-2'-methyl-4-(1-methyl-7-indolylamino)benzophenone oxime
2-Chloro-2'-methyl-4-(1-methyl-5-indolyiamiano)benzophenone oxime
2-Chloro-2',5'-dimethyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime, 2-Chloro-2',5'-dimethyl-4-(4-isoquinolylamino)benzophenone
oxime,
2-Chloro-4-(4-isoquinolylamino)-2',4',5'-trimethylbenzophenone
oxime,
2,3'-Dichloro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime, 2-Fluoro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime,
2,4'-Dichloro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime,
2-Chloro-4'-fluoro-4-(4-isoquinolylamino)-2'-methylbenzophenone
oxime,
4'-n-Butyl-2-chloro-4-(4-isoquinolylamino)-2'-methylbenzophenone
oxime, 2-Chloro-4-(5-isoquinolylamino)-2'-methylbenzophenone oxime,
2-Chloro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylbenzophenone
oxime,
2-Fluoro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylbenzophenone
oxime,
2,4'-Dichloro-2'-methyl-4-(1-methyl-7-indolylamino)benzophenone
oxime,
2-Chloro-4-(1-methyl-7-indolylamino)-2',4',5'-trimethylbenzophenone
oxime,
2-Chloro-2',5'-dimethyl-4-(1-methyl-7-indolylamino)benzophenone
oxime,
2-Chloro-4-(3-ethoxy-4-isoquinolylamino)-2'-methylbenzophenone
oxime,
2-Chloro-4-(1-ethoxy-4-isoquinolylamino)-2'-methylbenzophenone
oxime, 4-(2-Benzoxazolylamino)-2-chloro-2'-methylbenzophenone
oxime,
4-(1-Methyl-2-benzimidazolylamino)-2-chloro-2'-methylbenzophenone
oxime, 4-(-2-Benzothiazolylamino)-2-chloro-2'-methylbenzophenone
oxime, 2-Chloro-2'-methyl-4-(2-pyrimidylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(7-methyl-purin-6-ylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(2-methyl-5-benzothiazolylamino)benzophenone
oxime, 2-Chloro-2'-methyl-4-(pyrazin-2-ylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(5-pyrimidylamino)benzophenone oxime, and
salts thereof with pharmaceutically acceptable acids, hydrates and
solvates.
29. A pharmaceutical composition containing as an active component
a compound of general formula I according to claim 1 together with
a pharmaceutically acceptable excipient or carrier.
30. A composition according to claim 29 further comprising a second
active ingredient optionally selected from the group consisting of
glucocorticoids, vitamin D or vitamin D analogues, anti-histamines,
platelet activating factor (PAF) antagonists, anticolinergic
agents, methyl xanthines, --adrenergic agents, salicylates,
indomethacin, flufenamate, naproxen, timegadine, gold salts,
penicillamine, serum cholesterol-reducing agents, retinoids, zinc
salts, and salicylazosulfapyridin.
31. A composition according to claim 29 in unit dosage form
containing between 0.05 and 1000 mg of the active ingredient.
32. A method for the treatment or prophylaxis of inflammatory
diseases or conditions, the method comprising administering, to a
patient in need thereof, an effective amount of one or more
compounds of general formula I according to claim 1.
33. The method of claim 32 further comprising administering a
second active component selected from the group consisting of
glucocorticoids, vitamin D's, anti-histamines, platelet activating
factor (PAF) antagonists, anticolinergic agents, methyl xanthines,
.beta.-adrenergic agents, salicylates, indomethacin, flufenamate,
naproxen, timegadine, gold salts, penicillamine, serum
cholesterol-reducing agents, retinoids, zinc salts, and
salicylazosulfapyridin.
34. The method of claim 32, wherein the disease or condition is
selected from the group consisting of asthma and allergy.
35. The method of claim 32, wherein the disease or condition is
selected from the group consisting of arthritis, including
rheumatoid arthritis, osteoarthritis and spondyloarthritis, gout,
atherosclerosis, inflammatory bowel disease, Crohn's disease,
uveitis, sepsis and septic shock.
36. The method of claim 32, wherein the disease or condition is a
proliferative and/or inflammatory skin disorder such as psoriasis,
atopic dermatitis and acne vulgaris.
37. A method for the treatment and/or prophylaxis of osteoporosis,
the method comprising administering to a patient in need thereof an
effective amount of one or more compounds of general formula I
according to claim 1.
38. A method for the treatment of AIDS related diseases, the method
comprising administering to a patient in need thereof an effective
amount of one or more compounds of general formula I according to
claim 1.
39. The method of any one of claims 32-38 comprising administering
to a patient in need of systemic treatment a dose of from 0.01 to
400 mg/kg body weight, preferably a dose of from 0.1 to 100 mg/kg
body weight one or more times daily of a compound of general
formula I according to claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel class of compounds,
including heteroaryl aminobenzophenone derivatives, which show
anti-inflammatory effects, to pharmaceutical compositions
containing these compounds, and to their use in the treatment and
prophylaxis of inflammatory diseases.
BACKGROUND OF THE INVENTION
[0002] A series of aminobenzophenones (e.g.
4-(2-amino-4-nitrophenylamino)- benzophenone) have been described
previously (Hussein, F.A. et al., Iraqi J. Sci., 22, 54-66 (1981)).
In this publication, however, there is no description of any
potential therapeutic use of such compounds. WO 98/32730 discloses
aminobenzophenone inhibitors of interleukin 1.beta. (IL-1.beta.)
and tumour necrosis factor .alpha.. (TNF-.alpha.) secretion in
vitro, and indicates the potential utility of these compounds in
the treatment of inflammatory diseases in which the production of
pro-inflammatory cytokines is involved in the pathogenesis, e.g.
asthma, rheumatoid arthritis, psoriasis, contact dermatitis, and
atopic dermatitis. Furthermore the compounds disclosed in WO
98/32730 were tested in vivo for anti-inflammatory properties in
the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced murine
chronic skin inflammation model (De Young, L.M. et al., Agents
Actions 26, 335-341 (1989); Carlson, R.P. et al., Agents Actions
17, 197-204 (1985); Alford, J. G. et al., Agents Action 37, (1992);
Stanley, P. L. et al., Skin Pharmacol. 4, 262-271 (1991)). In this
chronic skin inflammation model the compounds had the same potency
compared to the reference 25 compound hydrocortisone.
[0003] It is the object of the present invention is to provide
further pharmacologically active benzophenone derivatives which
differ structurally from those disclosed in WO 98/32730.
SUMMARY OF THE INVENTION
[0004] It has surprisingly been found that novel benzophenone
derivatives are potent inhibitors of interleukin 1.beta.
(IL-1.beta.) and tumour necrosis factor .alpha. (TNF-.alpha.)
secretion in vitro, making them potentially useful for the
treatment and/or prevention of inflammatory diseases and other
conditions in which the secretion and regulation of cytokines or
more specifically interleukin 1.beta. (IL-1.beta.) and tumour
necrosis factor .alpha. (TNF-.alpha.) are involved in the
pathogenesis. The inhibition or downregulation of the cytokines is
possibly due to an inhibition of MAP kinases, more specifically the
p38 MAP kinase, a stress-activated protein which is an important
element in the signal transduction pathway leading to the
production of pro-inflammatory cytokines.
[0005] Accordingly, the present invention relates to a compound
with the general formula I 1
[0006] wherein R.sub.1 is selected from the group consisting of
halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy,
mercapto, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl,
aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl,
alkylcarbonyloxy, alkoxycarbonyloxy, alkylsulfonyloxy,
alkyloxysulfonyl, alkylcarbonylamino, aminocarboaminoalkyl,
aminosulfonyl, alkylsulfonylamino, alkanoyl, alkylcarbonyl,
--NR.sub.9R.sub.10 or --CONR.sub.9R.sub.10, wherein R.sub.9 and
R.sub.10 are the same or different and individually represent
hydrogen, alkyl or aryl;
[0007] R.sub.2 represents one or more, same or different
substituents selected from the group consisting of hydrogen,
halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy,
mercapto, cyano, carboxy, nitro, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl,
aralkyl, alkylaryl, alkoxy, aralkoxy, alkylthio, alkoxycarbonyl,
alkylcarbonyloxy, alkoxycarbonyloxy, al kylsu Ifonyloxy, al
kyloxysu Ifonyl, alkylcarbonylamino, aminocarboaminoalkyl,
aminosulfonyl, alkylsulfonylamino, alkanoyl, alkylcarbonyl,
--NR.sub.9R.sub.10 or --CONR.sub.9R.sub.10, wherein R.sub.9 and
R.sub.10 are the same or different and individually represent
hydrogen, alkyl or aryl;
[0008] R.sub.3 represents one or more, same or different
substituents selected from the group consisting of hydrogen,
halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto, cyano, nitro,
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, alkylaryl,
alkoxy, aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonylamino,
alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl
--NR.sub.9R.sub.10 or --CONR.sub.9R.sub.10, wherein R.sub.9 and
R.sub.10 are the same or different and individually represent
hydrogen, alkyl or aryl;
[0009] R.sub.4 represents hydrogen, alkyl, alkenyl , alkynyl,
cycloalkyl, cycloalkenyl, carboxy or aryl;
[0010] R.sub.5 represents a heteroaromatic mono-or bicyclic ring
system comprising 1-4 heteroatoms, except for triazine, said ring
system being optionally substituted by hydrogen, halogen,
haloalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, mercapto, cyano,
carboxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, aryl, heteroaryl, aralkyl, alkylaryl, alkoxy,
aralkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyloxy,
alkoxycarbonyloxy, alkylsulfonyloxy, alkyloxysulfonyl,
alkylcarbonylamino, aminocarboaminoalkyl, aminosulfonyl,
alkylsulfonylamino, alkanoyl, alkylcarbonyl, --NR.sub.9R.sub.10 or
--CONR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10 are the same or
different and individually represent hydrogen, alkyl or aryl;
[0011] X represents oxygen, sulphur, N--OH or NR.sub.11 wherein
R.sub.11 is hydrogen or alkyl; or pharmaceutically acceptable salts
hydrates, solvates or esters thereof as well as N--oxides wherein
an N-atom of R.sub.5 is oxidised.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Definitions
[0013] In the present context, the term "alkyl" is intended to
indicate a univalent radical derived from straight or branched
alkane by removing a hydrogen atom from any carbon atom.
[0014] The alkyl chain typically comprises 1-10 carbon atoms, in
particular 1-6 carbon atoms. The term includes the subclasses
normal alkyl (n-alkyl), secondary and tertiary alkyl, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl,
tert.-butyl, pentyl, 30 isopentyl, hexyl and isohexyl.
[0015] The term "haloalkyl" is intended to indicate an alkyl
radical as defined above substituted by one or more halogens such
as chloro, fluoro, bromo or iodo.
[0016] The term "hydroxyalkyl" is intended to indicate an alkyl
radical as defined above substituted by one or more hydroxy
groups.
[0017] The term "alkoxy" is intended to indicate a radical of
formula OR', wherein R' is alkyl as defined above, e.g. methoxy,
ethoxy, propoxy, butoxy, etc.
[0018] The term "hydroxyalkyloxy" is intended to indicate an alkoxy
group as defined above substituted by one or more hydroxy
groups.
[0019] The term "alkenyl" is intended to indicate a mono-, di-,
tri-, tetra-or pentaunsaturated alkane radical typically comprising
2-10 carbon atoms, in particular 2-6 carbon atoms, e.g. ethenyl,
propenyl, butenyl, pentenyl or hexenyl. The term "alkynyl" is
intended to indicate an alkane radical comprising 1-5 triple C-C
bonds, the alkane chain typically comprising 2-10 carbon atoms, in
particular 2-6 carbon atoms, such as ethynyl, propynyl, butynyl,
pentynyl or hexynyl.
[0020] The term "alkoxycarbonyl" is intended to indicate a radical
of formula --COOR' wherein R' is alkyl as defined above, e.g.
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, etc.
[0021] The term "cycloalkyl" is intended to indicate a saturated
cycloalkane radical typically comprising 3-10 carbon atoms, in
particular 3-8 carbon atoms, e.g. cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. The term "cycloalkenyl" is intended to
indicate mono-, di- tri- or tetraunsaturated cycloalkane radicals,
e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
The term "heterocycloalkyl" is intended to indicate a cycloalkane
radical as defined above, comprising one or more heteroatoms
selected from 0, N, or S.
[0022] The term "aryl" is intended to include radicals of
carbocyclic aromatic rings, in particular 5-or 6-membered rings,
optionally fused bicyclic rings, e.g. phenyl or naphthyl. The term
"heteroaryl" is intended to include radicals of heterocyclic
aromatic rings, in particular 5-or 6-membered rings with 1-4
heteroatoms selected from 0, S and N, or optionally fused bicyclic
rings with 1-4 heteroatoms, e.g. pyridyl, quinolyl, isoquinolyl,
indolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl and
benzofuranyl.
[0023] The term "alkylcarbonyloxy" refers to a radical of formula
R'--COO--, wherein R' is alkyl as indicated above. The term
"alkoxycarbonyloxy" refers to a radical of formula R'O--COO--,
wherein R' is alkyl as defined above. The term "alkylsulfonyloxy"
refers to a radical of formula R'--(SO.sub.2)--O--, wherein R' is
alkyl as defined above. The term "alkyloxysulfonyl" refers to a
radical of formula R'O--(SO.sub.2)--, wherein R' is alkyl as
defined above.
[0024] The term "aralkyl" is intended to indicate an aromatic ring
with an alkyl side chain as defined above, e.g. benzyl. The term
"alkylaryl" is intended to indicate an alkyl radical as defined
above comprising an aromatic side chain.
[0025] The term "halogen" is intended to indicate fluoro, chloro,
bromo or iodo. The term "alkylthio" is intended to indicate a
radical of the formula --SR, where R is alkyl as defined above and
includes methylthio, ethylthio, n-propylthio, and 2-propylthio.
[0026] The term "alkylamino" is intended to indicate a radical of
the formula --NHR or --NR.sub.2, where R is alkyl as defined above
having from 1-6 carbon atoms and includes, for example,
methylamino, dimethylamino, di-(n-propyl)amino, and
n-butyl(ethyl)amino.
[0027] The term "carbamoyl" is intended to indicate the group
--OCONH.sub.2, --OCONHR, and --OCONRR' where R and R' represent
alkyl as defined above.
[0028] The term "pharmaceutically acceptable salt" is intended to
indicate alkali metal or alkaline earth metal salts, for instance
sodium, potassium, magnesium or calcium salts, as well as silver
salts and salts with suitable organic or inorganic acids such as
hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric,
phosphoric, acetic, lactic, maleic, phthalic, citric, propionic,
benzoic, glutaric, gluconic, methanesulfonic, salicylic, succinic,
tartaric, toluenesulfonic, sulfamic or fumaric acid.
[0029] The term "pharmaceutically acceptable esters" is intended to
indicate easily hydrolysable esters such as alkanoyloxyalkyl,
aralkanoyloxyalkyl, aroyloxyalkyl, e.g. acetoxymethyl,
pivaloyloxymethyl, benzoyloxymethyl esters and the corresponding
1'-oxyethyl derivatives, or alkoxycarbonyloxyalkyl esters, e.g.
methoxycarbonyloxymethyl esters and ethoxycarbonyloxymethyl esters
and the corresponding 1'-oxyethyl derivatives, or lactonyl esters,
e.g. phthalidyl esters, or dialkylaminoalkyl esters, e.g.
dimethylaminoethyl esters. Easily hydrolysable esters include in
vivo hydrolysable esters of the compounds of formula I. Such esters
may be prepared by conventional methods known to persons skilled in
the art, such as method disclosed in GB patent No. 1 490 852
incorporated herein by reference.
[0030] "p38 MAP kinase" is a stress-activated protein kinase
existing in several isoforms (p38c.alpha., p38.beta.p, p38.beta.2,
p38.gamma. and p38.delta.). The p38 MAP kinase is activated by
different stimuli including heat, chemical, osmotic, pH and
oxidative stress, growth factor withdrawal, high or low glucose and
ultraviolet radiation. p38 is also stimulated by agents that
mediate the initial physiological response to injury, infection and
inflammation, such as LPS and pro-inflammatory cytokines
IL-1.beta., TNF-.alpha., FasL, CD40L and TGF-.beta.. Like other MAP
kinases, p38 is phosphorylated by kinases, including MKK3, MEK6 and
MKK6, on a threonine and tyrosine in an activation loop
(Thr-Xaa-Tyr) close to the ATP and substrate binding site. In turn,
p38 phosphorylates and activates the serine-threonine protein
kinases MAPKAP kinase-2, MAPKAP kinase-3, MAPKAP kinase-5, MNK-1
and MSK-1. It has been established that activation of p38 regulates
cytokine biosynthesis in many cell types either directly by
phosphorylating and activating transcription factors involved in
the expression of cytokines or indirectly, e.g. by phosphorylating
MSK-1 which, when activated, activates the transcription factor
CREB. It has also been shown that certain pyridinyl imidazoles,
e.g. SB203580, inhibit the production of IL-1.beta.and TNF-.alpha.
from LPS-treated human monocytes, are inhibitors of p38 kinase. It
has therefore been concluded that p38 constitutes a potentially
highly interesting target for the development of anti-inflammatory
compounds (cf. JC Lee et al., Immunopharmacology 47, 2000, pp.
185-201 and references reviewed therein; PR Young, "Specific
Inhibitors of p38 MAP kinase" in Signaling Networks and Cell Cycle
Control: The Molecular Basis of Cancer and Other Diseases, JS
Gutkind (Ed.), Humana Press, Inc., Totowa, N.J., and references
reviewed therein).
