Note: Descriptions are shown in the official language in which they were submitted.
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2-(3-SUBSTITUTED-ARYL)AMINO-4-ARYL-THIAZOLES AS TYROSINE KINASE INHIBITORS
The present invention relates to novel compounds selected from 2-(3-
substitutedary!)amino-4-aryl-thiazoles that selectively modulate, regulate,
and/or inhibit
signal transduction mediated by certain native and/or mutant tyrosine kinases
implicated
in a variety of human and animal diseases such as cell proliferative,
metabolic, allergic,
l0 and degenerative disorders. More particularly, these compounds are potent
and selective
c-kit inhibitors.
Tyrosine kinases are receptor type or non-receptor type proteins, which
transfer the
terminal phosphate of ATP to tyrosine residues of proteins thereby activating
or
inactivating signal transduction pathways. These proteins are known to be
involved in
many cellular mechanisms, which in case of disruption, lead to disorders such
as
abnormal cell proliferation and migration as well as inflammation.
As of today, there are about 58 known receptor tyrosine kinases. Other
tyrosine kinases
2o are the well-known VEGF receptors (I~im et al., Nature 362, pp. 841-844,
1993), PDGF
receptors, c-kit and the FLK family. These receptors can transmit signals to
other
tyrosine kinases including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak,
Ack. etc.
Among tyrosine kinase receptors, c-kit is of special interest. Indeed, c-leit
is a key
receptor activating mast cells, which have proved to be directly or indirectly
implicated
in numerous pathologies for which the Applicant filed WO 03/004007, WO
03/004006,
WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03!002108, WO
03/002107, WO 03!002106, WO 03/002105, WO 03/039550, WO 03/035050, WO
03!035049, US 601359,652 and US 60/359651.
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It was found that mast cells present in tissues of patients are implicated in
or contribute
to the genesis of diseases such as autoimmune diseases (rheumatoid arthritis,
inflammatory bowel diseases (IBD)) allergic diseases, tumor angiogenesis,
inflammatory
diseases, and interstitial cystitis. In these diseases, it has been shown that
mast cells
participate in the destruction of tissues by releasing a cocktail of different
proteases and
mediators such as histamine, neutral proteases, lipid-derived mediators
(prostaglandins,
thromboxanes and leucotrienes), and various cytokines (IL-1, 1L-2, IL-3, IL-4,
IL-5, IL-
6,1L-8, TNF-a, GM-CSF, MIl'-la, MIP-lb, MIP-2 and IFN-y).
to
The c-kit receptor also can be constitutively activated by mutations leading
to
abnormal cell proliferation and development of diseases such as mastocytosis
and
various cancers.
For this reason, it has been proposed to target c-kit to deplete the mast
cells responsible
for these disorders.
The main objective underlying the present invention is therefore to fmd potent
and
selective compounds capable of inhibiting wild type and/or mutated c-kit.
Many different compounds have been described as tyrosine kinase inhibitors,
for
example, bis monocyclic, bicyclic or heterocyclic aryl compounds (WO
92/20642),
vinylene-azaindole derivatives (WO 94/14808) and 1-cycloproppyl-4-pyridyl-
quinolones
(LJS 5,330,992), styryl compounds (LTS 5,217,999), styryl-substituted pyridyl
compounds
(LJS 5,302,606), selenoindoles and selenides (WO 94/03427), tricyclic
polyhydroxylic
compounds (WO 92/21660) and benzylphosphonic acid compounds (WO 91/15495),
pyrimidine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives
and
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pyrrole-substituted indolinones (LJS 5,792,783, EP 934 931, US 5,834,504, US
5,883,116, US 5,883,113, US 5, 886,020, WO 96/40116 and WO 00/38519), as well
as
bis monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222, US
5,656,643 and
WO 92/20642), quinazoline derivatives (EP 602 851, EP 520 722, US 3,772,295
and US
4,343,940) and aryl and heteroaryl quinazoline (IJS 5,721,237, US 5,714,493,
US
5,710,158 and WO 95/15758).
However, none of these compounds have been described as potent and selective
inhibitors of c-kit or of the c-kit pathway.
In connection with our previous invention which is described in W02004014903,
we
found that compounds corresponding to the 2-(3-aminoaryl)amino-4-aryl-
thiazoles are
potent and selective inhibitors of c-kit or c-kit pathway. These compounds are
good
candidates for treating diseases such as autoimmunes diseases, inflammatory
diseases,
1~5 cancer and mastocytosis.
We now have determined that other 2-(3-substitutedaryl)amino-4-aryl-thiazole
derivatives display very strong inhibitory activity on several forms of c-kit.
2o Description
Therefore, the present invention relates to compounds belonging to the 2-(3-
lcetoarylamino-4-aryl-thiazoles. These compounds are capable of selectively
inhibiting
signal transduction involving the tyrosine phosphokinase c-kit and mutant
forms thereof.
25 In a first embodiment, the invention is aimed at compounds of formula I,
which may
represent either free base forms of the substances or pharmaceutically
acceptable salts
thereof
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R3
R6-W R4 / R2
N
R7~ ~ ~ \ ~ ~B~ ~.R1
~/~/ ~ N A B
S
Rg R5
FORMULA I
and wherein
R6 and R' are independently from each other chosen from one of the following:
i) hydrogen, a halogen (selected from F, Cl, Br or 1),
ii) an alkyh group defined as a linear, branched or cycloallcyl group
containing from 1 to
l0 10 carbon atoms, or from 2 or 3 to l0,carbon atoms, (for example methyl,
ethyl, propyl,
butyl, pentyl, hexyl...) and optionally substituted with one or more
hetereoatoms such as
halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter
optionally in the
form of a pendant basic nitrogen functionality); as well as trifluoromethyl,
carboxyl,
cyano, vitro, formyl;
(iii) an aryh group defined as phenyl or a substituted variant thereof bearing
any
combination, at any one ring position, of one or more substituents such as
- halogen(selected from I, F, Cl or Br);
- an alkyls group;
- a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant
2o basic nitrogen functionality;
- trifluoromethyl, O-all~yll, carboxyl, cyano, vitro, formyl, hydroxy, NH-
alkyls,
N(alkyll)(alkyh), and amino, the latter nitrogen substituents optionally in
the
form of a basic nitrogen functionality;
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(iv) a heteroaryh group defined as a pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl,
thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl,
isoxazolyl , triazolyl,
tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally
bear any
combination, at any one ring position, of one or more substituents such as
5 - halogen (selected from F, Cl, Br or >];
- an alkyl s group;
- a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant
basic nitrogen functionality,
- trifluoromethyl, O-alkyls, carboxyl, cyano, vitro, formyl, hydroxy, NH-
allcyh,
1o N(alkyll)(alkyll), and amino, the latter nitrogen substituents optionally
in the
form of a basic nitrogen functionality;
(v) trifluoromethyl, carboxyl, cyano, vitro, formyl, hydroxy, N(alkyh)(alkyh),
and
amino, the latter nitrogen substituents optionally in the form of a basic
nitrogen
functionality.
R8 is one of the following:
(i) hydrogen, or
(ii) a linear or branched alkyl group containing from 1 to 10 carbon atoms and
optionally
substituted with one or more hetereoatoms such as halogen (selected from F,
Cl, Br or 1~,
oxygen, and nitrogen, the latter optionally in the form of a pendant basic
nitrogen
functionality, or
(iii) CO-R8 or COOR8 or CONHRB or S02R8 wherein R8 may be
- a linear or branched alkyl group containing from 1 to 10 carbon atoms and
optionally substituted with one or more hetereoatoms such as halogen (selected
from F,
Cl, Br or 1], oxygen, and nitrogen, the latter optionally in the form of a
pendant basic
nitrogen functionality, or
- an aryl group such as phenyl or a substituted variant thereof bearing any
combination, at any one ring position, of one or more substituents such as
halogen
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(selected from F, Cl, Br or 17, alkyl groups containing from 1 to 10 carbon
atoms and
optionally substituted with one or more hetereoatoms such as halogen (selected
from F,
Cl, Br or ~, oxygen, and nitrogen, the latter optionally in the form of a
pendant basic
nitrogen functionality; as well as trifluoromethyl, C1_6alkyloxy, carboxyl,
cyano, vitro,
formyl, hydroxy, Cl_6alkylamino, di(Cl_6alkyl)amino, and amino, the latter
nitrogen
substituents optionally in the form of a pendant basic nitrogen functionality;
as well as
CO-R, COO-R, CONH-R, S02-R, and S02NH-R wherein R is a linear or branched
alkyl group containing from 1 to 10 carbon atoms and optionally substituted
with at
least one heteroatom, notably a halogen (selected from F, Cl, Br or 1~,
oxygen, and
to nitrogen, the latter optionally in the form of a pendant basic nitrogen
functionality, or
- a heteroaryl group such as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
thienyl,
thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl,
triazolyl,
tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally
bear any
combination, at any one ring position, of one or more substituents such as
halogen
(selected from F, Cl, Br or 1], alkyl groups containing from 1 to 10 carbon
atoms and
optionally substituted with one or more hetereoatoms such as halogen (selected
from F,
Cl, Br or 1], oxygen, and nitrogen, the latter optionally in the form of a
pendant basic
nitrogen functionality; as well as trifluoromethyl, C1_6alkyloxy, carboxyl,
cyano, vitro,
formyl, hydroxy, C1_6alkylamino, di(Cl_6alkyl)amino, and amino, the latter
nitrogen
2o substituents optionally in the form of a basic nitrogen functionality; as
well as CO-R,
COO-R, CONH-R, S02-R, and S02NH-R wherein R is a linear or branched alkyl
group
containing from 1 to 10 carbon atoms and optionally substituted with at least
one
heteroatom, notably a halogen (selected from F, Cl, Br or >7, oxygen, and
nitrogen, the
latter optionally in the form of a pendant basic nitrogen functionality.
R2, R3, R4 and RS each independently are selected from hydrogen, halogen
(selected
from F, Cl, Br or 1], a linear or branched alkyl group containing from 1 to 10
carbon
atoms and optionally substituted with one or more hetereoatoms such as halogen
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(selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in
the form of a
pendant basic nitrogen functionality; as well as trifluoromethyl,
Cl_6alkyloxy, amino, Cl_
6alkylamino, di(Cl_6alkyl)amino, carboxyl, cyano, vitro, formyl, hydroxy, and
CO-R,
COO-R, CONH-R, S02-R, and S02NH-R wherein R is a linear or branched alkyl
group
containing from 1 to 10 carbon atoms and optionally substituted with at least
one
heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and
nitrogen, the
latter optionally in the form of a pendant basic nitrogen functionality.