[0031] Preferred Embodiments of the Invention
[0032] In compounds of formula I, R.sub.1 preferably represents a
substituent selected from the group consisting of halogen, hydroxy,
mercapto, trifluoromethyl, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6) alkoxycarbonyl, cyano, --CONH.sub.2, phenyl, and
nitro, in particular fluoro, chloro, bromo, hydroxy,
trifluoromethyl, amino, (C.sub.1-C.sub.3)alkyl,
(C.sub.2-C.sub.3)alkenyl, (C.sub.1-C.sub.3)alkoxy- ,
(C.sub.1-C.sub.3) alkoxycarbonyl, cyano, or --CONH.sub.2;
[0033] R.sub.2 represents one or more, same or different
substituents selected from the group consisting of hydrogen,
halogen, hydroxy, mercapto, trifluoromethyl, amino,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylthio,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkoxycarbonyl,
cyano, --CONH.sub.2, phenyl, and nitro; in particular hydrogen,
fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino,
(C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl,
(C.sub.1-C.sub.3)alkoxy, (C.sub.1-C.sub.3) alkoxycarbonyl, cyano,
or --CONH.sub.2;
[0034] R.sub.3 represents one or more, same or different
substituents selected from the group consisting of hydrogen,
halogen, hydroxy, mercapto, trifluoromethyl, amino,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylthio,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6) alkoxycarbonyl,
cyano, --CONH.sub.2, phenyl, and nitro, in particular hydrogen,
fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino,
(C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)alkenyl, and
(C.sub.1-C.sub.3)alkoxy;
[0035] R.sub.4 represents hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6) alkenyl, or (C.sub.3-C.sub.6) cycloalkyl or
cycloalkenyl, in particular hydrogen, (C.sub.1-C.sub.4) alkyl, or
(C.sub.2-C.sub.4) alkenyl;
[0036] X represents oxygen or NH;
[0037] In the mono-or bicyclic heteroaromatic ring system
represented by R.sub.5, the heteroatom(s) may be selected from N, S
or O. Each ring preferably comprises 5 or 6 ring atoms. Examples of
suitable heteroaromatic ring systems are selected from the group
consisting of pyridyl, pyrazinyl, pyrimidinyl, quinolyl,
isoquinolyl, quinazolinyl, pyridazinyl, phthalazinyl, purinyl,
quinoxalyl, allopurinyl, benzofuranyl, isobenzofuranyl,
benzimidazolyl, benzoxazolyl, benzothienyl, isobenzothienyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolizinyl,
isoindolyl, indolyl, indazolyl, triazolyl, oxazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl or isoxazolyl.
[0038] R.sub.5 is preferably selected from heteroaromatic ring
systems comprising 1 or 2 nitrogen atoms, e.g. rings of the
structures: 2
[0039] The R.sub.5 ring-systems may optionally be oxidised to the
corresponding N-oxides as exemplified below for the isoquinoline
ring system: 3
[0040] R.sub.6 and R.sub.7 represent one or more, same or different
substituents selected from the group consisting of hydrogen,
halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy,
carbamoyl, amino, nitro, (C.sub.1-C.sub.10)alkyl,
(C.sub.2-C.sub.10)alkenyl, (C.sub.3-C.sub.8)cycloalkyl or
-cycloalkenyl, (C.sub.1-C.sub.10)alkoxy,
(C.sub.1-C.sub.10)alkylthio, (C.sub.1-C.sub.10) alkoxycarbonyl, and
phenyl. In particular R.sub.6 and R.sub.7 represent one or more,
same or different substituents selected from the group consisting
of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl,
amino, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , (Cl-C.sub.6) alkoxycarbonyl, cyano,
carboxy, and --CONH.sub.2; and 4
[0041] R.sub.8 represents hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.3-C.sub.6)cycloalkyl or
-cycloalkenyl.
[0042] In compounds of formula I it is more preferred that R.sub.1
represents a substituent selected from the group consisting of
fluoro, chloro, bromo, hydroxy, methyl, and methoxy;
[0043] R.sub.2 represents one or more, same or different
substituents selected from the group consisting of hydrogen,
fluoro, chloro, bromo, hydroxy, trifluoromethyl, methyl, ethyl, and
methoxy;
[0044] R.sub.3 represents one or more, same or different
substituents selected from the group consisting of hydrogen,
fluoro, chloro, bromo, hydroxy, methyl, and methoxy;
[0045] R.sub.4 represents hydrogen, methyl, or ethyl;
[0046] R.sub.5 is selected from the group consisting of substituted
or non-substituted 3-pyridyl, 2-pyridyl, 3-quinolyl, 4-isoquinolyl,
4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl moieties, and the
corresponding N-oxides;
[0047] R.sub.6 and R.sub.7 represent one or more, same or different
substituents selected from the group consisting of hydrogen,
fluoro, chloro, bromo, hydroxy, methyl, methoxy, cyano, and
carboxy;
[0048] R.sub.8 represents hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.6)alkenyl, such as allyi; and more preferably,
R.sub.8 represents hydrogen, methyl, ethyl, allyl, propyl, or
t-butyl; and/or X represents oxygen.
[0049] The phenyl group of R.sub.1, R.sub.2, R.sub.3, R.sub.6 and
R.sub.7 may optionally be substituted, e.g. with hydroxy, amino,
nitro, cyano or halogen, preferably fluoro or chloro.
[0050] Specific compounds of the invention are:
2-Chloro-2'-methyl-4-(4-py- ridylamino)benzophenone (Compound 101),
2-Chloro-2'-methyl-4-(2-pyridylami- no)benzophenone (Compound 102),
2-Chloro-2'-methyl-4-(5-nitro-2-pyridylami- no)benzophenone
(Compound 103), 4-(6-Amino-5-nitro-2-pyridylamino)-2-chlor-
o-2'-methylbenzophenone (Compound 104),
6-Chloro-2-(3-chloro-4-(2-methylbe- nzoyl)phenylamino) isonicotinic
acid (Compound 105),
4-(6-carbonitrile-2-pyridylamino)-2-chloro-2'-methylbenzophenone
(Compound 106), 2-Chloro-2'-methyl-4-(3-pyridylamino)benzophenone
(Compound 107),
2-Chloro-4-(5,6-diamino-2-pyridylamino)-2'-methylbenzophe- none
(Compound 108),
2-Chloro-2'-methyl-4-(3-nitro-2-pyridylamino)benzophe- none
(Compound 109),
4-(3-Amino-2-pyridylamino)-2-chloro-2'-methylbenzophe- none
(Compound 110),
4-(5-Amino-2-pyridylamino)-2-chloro-2'-methylbenzophe- none
(Compound 111),
2-Chloro-4-(4-isoquinolylamino)-2'-methylbenzophenone (Compound
114), t-Butyl 5-(3-chloro-4-(2-methylbenzoyl)phenylamino)
nicotinoate (Compound 115,)
2-Chloro-2'-methyl-4-(4-methyl-3-pyridylamino- )benzophenone
(Compound 116), 2-Chloro-2'-methyl-4-(6-methyl-3-pyridylamin-
o)benzophenone (Compound 117),
4-(5-Bromo-3-pyridylamino)-2-chloro-2'-meth- ylbenzophenone
(Compound 118), 4-(5-Carbonitrile-3-pyridylamino)-2-chloro--
2'-methylbenzophenone (Compound 119),
4-(3-Bromo-2-pyridylamino)-2-chloro-- 2'-methylbenzophenone
(Compound 120), 2-Chloro-2'-methyl-4-(8-quinolylamin-
o)benzophenone (Compound 121),
2-Chloro-4-(6-ethoxy-3-pyridylamino)-2'-met- hylbenzophenone
(Compound 122), 4-(4-Bromo-1-isoquinolylamino)-2-chloro-2'-
-methylbenzophenone (Compound 123),
2-Chloro-2'-methyl-4-(2-methyl-5-trifl-
uoromethyl-3-pyridylamino)benzophenone (Compound 124),
2-Chloro-2'-methyl-4-(3-quinolylamino)benzophenone (Compound 125),
2-Chloro-4-(4-ethoxy-3-pyridylamino)-2'-methylbenzophenone
(Compound 126),
2-Chloro-4-(2-ethoxy-3-pyridylamino)-2'-methylbenzophenone
(Compound 127),
2-Chloro-2'-methyl-4-(2-methyl-6-quinolylamino)benzopheno- ne
(Compound 129),
2-Chloro-4-(7-chloro-4-quinoylamino)-2'-methylbenzophen- one
(Compound 130), 2-Chloro-2'-methyl-4-(2-quinolylamino)benzophenone
(Compound 131),
2-Chloro-2'-methyl-4-(4-quinolylamino)benzophenone(Compou- nd 132),
2-Chloro-2'-methyl-4-(1-methyl-7-indolylamino)benzophenone
(Compound 133),
2-Chloro-2'-methyl-4-(2-methyl-5-indolylamino)benzophenon- e
(Compound 134),
2-Chloro-2',5'-dimethyl-4-(4-methyl-3-pyridylamino)benzo- phenone
(Compound 135), 2-Chloro-2',5'-dimethyl-4-(4-isoquinolylamino)benz-
ophenone (Compound 136),
2-Chloro-4-(4-isoquinolylamino)-2',4',5'-trimethy- lbenzophenone
(Compound 137), 2,3'-Dichloro-2'-methy-4-(4-methyl-3-pyridyl-
amino)benzophenone (Compound 138),
2-Fluoro-2'-methyl-4-(4-methyl-3-pyridy- lamino)benzophenone
(Compound 139), 2',4'-Dichloro-2'-methyl-4-(1-methyl-3-
-pyridylamino)benzophenone (Compound 140),
2-Chloro-4'-fluoro-4-(4-isoquin- olylamino)-2'-methylbenzophenone
(Compound 141), 4'-n-Butyl-2-chloro-4-(4--
isoquinolylamino)-2'-methylbenzophenone (Compound 142),
2-Chloro-4-(5-isoquinolylamino)-2'-methylbenzophenone (Compound
143),
2-Chiloro-4-(4-isoquinoylamino)-4'-methoxy-2'-methyibenzophenone
(Compound 144),
2-Fluoro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylbenzo- phenone
(Compound 145), 2,4'-Dichloro-2'-methyl-4-(4-methyl-7-indolylamino-
)benzophenone (Compound 146),
2-Chloro-4-(1-methyl-7-indolyamino)2',4',5'-- trimethylbenzophenone
(Compound 147), 2-Chloro-2',5'-dimethyl-4-(1-methyl--
7-indolylamino)benzophenone (Compound 148),
2-Chloro-4-(3-ethoxy-4-isoquin- olylamino)-2'-methylbenzophenone
(Compound 149), 2-Chloro-4-(1-ethoxy-4-is-
oquinolylamino)-2'-methylbenzophenone (Compound 150),
4-(2-Benzoxazolylamino)-2chloro-2'-methylbenzophenone (Compound
151), 4(1Methyl-2benzimidazolylamino)-2chloro-2'-methylbenzophenone
(Compound 152),
4(2Benzothiazolylamino)-2chloro-2'methylbenzophenone (Compound
153), 2Chloro-2'methyl-4(2pyrimidylamino)benzophenone (Compound
154), 2Chloro-2'methyl-4(7methyl-purin-6-ylamino)benzophenone
(Compound 155),
2Chloro-2'methyl-4(2methyl-5benzothiazolylamino)benzophenone
(Compound 156), 2Chloro-2'methyl-4(pyrazin-2ylamino)benzophenone
(Compound 157), 2Chloro-2'methyl-4(5pyrimidylamino)benzophenone
(Compound 158),
2Chloro-2'methyl-4(5nitro-2thiazolylamino)benzophenone (Compound
159),
2Chloro-2'methyl-4((4methyl-3nitro-(1,2,4triazol-5ylamino))benzophenone
(Compound 160) and the N-oxides thereof wherein the nitrogen atom
of the heterocyclic R.sub.5 substituent is specifically
oxidised.
[0051] More preferred compounds are:
2Chloro-2'methyl-4(3pyridylamino)benz- ophenone (Compound 107),
4(3Amino-2pyridylamino)-2chloro-2'methylbenzophen- one (Compound
110), 2Chloro-4(4isoquinolylamino)- 2'methylbenzophenone (Compound
114), 2Chloro-2'methyl-4(4methyl-3pyridylamino)benzophenone
(Compound 116),
2Chloro-2'methyl-4(6methyl-3pyridylamino)benzophenone (Compound
117), 4(5Bromo-3pyridylamino)-2chloro-2'methylbenzophenone
(Compound 118), 2Chloro-2'methyl-4(8-quinolylamino)benzophenone
(Compound 121),
2Chloro-4(6ethoxy-3pyridylamino)-2'methylbenzophenone (Compound
122), 2Chloro-2'methyl-4(3quinolylamino)benzophenone (Compound
125), 2Chloro-4(4ethoxy-3pyridylamino)-2'methylbenzophenone
(Compound 126),
2Chloro-2'methyl-4(1methyl-7indolylamino)benzophenone (Compound
133), 2Chloro-2'methyl-4((1methyl-5indolylamino)benzophenone
(Compound 134),
2Chloro-2',5'-dimethyl-4(4methyl-3pyridylamino)benzophenone
(Compound 135)
2Chloro-2',5'-dimethyl-4(4isoquinoiylamino)benzophenone (Compound
136), 2Chloro-4(4isoquinolylamino)-2',4',5'-trimethylbenzophenone
(Compound 137),
2Fluoro-2'methyl-4(4methyl-3pyridylamino)benzophenone (Compound
139), 2,4'-Dichloro-2'methyl-4(4methyl-3pyridylamino)benzopheno- ne
(Compound 140),
2Chloro-4'-fluoro-4(4isoquinolylamino)-2'methylbenzophe- none
(Compound 141), 2Chloro-4(5isoquinolylamino)-2'methylbenzophenone
(Compound 143),
2Chloro-4(4isoquinolylamino)-4'-methoxy-2'methylbenzophen- one
(Compound 144),
2Fluoro-4(4isoquinolylamino)-4'-methoxy-2'methylbenzop- henone
(Compound 145),
2Chloro-4((3ethoxy)-4isoquinolylamino)-2'methylbenz- ophenone
(Compound 149), 2Chloro-4((1ethoxy)-4isoquinolylamino)-2'methylbe-
nzophenone (Compound 150) and the N-oxides
2Chloro-2'methyl-4((2pyridyl-N-- oxide)amino)benzophenone (Compound
112), 2Chloro-2'methyl-4((3pyridyl-N-ox- ide)amino)benzophenone
(Compound 113), 2Chloro-4((4isoquinolyi-N-oxide)ami-
no)-2'methylbenzophenone (Compound 128), Compounds of formula Ia
wherein X=S and wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are as indicated above, and
compounds of formula Ib wherein X=N--OH and wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8
are as indicated above are also generally preferred. 5
[0052] Specific compounds of formula Ia are:
2Chloro-2'methyl-4(4pyridylam- ino)thiobenzophenone,
2Chloro-2'methyl-4(2pyridylamino)thiobenzophenone,
2Chloro-2'methyl-4(5nitro-2pyridylamino)thiobenzophenone,
4(6Amino-5nitro-2pyridylamino)-2chloro-2'-methyl(thiobenzophenone),
6Chloro-2-(3chloro-4(2methylthiobenzoyl)phenylamino) isonicotinic
acid,
4(6carbonitrile-2pyridylamino)-2chloro-2'methyl(thiobenzophenone),
2Chloro-2'-methyl-4(3pyridylamino)thiobenzophenone, 5Chloro-4(5,
6diamino-2pyridylamino)-2'methyl(thiobenzophenone),
2Chloro-2'methyl-4(3nitro-2-pyridylamino)thiobenzophenone,
4(3Amino-2pyridylamino)-2chloro-2'-methyl(thiobenzophenone),
4(5Amino-2pyridylamino) -2chloro-2'- methy (thiobenzophenone) ,
2Chloro-4(4isoquinolylamino)-2'methyl(thiobenzophenone), t-Butyl
5(3chloro-4(2methylthiobenzoyl)phenylamino)nicotinoate,
2-Chloro-2'methyl-4(4methyl-3pyridylamino)thiobenzophenone,
2Chloro-2'methyl-4(6methyl-3pyridylamino)thiobenzophenone,
4-(5-Bromo-3pyridylamino)-2chloro-2'methyl(thiobenzophenone),
4-(5Carbonitrile-3-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone),
4-(3-Bromo-2-pyridylamino)-2-chloro-2'-methyl(thiobenzophenone),
2-Chloro-2'-methyl-4-(8-quinolylamino)thiobenzophenone,
2-Chloro-4-(6ethoxy-3-pyridy(amino)-2'-methyl(thiobenzophenone),
4-(4Bromo-1-isoquinolylamino)-2-chloro-2'-methyl(thiobenzophenone),
2-Chloro- 2'-methyl-4-(2-methyl-5-trifluoromethyl-3-pyridyla
mino)thiobenzophenone,
2-Chloro-2'-methyl-4-(3-quinolylamino)thiobenzophe- none,
2-Chloro-4-(4ethoxy-3-pyridylamino)-2'-methyl(thiobenzophenone),
2-Chloro-4-(2ethoxy- 3-pyridyla mino)-2'-methyl (thiobenzophenone),
2-Chloro-2'-methyl-4-(2-methyl-6-quinolylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(2-quinolylamino)thiobenzophenone,
2-Chloro-4-(7chloro-4-quinolylamino)-2'-methyl(thiobenzophenone),
2-Chloro-2'-methyl-4-(4-quinolylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(4-methyl-7-indolylamino)thiobenzophenone, and
2-Chloro-2'-methyl-4-(1-methyl-5-indolylamino)thiobenzophenone,
2-Chloro-2',5'-dimethyl-4-(4methyl-3pyridylamino)thiobenzophenone,
2-Chloro-2',5'-dimethyl-4-(4isoquinoylamino)thiobenzophenone,
2Chloro-4(4isoquinolylamino)-2',4',5'-trimethyl(thiobenzophenone),
2,3'-Dichloro-2'methyl-4(4methyl-3pyridylamino)thiobenzophenone,
2Fluoro-2'methyl-4(4methyl-3-pyridylamino) thiobenzophenone,
2,4'-Dichloro-2'methyl-4(4methyl-3pyridylamino)thiobenzophenone,
2Chloro-4'-fluoro-4(4isoquinolylamino)-2'methyl(thiobenzophenone),
4'-n-Butyl-2chloro-4(4isoquinolylamino)-2'methyl(thiobenzophenone),
2Chloro-4(5isoquinolylamino)-2'methyl(thiobenzophenone),
2Chloro-4(4isoquinolylamino)-4'-methoxy-2'methyl(thiobenzophenone),
2Fluoro-4(4isoquinolylamino)-4'-methoxy-2'methyl(thiobenzophenone),
2,4'-Dichloro-2'-methyl-4-(-methyl-7-indolylamino)thiobenzophenone,
2-Chloro-4-(1-methyl-7-indolylamino)-2',4',5'-trimethyl(thiobenzophenone)-
, 2-4-(1-methyl-7-indolylamino)thiobenzophenone,
2-Chloro-4-(3-ethoxy-4-is-
oquinolylamino)-2'-methyl(thiobenzophenone),
2-Chloro-4-(1-ethoxy-4-isoqui-
nolylamino)-2'-methyl(thiobenzophenone),
4-(2-Benzoxazolylamino)-2-chloro-- 2'-methyl(thiobenzophenone),
4-(-Methyl- 2-benzimidazolylamino)-2-chloro-2-
'-methyl(thiobenzophenone),
4-(2-Benzothiazolylamino)-2-chloro-2'-methyl(t- hiobenzophenone),
2-Chloro-2'-methyl-4-(2-pyrimidylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(2-methyl-purin-6-ylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(2-methyl-5-benzothiazolylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(pyrazin-2-ylamino)thiobenzophenone,
2-Chloro-2'-methyl-4-(5-pyrimidylamino)thiobenzophenone and salts
thereof with pharmaceutically acceptable acids, hydrates and
solvates.