A is : CH2, O, S, 502, CO, or COO,
1o B is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, 502, CO, or
COO,
B' is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, 502, CO or COO;
R* being an alkyls, aryls or heteroaryh
W is a bond or a linker selected from NH, NHCO, NHCOO, NHCONH, NHS02,
NHS02NH, CO, CONH, COO, COCH2, (CH2)n (n is 0, 1 or 2), CH2-CO, CH2C00,
CH2-NH, O, OCH2, S, 502, and S02NH
Rl is
a) a linear or branched alkyl group containing from 1 to 10 carbon atoms
optionally
substituted with at least one heteroatom, notably a halogen selected from I,
Cl, Br and F,
2o and / or bearing a pendant basic nitrogen functionality;
b) an aryl or heteroaryl group optionally substituted by an allcyl or aryl
group optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
a pendant basic nitrogen functionality
c) an alkyls, aryls or heteroaryh.
It will be understood that a Cl-C10 alkyl encompasses a methyl, ethyl, propyl,
and a C2
to C4 alkyl or a C2 to C 10 alkyl.
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For example, a subset of compounds may correspond to
R6 R4
N
A~B~B~.R1
S N
t
H
Wherein R1, R4 and R6 have the meaning as defined above.
It will be understood that A-B-B' includes but is not limited to
CH2, CH2-CO, CH2-CO-CH2, CH2C00, CH2-CH2-CO, CH2-CH2-COO, CH2-NH,
CH2-CH2-NH, CH2-NH-CH2 or CH2-NH-CO or CH2-CO-NH
It will be understood that A-B-B' also includes but is not limited to
to CO-CH2, COO-CH2, CO-CH2-CH2, CO-NH, or CO-NH-CH2
as well as O-CH2
It will also be understood that NH in B or B' can also be NCH3
In the above formula I, when W is other than a single bond, it will be
understood that A
can be also be NH or NCH3.
In the above formula, the following combinations are contemplated
- R6 is (iv), R4 is H or CH3, A-B-B' is CO-NH and Rl is as defined above.
- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-CO-NH and Rl is as defined above.
- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-CO and R1 is as defined above.
- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-NH-CO and Rl is as defined above.
- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-NH and R1 is as defined above.
- R6 is (iv), R4 is H or CH3, A-B-B' is CH2 and R1 is as defined above.
- R6 is W-(iv), R4 is a C1-C2 allcyl, A-B-B' is CO-NH and Rl is as defined
above.
- R6 is (iv), R4 is a C1-C2 alkyl, A-B-B' is CH2-CO-NH and R1 is as defined
above.
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- R6 is (iv), R4 is a C1-C2 alkyl, A-B-B' is CH2-CO and Rl is as defined
above.
- R6 is a pyridyl according to (iv), R4 is a C 1-C2 alkyl, A-B-B' is CO-NH,
CH2-CO-NH,
CH2-CO, CH2-NH, CH2-NH-CO and Rl is as defined above.
In the above combination, Rl can be an alkyls.
In the above combination, Rl can be an aryls.
In the above combination, Rl can be an heteroaryh.
In one preferred embodiment, when ABB' is CONH, the invention is directed to
to compounds of the following formula I-1:
H
\ ~N ~ w
N
N.R
N '/ H I_ 1
wherein R is H or an organic group that can be selected for example from a
linear or
branched alkyl group containing from 1 to 10 carbon atoms optionally
substituted with at
least one heteroatom or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an
aryl or heteroaryl group optionally substituted by an alkyl, a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with a heteroatom, notably a halogen
selected
from I, Cl, Br and F and l or bearing a pendant basic nitrogen functionality.
In one other preferred embodiment, the invention is directed to amide-aniline
compounds of the following formula I-2:
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H
II N I ~ H
N / , N.R
I
O N
N ~ H I_2
wherein R is H or an organic group that can be selected for example from a
linear or
branched alkyl group containing from 1 to 10 carbon atoms optionally
substituted with at
least one heteroatom or bearing a pendant basic nitrogen functionality; a
cycloallcyl, an
5 aryl or heteroaryl group optionally substituted with a heteroatom, notably a
halogen
selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen
functionality; or a
a cycloalkyl, an aryl or heteroaryl group optionally substituted with a
cycloalkyl, an aryl
or heteroaryl group optionally substituted with
- a heteroatom, notably a halogen selected from I, Cl, Br and F and / or
bearing a pendant
to basic nitrogen functionality;
- a S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F and / or
bearing a pendant basic nitrogen functionality;
- a CO-R or a CO-NRR' group, wherein R and R' are independently chosen from H,
an
alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with
at least one
heteroatom, notably selected from I, Cl, Br and F, and / or bearing a pendant
basic
nitrogen functionality.
Among the particular compounds in which Rl has the meaning as depicted above,
the
2o invention is directed to amide-benzylamine compounds of the following
formula I-3:
H
\ YN I w
N ~ / .R
~ I H
/) O N
NJ H I-3
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wherein R is H or an organic group that can be selected for example from a
linear or
branched alkyl group containing from 1 to 10 carbon atoms optionally
substituted with at
least one heteroatom, notably a halogen selected from I, Cl, Br and F, and /
or bearing a
pendant basic nitrogen functionality; a cycloallcyl, aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality; or an alkyl, cycloalkyl, aryl
or heteroaryl
group substituted by a allcyl, cycloalkyl, aryl or heteroaryl group optionally
substituted
with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing
a pendant
basic nitrogen functionality;
to a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR'
group,
wherein R and R' are independently chosen from H or an aryl heteroaryl, alkyl
and
cycloalkyl group optionally substituted with at least one heteroatom and / or
bearing a
pendant basic nitrogen functionality.
Among the particular compounds in which R1 has the meaning as depicted above,
the
invention is directed to amide-phenol compounds of the following formula I-4:
H
\ YN ~ w
N / / O.R
/, O N
NJ H I-4
wherein R is H or an organic group that can be selected for example from a
linear or
branched allcyl group containing from 1 to 10 carbon atoms optionally
substituted with at
least one heteroatom, notably a halogen selected from I, Cl, Br and F, and /
or bearing a
pendant basic nitrogen functionality;
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a cycloallcyl, aryl or heteroaryl group optionally substituted with a
heteroatom, notably a
halogen selected from I, Cl, Br and F and / or bearing a pendant basic
nitrogen
functionality; or an alkyl, cycloalkyl, aryl or heteroaryl group substituted
by a alkyl,
cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom,
notably a
halogen selected from I, Cl, Br and F and / or bearing a pendant basic
nitrogen
functionality;
a -S02-R group wherein R is an allcyl, cycloalkyl, aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F and / or
bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR'
group,
wherein R and R' are independently chosen from H or an aryl, heteroaryl, alkyl
and
cycloalkyl group optionally substituted with at least one heteroatom and / or
bearing a
pendant basic nitrogen functionality.
Among compounds of formula I, the invention is particularly directed to 3-
(thiazol-2-
ylamino)-benzamide compounds of the following formula I-5:
~ Rs
N R5 / R2
6
O Y~z
I-5
wherein Y is a single bond, a linear or branched alkyl group containing from 1
to 10
carbon atoms, especially CH2 or CH2-CH2; or NH
wherein Z represents an aryl or heteroaryl group, optionally substituted at
one or more
ring position with any permutation of the following groups:
- a halogen such as F, Cl, Br, I;
- a linear or branched alkyl group containing from 1 to 10 carbon atoms
optionally
substituted with at least one heteroatom (for example a halogen) and / or
bearing
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a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl
group
optionally substituted with at least one heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an
aryl or heteroaryl group optionally substituted with an heteroatom, notably a
halogen selected from I, Cl, Br and F, and / or bearing a pendant basic
nitrogen
functionality;
- an O-R, where R is a linear or branched alkyl group containing from 1 to 10
carbon atoms optionally substituted with at least one heteroatom (for example
a
1o halogen) and / or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an
aryl or heteroaryl group optionally substituted with at least one heteroatom,
notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant
basic
nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group
substituted by
an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted
with an
heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing
a
pendant basic nitrogen functionality;
- an NRaRb, where Ra and Rb represents a hydrogen, or a linear or branched
alkyl
group containing from 1 to 10 carbon atoms optionally substituted with at
least
one heteroatom (for example a halogen) and / or bearing a pendant basic
nitrogen
functionality or a cycle; a cycloallcyl, an aryl or heteroaryl group
optionally
substituted with at least one heteroatom, notably a halogen selected from I,
Cl, Br
and F, and / or bearing a pendant basic nitrogen functionality; or a
cycloalkyl, an
aryl or heteroaryl group substituted by an allcyl, a cycloalkyl, an aryl or
heteroaryl
group optionally substituted with an heteroatom, notably a halogen selected
from
I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
R2 is hydrogen, halogen or a linear or branched allcyl group containing from 1
to 10
carbon atoms, trifluoromethyl, cyano or alkoxy;
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R3 is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl, cyano or alkoxy;
R4 is hydrogen, halogen or a linear or branched allcyl group containing from 1
to 10
carbon atoms, trifluoromethyl, cyano or alkoxy;
RS is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl, cyano or alkoxy;
R6 is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
at any one ring position, of one or more substituents such as halogen, alkyl
groups
to containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
any combination of one or more substituents such as halogen, alkyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
(iii) a five-membered ring aromatic heterocyclic group such as for example 2-
thienyl, 3-
thienyl, 2-thia.zolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear
any
combination of one or more substituents such as halogen, an alkyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
iv) H, a .halogen selected from I, F, Cl or Br; NH2, N02 or S02-R, wherein R
is a linear
or branched alkyl goup containing one or more group such as 1 to 10 carbon
atoms, and
optionally substituted with at least one heteroatom, notably a halogen
selected from I, Cl,
Br and F, and / or bearing a pendant basic nitrogen functionality;
and R~ is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
at any one ring position, of one or more substituents such as halogen, alkyl
groups
containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
any combination of one or more substituents such as halogen, alkyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
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(iii) a five-membered ring aromatic heterocyclic group such as for example 2-
thienyl, 3-
thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear
any
combination of one or more substituents such as halogen, an allcyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
5 iv) H, an halogen selected from I, F, Cl or Br; NH2, N02 or S02-R, wherein R
is a
linear or branched alkyl goup containing one or more group such as 1 to 10
carbon
atoms, and optionally substituted with at least one heteroatom, notably a
halogen
selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality.