[0053] Specific compound of formula Ib are:
2-Chloro-2'-methyl-4-(4-pyridy- lamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(2-pyridylamino)benzopheno- ne oxime,
2-Chloro-2'-methyl-4-(5-nitro-2-pyridylamino)benzophenone oxime,
4-(6-Amino-5-nitro-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime,
6-Chloro-2-((3-chloro-4((hydroxyimino)(2-methylphenyl)methyl))phenylamino-
) isonicotinic acid,
4-(6-carbonitrile-2-pyridylamino)-2-chloro-2'-methylb- enzophenone
oxime, 2-Chloro-2'-methyl-4-(3-pyridylamino)benzophenone oxime,
2-Chloro-4-(5,6-diamino-2-pyridylamino)-2'-methylbenzophenone
oxime, 2-Chloro-2'-methyl-4-(3-nitro-2-pyridylamino)benzophenone
oxime, 4-(3Amino-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime, 4-(5Amino-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime, 2-Chloro-4-(4-isoquinolylamino)- 2'-methylbenzophenone
oxime, t-Butyl
5-((3-chloro-4-((hydroxyimino)(2-methylphenyl)methyl))phenylamino)
nicotinoate,
2-Chloro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(6-methyl-3-pyridylamino)benzophenone oxime,
4-(5-Bromo-3-pyridylamino)-2-chloro-2'-methylbenzophenone oxime,
4-(5-Carbonitrile-3-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime, 4-(3-Bromo-2-pyridylamino)-2-chloro-2'-methylbenzophenone
oxime, 2-Chloro-2'-methyl-4-(8-quinolylamino)benzophenone oxime,
2-Chloro-4-(6-ethoxy-3-pyridylamino)-2'-methylbenzophenone oxime,
4-(4Bromo-1-isoquinolylamino)-2-chloro-2'-methylbenzophenone oxime,
2-Chloro-2'-methyl-4-(2-methyl-5-trifluoromethyl-3-pyridylamino)benz
ophenone oxime, 2-Chloro-2'-methyl-4-(3-quinolylamino)benzophenone
oxime, 2-Chloro-4-(4-ethoxy-3-pyridylamino)-2'-methylbenzophenone
oxime, 2-Chloro-4-(2-ethoxy-3-pyridylamino)-2'-methylbenzophenone
oxime, 2-Chloro-2'-methyl-4-(2-methyl-6-quinolylamino)benzophenone
oxime, 2-Chloro-2'-methyl-4-(2-quinolylamino)benzophenone oxime,
2-Chloro-4-(7chloro-4-quinolylamino)-2'-methylbenzophenone oxime,
2-Chloro-2'-methyl-4(4-quinolylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(1methyl-7-indolylamino)benzophenone oxime,
and 2-Chloro-2'-methyl-4-(1methyl-5-indolylamino)benzophenone
oxime,
2-Chloro-2',5'-dimethyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime, 2-Chloro-2',5'-dimethyl-4-(4-isoquinolylamino)benzophenone
oxime,
2-Chloro-4-(4-isoquinolylamino)-2',4',5'-trimethylbenzophenone
oxime,
2,3'-Dichloro-2'methyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime, 2-Fluoro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime,
2,4'-Dichloro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophenone
oxime,
2-Chloro-4'-fluoro-4-(4-isoquinolylamino)-2'-methylbenzophenone
oxime,
4'-n-Butyl-2-chloro-4-(4isoquinolylamino)-2'-methylbenzophenone
oxime, 2-Chloro-4-(5-isoquinolylamino)-2'-methylbenzophenone oxime,
2-Chloro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylbenzophenone
oxime,
2-Fluoro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylbenzophenone
oxime, 2,4'-Dichloro-2'-methyl-4-(1
-methyl-7-indolylamino)benzophenone oxime,
2-Chloro-4-(1methyl-7-indolylamino)-2',4',5'-trimethylbenzophenone
oxime,
2-Chloro-2',5'-dimethyl-4-(1methyl-7-indolylamino)benzophenone
oxime,
2-Chloro-4-(3-ethoxy-4-isoquinolylamino)-2'-methylbenzophenone
oxime,
2-Chloro-4-(1-ethoxy-4-isoquinolylamino)-2'-methylbenzophenone
oxime, 4-(2-Benzoxazolylamino)-2-chloro-2'-methylbenzophenone
oxime,
4-(1Methyl-2benzimidazolylamino)-2chloro-2'methylbenzophenone
oxime, 4-(2Benzothiazolylamino)-2-chloro-2'-methylbenzophenone
oxime, 2-Chloro-2'-methyl-4-(2-pyrimidylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(7-methyl-purin-6-ylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(2-methyl-5-benzothiazolylamino)benzophenone
oxime, 2-Chloro-2'-methyl-4-(pyrazin-2-ylamino)benzophenone oxime,
2-Chloro-2'-methyl-4-(5-pyrimidylamino)benzophenone oxime, and
salts thereof with pharmaceutically acceptable acids, hydrates and
solvates 6
[0054] wherein R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and X are as indicated above, and R.sub.3
represents (C.sub.1-C.sub.3)alkyl, fluoro, chloro, bromo, methoxy,
and hydroxy, and salts thereof with pharmaceutically acceptable
acids, hydrates and solvates, are generally preferred.
[0055] In formula Ic, R.sub.1 preferably represents methyl or
halogen, more preferably F or Cl; R.sub.2 represents one or more
substituents, preferably hydrogen, halogen, (C.sub.1-C.sub.3)alkyl,
methoxy or ethoxy, and R.sub.3 represents methyl, methoxy or
chloro.
[0056] Pharmacological Methods
[0057] To study the effect of the compound of the present invention
in vitro the inhibition of the IL-1.GAMMA. and TNF-.alpha.
secretion was measured using the following procedure: Cytokine
production was measured in the media from lipopolysaccharide (LPS)
stimulated peripheral blood mononuclear cells. The mononuclear
cells were isolated from human peripheral blood by Lymphoprep.RTM.
(Nycomed, Norway) fractionation and suspended in RPMI 1640 (growth
medium) with foetal calf serum (FCS, 2%), at a concentration of
5.times.10.sup.5 cells/mi. The cells were incubated in 24-well
tissue culture plates in 1 mL aliquots. Test compounds were
dissolved in dimethylsulfoxide (DMSO, 10 mM) and were diluted with
the medium. Compounds were added to the cells for 30 minutes, then
LPS (1 mg/mL final concentration) was added. The plates were
incubated for 18 hours, and the concentration of IL-1.alpha.and
TNF-.alpha. in the medium was determined by enzyme-linked
immunosorbent assays. The median inhibitory concentrations
(IC.sub.50) of the compounds were calculated. The results are shown
in Table 1.
[0058] The compounds of the present invention also show similar
activities in the ability to inhibit PMN (polymorphonuclear)
superoxide secretion which is also indicative of potentially useful
anti-inflammatory drugs. The compounds were tested using the
following procedure: Human polymorphonuclear (PMN) granulocytes
were isolated from human blood by dextran sedimentation,
Lymphoprep.RTM. fractionation and hypotonic lysis of contaminating
erythrocytes.
[0059] Superoxide anion generation was measured as the superoxide
dismutase inhibitable reduction of ferricytochrome C (Madhu, S. B.
et al, Inflammation, 16, 241, (1992)). The cells were suspended in
Hanks' balanced salt solution, and incubated for 10 minutes at
37.degree. C. with test compounds. The cells were primed by the
addition of TNF-.alpha. (3 ng/mL final concentration) for 10
minutes, and then ferricytochrome C, (final concentration
750.mu.g/mL), bovine serum albumin (BSA, final concentration 1
mg/mL) and formyl-methionyl-leucyl-phenylalanine (fMLP, final
concentration 10.sup.-7 M) were added for 3 minutes. The cells were
chilled on ice, and were spun down. The optical densities in the
cell-free supernatant was measured in a spectrophotometer. The
median inhibitory concentration (IC.sub.50) of the compounds was
calculated. The results, together with log P of the testet
compounds are shown in Table 1.
1 TABLE 1 Inhibition of cytokines and PMN-superoxide production in
vitro Log P by compounds of the present of com- invention. The
median inhibition pounds concentration (IC.sub.50, nM) of the PMN
present Comp. No. IL-1.beta. TNF-.alpha. superoxide invention Comp.
114 31 5.0 15 4.2 Comp. 128 15.8 3.1 12.6 4.4 Ref. comp. 13 7.1 5.0
4.9
[0060] Ref. comp.
(4(2aminophenylamino)-2chloro-2'methylbenzophenone, Compound 156
disclosed in WO 98/32730.
[0061] These results show that the compounds of the present
invention are able to inhibit the production of IL-1.beta.,
TNF-.alpha. and PMN-superoxide, and showing a pharmacological
activity comparable to a reference compound, thus making them
potentially useful in the treatment of inflammatory diseases. The
lower log P values of the compounds of the present invention
reflects a lower lipophilicity, which indicate compounds with an
improved bioavailability as compared to the reference compound.
[0062] P38a MAP Kinase Assay
[0063] Cell Culture
[0064] COS-1 cells (derived from African green monkey kidney
fibroblast-like cell containing wild-type T antigen under control
of the SV40 promotor) were obtained from ATCC (ATCC no. CRL-1650)
and grown in growth medium (DMEM without phenolred, 10% FCS, 2 mM
L-glutamine, 100U penicillin and 100 .mu.g streptomycin/mI) at
37.degree. C. with 5% CO.sub.2. The cells were passaged twice a
week by trypsination (0.25% trypsin, 1 mM EDTA in PBS) and were
split 1:10. The medium was changed every second or third day. The
cell line was regularly tested with the Mycoplasma PCR Primer Set
(Stratagene) and found to be free of Mycoplasma. Tissue culture
media, FCS, L-glutamine and penicilin and streptomycin are from
Bribco BRL, Gaithersburg, Md., USA.
[0065] Transient Expression of COS-1 Cells
[0066] On day one COS-1 cells were seeded in 143 cm.sup.2 petridish
with a density of 2.times.10.sup.4cells/cm.sup.2 in growth medium.
At day 2 the cells were co-transfected with 5 .mu.g (total) of
experimental plasmid DNA, expressing the FLAG-p38.alpha. and
FLAG-MKK6(EE). The plasmids were introduced into the COS-1 cells in
serum-free medium using DOTAP.RTM. (Boehringer-Mannheim, Mannheim,
Germany). Plasmid DNA was prepared and purified using the QIAGEN
EndoToxin-free Maxiprep-500 kit (Hilden, Germany). Briefly, DNA and
DOTAP.RTM. were mixed for exactly 15 min. at 37.degree. C. in the
CO.sub.2 incubator. The transfection-mixture was hereafter
transferred to a 15mL falcon-tube and transfection-medium (DMEM
with L-Glutamine and Pen./Strep. but without serum) was added to
the transfection-mixture, followed by addition to the
cell-monolayer. After 4 hours of incubation with DOTAP.RTM. and
plasmids, the medium containing double amount of serum was added to
the cells bringing the final concentration of serum up to 10%. The
cells were then incubated for 24 hours before kinase reaction.
[0067] Immunoprecipitation
[0068] After 24 hrs of incubation the reaction was stopped by
putting the petridish on an ice-bath. The medium was aspirated, and
the cell monolayer was washed once in ice-cold PBS (137 mM NaCI,
1.5 mM KH.sub.2PO.sub.4, 2.7 mM KCI, 8.1 mM
Na.sub.2HPO.sub.4.multidot.2H.sub.2O- ), and hereafter solubilised
for 10 min. in 1.5 mL lysis buffer (50 mM HEPES, pH 7.5, 150 mM
NaCl, 10 mM EDTA, 10 mM Na.sub.4P.sub.2O.sub.7, 100 mM NaF, 2 mM
Na.sub.3VO.sub.4,1% Triton-X-100, Pefabloc 500 .mu.M, Leupeptin 10
.mu.g/.mu.l, Aprotinin 10 .mu.g/.mu.l) was added. The
cell-monolayer was scraped by a rubber-policeman, and transferred
to an Eppendorf tube. The solubilised cells were clarified by
centrifugation at 10.000xg for 10 min. at 4.degree. C. The
supernatant was transferred to 50 .mu.l prewashed Protein G
Sepharose beads in HNT-buffer (30 mM HEPES, pH 7.5, 30 mM NaCl,
0.1% Triton X-100) and were incubated with 2 .mu.g/sample of
monoclonal anti-FLAG.RTM. M2 antibody (raised against the
FLAG-epitope, NH.sub.2Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys-COOH) for 1
hour at room temperature. The anti-FLAG M2 monoclonal antibody was
obtained from Sigma (cat. no. F-3165). Approx. 60 .mu.g protein of
clarified cell lysate were added to the preadsorbed anti-FLAG.RTM.
antibodies on Protein G Sepharose beads and incubated for 90 min.
at 4.degree. C. in a blood sample mixer. After the
immunoprecipitation period the Sepharose beads were washed twice in
lysis buffer and twice in a kinase reaction buffer (25 mM HEPES pH
7.5, 10 mM magnesium acetate, 5011M ATP).
[0069] Incubation of the Compounds with Purified P38.alpha.
Kinase
[0070] The pre-washed immunoprecipitated anti-FLAG-p38 adsorbed on
Protein G Sepharose beads was washed twice in 1.times.kinase-buffer
(25 mM HEPES pH 7.5, 10 mM magnesium acetate, 50.mu.M ATP), and the
supernatant was aspirated. The compounds were diluted in
1.times.kinase buffer at the appropriate concentration. The
compounds were added to the washed immunoprecipitated and activated
FLAG-p38 adsorbed on the Protein G Sepharose beads for 30 min. at
30.degree. C. in a volume of 100 .mu.l. Every 10 min. the Eppendorf
tubes were tapped to ensure that the beads and the compounds were
in the solution. After 30 min. incubation, the beads were spinned
down and the supernatant was aspirated.
[0071] P38.alpha. MAP Kinase Reaction
[0072] The kinase reaction was started by adding 1 .mu.g GST-ATF-2
substrate (Santa Cruz, Laiolla, Calif., USA, cat. no. sc-4114)
together with 2 .mu.Ci -.gamma.--.sup.32P-ATP in
1.times.kinase-buffer per sample. The reaction was allowed to
proceed for 30 min. at 30.degree. C., and it was stopped by adding
40 .mu.l of 2.times.SDS-sample buffer to the kinase reaction. The
samples were boiled, spinned down, and resolved on a 15% SDS-PAGE.
The dried SDS-PAGE gel was exposed to a Phospho-Imager screen and
the radioactive PHAS-1 bands were quantified by the STORM860
Phospho-Imager (Molecular Dynamics, Sunnyvale, Calif., USA) using
the ImageQuaNT software.
[0073] The inhibition exhibited by compound 114 in this assay is
shown in table 2 below:
2TABLE 2 IC.sub.50 values for the inhibition of p38.alpha. MAP
Compound No. kinase, mean concentration (nM) Compound 114 12.8
Reference compound, SB 203580 1056.6
[0074] Reference compound SB 203580 is a widely used reference
compound for p38.alpha. MAP kinase inhibition. The compound is
commercially available at Calbiochem (Calbiochem-Novabiochem
LaJolla, Calif., USA).
[0075] These results show, that the compounds of this invention are
potent p38.alpha. MAP kinase inhibitors with an improved
pharmacological activity compared to a reference compound, thus
making them potentially useful in the treatment of inflammatory
diseases.
[0076] To study the compounds of the present invention in vivo the
12-0-tetradecanoylphorbol -13-acetate (TPA) induced murine chronic
skin inflammation model can be used (De Young, L. M. et al., Agents
Actions 26, 335-341 (1989); Carlson, R. P. et al., Agents Actions
17, 197-204 (1985); Alford, J. G. et al., Agents Action 37, (1992);
Stanley, P. L. et al., Skin Pharmacol. 4, 262-271 (1991)), cf. the
description of method in WO 98/32730 hereby incorporated by
reference. These results show that compounds of the present
invention are of the same potency compared to known reference
compounds, e.g. hydrocortisone with its known side effects, whereas
the compounds of the present invention are well tolerated and are
non-toxic. Some members of the present class of compounds show a
very low absorption, thus making them especially useful in the
treatment of various dermatological diseases. In general, they may
be administered by e.g. oral, intravenous, intranasal, topically or
transdermal routes.
[0077] Methods of Preparing Compounds of Formula I
[0078] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art of organic
synthesis. The compounds of the present invention may be
synthesised using the methods outlined below, together with methods
known in the art of synthetic organic chemistry, or variations
thereof as appreciated by those skilled in the art. Preferred
methods include, but are not limited to, those described below.
[0079] The novel compounds of formula I, Ia, and lb may be prepared
using the reactions and techniques described in this section. The
reactions are performed in solvents appropriate to the reagents and
materials employed and are suitable for the transformations being
effected. Also, in the synthetic methods described below, it is
understood that all proposed reaction conditions, including choice
of solvent, reaction atmosphere, reaction temperature, duration of
experiment and work-up procedures, are chosen as standard
conditions for that reaction, which should be readily recognised by
one skilled in the art. It is understood by one skilled in the art
of organic synthesis that the functionality present on various
portions of the educt molecule must be compatible with the reagents
and reactions proposed. Not all compounds of formula I falling into
a given class may be compatible with some of the reaction
conditions required in some of the methods described. Such
restrictions to the substituents which are compatible with the
reaction ready apparent to on skilled in the art and alternate
methods can be used.
[0080] The following abbreviations have been used throughout this
specification: BINAP=racemic or non-racemic
2,2'bis(diphenylphosphino)-1,- 1'-binaphthyl,
CDC1.sub.3=deuteriochloroform, DMF=N,N-dimethyl-formamide,
DMSO-d.sub.6=hexadeuterodimethylsulfoxide, DMSO=dimethylsulfoxide,
EtOAc =ethyl acetate, Et.sub.2O=diethylether,
Pd.sub.2(dba).sub.3=tris(dibenzyl- ideneacetone)dipalladium(O),
mCPBA=meta-chloroperbenzoic acid, MeOH=methanol,
NaOt-Bu=sodium-tert-butoxide, KOt-Bu=potassium-tert-butoxi- de
THF=tetrahydrofurane, TLC=thin layer chromatography. 7
[0081] L: F, Cl, Br, I, or OSO.sub.2CF.sub.3
[0082] Y: Cl, Br, I, OSO.sub.2R'
[0083] FGI: Functional Group Interconversion
[0084] Compounds according to the present invention may be prepared
by a process comprising coupling of an amine of the formula III
with an bromide, iodide, fluoride, chloride or triflate with the
formula II, as shown in Scheme 1, where R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, and X are as defined in general formula I, except
that any substituents or functional group which are potentially
reactive in the coupling reaction may themselves be protected
before the coupling reaction is performed and subsequently
removed.
[0085] The coupling reaction is carried out using any of the
methods for the formation of diphenylamines known to one skilled in
the art of organic synthesis.
[0086] The preferred method is the palladium catalysed amination
method which comprises coupling of an amine with an
heteroarylhalogenide (or heteroaryltriflate) in the presence of a
base, a suitable Pd source, and a suitable phosphine ligand in an
inert solvent. (References: Wolfe, J. P.; Wagaw, S.; Buchwald, S.
L.;J. Am. Chem. Soc., (1996), 118, 7215-16; Wagaw, S.; Buchwald, S.
L.; J. Org. Chem., (1996), 61, 7240-41; Wolfe, J. P.; Buchwald, S.
L.; Tetrahedron Lett., (1997), 38, 6359-62; Hong. Y. etal.,
Tetrahedron Lett., (1997), 38, 5607-10).
[0087] The palladium compound used in the process is not
particularly limited, and as specific examples are palladium(II)
acetate, palladium(II) chloride, palladium(II) bromide,
dichlorobis(triphenylphosp- hine)palladium(II),
tetrakis(triphenylphosphine)palladium(0),
tris(dibenzylideneacetone)dipalladium(0). The preferred ligand
include, but are not limited to, racemic or non-racemic
2,2'-bis(diphenylphosphino- )-1,1'-binaphthyl (hereinafter referred
to as BINAP), tri-o-tolylphosphine, tri-tert-butylphosphine,
1,1'-bis(diphenylphosphino- )-ferrocene,
bis[(2diphenylphosphino)phenyl]ether (DPEphos),
2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl,
2-(di-tert-butylphosphino)biphenyl, and
9,9-dimethyl-4,6-bis(diphenylphos- phino)xanthene (Xantphos). The
amount of palladium and ligand used in this process is typically in
the range 0.1 to 10% by mole relative to the amount of the aromatic
halide (or triflate) used.
[0088] Especially NaOt-Bu and caesium carbonate (Cs.sub.2CO.sub.3)
have proven to be the best bases in this process, but other bases
may be used as well.
[0089] The reaction is typically performed at elevated temperature
(80-120 .degree. C.) in inert solvents like 1,4-dioxane, toluene,
benzene and tetrahydrofurane under an inert atmosphere like argon
or nitrogen.
[0090] The coupling reaction may also be carried out by
nucleophilic substitution of a heteroarylhalogenide with an amine,
either in the presence of a base in a polar aprotic solvent, or
without a solvent. The preferred base is KOt-Bu or NaH, but other
bases may be used as well. The preferred solvent is dimethyl
sulfoxide, but other solvents such as DMF may be used as well. The
reaction is carried out at elevated temperature (120.degree. C.
-150.degree. C.) for 12-24h.
[0091] Compounds according to the present invention in which
R.sub.4 is not hydrogen may be prepared by a process comprising
coupling of an amine of the formula I (R.sub.4=H) with an
alkylating agent, as shown in Scheme 1, where R.sub.1, R.sub.2,
R.sub.3, R.sub.5, and X are as defined in general formula I, except
that any substituents or functional group which are potentially
reactive in the coupling reaction may themselves be protected
before the coupling reaction is performed and subsequently
removed.
[0092] Typically alkylating agents of the general formula R-Y
include, but are not limited to, iodides (Y=I), bromides (Y=Br),
chlorides (Y=Cl) and sulfonates (Y=OSO.sub.2R', where R' represents
methyl, trifluoromethyl or 4-methylphenyl).
[0093] Compounds according to the present invention may in special
cases be prepared by a simple functional group interconversion
(FGI), meaning a standard process, known to those skilled in the
art of organic synthesis, where a functional group in compounds
with the general formula I is transformed into a different
functional group in one or more synthetic steps, leading to a new
compound with the general formula I. Examples of such processes
are, but are not limited to, hydrolysis of an ester to give an acid
under basic conditions; deprotection of an methylether to give an
phenol by treatment with e.g. borontribromide (BBr.sub.3);
catalytic hydrogenation of an olefin to give an saturated
hydrocarbon and reduction of a nitro group to give an amine.
[0094] Compounds according to the present invention with the
general formula I were X=S may be prepared from the ketone (with
the general formula I, C=O) by such a FGI process, by using one of
the many thiocarbonylating reagent, known to those skilled in the
art of organic synthesis. Examples of such thiocarbonylating
reagents include, but are not limited to, phosphorous pentasulfide
(P.sub.4S10), or Lawesson's reagent
(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide-
) or the like. Compounds accordingly to the present invention with
the general formula I were X=N--OH may be prepared from the ketone
(with the general formula I, C=O) by treatment with hydroxylamine,
or a protected derivative thereof followed by deprotection, in an
appropriate solvent like e.g. pyridine or methanol. 8
[0095] Compounds according to the present invention with the
general formula III may be prepared by several methods known to
those skilled in the art of organic synthesis. One useful sequence
is shown in Scheme 2. The key step comprising coupling of a bromide
(or iodide) with the general formula VI with an acid chloride with
the general formula V to afford the benzophenone with the general
formula IV. This compound IV may then be reduced to the
corresponding amine with the general formula III by treatment with
standard reducing agents. Examples of such reducing agents include,
but are not limited to, stannous chloride dihydrate; hydrogen,
ammonium formiate, or hydrazine hydrate and a catalytic amount of
palladium on carbon. The coupling reaction is done by transforming
the bromide (VI) into a reactive organometallic intermediate, e.g.
by treatment with butyllithium to afford the lithium derivative or
by treatment with magnesium to afford the magnesium derivative. The
reactivity of this intermediate is then modulated by
transmetalation to e.g. zinc, by treatment with ZnCl.sub.2,
ZnBr.sub.2, or ZnI.sub.2. This organozinc compound is then coupled
with the acid chloride, with the general formula V, under the
influence of a palladium(O) complex in catalytic amount. Examples
of such catalyst include but are not particularly limited to
tetrakis(triphenylphosphine)palladium(0),
tetrakis(triphenylarsine)palladium(O),
dichlorobis(triphenylphosphine)pal- ladium(II), or
benzylchlorobis(triphenylphosphine)palladium(II).
[0096] As shown in Scheme 2 compounds with the general formula IV
(X=O) may be transformed by a FGI process to give compounds with
the general formula IV (X=S or X =N--OH) as described above. This
is only to illustrate the flexibility in the synthesis and in
general the described sequence of processes is only one of many
possible strategies for the synthesis of compound of the present
invention. That is, it may be more advantageous in some cases to
alter the sequence of the processes described above. The described
sequence of processes is not considered as being limited for the
preparation of the compounds of the present invention with the
general formula I and alteration of the reaction sequence is an
obvious alternative for those skilled in the art of organic
synthesis.
[0097] Pharmaceutical Compositions
[0098] In another aspect, the invention relates to a pharmaceutical
composition comprising, as an active component, a compound of
formula I, Ia, Ib or Ic together with a pharmaceutically acceptable
excipient or carrier. The term "pharmaceutically acceptable" is
intended to indicate that the excipent or carrier included in the
composition is compatible with the other ingredients and not toxic
or otherwise deleterious to a patient to whom the composition is
administered.
[0099] Pharmaceutical compositions of the invention may be in unit
dosage form such as tablets, pills, capsules, powders, granules,
elixirs, syrups, emulsions, ampoules, suppositories or parenteral
solutions or suspensions; for oral, parenteral, opthalmic,
transdermal, intra-articular, topical, pulmonal, nasal, buccal or
rectal administration or in any other manner appropriate for the
formulation of anti-inflammatory compounds and in accordance with
accepted practices such as those disclosed in Remington: The
Science and Practice of Pharmacy. 19.sup.th Ed., Mack Publishing
Company, 1995. The term "unit dosage" is intended to indicate a
unitary, i.e. a single dose which is capable of being administered
to a patient, and which may be readily handled and packed,
remaining as a physically and chemically stable unit dose
comprising either the active component as such or a mixture of it
with solid or liquid pharmaceutical excipients or carriers. In the
composition of the invention, the active component may be present
in an amount of from about 0.1-100% by weight of the
composition.
[0100] For oral administration in the form of a tablet or capsule,
a compound of formula I may suitably be combined with an oral,
non-toxic, pharmaceutically acceptable carrier such as ethanol,
glycerol, water or the like. Furthermore, suitable binders,
lubricants, disintegrating agents, flavouring agents and colourants
may be added to the mixture, as appropriate. Suitable binders
include, e.g., lactose, glucose, starch, gelatin, acacia gum,
tragacanth gum, sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes or the like. Lubricants include, e.g.,
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride or the like.
Disintegrating agents include, e.g., starch, methyl cellulose,
agar, bentonite, xanthan gum or the like.
[0101] For the preparation of solid compositions such as tablets,
the active compound of formula I is mixed with one or more
excipients, such as the ones described above, and other
pharmaceutical diluents such as water to make a solid
preformulation composition containing a homogenous mixture of a
compound of formula I. The term "homogenous" is understood to mean
that the compound of formula I is dispersed evenly throughout the
composition so that the composition may readily be subdivided into
equally effective unit dosage forms such as tablets or capsules.
The preformulation composition may then be subdivided into unit
dosage forms containing from about 0.05 to about 1000 mg, in
particular from about 0.1 to about 500 mg, of the active compound
of the invention.
[0102] Liquid formulations for either oral or parenteral
administration of the compound of the invention include, e.g.,
aqueous solutions, syrups, aqueous or oil suspensions and emulsion
with edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil. Suitable dispersing or suspending agents for aqueous
suspensions include synthetic or natural gums such as tragacanth,
alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin,
methylcellulose or polyvinylpyrolidone.
[0103] For parenteral administration, e.g. intramuscular,
intraperitoneal, subcutaneous or intravenous injection or infusion,
the pharmaceutical composition preferably comprises a compound of
formula I dissolved or solubilised in an appropriate,
pharmaceutically acceptable solvent. For parenteral administration,
the composition of the invention may include a sterile aqueous or
non-aqueous solvent, in particular water, isotonic saline, isotonic
glucose solution, buffer solution or other solvent conventionally
used for parenteral administration of therapeutically active
substances, in particular antiproliferative agents. The composition
may be sterilised by, for instance, filtration through a
bacteria-retaining filter, addition of a sterilising agent to the
composition, irradiation of the composition, or heating the
composition. Alternatively, the compound of the invention may be
provided as a sterile, solid preparation, e.g. a freeze-dried
powder, which is dissolved in sterile solvent immediately prior to
use.
[0104] The composition intended for parenteral administration may
additionally comprise conventional additives such as stabilisers,
buffers or preservatives, e.g. antioxidants such as
methylhydroxybenzoate or the like.
[0105] Compositions for rectal administration may be in the form of
a suppository incorporating the active ingredient and a carrier
such as cocoa butter, or in the form of an enema.
[0106] Compositions suitable for intra-articular administration may
be in the form of a sterile aqueous preparation of the active
ingredient which may be in microcrystalline form, for example, in
the form of an aqueous microcrystalline suspension. Liposomal
formulations or biodegradable polymer systems may also be used to
present the active ingredient for both intra-articular and
ophthalmic administration.
[0107] Compositions suitable for topical administration, including
eye treatment, include liquid or semi-liquid preparations such as
liniments, lotions, gels, applicants, oil-in-water or water-in-oil
emulsions such as creams, ointments or pastes; or solutions or
suspensions such as drops. For topical administration, the active
component preferably comprises from 1% to 20% by weight of the
composition, but the active ingredient may comprise as much as 50%
w/w.
[0108] Compositions suitable for administration to the nasal or
buccal cavity or for inhalation include powder, self-propelling and
spray formulations, such as aerosols and atomizers. Compositions
suitable for nasal or buccal administration may comprise 0.1% to
20% w/w. for example about 2% w/w of active ingredient.
[0109] The composition may additionally comprise one or more other
active components conventionally used in the treatment of various
inflammatory diseases and conditions. Examples of such additional
active components may be selected from the group consisting of
glucocorticoids, vitamin D and vitamin D analogues, antihistamines,
platelet activating factor (PAF) antagonists, anticholinergic
agents, methylxanthines, .beta.-adrenergic agents, COX-2
inhibitors, salicylates, infomethacin, flufenamate, naproxen,
timegadine, gold salts, penicillamine, serum cholesterol lowering
agents, retinoids, zinc salts and salicylazosulfapyridine.
[0110] In a further aspect, the invention relates to the use of a
compound of formula I for the preparation of a medicament for the
treatment or prophylaxis of inflammatory diseases or conditions. In
a still further aspect, the invention relates to a method of
treating inflammatory diseases or conditions, the method comprising
administering, to a patient in need thereof, an effective amount of
a compound of formula I.
[0111] A suitable dosage of the compound of the invention will
depend, inter alia, on the particular compound selected for the
treatment, the route of administration, the age and condition of
the patient, the severity of the disease to be treated and other
factors well known to the practising physician. The compound may be
administered either orally or parenterally according to different
dosing schedules, e.g. daily or with weekly intervals. In general a
single dose will be in the range from 0.01 to 400 mg/kg body
weight, such as from 0.1 to 100 mg/kg body weight. The compound may
be administered as a bolus (i.e. the entire daily dosis is
administered at once) or in divided doses two or more times a
day.
[0112] Inflammatory diseases or conditions contemplated for
treatment with the present compounds are inflammatory diseases
where modulation of cytokine expression and secretion may be
mediated by MAP kinases such as the p38 MAP kinase as discussed
above. Examples of inflammatory diseases or conditions believed to
be mediated by the p38 MAP kinase are selected from the group
consisting of asthma, allergy, arthritis, including rheumatoid
arthritis, osteoarthritis and spondyloarthritis, gout,
atherosclerosis, inflammatory bowel diease, Crohn's disease,
proliferative and inflammatory skin disorders, such as psoriasis,
atopic dermatitis and acne vulgaris, uveitis, sepsis, septic shock,
AIDS related diseases and osteoporosis.
[0113] The treatment may additionally involve administration of one
or more other anti-inflammatory active components such as
glucocorticoids, vitamin D and vitamin D analogues, antihistamines,
platelet activating factor (PAF) antagonists, anticholinergic
agents, methylxanthines, .beta.-adrenergic agents, COX-2
inhibitors, salicylates, infomethacin, flufenamate, naproxen,
timegadine, gold salts, penicillamine, serum cholesterol lowering
agents, retinoids, zinc salts and salicylazosulfapyridine.
[0114] The invention is further described in the following general
procedures, preparations and examples which are not in any way
intended to limit the scope of the invention as claimed.
EXAMPLES
[0115] General Procedures, Preparations and Examples
[0116] Specific examples of compounds of formula I are listed in
Table 3. All melting points are uncorrected. For .sup.1H and
.sup.13C nuclear magnetic resonance (NMR) spectra (300 MHz for
.sup.1H) chemical shift values (.delta.) (in ppm) are quoted,
unless otherwise specified, for deuteriochloroform and
hexadeuterodimethyl-sulfoxide solutions relative to internal
tetramethylsilane (.delta.0.00) or chloroform (.sup.1H NMR
.delta.7.25, .sup.13C NMR .delta.76.81). The value for a multiplet
(m), eventually defined as a doublet (d), triplet (t) or quartet
(q) is given at the approximate mid point unless a range is quoted.
A signal may also be defined as a singlet (s) or broad singlet (b).
The organic solvents used were anhydrous. The term "chromatography"
refers to column chromatography using the flash technique and was
performed on silica gel.
3TABLE 3 Compounds of General formula I Comp. No. Example No. X
R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 Comp. 101
Ex. 1 O CH.sub.3 H 2-Cl H 9 H -- Comp. 102 Ex. 2 O CH.sub.3 H 2-Cl
H 10 H -- Comp 103 O CH.sub.3 H 2-Cl H Same as ex. 2 5-NO.sub.2 --
Ex. 3 Comp. 104 O CH.sub.3 H 2-Cl H Same as ex. 2
5-NO.sub.2,6-NH.sub.2 -- Ex. 4 Comp. 105 O CH.sub.3 H 2-Cl H Same
as ex. 2 4-COOH,6-Cl -- Ex. 5 Comp. 106 O CH.sub.3 H 2-Cl H Same as
ex. 2 3-CN -- Ex. 6 Comp. 107 Ex. 7 O CH.sub.3 H 2-Cl H 11 H --
Comp. 108 O CH.sub.3 H 2-Cl H Same as ex. 2 5,6-di-NH.sub.2 -- Ex.
8 Comp. 109 O CH.sub.3 H 2-Cl H Same as ex. 2 3-NO.sub.2 -- Ex. 9
Comp. 110 O CH.sub.3 H 2-Cl H Same as ex. 2 3-NH.sub.2 -- Ex. 10
Comp. 111 O CH.sub.3 H 2-Cl H Same as ex.2 5-NH.sub.2 -- Ex. 11
Comp. 112 Ex. 12 O CH.sub.3 H 2-Cl H 12 H -- Comp. 113 Ex. 13 O
CH.sub.3 H 2-Cl H 13 H -- Comp. 114 Ex. 14 O CH.sub.3 H 2-Cl H 14 H
H Comp. 115 Ex. 15 O CH.sub.3 H 2-Cl H 15 3-COOC.sub.4H.sub.9 --
Comp. 116 O CH.sub.3 H 2-Cl H Same as ex. 7 4-CH.sub.3 -- Ex. 16
Comp. 117 O CH.sub.3 H 2-Cl H Same as ex. 7 6-CH.sub.3 -- Ex. 17
Comp. 118 O CH.sub.3 H 2-Cl H Same as ex. 7 5-Br -- Ex. 18 Comp.
119 O CH.sub.3 H 2-Cl H Same as ex. 7 5-CN -- Ex. 19 Comp. 120 O
CH.sub.3 H 2-Cl H same as ex. 2 3-Br -- Ex. 20 Comp. 121 Ex. 21 O
CH.sub.3 H 2-Cl H 16 H H Comp. 122 O CH.sub.3 H 2-Cl H same as ex.