to An example of preferred compounds of the above formula is depicted below:
001 : 4-[4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoylamino]-benzoic
acid 2-
diethylamino-ethyl ester
N
N
~>-N H
S / \
_ O
O
HN \ / O r-
~--N
Among the compounds of formula I, the invention is particularly embodied by
the
compounds of the following formula II
\ ~N ( ~ R3
'N1
R Rs ~ R2
6
O N~X
H
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FORMULA II
wherein X is R or NRR' and wherein R and R' are independently chosen from H,
an
s aryl, a heteroaryl, an alkyl , or a cycloalkyl group optionally substituted
with at least one
heteroatom, such as for example a halogen chosen from F, I, Cl and Br and
optionally
bearing a pendant basic nitrogen functionality; or an aryl, a heteroaryl, an
alkyl or a
cycloalkyl group substituted with an aryl, a heteroaryl, an alkyl or a
cycloalkyl group
optionally substituted with at least one heteroatom, such as for example a
halogen
to chosen from F, I, Cl and Br and optionally bearing a pendant basic nitrogen
functionality,
RZ is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl or allcoxy;
R3 is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
1 s carbon atoms, trifluoromethyl or alkoxy;
R4 is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl or alkoxy;
RS is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl or alkoxy;
2o R6 is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
at any one ring position, of one or more substituents such as halogen, alkyl
groups
containing from 1 to 10 carbon atoms, trifluoromethyl, and allcoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
25 any combination of one or more substituents such as halogen, alkyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
(iii) a five-membered ring aromatic heterocyclic group such as for example 2-
thienyl, 3-
thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear
any
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17
combination of one or more substituents such as halogen, an allcyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and allcoxy.
iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or S02-R, wherein R is
a linear
or branched alkyl goup containing one or more group such as 1 to 10 carbon
atoms, and
optionally substituted with at least one heteroatom, notably a halogen
selected from I, Cl,
Br and F, and / or bearing a pendant basic nitrogen functionality.
In another alternative, substituent R6, which in the formula II is connected
to position 4
of the thiazole ring, may instead occupy position 5 of the thiazole ring.
to
Among the preferred compounds corresponding formulas I and II, the invention
is
directed to compounds in which Rl and X, respectively, is a substituted
allcyl, aryl or
heteroaryl group bearing a pendant basic nitrogen functionality represented
for example
by the structures a to m shown below, wherein the wavy line and the arrow line
correspond to the point of attachment to core structure of formula I or II.
~N
'~,.,~N ~ ~ N w N
''~,t
a b c
~N/ I / i ~ \ N
/ J i / ~N~
d a f
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1~
H2N\ /'O I S02
N 'N~ N N O O N
N N N
g h i j k 1 m
Among group a to f and g to m Rl of formula I and X of formula II is
preferentially
group d. Also, for g to m, the arrow includes a point of attachment to the
core structure
via a phenyl group.
Furthermore, among the preferred compounds of formula I or II, the invention
concerns
to the compounds in which R2 and R3 are hydrogen. Preferentially, R4 is
a.methyl group
and RS is H. In addition, R6 is preferentially a 3-pyridyl group (cf.
structure g below), or
a 4-pyridyl group (cf. structure h below). The wavy line in structure g and h
correspond
to the point of attachment to the core structure of formula I or II.
N N
s
g h
~s
Thus, the invention contemplates:
1- A compound of formula II as depicted above, wherein X is group d and R6 is
a 3-
pyridyl group.
2- A compound of formula II as depicted above, wherein X is group d and R4 is
a
2o methyl group.
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19
3- A compound of formula I or II as depicted above, wherein R1 is group d and
Ra
is H.
4- A compound of formula I or II as depicted above, wherein Rl is group d and
R3
is H.
5- A compound of formula I or II as depicted above, wherein Rl is group d and
R2
and/or R3 and/or RS is H.
6- A compound of formula I or II as depicted above, wherein R6 is a 3-pyridyl
group
and R3 is a methyl group.
7- A compound of formula I or II as depicted above, wherein R6 is a 3-pyridyl
group
1 o and R2 is H.
8- A compound of formula I or II as depicted above, wherein RZ and/or R3
andlor RS
is H and R4 is a methyl group.
9- A compound of formula I or II as depicted above wherein RZ and/or R3 and/or
RS
is H, R4 is a methyl group and R6 is a 3-pyridyl group.
Among the compounds of formula II, the invention is particularly embodied by
the
compounds wherein R2, R3, RS are hydrogen, corresponding to the following
formula
II-1
R4
\ ~N ~ w
N
R6
.X
2o FORMULA 1I-1 ~ H
wherein X is R or NRR' and wherein R and R' are independently chosen from H or
an
organic group that can be selected for example from a linear or branched alkyl
group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or
heteroaryl
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group optionally substituted with an heteroatom, notably a halogen selected
from I, Cl,
Br and F or bearing a pendant basic nitrogen functionality; or a a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
5 F or bearing a pendant basic nitrogen functionality;
R4 is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl or alkoxy;
R6 is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
1 o at any one ring position, of one or more substituents such as halogen,
alkyl groups
containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
any combination of one or more substituents such as halogen, alkyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
1 5 (iii) a five-membered ring aromatic heterocyclic group such as for example
2-thienyl, 3-
thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear
any
combination of one or more substituents such as halogen, an alkyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and alkoxy.
iv) H, a halogen selected from I, F, Cl or Br; NH2, N02 or S02-R, wherein R is
a linear
20 or branched alkyl goup containing one or more group such as 1 to 10 carbon
atoms, and
optionally substituted with at least one heteroatom, notably a halogen
selected from I, Cl,
Br and F, and / or bearing a pendant basic nitrogen functionality.
In another alternative, substituent R6, which in the formula II is connected
to position 4
of the thiazole ring, may instead occupy position 5 of the thiazole ring.
Examples
002 : N-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-
ylamino)-
benzamide
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21
H
II N ~ w CFa
N / /
v ~ O H W CFs
N
1H NMR (DMSO-d6) 8 = 2.36 (s, 3H, ArCH3); 7.43 (d, 1H, J = 7.SHz, Ar-H); 7.68
(dd,
1H, J = 7.5, l.SHz, Ar-H) ; 7.73 (s, 1H, thia,zol-H) ; 7.82 (m, 3H, pyridyl-
H+Ar-H) ; 8.54
(m, 4H, pyridyl-H+2xAr-H) ; 8.85 (br s, 1H, Ar-H) ; 9.67 (s, 1H, NH), 10.84
(s, 1H,
NH).