7 6-OC.sub.2H.sub.5 -- Ex. 22 Comp. 123 Ex. 23 O CH.sub.3 H 2-Cl H
17 4-Br H Comp. 124 O CH.sub.3 H 2-Cl H same as ex. 7 2-CH.sub.3,
5-CF.sub.3 -- Ex. 24 Comp. 125 Ex. 25 O CH.sub.3 H 2-Cl H 18 H H
Comp. 126 O CH.sub.3 H 2-Cl H same as ex. 7 4-OC.sub.2H.sub.5 --
Ex. 26 Comp. 127 O CH.sub.3 H 2-Cl H same as ex. 7
2-OC.sub.2H.sub.5 -- Ex. 27 Comp. 128 Ex. 28 O CH.sub.3 H 2-Cl H 19
H H Comp. 129 Ex. 29 O CH.sub.3 H 2-Cl H 20 H 2- CH.sub.3 Comp. 130
Ex. 30 O CH.sub.3 H 2-Cl H 21 H 7-Cl Comp. 131 Ex. 31 O CH.sub.3 H
2-Cl H 22 H H Comp. 132 O CH.sub.3 H 2-Cl H same as ex. 30 H H Ex.
32 Comp. 133 Ex. 33 O CH.sub.3 H 2-Cl H 23 H H Comp. 134 Ex. 34 O
CH.sub.3 H 2-Cl H 24 H H Comp. 135 O CH.sub.3 5- 2-Cl H Same as ex.
7 4-CH.sub.3 -- Ex. 35 CH.sub.3 Comp. 136 O CH.sub.3 5- 2-Cl H Same
as ex. 14 H H Ex. 36 CH.sub.3 Comp. 137 O CH.sub.3 4- 2-Cl H Same
as ex. 14 H H Ex. 37 CH.sub.3, 5- CH.sub.3 Comp. 138 O CH.sub.3
3-Cl 2-Cl H Same as ex. 7 4-CH.sub.3 -- Ex. 38 Comp. 139 O CH.sub.3
H 2-F H Same as ex. 7 4-CH.sub.3 -- Ex. 39 Comp. 140 O CH.sub.3
4-Cl 2-Cl H Same as ex. 7 4-CH.sub.3 -- Ex. 40 Comp. 141 O CH.sub.3
4-F 2-Cl H Same as ex. 14 H H Ex. 41 Comp. 142 O CH.sub.3 4-n- 2-Cl
H Same as ex. 14 H H Ex. 42 butyl Comp. 143 Ex. 43 O CH.sub.3 H
2-Cl H 25 H H Comp. 144 O CH.sub.3 4- 2-Cl H Same as ex. 14 H H Ex.
44 OC H.sub.3 Comp. 145 O CH.sub.3 4- 2-F H Same as ex. 14 H H
Ex.45 OC H.sub.3 Comp. 146 O CH.sub.3 4-Cl 2-Cl H Same as ex. 33 H
H Ex. 46 Comp. 147 O CH.sub.3 4- 2-Cl H Same as ex. 33 H H Ex. 47
CH.sub.3, 5- CH.sub.3 Comp. 148 O CH.sub.3 5- 2-Cl H Same as ex. 33
H H Ex. 48 CH.sub.3 Comp. 149 O CH.sub.3 H 2-Cl H Same as ex. 14
3-OC.sub.2H.sub.5 H Ex. 49 Comp. 150 O CH.sub.3 H 2-Cl H Same as
ex. 14 1-OC.sub.2H.sub.5 H Ex. 50 Comp. 151 Ex. 51 O CH.sub.3 H
2-Cl H 26 -- -- Comp. 152 Ex. 52 O CH.sub.3 H 2-Cl H 27 -- -- Comp.
153 Ex. 53 O CH.sub.3 H 2-Cl H 28 -- -- Comp. 154 Ex. 54 O CH.sub.3
H 2-Cl H 29 -- -- Comp. 155 Ex. 55 O CH.sub.3 H 2-Cl H 30 -- --
Comp. 156 Ex. 56 O CH.sub.3 H 2-Cl H 31 -- -- Comp. 157 Ex. 57 O
CH.sub.3 H 2-Cl H 32 -- -- Comp. 158 Ex. 58 O CH.sub.3 H 2-Cl H 33
-- -- Comp. 159 Ex. 59 O CH.sub.3 H 2-Cl H 34 -- -- Comp. 160 Ex.
60 O CH.sub.3 H 2-Cl H 35 -- --
[0117] The numbering in Table 2 refers to the numbering in the
formula below, R.sub.6 and R.sub.7 being defined as for general
formula I: 36
[0118] General Procedure 1
[0119] Coupling of compounds of the general formula II with
compounds of the general formula III to give compounds of the
general formula I, or a protected derivative thereof.
[0120] In a screw cap vessel an amine (1.0 eq.) with the general
formula III was dissolved in 1,4-dioxane or toluene, and a
halogenide (1.0-1.1 eq.), with the general formula II was added.
The vessel was flushed with argon, the base (Cs.sub.2CO.sub.3 or
NaOt-Bu, 1.4 eq.), Pd.sub.2(dba).sub.3 (0.02 eq.), and BINAP (0.04
eq.) were added, the vessel was again flushed with argon and
closed. The resulting suspension was first shaken vigorously at
room temperature for 5 min and then at 100.degree. C. -110.degree.
C. for 4-20 h or until the halogenide II had disappeared as seen on
TLC. The reaction mixture was allowed to cool to room temperature.
The reaction mixture was poured into a mixture of EtOAc and water.
The organic phase was separated, and the water phase was extracted
with EtOAc three times. The combined organic phases were washed
with water and saturated aqueous NaCI ,dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue was purified either by
chromatography and/or crystallisation to afford the coupled product
with the general formula I, or a protected derivative thereof.
[0121] General Procedure 2
[0122] Coupling of compounds of the general formula II with
compounds of the general formula III to give compounds of the
general formula I, or a protected derivative thereof.
[0123] An amine of the general formula (III) (1 eq.) was dissolved
in DMSO (0.1- 0.2M), and a heteroarylchloride or heteroarylfluoride
(1 eq.) of the general formula (II) was added. Potassium t-butoxide
, 2 eq., or 3 eq. if compound II was provided as the hydrochloride,
was dissolved in DMSO (0.2- 0.4M), and the solution was added
dropwise to the reaction mixture. The reaction was stirred under an
argon atmosphere at 120-150.degree. C. for 12-24h. The reaction
mixture was poured into water and extracted with EtOAc three times.
The combined organic phases were washed with saturated aq. NaCl,
dried (MgSO.sub.4), filtered and concentrated in vacuo, and the
crude product was purified by flash chromatography to afford the
coupled product with the general formula I, or a protected
derivative thereof.
[0124] General Procedure (3)
[0125] Coupling of compounds of the general formula VI with
compounds of the general formula V to give compounds of the general
formula IV, or a protected derivative thereof.
[0126] The bromide (80 mmol) with the general formula VI was
dissolved in dry THF (65 mL) and cooled with stirring to
-78.degree. C under an atmosphere of argon. n-Butyllithium (80
mmol, 1.6 M solution in hexane) was then added dropwise, keeping
the internal temperature below -65.degree. C. and stirring the
resulting mixture for further 15 min. A THF solution of ZnCl.sub.2
(100 mmol, 1.0 M) was added dropwise and the reaction mixture was
allowed to warm to room temperature. After 2 h the reaction mixture
was cooled to 0.degree. C., and tetrakis(triphenylphosph-
ine)palladium(O) (4.0 mmol) was added followed by the dropwise
addition of the acid chloride (84 mmol), with the general formula
V, in THF. The reaction mixture was allowed to warm to 20.degree.
C. and stirred for ca 16 h. The resulting yellow solution, was
filtered and the filtrate poured into a mixture of EtOAc/water 1:1,
shaken and separated. The aqueous phase was extracted with two more
portions of EtOAc. The organic phases were combined, dried
(MgSO.sub.4), filtered, and concentrated in vacuo to afford the
crude product. Further purification was done by flash
chromatography and/or crystallisation to give the title compound
IV, or a protected derivative thereof.
[0127] General Procedure (4)
[0128] Reduction of compounds of the general formula IV with
stannous chloride dihydrate to give compounds of the general
formula III, or a protected derivative thereof.
[0129] A mixture of a compound with the general formula IV (5 mmol)
and stannous chloride dihydrate (5.64 g, 25 mmol) in absolute
ethanol (50 mL) was heated to 70.degree. C. under argon. After 1
hour, or until the starting material had disappeared as seen on
TLC, the solution was allowed to cool to room temperature and then
poured into ice/water. The pH was made alkaline by the addition of
saturated sodium hydroxide (50 mL) before being extracted with
ethyl acetate (3.times.100 mL). The organic phase was dried
(MgSO.sub.4), filtered and evaporated to afford the crude product.
The crude product was further purified either by crystallisation or
flash chromatography to yield the title compound or a protected
derivative thereof.
[0130] General Procedure (5)
[0131] Oxidation of compounds of the general formula I with mCPBA
to give the corresponding N-oxides.
[0132] A compound of the general formula I (1 eq.) was dissolved in
CH.sub.2Cl.sub.2 and mCPBA (1.2 eq.) was added, and the reaction
mixture was stirred at room temperature for 1-3h.
Na.sub.2S.sub.2S.sub.2O.sub.5 (1.5 eq.) was added, and the
suspension was stirred and filtered. K.sub.2CO.sub.3 (3 eq.) was
added to the filtrate and stirred for 0.5-1h. MgSO.sub.4 was added,
the suspension was filtered, and the filtrate was concentrated in
vacuo. Purification by flash chromatography and/or by
crystallisation.
[0133] Preparation 1:
[0134] 2Chloro-4-nitro-2'-methylbenzophenone, (Compound 1) General
procedure: 3Starting compound VI: 2-Bromotoluene Starting compound
V: 2-Chloro-4-nitro-benzoyl chloride Purification: Chromatography
using EtOAc/pentane 1:9 as eluant .sup.13C NMR (CDCl-.sub.3):
.delta.195.1, 148.9, 145.5, 140.6, 135.0, 133.1, 132.7, 132.4,
131.9, 130.0, 125.9, 125.4, 121.9, 21.5
[0135] Preparation 2:
[0136] 4-Amino-2-chloro-2'-methylbenzophenone, (Compound 2) General
procedure: 4 Starting compound IV:
2-Chloro-4-nitro-2'-methylbenzophenone (Compound 1) Purification:
Chromatography using EtOAc/pentane 1:9 followed by 1:4 as eluant
.sup.13C NMR (CDCl.sub.3): .delta.196.7, 150.5, 139.5, 137.6,
135.1, 133.9, 131.2, 130.7, 129.5, 127.5, 125.3, 116.0, 112.2,
20.3
[0137] Preparation 3:
[0138] 2-Chloro-4'-methoxy-2'-methyl-4-nitrobenzophenone (compound
3) General procedure: 3Starting compound VI:
2-Bromo-5-methoxytoluene Starting compound V:
2-Chloro-4-nitro-benzoyl chloride Purification: Crystallization
from a MeOH/cyclohexane 10:1 .sup.13C NMR (CDCl.sub.3):
.delta.193.3, 163.3, 148.6, 146.3, 144.3, 135.5, 132.4, 129.6,
127.5, 125.3, 121.9, 118.1, 110.9, 55.5, 22.4
[0139] Preparation 4:
[0140] 4-Amino-2-chloro-4'-methoxy-2'-methylbenzophenone (compound
4) General procedure: 4Starting compound IV:
2-Chloro-4'-methoxy-2'-methyl-4- -nitrobenzophenone (compound 3)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.195.7, 161.7, 149.6, 141.6,
134.2, 133.3, 132.8, 131.4, 129.1, 117.0, 115.8, 112.4, 110.3,
55.3, 21.3
[0141] Preparation 5:
[0142] 2,4'-Dichloro-2'-methyl-4-nitrobenzophenone (compound 5)
General procedure: 3Starting compound VI: 2-Bromo-5-chlorotoluene
Starting compound V: 2-Chloro-4-nitro-benzoyl chloride
Purification: Chromatography using EtOAc/pentane 1:15 followed by
1:10 as eluant .sup.13C NMR (CDCl.sub.3): .delta.194.1, 149.0,
145.0, 142.6, 139.4, 133.5, 133.1, 132.7, 132.5, 130.1, 126.1,
125.5, 122.0, 21.4
[0143] Preparation 6:
[0144] 4-Amino-2,4'-dichloro-2'-methylbenzophenone (compound 6)
General procedure: 4Starting compound IV:
2,4'-Dichloro-2'-methyl-4-nitrobenzophe- none (compound 5) .sup.13C
NMR (CDCl.sub.3): .delta.195.4, 150.5, 139.8, 137.9, 136.5, 135.1,
133.7, 131.2, 130.9, 127.5, 125.6, 115.9, 112.3, 20.2
[0145] Preparation 7:
[0146] 2-Chloro-4'-fluoro-2'-methyl-4-nitrobenzophenone (compound
7) General procedure: 3Starting compound VI:
2-Bromo-5-fluorotoluene Starting compound V:
2-Chloro-4-nitro-benzoyl chloride Purification: Chromatography
using EtOAc/pentane 1:20 as eluant .sup.13C NMR (CDCl.sub.3):
.delta.193.7, 165.1, 148.9, 145.3, 144.6, 134.7, 132.6, 131.4,
129.9, 125.5, 122.0, 119.5, 113.0, 21.8
[0147] Preparation 8:
[0148] 4-Amino-2-chloro-4'-fluoro-2'-methylbenzophenone (compound
8) General procedure: 4Starting compound IV:
2-Chloro-4'-fluoro-2'-methyl-4-- nitrobenzophenone (compound 7)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.195.4, 163.9, 150.3, 141.5,
135.5, 134.9, 133.5, 132.2, 128.0, 118.1, 115.9, 112.4, 112.3,
20.6
[0149] Preparation 9:
[0150] 2-Fluoro-4-nitro-2'-methylbenzophenone (compound 9) General
procedure: 3Starting compound VI: 2-Bromotoluene Starting compound
V: 2-Fluoro-4-nitro-benzoyl chloride Purification: Crystallization
from a mixture of MeOH/cyclohexane 6:1 .sup.13C NMR (CDCl.sub.3):
.delta.193.1, 159.9, 150.3, 139.3, 136.4, 133.8, 132.6, 132.1,
131.7, 130.8, 125.8, 119.4, 112.4, 21.0
[0151] Preparation 10:
[0152] 4-Amino-2-fluoro-2'-methylbenzophenone (compound 10) General
procedure: 4Starting compound IV:
2-Fluoro-4-nitro-2'-methylbenzophenone (compound 9) Purification:
Filtered through a short column of silica gel .sup.13C NMR
(CDCl.sub.3): .delta.194.3, 163.8, 153.0, 140.7, 136.1, 134.0,
130.8, 129.9, 127.9,
[0153] 125.3, 116.8, 110.1, 101.3, 19.8
[0154] Preparation 11:
[0155] 2-Chloro-2',5'-dimethyl-4-nitrobenzophenone (compound 11)
General procedure: 3Starting compound VI:
2-Bromo-1,4-dimethylbenzene Starting compound V:
2-Chloro-4-nitro-benzoyl chloride Purification: Filtered through a
short column of silica gel .sup.13C NMR (CDCl.sub.3): .delta.195.3,
148.9, 145.6, 137.4, 135.5, 135.0, 133.9, 132.8, 132.3, 132.2,
130.0, 125.5, 121.9, 21.1, 20.8
[0156] Preparation 12:
[0157] 4-Amino-2-chloro-2',5'-dimethylbenzophenone (compound 12)
General procedure: 4Starting compound IV:
2-Chloro-2',5'-dimethyl-4-nitrobenzophe- none (compound 11)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.196.8, 150.2, 139.3, 135.1,
134.9, 134.5, 133.8, 131.4, 131.1, 130.0, 128.0, 116.0, 112.2,
20.8, 19.9
[0158] Preparation 13:
[0159] 2,3'-Dichloro-2'-methyl-4-nitrobenzophenone (compound 13)
General procedure: 3Starting compound VI: 2-Bromo-3-chlorotoluene
Starting compound V: 2-Chloro-4-nitro-benzoyl chloride
Purification: Crystallization from a mixture of MeOH/cyclohexane
9:1 .sup.13C NMR (CDCl.sub.3): .delta.194.6, 149.2, 144.5, 138.2,
137.3, 137.0, 133.5, 133.2, 130.7, 129.0, 126.5, 125.7, 122.0,
17.3
[0160] Preparation 14:
[0161] 4-Amino-2,3'-dichloro-2'-methylbenzophenone (compound 14)
General procedure: 4 Starting compound IV:
2,3'-Dichloro-2'-methyl-4-nitrobenzoph- enone (compound 13)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.195.3, 150.9, 142.4, 135.8,
135.8, 134.8, 134.6, 131.0, 126.8, 126.7, 126.4, 116.2, 112.2,
17.1
[0162] Preparation 15:
[0163] 2-Fluoro-4'-methoxy-2'-methyl-4nitrobenzophenone (compound
15) General procedure: 3Starting compound VI:
2-Bromo-5-methoxytoluene Starting compound V:
2-Fluoro-4-nitro-benzoyl chloride Purification: Recrystallization
from a mixture of MeOH/cyclohexane/CH.sub.2Cl.sub.2 .sup.13C NMR
(CDCl.sub.3): .delta.191.3, 163.1, 159.3, 143.6, 135.0, 134.8,
131.2, 128.5, 119.4, 117.8, 112.2, 110.8, 55.5, 22.1
[0164] Preparation 16:
[0165] 4-Amino-2-fluoro-4'-methoxy-2'-methylbenzophenone (compound
16) General procedure: 4Starting compound IV:
2-Fluoro-4'-methoxy-2'-methyl-4- -nitrobenzophenone (compound 15)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.193.4, 163.1, 161.2, 152.2,
140.1, 133.7, 132.6, 131.7, 117.8, 116.6, 110.3, 110.1, 101.3,
55.3, 20.7
[0166] Preparation 17:
[0167] 2-Chloro-4-nitro-2',4',5'-trimethylbenzophenone (compound 17
General procedure: 3Starting compound VI:
5-Bromo-1,2,4-trimethylbenzene Starting compound V:
2-Chloro-4-nitro-benzoyl chloride Purification: Recrystallisation
from EtOAc EO 01720-000 (CDCL3) .sup.13C NMR (CDCl.sub.3):
.delta.194.8, 148.7, 146.1, 143.0, 138.3, 134.1, 134.0, 133.4,
132.6, 132.5, 129.8, 125.4, 121.9, 21.2, 19.9, 19.2
[0168] Preparation 18:
[0169] 4-Amino-2-chloro-2',4',5'-trimethylbenzophenone (compound
18) General procedure: 4Starting compound IV:
2-Chloro-4-nitro-2',4',5'-trime- thylbenzophenone (compound 17)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.196.6, 149.9, 140.0, 136.6,
135.5, 134.7, 133.4, 132.7, 131.4, 128.5, 115.9, 112.2, 20.0,
19.7,19.1
[0170] Preparation 19:
[0171] 4'-n-Butyl-2-chloro-2'-methyl-4-nitrobenzophenone (compound
19) General procedure: 3Starting compound VI:
4-n-Butyl-2-methyliodobenzene Starting compound V:
2-Chloro-4-nitro-benzoyl chloride Purification: Chromatography,
eluent EtOAc: Petroleumethet 1:15 .sup.13C NMR (CDCl.sub.3):
.delta.194.6, 149.2, 148.7, 146.0, 141.1, 132.7, 132.7, 132.6,
132.3, 129.8, 125.9, 125.3, 121.8, 35.7,33.1, 22.4, 21.8, 13.9
[0172] Preparation 20:
[0173] 4-Amino-4'-n-butyl-2-chloro-2'-methylbenzophenone (compound
20) General procedure: 4Starting compound IV:
4'-n-Butyl-2-chloro-2'-methyl-4- -nitrobenzophenone (compound 19)
Purification: Filtered through a short column of silica gel
.sup.13C NMR (CDCl.sub.3): .delta.196.5, 150.0, 146.3, 138.3,
136.5, 134.7, 133.4, 131.5, 130.4, 128.4, 125.3, 115.9, 112.2,
35.6, 33.3, 22.4, 20.6, 13.9
[0174] Example 1: 2-Chloro-2'-methyl-4-(4-pyridylamino)benzophenone
(Compound 101), General procedure: 2Starting compound II:
4-chloro-pyridine hydrochloride (0.30g, 2.0 mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g,
2.0 mmol) Solvent: DMSO (15 mL) Base: t-BuOK (0.67g, 6.0mmol) in
DMSO (10 mL) Reaction time: 22h Reaction temperature: 150.degree.
C. Purification: Chromatography using EtOAc:MeOH 15:1 Product:
Compound 101, 0.20g oil .sup.1H NMR (CDCl.sub.3):
.delta.8.39(d,1H), 7.43(d,1H), 7.40-7.20(m,5H), 7.08(dd,1H),
6.97(d,3H), 2.50(s,3H)
[0175] Example 2: 2-Chloro-2'-methyl-4-(2-pyridylamino)benzophenone
(Compound 102), General procedure:2Starting compound II:
2-chloro-pyridine (0.19 mL, 2.0mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g,
2.0mmol) Solvent: DMSO (15mL) Base: t-BuOK (0.45g, 4.0 mmol) in
DMSO (10 mL) Reaction time: 22 h Reaction temperature: 150.degree.
C. Purification: Chromatography using EtOAc : petroleum ether
1:5Product: Compound 102, 0.21g oil. .sup.1H NMR (CDCl.sub.3):
.delta.8.28(d,1H), 7.65(d,1H), 7.58(t,1H), 7.41(d,1H),
7.40-7.25(m,4H), 7.19(t,1H), 6.95(s,1H), 6.86(m,2H), 2.47(s,3H)
[0176] Example 3:
2-Chloro-2'-methyl-4-(5-nitro-2-pyridylamino)benzophenon- e
(Compound 103), General procedure:2Starting compound II:
2-chloro-5-nitro-pyridine (0.32g, 2.0 mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g,
2.0mmol) Solvent: DMSO (10mL) Base: t-BuOK (0.45g, 4.0mmol) in DMSO
(20 mL) Reaction time: 18h Reaction temperature: 150.degree. C.
Purification: Chromatography using EtOAc : petroleum ether
2:7-1:3Product: Compound 103, 0.09g crystalline compound .sup.13C
NMR (acetone d-6): .delta.196.7, 159.4, 146.2, 144.2, 139.2, 139.0,
138.8, 133.8, 133.6, 133.5, 132.4, 132.4, 132.3, 131.0, 126.5,
121.0, 118.3, 112.1, 20.8
[0177] Example 4:
4(6-Amino-5-nitro-2-pyridylamino)-2-chloro-2'-methylbenz- ophenone
(Compound 104), General procedure:2Starting compound II:
2-amino-6-chloro-3-nitro-pyridine (0.69g, 4.0mmol) Starting
compound III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2)
(0.98g, 4.0mmol) Solvent: DMSO (15mL) Base: t-BuOK (0.90g, 8.0mmol)
in DMSO (25mL) Reaction time: 48h Reaction temperature: 150.degree.
C. Purification: Chromatography using CH.sub.2Cl.sub.2: EtOAc
50:1-30:1Product: Compound 104, 0.58g crystalline compound .sup.13C
NMR (DMSO): .delta.195.9, 157.7, 154.7, 143.5, 138.0, 137.4, 135.7,
131.9, 131.8, 131.5, 131.4, 129.9, 125.8, 119.9, 119.5, 117.5,
103.2, 20.2
[0178] Example 5:
6-Chloro-2-(3-chloro-4-(2-methylbenzoyl)phenylamino) isonicotinic
acid (Compound 105), General procedure:2Starting compound II:
2,6-dichloro-4-cyano-pyridine (0.70g, 4.0mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.98g,
4.0mmol) Solvent: DMSO (15 mL) Base: t-BuOK (0.90g, 8.0mmol) in
DMSO (25 mL) Reaction time: 48h Reaction temperature: 150.degree.
C. Purification: Chromatography using EtOAc:MeOH 5:1Product:
Compound 105, 0.52g oil, the cyano substituent has been hydrolysed
during reaction or work up. .sup.13C NMR (DMSO): .delta.195.7,
166.6, 154.8, 150.5, 147.2, 145.0, 138.4, 137.0, 132.3, 132.1,
131.2, 131.1, 129.5, 129.4, 125.7, 118.0, 115.6, 114.8, 111.3,
20.0
[0179] Example 6:
4-(6-carbonitrile-2-pyridylamino)-2-chloro-2'-methylbenz- ophenone
(Compound 106), General procedure:2Starting compound II:
2-chloro-3-cyano-pyridine (0.28g, 2.0 mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g, 2.0
mmol) Solvent: DMSO (10 mL) Base: t-BuOK (0.45g, 4.0mmol) in DMSO
(20 mL) Reaction time: 18h Reaction temperature: 150.degree. C.
Purification: Chromatography using EtOAc : petroleum ether
1:1-1:0Product: Compound 106, 0.07g crystalline compound .sup.13C
NMR (CDCl.sub.3): .delta.195.9, 155.5, 144.3, 142.9, 142.1, 140.3,
140.0, 136.0, 133.2, 132.6, 132.1, 131.8, 131.1, 128.8, 125.7,
125.3, 115.7, 105.7, 102.4, 21.3
[0180] Example 7: 2-Chloro-2'-methyl-4-(3-pyridylamino)benzophenone
(Compound 107), General procedure:1Starting compound II:
3-chloro-pyridine (1.18 mL, 12.0mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (2.95g,
12.0mmol) Solvent: Toluene (60 mL) Base: t-BuONa Reaction time: 45h
Reaction temperature: 110.degree. C. Purification: Chromatography
using CH.sub.2 Cl.sub.2: acetone 4:1Product: Compound 107, 2.05g
crystalline compound .sup.13C NMR (CDCl.sub.3): .delta.196.5,
146.8, 144.4, 142.7, 138.7, 138.1, 137.3, 134.9, 133.3, 131.4,
131.1, 130.4, 129.9, 127.1, 125.4, 124.0, 117.0, 113.4, 20.5
[0181] Example 8: 2-Chloro-4-(5,
6-diamino-2-pyridylamino)-2'-methylbenzop- henone (Compound 108),
Compound 104 (0.38g, 1.0mmol) was dissolved in EtOH (10mL) and DMF
(10mL). SnCl.sub.2*H.sub.2O (1.12g, 5.0mmol) was added and the
solution was stirred at 90.degree. C. for 20h. The reaction mixture
was poured into ice water (100mL), 2 N NaOH (50mL) was added, and
the water phase was extracted with EtOAc (50mL) and Et.sub.2O
(2.times.50 mL). The combined organic phases were washed with
saturated aqueous NaCl (50 mL), dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. The residue was purified by flash
chromatography EtOAc : petroleum ether 2:1-1:0. Product: Compound
108, 0.05g oil .sup.13C NMR (CDCl.sub.3): .delta.196.7, 148.9,
146.2, 145.6, 139.2, 137.9, 134.6, 133.1, 131.2, 130.8, 129.7,
129.2, 126.7, 125.4, 122.5, 117.4, 114.0, 102.1, 20.4
[0182] Example 9:
2-Chloro-2'-methyl-4-(3-nitro-2-pyridylamino)benzophenon- e
(Compound 109), -2Chloro-3-nitro-pyridine (0.32g, 2.0mmol) and
4-amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g,
2.0mmol) was mixed thoroughly. The reaction mixture was warmed at
100.degree. C. for 0.5h and then at 160.degree. C. for 0.5h. The
reaction mixture was cooled to room temperature, and dissolved in
saturated aqueous NaHCO.sub.3 (10 mL) and EtOAc (30 mL). The phases
were separated, and the organic phase was washed with saturated
aqueous NaHCO.sub.3 (10mL), dried (MgSO.sub.4), filtered and
concentrated in vacuo. Purification by flash chromatography using
EtOAc: petroleum ether 1:7. Product: Compound 109, 0.26g
crystalline compound which was recrystallised from Et.sub.2O
.sup.13C NMR (CDCl.sub.3): .delta.196.6, 154.8, 149.2, 141.4,
138.9, 137.9, 135.6, 134.2, 133.4, 131.6, 131.6, 131.5, 130.6,
129.4, 125.5, 122.5, 119.0, 115.3, 20.9
[0183] Example 10:
4-(3-Amino-2-pyridylamino)-2-chloro-2'-methylbenzopheno- ne
(Compound 110), Compound 109 (0.15g, 0.4mmol) was suspended in EtOH
(10mL) and SnCl.sub.2 *H.sub.2O (0.46g, 2.0mmol) was added. The
reaction mixture was stirred at 70.degree. C. for 1h, after which
it was poured into ice water (50mL) 2N NaOH (50mL) was added and
the water phase was extracted with EtOAc (3.times.20mL). The
combined organic phases were dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash chromatography using
EtOAc: petroleum ether 2:3. Product: Compound 110, 0.12g oil.
.sup.13C NMR (CDCl.sub.3): .delta.196.9, 145.3, 143.9, 139.2,
138.9, 138.1, 134.2, 132.7, 131.7, 131.3, 131.0, 130.3, 130.0,
125.4, 124.6, 118.8, 118.5, 114.9, 20.5
[0184] Example 11:
4-(5-Amino-2-pyridylamino)-2-chloro-2'-methylbenzopheno- ne
(Compound 111), Compound 103 (0.07g, 0.19mmol) was suspended in
EtOH (5mL) and SnCl.sub.2 *H.sub.2O (0.21g, 1.0mmol) was added. The
reaction mixture was stirred at 70.degree. C. for 3h and the
reaction mixture was worked up as described for Compound 110.
Purification by flash chromatography using EtOAc:petroleum ether
3:2. Product: Compound 111, 0.038g oil .sup.13C NMR (CDCl.sub.3):
.delta.196.7, 146.3, 146.0, 139.1, 137.9, 137.6, 135.1, 134.6,
133.1, 131.3, 130.9, 129.8, 129.6, 125.5, 125.4, 117.3, 113.9,
112.7, 20.5
[0185] Example 12:
2-Chloro-2'-methyl-4((2-pyridyl-N-oxide)amino)benzophen- one
(Compound 112) General procedure:5Starting compound I: Compound 102
(0.16g, 0.5mmol) Reaction time: 1h Purification by chromatography
using EtOAc:MeOH 8:1 Product: Compound 112, 0.098g crystalline
compound which could be recrystallised from MeOH .sup.13C NMR
(DMSO): .delta.195.8, 146.0, 142.8, 137.7, 137.5, 132.2, 132.0,
131.8, 131.6, 131.4, 130.0, 127.0, 125.8, 121.0, 117.7, 116.1,
109.8, 20.2
[0186] Example 13:
2-Chloro-2'-methyl-4((3-pyridyl-N-oxide)amino)benzophen- one
(Compound 113) General procedure:5Starting compound I: Compound 107
(0.18g, 0.54 mmol) Reaction time: 2h Purification by chromatography
using EtOAc:MeOH 7:1Product: Compound 113, 0.12g crystalline
compound .sup.13C NMR (CD.sub.3OD): .delta.198.5, 146.6, 143.7,
139.7, 139.4, 135.4, 134.0, 133.2, 133.0, 132.7, 132.6, 131.2,
130.4, 128.1, 126.8, 120.0, 119.6, 116.5, 20.8
[0187] Example 14: 2-Chloro-4-(4-isoquinolylamino)-
2'-methylbenzophenone (Compound 114), General procedure:1Starting
compound II: 4-bromo-isoquinoline (0.42g, 2.0mmol) Starting
compound III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2)
(0.49, 2.0mmol) Solvent: 1,4-dioxane (6mL) Base: t-BuONa Reaction
time: 18h Reaction temperature: 100.degree. C. Purification:
Chromatography using CH.sub.2Cl.sub.2: acetone 10:1Product:
Compound 114, 0.64g amorphous compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.6, 150.1, 149.3, 139.0, 138.6, 137.9, 135.1, 133.5,
132.1, 131.3, 131.1, 130.9, 130.8, 129.7, 129.3, 129.3, 128.2,
127.9, 125.4, 121.6, 116.3, 112.6, 20.5
[0188] Example 15: t-Butyl
5-(3-chloro-4-(2-methylbenzoyl)phenylamino) nicotinoate (Compound
115,) 5-Bromonicotinic acid (4.7g, 23mmol) was added to 7 mL
condensed isobutylene in CH.sub.2Cl.sub.2(15mL), and afterwards
conc. H.sub.2SO.sub.4 (0.75mL) was added. The reaction mixture was
stirred in a screw cap vessel for 24h at room temperature, after
which it was poured into saturated aqueous NaHCO.sub.3 (100mL). The
aqueous phase was extracted with EtOAc (100mL), the organic phase
was washed with NaHCO.sub.3, dried (MgSO.sub.4), filtered and
concentrated. The crude product was purified by chromatography
using the eluent EtOAc:petroleum ether 1:10. Product: t-butyl
5-bromonicotinoate, crystalline compound. .sup.13C NMR
(CDCl.sub.3): .delta.163.06, 154.02, 148.85, 139. 38, 129.10,
120.48, 82.82, 28.12General procedure:1Starting compound II:
t-Butyl 5-bromonicotinoate, (0.12g, 0.45mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.13g,
0.53mmol) Solvent: toluene (3mL) Base: t-BuONa Reaction time: 12h
Reaction temperature: 100.degree. C. Purification: Chromatography
using EtOAc:petroleum ether 1:2Product: Compound 115, 0.035g oil
.sup.13C NMR (CDCl.sub.3): .delta.196.7, 164.1, 146.1, 145.1,
144.8, 138.5, 138.2, 137.4, 134.8, 133.2, 131.5, 131.3, 131.0,
130.1, 128.4, 126.9, 125.5, 117.7, 113.7, 82.5, 28.1, 20.6
[0189] Example 16:
2-Chloro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophen- one
(Compound 116), General procedure:1Starting compound II:
3-bromo-4-methyl pyridine (0.172g, 1.0mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2)(0.25g, 10mmol)
Solvent: 1,4dioxane (5mL) Base: t-BuONa Reaction time: 18h Reaction
temperature: 110.degree. C. Purification: Chromatography using
EtOAc:petroleum ether 1:3-1:1Product: Compound 116, 0.08g oil
.sup.13C NMR (CDCl.sub.3): .delta.196.5, 148.5, 146.5, 146.1,
142.1, 139.0, 138.0, 135.4, 135.1, 133.5, 131.3, 131.0, 129.8,
129.3, 125.9, 125.4, 116.0, 112.3, 20.5, 17.5
[0190] Example 17:
2-Chloro-2'-methyl-4-(6-methyl-3-pyridylamino)benzophen- one
(Compound 117), General procedure:1Starting compound II:
5-bromo-2-methyl pyridine (0.172g, 1.0mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g, 1.0
mmol) Solvent: 1,4dioxane (5mL) Base: t-BuONa Reaction time: 18h
Reaction temperature: 110.degree. C. Purification: Chromatography
using EtOAc:petroleum ether 1:4-1:2Product: Compound 117, 0.15g oil
.sup.1H NMR (CDCl.sub.3): .delta.8.37(d,1H), 7.45(dd,1H),
7.4-7.15(m,6H), 6.93(d,1H), 6.78(dd,1H), 6.29(s,1H), 2.54(s,3H),
2.44(s,3H)
[0191] Example 18:
4-(5-Bromo-3-pyridylamino)-2-chloro-2'-methylbenzopheno- ne
(Compound 118), General procedure:1Starting compound II:
3,5-dibromo-pyridine (0.237g, 1.0 mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g, 1.0
mmol) Solvent: 1,4dioxane (5mL) Base: t-BuONa Reaction time: 5h
Reaction temperature: 110.degree. C. Purification: Chromatography
using acetone:CH.sub.2Cl.sub.21:10Product: Compound 118, 0.05g oil
.sup.13C NMR (CDCl.sub.3): .delta.196.6, 145.4, 144.7, 139.9,
138.6, 138.4, 138.3, 134.8, 133.0, 131.6, 131.6, 131.4, 130.2,
128.3, 125.5, 120.8, 118.1, 114.3, 20.7
[0192] Example 19:
4(5-Carbonitrile-3-pyridylamino)-2-chloro-2'-methylbenz- ophenone
(Compound 119), General procedure:1Starting compound II:
5-bromonicotinonitrile (0.22g, 1.2mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g, 1.0
mmol) Solvent: Toluene (5mL) Base: Cs.sub.2CO.sub.3Reaction time:
18h Reaction temperature: 100.degree. C. Purification:
Chromatography using EtOAc:petroleum ether 1:2 Product: Compound
119, 0.11g oil .sup.13C NMR (DMSO): .delta.195.6, 145.8, 144.5,
144.5, 138.4, 138.1, 137.1, 133.0, 131.3, 131.3, 129.8, 129.5,
126.6, 125.8, 117.3, 116.9, 114.2, 109.3, 20.1
[0193] Example 20:
4(3-Bromo-2-pyridylamino)-2-chloro-2'-methylbenzophenon- e
(Compound 120), General procedure:1Starting compound II:
3-bromo-2-chloro-pyridine (0.23g, 1.2mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g,
1.0mmol) Solvent: 1,4-dioxane (5mL) Base: t-BuONa Reaction time:
18h Reaction temperature: 100.degree. C. Purification: reversed
phase HPLC, (0.1% TFA in H.sub.2O):(0.1% TFA in 90% CH3CN+10%
H.sub.2O)1:1-0:1Product: Compound 120 .sup.13C NMR (CDCl.sub.3):
.delta.196.7, 150.8, 146.5, 143.3, 140.6, 138.5, 133.8, 132.1,
131.5, 131.3, 130.3, 125.4, 119.9, 117.2, 116.4, 107.0, 20.7
[0194] Example 21:
2-Chloro-2'-methyl-4-(8-quinolylamino)benzophenone (Compound 121),
General procedure: 1Starting compound II: 8-bromo-quinoline
(0.16mL, 1.25mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.28g,
1.14mmol) Solvent: 1,4-dioxane (5mL) Base: t-BuONa Reaction time:
18h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using Et.sub.2O: petroleum ether 1:3Product:
Compound 121, 0.28g crystalline compound which was recrystallised
from Et.sub.2O .sup.13C NMR (CDCl.sub.3): .delta.196.5, 147.9,
145.9, 139.0, 138.9, 138.1, 137.7, 136.4, 134.7, 133.1, 131.4,
131.0, 130.6, 129.9, 128.8, 127.0, 125.4, 121.9, 119.1, 118.7,
115.3, 110.7, 20.6
[0195] Example 22:
2-Chloro-4-(6-ethoxy-3-pyridylamino)-2'-methylbenzophen- one
(Compound 122), General procedure: 1Starting compound II:
5-bromo-2-ethoxy-pyridine (0.24g, 1.2mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g,
1.0mmol) Solvent: 1,4-dioxane (5mL) Base: t-BuONa Reaction time:
18h Reaction temperature: 100.degree. C. Purification: reversed
phase HPLC Product: Compound 122 .sup.1H NMR (CDCl.sub.3):
.delta.8.09(d,1H), 7.54(dd,1H), 7.40-7.20(m,5H), 6.80(m,2H),
6.66(dd,1H), 4.35(q,2H), 2.43(s,3H), 1.42(t,3H)
[0196] Example 23:
4-(4-Bromo-1-isoquinolylamino)-2-chloro-2'-methylbenzop- henone
(Compound 123), General procedure: 1Starting compound II:
4-bromo-1-chloroisoquinoline (0.14g, 0.5mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.13g,
0.56mmol) Solvent: 1,4-dioxane (3mL) Base: t-BuONa Reaction time:
18h Reaction temperature: 100.degree. C. Purification: reversed
phase HPLC Product: Compound 123 .sup.1H NMR (CDCl.sub.3):
.delta.8.24(s,1H), 8.18(d,1H), 8.00(d,1H), 7.85(t,1H), 7.77(d,1H),
7.65(t,1H), 7.45-7.35(m,4H), 7.28(d,1H), 7.20(t,1H), 2.52(s,3H)
[0197] Example 24:
2-Chloro-2'-methyl-4-(2-methyl-5-trifluoromethyl-3-pyri-
dylamino)benzophenone (Compound 124), General procedure: 1, without
Pd.sub.2(dba).sub.3 and BINAP Starting compound II:
3-Chloro-2-methyl-5-(trifluoromethyl)pyridine (0.20, 1.0mmol)
Starting compound III: 4-Amino-2-chloro-2'-methylbenzophenone
(compound 2) (0.25g, 1.0mmol) Solvent: 1,4-dioxane (5mL) Base:
t-BuONa Catalyst: Pd(P(cyclohexyl).sub.3).sub.2Cl.sub.2 (30 mg,
0.04mmol) Reaction time: 18h Reaction temperature: 110.degree. C.