003 : N-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-
ylamino)-
benzamide
H
II N ~ w CFs
N / /
-~ O H w CF3
~ N
092: N-Cyclohexyl-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide
H
\ YN ~
N
\ ~ O H
N
1H NMR (DMSO-d6) ~ = 1.00-1.40 (m, SH, cyclo-H); 1.50-1.85 (m, SH, cyclo-H);
2.34
(s, 3H, ArCH3); 7.28 (d, 1H, J = 7.9Hz, Ar-H); 7.48 (dd, 1H, J = 7.9, l.SHz,
Ar-H) ; 7.67
(s, 1H, thiazol-H) ; 7.82 (d, 2H, J = 6.OHz, pyridyl-H); 8.57 (d, 2H, J =
6.OHz, pyridyl-
H) ; x.63 (d, 1H, J = l.SHz, Ar-H) ; 9.55 (s, 1H, NH).
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22
093: 4-Methyl-N-( 1-methyl-1 H-indol-6-yl)-3-(4-pyridin-3-yl-thiazol-2-
ylamino)-
benzamide
H
\ ~N ~ w
N
-~ O H ~ N
N
094: N-(2,-Methoxy-ethyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ ~N ~ w
N
O N~Ow
H
N
096: N-(2-Cyano-ethyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide
H
\ YN ~ w
N
O H~CN
N
Among the compounds of formula II, the invention is particularly embodied by
the
compounds wherein X is a -substituted Aryl group, corresponding to the N-[3-
(Thiazol-
2-ylamino)-phenyl]-amide family and the following formula II-3
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23
R6
Ra
N / N ~ Rb
ORe ~ / Rc
FORMITLA II-3 Rd
wherein Ra, Rb, Rc, Rd, Re are independently chosen from H or an organic group
that
can be selected for example from a linear or branched alkyl group containing
from 1 to
carbon atoms optionally substituted with at least one heteroatom and / or
bearing a
pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl
group optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
to optionally substituted with a cycloallcyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality;
a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl
optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group,
wherein R and
R' are independently chosen from H, an alkyl, a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with at least one heteroatom, notably selected from I,
Cl, Br and F,
and or bearing a pendant basic nitrogen functionality;
Ra, Rb, Rc, Rd, Re may also be
- a halogen such as I, Cl, Br and F
- a NRR' group where R and R' are H or a linear or branched alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with a heteroatom, notably a halogen selected
from I, Cl, Br
and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl group
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24
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
F or bearing a pendant basic nitrogen functionality;
- an OR group where R is H or a linear or branched alkyl group containing from
1
to 10 carbon atoms optionally substituted with at least one heteroatom and /
or bearing a
pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl
group optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
optionally substituted with a cycloallcyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
to bearing a pendant basic nitrogen functionality; a -S02-R' group wherein R'
is an alkyl,
cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom,
notably a halogen
selected from I, Cl, Br and F or bearing a pendant basic
nitrogen'functionality;
- a NRaCORb group where Ra and Rb are H or a linear or branched alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with a heteroatom, notably a halogen selected
from I, Cl, Br
and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with a cycloallcyl, an aryl or
heteroaryl group
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
2o F or bearing a pendant basic nitrogen functionality;
- a NRaCONRbRc group where Ra and Rb are H or a linear or branched alkyl
group containing from 1 to 10 carbon atoms optionally substituted with at
least one
heteroatom and / or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an aryl
or heteroaryl group optionally substituted with a heteroatom, notably a
halogen selected
from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a
cycloalkyl, an
aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl
group optionally substituted with an heteroatom, notably a halogen selected
from I, Cl,
Br and F or bearing a pendant basic nitrogen functionality;
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- a COOR, where R is a linear or branched alkyl group containing from 1 to 10
carbon atoms atoms optionally substituted with at least one heteroatom (for
example a
halogen) and / or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an aryl or
heteroaryl group optionally substituted with at least one heteroatom, notably
a halogen
5 selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality; or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
- a CONRaRb, where Ra and Rb are a hydrogen or a linear or branched allcyl
group
to containing from 1 to 10 carbon atoms atoms optionally substituted with at
least one
heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen
functionality; a cycloallcyl, an aryl or heteroaryl group optionally
substituted with at least
one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality; or a cycloallcyl, an aryl or heteroaryl
group
15 substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group
optionally substituted
with an heteroatom, notably a halogen selected from I, Cl, Br and° F,
and / or bearing a
pendant basic nitrogen functionality;
- an NHCOOR, where R is a linear or branched alkyl group containing from 1 to
10
carbon atoms atoms optionally substituted with at least one heteroatom (for
example a
2o halogen) and l or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an aryl or
heteroaryl group optionally substituted with at least one heteroatom, notably
a halogen
selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality; or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
25 from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality;
- an OSOZR, where R is a linear or branched alkyl group containing from 1 to
10
carbon atoms atoms optionally substituted with at least one heteroatom (for
example a
halogen) and / or bearing a pendant basic nitrogen functionality; a
cycloallcyl, an aryl or
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26
heteroaryl group optionally substituted with at least one heteroatom, notably
a halogen
selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality; or a
cycloalkyl, an aryl or heteroaryl . group substituted by an alkyl, a
cycloalkyl, an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
- an NRaOS02Rb, where Ra and Rb are a linear or branched alkyl group
containing
from 1 to 10 carbon atoms atoms optionally substituted with at least one
heteroatom (for
example a halogen) and / or bearing a pendant basic nitrogen functionality; Ra
can also
be a hydrogen; a cycloalkyl, an aryl or heteroaryl group optionally
substituted with at
to least one heteroatom, notably a halogen selected from I, Cl, Br and F, and
/ or bearing a
pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally
substituted
with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality;
- a GN group
- a trifluoromethyl group
R4 is hydrogen, halogen or a linear or branched alkyl group containing from 1
to 10
carbon atoms, trifluoromethyl or allcoxy;
2o R6 is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
at any one ring position, of one or more substituents such as halogen, alkyl
groups
containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
any combination of one or more substituents such as halogen, alkyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
(iii) a five-membered ring aromatic heterocyclic group such as for example 2-
thienyl, 3-
thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear
any
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27
combination of one or more substituents such as halogen, an alkyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
iv) H, a halogen selected from I, F, Cl or Br; NH2, N02 or S02-R, wherein R is
a linear
or branched alkyl goup containing one or more group such as 1 to 10 carbon
atoms, and
optionally substituted with at least one heteroatom, notably a halogen
selected from I, Cl,
Br and F, and / or bearing a pendant basic nitrogen functionality.