Purification: reversed phase HPLC Product: Compound 124 .sup.13C
NMR (CDCl.sub.3): .delta.196.4, 152.6, 144.5, 138.8, 137.9, 137.5,
137.2, 134.8, 133.0, 132.9, 131.7, 130.4, 125.6, 123.8, 119.4,
115.4, 20.8, 19.5
[0198] Example 25:
2-Chloro-2'-methyl-4-(3-quinolylamino)benzophenone (Compound 125),
General procedure: 1Starting compound II: 3-bromo-quinoline (0.23g,
1.1mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2)(0.25g, 1.0mmol)
Solvent: 1,4-dioxane (5mL) Base: t-BuONa Reaction time: 18h
Reaction temperature: 100.degree. C. Purification by flash
chromatography using EtOAc:petroleum ether 2:3Product: Compound
125, 0.23g amorphous compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.5, 146.6, 146.1, 144.9, 138.7, 138.2, 135.0, 134.2,
133.3, 131.4, 131.2, 130.7, 130.0, 129.2, 128.4, 128.0, 127.5,
126.9, 125.5, 122.4, 117.2, 113.6, 20.6
[0199] Example 26:
2-Chloro-4-(4-ethoxy-3-pyridylamino)-2'-methylbenzophen- one
(Compound 126), General procedure: 1Starting compound II:
3-bromo-4-ethoxypyridine (0.22 g, 1.1mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g,
1.0mmol) Solvent: 1,4-dioxane (6mL) Base: t-BuONa Reaction time: 7h
Reaction temperature: 100.degree. C. Purification by flash
chromatography using EtOAc:petroleum ether 1:3-1:0 followed by
reversed phase HPLC. Product: Compound 126, oil. .sup.13C NMR
(CDCl.sub.3): .delta.196.3, 158.5, 142.6, 138.9, 137.5, 136.5,
134.3, 134.1, 132.5, 131.9, 131.8, 131.6, 130.7, 126.8, 125.7,
120.8, 116.8, 107.7, 66.9, 20.9, 14.2
[0200] Example 27:
2-Chloro-4-(2-ethoxy-3-pyridylamino)-2'-methylbenzophen- one
(Compound 127), General procedure: 1Starting compound II:
3-bromo-2-ethoxypyridine (0.22 g, 1.1mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g,
1.0mmol) Solvent: 1,4-dioxane (6mL) Base: t-BuONa Reaction time: 3h
Reaction temperature: 100.degree. C. Purification by flash
chromatography using EtOAc:petroleum ether 1:5Product: Compound
127, 0.20g oil. .sup.13C NMR (CDCl.sub.3): .delta.196.4, 154.1,
145.9, 138.8, 138.7, 138.2, 134.8, 133.1, 131.4, 131.1, 130.5,
129.9, 125.4, 125.2, 122.8, 117.8, 116.6, 114.3, 62.2, 20.5,
14.7
[0201] Example 28:
2-Chloro-4((4-isoquinolyl-N-oxide)amino)-2'-methylbenzo- phenone
(Compound 128) General procedure:5Starting compound I: Compound 114
(0.37g, 1.0mmol) Reaction time: 2h Purification by chromatography
using EtOAc:MeOH 8:1Product: Compound 128, 0.22g crystalline
compound .sup.13C NMR (DMSO): .delta.195.5, 147.5, 138.3, 137.0,
136.0, 132.9, 131.2, 131.2, 130.9, 129.9, 129.7, 129.5, 127.9,
125.7, 125.3, 123.4, 122.1, 117.7, 114.6, 20.0
[0202] Example 29:
2-Chloro-2'-methyl-4-(2-methyl-6-quinolylamino)benzophe- none
(Compound 129), General procedure: 1Starting compound II:
6-bromoquinaldine (0.24 g, 1.1mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25g,
1.0mmol) Solvent: 1,4-dioxane (6mL) Base: t-BuONa Reaction time:
18h Reaction temperature: 100.degree. C. Purification by flash
chromatography using EtOAc: petroleum ether 1:1Product: Compound
129, 0.27g oil. .sup.13C NMR (CDCl.sub.3): .delta.196.6, 157.7,
147.3, 144.9, 139.0, 138.0, 137.9, 135.2, 135.0, 133.4, 131.3,
131.0, 130.2, 129.9, 129.8, 127.3, 125.4, 124.6, 122.7, 117.1,
115.2, 113.5, 25.1, 20.5
[0203] Example 30:
2-Chloro-4-(7-chloro-4-quinolylamino)-2'-methylbenzophe- none
(Compound 130), 4,7-Dichloroquinoline (0.20 g, 1.0mmol) was
dissolved in i-PrOH (10 mL) and
4-amino-2-chloro-2'-methylbenzophenone (compound 2) (0.27g,
1.1mmol) was added. The reaction mixture was stirred at reflux for
2 h, after which it was poured into saturated aqueous NaHCO.sub.3
(30 mL). The water phase was extracted with EtOAc (3.times.30 mL),
the combined organic phases were washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. Purification by
flash chromatography using EtOAc:petroleum ether 1:3-1:1. Product:
Compound 130, 0.28g crystalline compound. .sup.13C NMR (DMSO):
.delta.195.67, 152.08, 149.58, 145.60, 145.01, 137.84, 137.39,
134.19, 132.34, 132.26, 131.50, 131.39, 129.82, 127.78, 125.76,
125.65, 124.51, 120.52, 119.25, 117.52, 105.38, 20.13
[0204] Example 31:
2-Chloro-2'-methyl-4-(2-quinolylamino)benzophenone (Compound 131),
2-Chloroquinoline (0.16 g, 1.0mmol) was dissolved in i-PrOH (10 mL)
and 4-amino-2-chloro-2'-methylbenzophenone (compound 2) (0.27g,
1.1mmol) was added. The reaction mixture was stirred at reflux for
18 h, and the reaction mixture was worked up as described for the
synthesis of Compound 130Purification by flash chromatography using
EtOAc:petroleum ether 1:4. Product: Compound 131, 0.24g oil
.sup.13C NMR (CDCl.sub.3): .delta.196.9, 152.6, 147.1, 144.1,
138.6, 138.4, 138.1, 134.0, 132.4, 131.6, 131.4, 131.2, 130.2,
130.1, 127.4, 127.3, 125.5, 124.5, 124.1, 119.8, 116.1, 112.9,
20.7
[0205] Example 32:
2-Chloro-2'-methyl-4-(4-quinolylamino)benzophenone(Comp- ound 132),
4-Chloroquinoline (0.16g, 1.0mmol) was dissolved in I-PrOH (10 mL)
and 4-amino-2-chloro-2'-methylbenzophenone (compound 2) (0.27g,
1.1mmol) was added. The reaction mixture was stirred at reflux for
18 h, after which it was poured into saturated aqueous NaHCO.sub.3
(30mL). The water phase was extracted with EtOAc (3.times.30 mL),
the combined organic phases were washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. Purification by
flash chromatography using EtOAc:petroleum ether 1:3-1:1. Product:
Compound 132, 0.16g amorphous compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.58, 150.79, 149.37, 145.25, 144.37, 138.74, 137.98,
134.30, 133.22, 132.51, 131.67, 131.61, 130.45, 130.28, 129.84,
126.10, 125.54, 121.10, 120.75, 120.07, 117.54, 105.43, 20.80
[0206] Example 33:
2-Chloro-2'-methyl-4-(1-methyl-7-indolylamino)benzophen- one
(Compound 133), 7-Bromoindole(0.37g, 1.9mmol) was dissolved in dry
DMF. K.sub.2CO.sub.3 (0.52g, 3.8mmol) and methyliodide (0.13mL,
2.08mmol) were added. The reaction was stirred at room temperature
for 5 days, after which H.sub.2O (20mL) was added, the water phase
was extracted with Et.sub.2O (3.times.20mL), and the combined
organic phases were washed with brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The crude product was purified by
chromatography, eluent EtOAc:petroleum ether 1:20 to give
7-bromo-1-methylindole as a crystalline compound. .sup.13C NMR
(CDCl.sub.3): .delta.133.07, 131.75, 126.54, 120.46, 120.34,
103.89, 101.18, 36.84
[0207] Compound 133 was prepared according to General procedure:
1Starting compound II: 7-bromo-1-methylindole (0.23g, 1.1mmol)
Starting compound III: 4-amino-2-chloro-2'-methylbenzophenone
(compound 2) (0.25g, 1.0mmol) Solvent: 1,4-dioxane (6mL) Base:
t-BuONa Reaction time: 18h Reaction temperature: 100.degree. C.
Purification: Chromatography using EtOAc:petroleum ether
1:3Product: compound 133, 0.23g amorphous compound. .sup.13C NMR
(CDCl.sub.3): .delta.196.55, 151.82, 139.37, 137.71, 135.36,
133.85, 132.97, 131.62, 131.19, 131.05, 130.68, 129.50, 127.92,
125.30, 123.76, 121.83, 120.53, 120.19, 115.06, 111.34, 101. 50,
35.49, 20.35
[0208] Example 34:
2-Chloro-2'-methyl-4-(1-methyl-5-indolylamino)benzophen- one
(Compound 134), 5-Bromo-1-methylindole was prepared from
5-bromoindole as described for the preparation of
7-bromo-1-methylindole from 7-bromoindole. Purification by
chromatography using EtOAc: petroleum ether 1:10 .sup.13C NMR
(CDCl.sub.3): .delta.135.37, 130.12, 129.94, 124.30, 123.27,
112.66, 110.63, 100.53, 32.96
[0209] Compound 134 was prepared according to General procedure:
1Starting compound II: 5-bromo-1-methylindole (0.23g, 1.1mmol)
Starting compound III: 4-amino-2-chloro-2'-methylbenzophenone
(compound 2) (0.25g, 1.0mmol) Solvent: 1,4-dioxane (6mL) Base:
t-BuONa Reaction time: 18h Reaction temperature: 100.degree. C.
Purification: Chromatography using EtOAc:petroleum ether
1:3Product: compound 134, 0.12g crystalline compound. .sup.13C NMR
(CDCl.sub.3): .delta.7.45(d,1H), 7.36-7.18(m,6H), 7.08(d,1H),
7.06(dd,1H), 6.82(d,1H), 6.66(dd,1H), 6.45(dd,1H), 6.01(s,1H),
3.80(s,3H), 2.41(s,3H)
[0210] Example 35:
2-Chloro-2',5'-dimethyl-4-(4-methyl-3-pyridylamino)benz- ophenone
(Compound 135) General procedure:1Starting compound II:
3-Bromo-4-methylpyridine (0.092 g, 0.5mmol) Starting compound III:
4-Amino-2-Chloro-2',5'-dimethylbenzophenone (0.134 g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 135, 0.078g
oil. .sup.13C NMR (CDCl.sub.3): .delta.196.7, 148.4, 146.5, 146.0,
142.1, 138.9, 135.5, 135.1, 134.9, 134.8, 133.5, 131.7, 131.2,
130.1, 129.4, 125.9, 116.0, 112.3, 20.8, 19.9, 17.5
[0211] Example 36:
2-Chloro-2',5'-dimethyl-4-(4-isoquinolylamino)benzophen- one
(Compound 136) General procedure: 1Starting compound II:
4-Bromoisoquinoline (0.103g, 0.49mmol) Starting compound III:
4-Amino-2-Chloro-2',5'-dimethylbenzophenone (0.131g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 4h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using EtOAc : petroleum ether 1:1Product: Compound 136, 0.18g
crystalline compound. .sup.13C NMR (CDCl.sub.3): .delta.196.8,
150.1, 149.2, 139.0, 138.6, 135.1, 134.9, 134.8, 133.5, 132.1,
131.7, 131.2, 131.1, 130.8, 130.1, 129.4, 129.3, 128.2, 127.9,
121.6, 116.4, 112.6, 20.8, 20.0
[0212] Example 37:
2-Chloro-4-(4-isoquinolylamino)-2',4',5'-trimethylbenzo- phenone
(Compound 137) General procedure: 1Starting compound II:
4-Bromoisoquinoline (0.103 g, 0.49mmol) Starting compound III:
4-Amino-2-chloro-2',4',5'-trimethylbenzophenone (0.148g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 137, 0.16g
crystalline compound. .sup.13C NMR (CDCl.sub.3): .delta.196.6,
149.9, 148.9, 140.3, 138.3, 136.2, 135.8, 134.6, 133.5, 133.0,
132.8, 132.0, 131.5, 131.3, 130.7, 130.0, 129.3, 128.1, 127.8,
121.6, 116.4, 112.7, 20.1, 19.7, 19.1
[0213] Example 38:
2,3'-Dichloro-2'-methyl-4-(4-methyl-3-pyridylamino)benz- ophenone
(Compound 138) General procedure: 1Starting compound II:
3-Bromo-4-methylpyridine (0.095 g, 0.5mmol) Starting compound III:
4-Amino-2,3'-dichloro-2'-methylbenzophenone (0.144 g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 138, 0.09g oil.
.sup.13C NMR (CDCl.sub.3): .delta.195.3, 149.2, 146.8, 146.4,
142.5, 142.0, 135.9, 135.8, 135.1, 134.9, 134.3, 131.2, 127.9,
126.9, 126.4, 126.0, 116.0, 112.1, 17.5, 17.1
[0214] Example 39:
2-Fluoro-2'-methyl-4-(4-methyl-3-pyridylamino)benzophen- one
(Compound 139) General procedure: 1Starting compound II:
3-Bromo-4-methylpyridine (0.092 g, 0.5mmol) Starting compound III:
4-Amino-2-fluoro-2'-methylbenzophenone (0.120 g, 0.5mmol) Solvent:
1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using EtOAc : petroleum ether 1:1Product: Compound 139, 0.02g oil.
.sup.13C NMR (CDCl.sub.3): .delta.194.3, 163.7, 151.3, 146.8,
146.6, 142.8, 140.3, 136.3, 135.2, 134.0, 130.9, 130.2, 128.1,
126.0, 125.3, 117.9, 109.9, 101.1, 19.9, 17.4
[0215] Example 40:
2,4'-Dichloro-2'-methyl-4-(4-methyl-3-pyridylamino)benz- ophenone
(Compound 140) General procedure: 1Starting compound II:
3-Bromo-4-methylpyridine (0.086 g, 0.5mmol) Starting compound III:
4-Amino-2,4'-dichloro-2'-methylbenzophenone (0.132g, 0.47mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 140, 0.12g oil.