Examples
028: N-(2-Fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-
2-
l0 ylamino)-benzamide
N \
I
N
~>--NH CH3
S /
O
HN ~
F CFg
029: N-(3-Fluoro-phenyl)-4--methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
N
N
~~-NH
S
F
O
HN \ /
030: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-(3-trifluoromethyl-
phenyl)-
benzamide
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28
N
N
~>--NH
F F
F
O
HN ~
031: 4-Methyl-N-(4-methyl-3-trifluorornethyl-phenyl)-3-(4-pyridin-4-yl-thiazol-
2-
ylamino)-benzamide
N
N
~>--NH
F F
F
O
HN
032: N-(2-Fluoro-5-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-
2-
ylamino)-benzamide
F
~ F F
N
, O N
N~ H F
1H NMR (DMSO-d6) ~ = 2.39 (s, 3H, ArCH3); 7.41 (d, 1H, J = 7.9Hz, Ar-H); 7.54-
7.70
(m, 3H, Ar-H); 7.72 (s, 1H, thiazol-H) ; 7.82 (d, 2H, J = 6.OHz, pyridyl-H);
8.10 (dd, 1H,
J = 6.8, 2.2Hz, Ar-H); 8.55 (d, 2H, J = 6.OHz, pyridyl-H) ; 8.84 (d, 1H, J =
l.BHz, Ar-H)
9.65 (s, 1H, NH); 10.31 (s, 1H, NH).
033: N-(4-Cyano-phenyl)-4-methyl-3-(4-pyriclin-4-yl-thiazol-2-ylamino)-
benzamide
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29
H
\ ~N I w
N / / iN
_-
O H
N
034: N-(4-Fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H CH3
\ YN ~ w
N / / F
O H
N
035: N-(3-Fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-
ylamino)-
benzamide
H
\ Y N ,I ~ F
N
O H
N
036:N-(4-tert-Butyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ ~N ~ w
N
O H
N
038: N-(3-Cyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H N
\ YN I ~ I I
N
/, O H
N-'
039: N-(3-Cyano-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
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H N
\ YN I ~ I I
N
v ~ O H
N
1H NMR (DMSO-d6) 8 = 2.37 (s, 3H, ArCH3); 2.46 (s, 3H, ArCH3); 7.43 (m, 2H, Ar-
H); 7.63 (dd, 1H, J = 7.9, l.BHz, Ar-H) ; 7.72 (s, 1H, thiazol-H) ; 7.83 (d,
2H, J = 6.OHz,
5 pyridyl-H); 7.96 (dd, 1H, J = 8.3, l.BHz, Ar-H); 8.19 (d, 1H, J = 2.3Hz, Ar-
H); 8.55 (d,
2H, J = 6.OHz, pyridyl-H) ; 8.81 (d, 1H, J = l.SHz, Ar-H) ; 9.65 (s, 1H, NH);
10.46 (s,
1H, NH).