.sup.13C NMR (CDCl.sub.3): .delta.195.4, 148.7, 146.7, 146.2,
142.2, 140.1, 137.4, 136.8, 135.3, 135.2, 133.4, 131.3, 131.1,
128.9, 125.9, 125.6, 115.8, 112.4, 20.4, 17.5
[0216] Example 41:
2-Chloro-4'-fluoro-4-(4-isoquinolylamino)-2'-methyl benzophenone
(Compound 141) General procedure: 1Starting compound II:
4-Bromoisoquinoline (0.104g, 0.5mmol) Starting compound III:
4-Amino-2-chloro-4'-fluoro-2'-methylbenzophenone (0.140g, 0.53mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 141, 0.13g
crystalline compound. .sup.13C NMR (CDCl.sub.3): .delta.195.4,
164.0, 150.3, 149.3, 141.8, 138.7, 135.0, 134.9, 133.1, 132.4,
132.4, 131.0, 130.8, 129.4, 129.3, 128.2, 127.9, 121.6, 118.2,
116.2, 112.7, 112.3, 20.8
[0217] Example 42:
4'-n-Butyl-2-chloro-4-(4-isoquinolylamino)-2'-methylben- zophenone
(Compound 142) General procedure: 1Starting compound II:
4-Bromoisoquinoline (0.104g, 0.5mmol) Starting compound III:
4-Amino-2'-n-butyl-2-chloro-2'-methylbenzophenone (0.150g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 142, 0.17g oil.
.sup.13C NMR (CDCl.sub.3): .delta.196.4, 150.0, 148.8, 146.7,
138.6, 138.5, 136.0, 134.7, 133.0, 132.1, 131.7, 131.2, 130.8,
130.7, 130.1, 129.3, 128.2, 127.9, 125.4, 121.6, 116.3, 112.7,
35.6, 33.3, 22.4, 20.8, 13.9
[0218] Example 43:
2-Chloro-4-(5-isoquinolylamino)-2'-methylbenzophenone (Compound
143) General procedure: 1Starting compound II: 5-Bromoisoquinoline
(0.104g, 0.5mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.122g,
0.5mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h
Reaction temperature: 100.degree. C. Purification: Flash
chromatography using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound
143, 0.16g oil. .sup.13C NMR (CDCl.sub.3): .delta.196.6, 153.0,
148.7, 143.4, 138.9, 138.0, 135.5, 135.0, 133.5, 131.6, 131.3,
131.0, 129.8, 129.5, 127.4, 125.4, 124.8, 123.8, 116.6, 115.1,
113.0, 20.5
[0219] Example 44:
2-Chloro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylben- zophenone
(Compound 144) General procedure: 1Starting compound II:
4-Bromoisoquinololine (0.104g, 0.5mmol) Starting compound III:
4-Amino-2-chloro-4'-methoxy-2'-methylbenzophenone (0.136g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using CH.sub.2Cl.sub.2:acetone 9:1Product: Compound 144, 0.19g
crystalline compound. .sup.13C NMR (CDCl.sub.3): .delta.195.5,
161.9, 149.9, 148.5, 142.0, 138.3, 134.2, 133.7, 132.4, 132.0,
131.4, 130.9, 130.7, 129.3, 128.2, 127.8, 121.6, 117.1, 116.3,
112.9, 110.4, 55.3, 21.5
[0220] Example 45:
2-Fluoro-4-(4-isoquinolylamino)-4'-methoxy-2'-methylben- zophenone
(Compound 145) General procedure: 1Starting compound II:
4-Bromoisoquinoline (0.103g, 0.5mmol) Starting compound III:
4-Amino-2-fluoro-4'-methoxy-2'-methylbenzophenone (0.130g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using EtOAc: petroleum ether 1:1 followed by recrystallization from
EtOAc. Product: Compound 145, 0.07g crystalline compound. .sup.1H
NMR (DMSO-D.sub.6): .delta.9.18 (s,1H), 9.13 (s,1H), 8.54 (s,1H),
8.20 (d,1H), 8.03 (d,1H), 7.83 (t,1H), 7.75 (t,1H), 7.42 (t,1H),
7.30 (d,1H), 6.87 (d,1H), 6.81 (dd,1H), 6.77 (dd,1H), 6.58 (dd,1H),
3.80 (s,3H), 2.34 (s,3H)
[0221] Example 46:
2,4'-Dichloro-2'-methyl-4-(1-methyl-7-indolylamino)benz- ophenone
(Compound 146) General procedure: 1Starting compound II:
7-Bromo-1-methylindole (0.115g, 0.55mmol) prepared as described in
example 33Starting compound III:
4-Amino-2,4'-dichloro-2'-methylbenzophen- one (0.140g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using EtOAc : petroleum ether 1:3Product: Compound 146, 0.08g
crystalline compound. .sup.13C NMR (CDCl.sub.3): .delta.195.5,
152.1, 139.8, 137.8, 136.5, 135.4, 133.8, 132.9, 131.6, 131.2,
131.1, 130.8, 127.5, 125.5, 123.6, 121.8, 120.6, 120.2, 115.0,
111.4, 101.5, 35.5, 20.2
[0222] Example 47:
2-Chloro-4-(1-methyl-7-indolylamino)-2',4',5'-trimethyl-
benzophenone (Compound 147) General procedure: 1Starting compound
II: 7-Bromo-1-methylindole (0.115g, 0.55mmol) prepared as described
in example 33Starting compound III:
4-Amino-2-chloro-2',4',5'-trimethylbenzo- phenone (0.137g, 0.5mmol)
Solvent: 1,4-dioxan (5 mL) Base: t-BuONa Reaction time: 6 h
Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc: petroleum ether 1:3Product: Compound
147, 0.097g crystalline compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.6, 151.5, 140.0, 136.6, 135.5, 135.0, 133.5, 133.4,
133.0, 132.7, 131.6, 131.3, 131.0, 128.6, 124.0, 121.8, 120.4,
120.2, 115.0, 111.3, 101.5, 35.5, 20.0, 19.7, 19.1
[0223] Example 48:
2-Chloro-2',5'-dimethyl-4-(1-methyl-7-indolylamino)benz- ophenone
(Compound 148) General procedure: 1Starting compound II:
7-Bromo-1-methylindole (0.115g, 0.55mmol) prepared as described in
example 33 Starting compound III:
4-Amino-2-chloro-2',5'-dimethylbenzophe- none (0.148 g, 0.5mmol)
Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h Reaction
temperature: 100.degree. C. Purification: Flash chromatography
using EtOAc : petroleum ether 1:3Product: Compound 148, 0.30g
crystalline compound. .sup.1H NMR (CDCl.sub.3): .delta.7.56 (d,1H),
7.28 (d,1H), 7.17-7.02 (m,4H), 6.98 (d,lH), 6.95 (d,lH), 6.61
(d,1H), 6.50 (d,1H), 6.42 (dd,1H), 5.93 (s,Br,1H), 3.81 (s,3H),
2.32 (s,3H), 2.27 (s,3H)
[0224] Example 49:
2-Chloro-4-(3-ethoxy-4-isoquinolylamino)-2'-methylbenzo- phenone
(Compound 149) General procedure: 1Starting compound II:
4-Bromo-3-ethoxyisoquinoline (0.097g, 0.39mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.095g,
0.39mmol) Solvent: 1,4-dioxan (3mL) Base: t-BuONa Reaction time: 6
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc : petroleum ether 1:3Product: Compound
149, 0.11g crystalline compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.6, 155.1, 149.9, 147.4, 139.3, 137.8, 134.8, 133.3,
131.2, 130.7, 130.5, 129.6, 128.7, 128.1, 125.6, 125.3, 124.5,
121.9, 116.2, 113.9, 112.4, 62.7, 20.4, 15.0
[0225] Example 50:
2-Chloro-4-(1-ethoxy-4-isoquinolylamino)-2'-methylbenzo- phenone
(Compound 150) General procedure: 1 Starting compound II:
4-Bromo-1-ethoxyisoquinoline (0.097g, 0.39mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.095g,
0.39mmol) Solvent: 1,4-dioxan (3mL) Base: t-BuONa Reaction time: 6
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc: petroleum ether 1:3Product: Compound
150, 0.11g crystalline compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.5, 159.7, 151.2, 139.4, 138.5, 137.7, 135.5, 135.3,
133.8, 131.2, 131.0, 130.7, 129.5, 128.0, 127.1, 125.3, 125.0,
124.6, 121.8, 120.3, 115.1, 111.4, 62.4, 20.4, 14.6
[0226] Example 51
4-(2-Benzoxazolylamino)-2-chloro-2'-methylbenzophenone (Compound
151) General procedure: 1Starting compound II: 2-Chlorobenzoxazole
(0.35mL, 3.0mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g,
2.0mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 16
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc : petroleum ether 1:4Product: Compound
151, 0.17g, crystalline compound. .sup.13C NMR (CDCl.sub.3):
.delta.196.9, 157.3, 147.8, 141.4, 141.3, 138.7, 138.0, 134.0,
133.1, 132.2, 131.6, 130.6, 125.5, 124.7, 124.5, 122.6, 119.3,
117.4, 115.7, 109.5, 20.8
[0227] Example 52
4-(1-Methyl-2-benzimidazolylamino)-2-chloro-2'-methylben- zophenone
(Compound 152) General procedure: 1Starting compound II:
2-Chloro-1-methylbenzoimidazole (0.33g, 2.0mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49 g,
2.0mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 24
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc: petroleum ether 1:2Product: Compound
152, 0.27g, crystalline compound .sup.13C NMR (CDCl.sub.3):
.delta.196.0, 147.0, 140.4, 139.0, 137.1, 135.4, 133.9, 132.0,
131.8, 130.9, 129.8, 125.6, 125.4, 124.6, 121.1, 117.6, 113.7,
110.1, 31.3, 20.9
[0228] Example 53
4-(2-Benzothiazolylamino)-2-chloro-2-methylbenzophenone (Compound
153) General procedure: 1Starting compound II:
2-Chlorobenzothiazole (0.26mL, 2.0mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.49g,
2.0mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 20
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using acetone:CH.sub.2Cl.sub.21:100Product: Compound
153, 0.24g, crystalline compound .sup.13C NMR (CDCl.sub.3):
.delta.196.9, 161.5, 151.1, 143.1, 138.7, 138.0, 134.1, 133.1,
132.3, 131.6, 130.5, 130.3, 126.5, 125.5, 123.4, 121.0, 120.3,
119.6, 116.0, 20.8
[0229] Example 54:
2-Chloro-2'-methyl-4-(2-pyrimidylamino)benzophenone (Compound 154)
General procedure: 1Starting compound II: 2-Bromopyrimidine (0.18g,
1.1mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25 g,
1.0mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 18
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using acetone:CH.sub.2Cl.sub.22:100Product: Compound
154, 0.14g, crystalline compound .sup.13C NMR (CDCl.sub.3):
.delta.196.8, 159.4, 158.1, 143.0, 138.4, 133.9, 132.1, 132.0,
131.5, 131.3, 130.3, 125.4, 119.8, 116.2, 113.8, 20.7
[0230] Example 55
2-Chloro-2'-methyl-4-(7-methyl-purin-6-ylamino)benzophen- one
(Compound 155) General procedure: 1Starting compound II:
6-Bromo-7-methylpurine (0.18g, 0.84mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.19g,
0.77mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 18
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc:petroleumether 1:3->1:0 followed by
recrystallisation from Et.sub.2O Product: Compound 155, 0.06g
crystalline compound .sup.13C NMR (CDCl.sub.3): .delta.196.7,
152.7, 151.4, 150.4, 142.3, 141.8, 138.7, 138.2, 133.7, 133.1,
131.9, 131.6, 131.4, 130.5, 125.5, 120.7, 120.6, 117.1, 30.0,
20.8
[0231] Example 56
2-Chloro-2'-methyl-4-(2-methyl-5-benzothiazolylamino)ben- zophenone
(Compound 156) General procedure: 1Starting compound II:
5-Bromo-2-methylbenzothiazole (0.25g, 1.1mmol) Starting compound
III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25 g,
1.0mmol) Solvent: 1,4-dioxan (6mL) Base: t-BuONa Reaction time: 18
h Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc:petroleumether 1:3->1:2Product:
Compound 156, 0.21g oil .sup.13C NMR (CDCl.sub.3): .delta.196.5,
168.7, 154.6, 147.8, 139.1, 138.8, 138.0, 135.1, 133.4, 131.3,
130.9, 130.8, 129.8, 129.5, 125.4, 122.2, 119.3, 116.5, 114.3,
113.0, 20.5, 20.2
[0232] Example 57
2-Chloro-2'-methyl-4-(pyrazin-2-ylamino)benzophenone (Compound 157)
General procedure: 1Starting compound II: 2-Iodopyrazine (0.23g,
1.1mmol) Starting compound III: 4-Amino-2-chloro-2'-methylbenzoph-
enone (compound 2) (0.25 g, 1.0mmol) Solvent: 1,4-dioxan (6mL)
Base: t-BuONa Reaction time: 6 h Reaction temperature: 100.degree.
C. Purification: Flash chromatography using EtOAc:petroleum ether
1:1 followed by purification on RP HPLC Product: Compound 157, oil
.sup.13C NMR (CDCl.sub.3): .delta.196.8, 151.0, 143.2, 141.6,
138.6, 138.3, 136.3, 134.5, 134.0, 132.4, 132.2, 131.6, 131.4,
130.4, 125.5, 119.7, 116.1, 20.7
[0233] Example 58
2-Chloro-2'-methyl-4-(5-pyrimidylamino)benzophenone (Compound 158)
General procedure: 1Starting compound II: 5-Bromopyrimidine (0.18g,
1.1mmol) Starting compound III:
4-Amino-2-chloro-2'-methylbenzophenone (compound 2) (0.25 g,
1.0mmol) Solvent: 1,4-dioxan (5mL) Base: t-BuONa Reaction time: 6 h
Reaction temperature: 100.degree. C. Purification: Flash
chromatography using EtOAc:petroleum ether 1:1->1:0 followed by
purification on RP HPLC Product: Compound 158, oil .sup.13C NMR
(CDCl.sub.3): .delta.196.3, 153.3, 148.0, 145.0, 138.6, 138.2,
134.9, 133.0, 132.2, 131.6, 131.5, 130.2, 125.5, 117.7, 114.2,
20.7
[0234] Example 59
2-Chloro-2'-methyl-4-(5-nitro-2-thiazolylamino)benzophen- one
(Compound 159) 4-Amino-2-chloro-2'-methylbenzophenone (compound 2)
(0.246g, 1.0mmol), 2bromo-5nitrothiazol (0.209g, 1.0mmol) and
N,N-diisopropyl ethylamine (0.18mL, 1.0mmol) were mixed in a 4 mL
screwcap vessel and kept at 60.degree. C. for 18h. The reaction
mixture was partitioned between EtOAc and water, and the organic
phase was washed with H.sub.2O (3.times.10 mL) and brine (10mL),
dried (MgSO.sub.4) and evaporated in vacuo. The crude compound was
purified by flash chromatografy using EtOAc:CH.sub.2Cl.sub.2 1:50
as the eluent. Product: Compound 159, 0.12g, crystalline compound.
.sup.13C NMR (DMSO-D-6): .delta.195.8, 166.5, 145.2, 142.1, 138.6,
137.8, 137.4, 133.1, 131.9, 131.8, 131.6, 130.3, 125.9, 119.3,
117.0, 54.9, 20.3
[0235] Example 60
2-Chloro-2'-methyl-4-((4-methyl-3-nitro-(1,2,4-triazol-5-
-ylamino))benzophenone (Compound 160) Preparation of
5-bromo-4-methyl-3-nitro-1,2,4-triazole:
5-Bromo-3-nitro-1,2,4-triazole (0.78g, 4.0 mmol) was dissolved in
DMF (20mL). K.sub.2CO.sub.3(1.11g, 8.0mmol) and CH.sub.3I (0.28mL,
4.4mmol) were added, and the mixture was stirred at room
temperature for 18h. H.sub.2O was added, and the water phase was
extracted three times with Et.sub.2O. The combined organic phases
were washed with brine, dried (MgSO.sub.4) and evaporated, and the
crude product was purified by flash chromatografy using
EtOAc:petroleum ether 1:1 as the eluent Product:
2-bromo-1-methyl-5-nitro-1,2,4-triazole, 0.44g .sup.13C NMR
(CDCl.sub.3): .delta.131.3, 80.6, 38.0Preparation of compound 160:
General procedure: 1Starting compound II:
5-Bromo-4-methyl-3-nitro-1,2,4-triazole (0.22g, 1.1mmol) Starting
compound III: 4-Amino-2-chloro-2'-methylbenzophenone (compound 2)
(0.24 g, 1.0mmol) Solvent: Toluene (5mL) Base:
Cs.sub.2CO.sub.3Reaction time: 18 h Reaction temperature:
100.degree. C. After 18h an extra portion of BINAP (24mg) and
Pd2(dba)3 (17mg) were added, and the reaction mixture was shaken
another 24h at 100.degree. C. Work up as described in General
procedure 1Purification: Flash chromatography using EtOAc:petroleum
ether 1:1 followed by purification on reversed phase HPLC Product:
Compound 160, oil .sup.13C NMR (DMSO-D-6): .delta.195.8, 158.3,
151.0, 142.8, 137.8, 137.4, 131.9, 131.6, 131.4, 131.4, 129.9,
125.8, 117.9, 115.6, 35.6, 20.1
4EXAMPLE 61 Tablet containing compound 116 Compound 116 (active
substance) 50 mg Lactose 125 mg Starch 12 mg Methyl cellulose 2 mg
Sodium carboxymethyl cellulose 10 mg Magnesium stearate 1 mg
[0236] The active substance, lactose and starch are mixed to a
homogeneous state in a suitable mixer and moistened with a 5
percent aqueous solution of methyl cellulose 15 cps. The mixing is
continued until granules are formed. If necessary, the wet
granulation is passed through a suitable screen and dried to a
water content of less than 1% in a suitable drier, e.g. fluid bed
or drying oven. The dried granules are passed through a 1 mm screen
and mixed to a homogeneous state with sodium carboxymethyl
cellulose. Magnesium stearate is added, and the mixing is continued
for a short period of time. Tablets with a weight of 200 mg are
produced from the granulation by means of a suitable tabletting
machine.
5EXAMPLE 62 Formulation for injection containing compound 116.
Compound 116 (active substance) 1% Sodium chloride q.s. Ethanol 10%
Water for injection to make 100%
[0237] The active substance is dissolved in ethanol (10%) then
water for injection made isotonic with sodium chloride is added to
make 100%. The mixture is filled into ampoules and sterilised.
[0238] Example 63 Cream formulation containing compound 116
Compound 116 (10 g) was dissolved in Octyidodecyl myristate (250g)
to form Part A. Methylparaben (1 g) and propylparaben (0.2 g) were
dissolved in phenoxyethanol (6 g) and mixed with a 0.025 M
Phosphate buffer pH=7.5 (632,8 g) to form Part B. Cetostearyl
alcohol (50 g) and ARLACEL 165.RTM. (50 g) was melted in a vessel
at 70.degree. to 80.degree. C. Part A was added and heated to
60-70.degree. C. The aqueous phase was likewise heated to
60-70.degree. C. and slowly added to the melted oil phase under
high speed stirring. The homogenised components were cooled to room
temperature.
* * * * *