040: N-(3-Bromo-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
~ ~N I ~ Br
N
O H
10 N
041: N-(3-Bromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
~ ~N I ~ Br
N
v ~ O H
N
042: N-(3,5-Dibromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-
ylamino)-
15 benzamide
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31
H
\ YN I ~ Br
N
O H \ Br
N
043: N-(3-Chloro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
~ YN I ~ CI
N
O H
N
044: N-(3-Chloro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-
ylamino)-
benzamide
H
~ ~N I ~ CI
N
O H
N
045: N-(3-Methoxy-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
~ ~N I ~ ~O
N
O H
N
046: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-m-tolyl-benzamide
H
\ ~N ~ w
N
O H
N
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32
047:N-(4-Fluoro-3-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ ~N ~ w
N / , F
O H
N
048: N-(3-Iodo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
II N I ~ I
N
O H
N
049: 4-Methyl-N-(3-nitro-phenyl)-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ ~ N I \ O\ N+ O_
N
~~ O H
N-'
050: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-p-tolyl-benzamide
H
\ YN ~ w
N
O H
N
051:4-Methyl-N-phenyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide
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33
H
\ ~N ~ w
N
v ~ O H
N
052: N-(3,4-Dimethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ YN ~ w
N
y O H
N
053: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-(3-trifluoromethoxy
phenyl)-
benzamide
H
~ YN I ~ OCF3
N
O H
N
l0 054: N-(3,4-Dicyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylarnino)-
benzamide
H
~ YN I ~ CN
N / , CN
y O H
N
055: N-(2-Fluoro-5-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-
ylamino)-
benzamide
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34
H
\ YN I w
N s
~I
/) O N
N~ H F
056: N-(2,4-Difluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ ~N I w
N / / F
~I
/) O N
NJ H F
057: N-(4-Cyano-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ YN I w
N / / CN
O N
N~ H F
058: N-(2-Fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-
ylamino)-
benzamide
H
\ ~N I w
N
~I
O N
N ~ H F
059: N-(2,4-Difluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-
benzamide
H
\ YN I w
N / , F
I
O H
N F
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060: N-(4-Cyano-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-
ylarnino)-
H
\ YN ~ w
N / , CN
~ H
benzamide N F
061: N-(2-Fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-
ylarnino)-
benzamide
H
\ YN ~ w
N
H
N F
062: N-(4-Cyano-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-
benzamide
H
\ YN ~ w
N / / CN
H
N
l0 065: N-(4-Fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-
benzamid.e
H
\ YN ~ w
N / / F
H
N
099: 4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-N-m-tolyl-benzamide
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36
H
\ YN ~ \
N
O H
N
100: 4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-N-(3-trifluoromethyl-
phenyl)-
benzamide
H
II N ~ \ CF3
N
H
N
101: 4-Methyl-N-(4-methyl-3-trifluoromethyl-phenyl)-3-(4-pyridin-3-yl-thiazol-
2-
ylamino)-benzasnide
H
II N ~ \ CF3
N
O H
N
102: N-(2-Fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-
2-
ylamino)-benzamide
H
\ ~N ~ \
N
O H \ CF3
N F
105: N-(4-Cyano-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-
ylamino)-benzamide
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37
H
\ YN ~ w
N ~ , CN
O H CF3
N
106: N-(4-Cyano-3-methyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-
benzamide
H
\ YN ~ w
N ~ , CN
O H
N
Among compounds of formula II, the invention is particularly embodied by the
compounds wherein X is a -substituted-aryl group, corresponding to the 4-(4-
substituted-1-ylinethyl)-N-[3-(thiazol-2-ylamino)-phenyl]-benzamide family and
the
to following formula II-4
R6
N R4 I ~ H Ra
S~N / N ~ Rb
O I / Rf
Re
R ,X.
FORMULA II-4 ~ h R g
wherein X is a heteroatom, such as O or N
wherein Ra, Rb, Rd, Re, Rf, Rg, Rh are independently chosen from H or an
organic
group that can be selected for example from a linear or branched allcyl group
containing
from 1 to 10 carbon atoms optionally substituted with at least one heteroatom
and l or
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3S
bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with a heteroatom, notably a halogen selected from I,
Cl, Br and F
or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or
heteroaryl
group optionally substituted with a cycloalkyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality;
- or a NRR' group where R and R' are H or a linear or branched alkyl group
containing
from 1 to 10 carbon atoms optionally substituted with at least one heteroatom
and / or
bearing a pendant basic nitrogen functionality; a cycloallcyl, an aryl or
heteroaryl group
optionally substituted with a heteroatom, notably a halogen selected from I,
Cl, Br and F
or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or
heteroaryl
group optionally substituted with a cycloalkyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl; Br and
F or
bearing a pendant basic nitrogen functionality;
- or an OR group where R is H or a linear or branched alkyl group containing
from 1 to
10 carbon atoms optionally substituted with at least one heteroatom and / or
bearing a
pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl
group optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
optionally substituted with a cycloalkyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality; a -S02-R' group wherein R' is
an alkyl,
cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom,
notably a halogen
selected from I, Cl, Br and F or bearing a pendant basic nitrogen
functionality;
~ - or a NRaCORb group where Ra and Rb are H or a linear or branched alkyl
group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with a heteroatom, notably a halogen selected
from I, Cl, Br
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39
and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
F or bearing a pendant basic nitrogen functionality;
- or a NRaCONRbRc group where Ra and Rb are H or a linear or branched alkyl
group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with a heteroatom, notably a halogen selected
from I, Cl, Br
and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
F or bearing a pendant basic nitrogen functionality;
- or a COOR, where R is a linear or branched alkyl group containing from 1 to
10 carbon
atoms atoms optionally substituted with at least one heteroatom (for example a
halogen)
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with at least one heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
2o from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality;
- or a CONRaRb, where Ra and Rb are a hydrogen or a linear or branched alkyl
group
containing from 1 to 10 carbon atoms atoms optionally substituted with at
least one
heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen
functionality; a cycloallcyl, an aryl or heteroaryl group optionally
substituted with at least
one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
substituted by an alkyl, a cycloallcyl, an aryl or heteroaryl group optionally
substituted
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with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality;
- or an NHCOOR, where R is a linear or branched allcyl group containing from 1
to 10
carbon atoms atoms optionally substituted with at least one heteroatom (for
example a
5 halogen) and / or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an azyl or
heteroaryl group optionally substituted with at least one heteroatom, notably
a halogen
selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality; or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
l0 from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality;
- an OS02R, where R is a linear or branched alkyl group containing from 1 to
10 carbon
atoms atoms optionally substituted with at least one heteroatom (for example a
halogen)
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with at least one heteroatom, notably a halogen
selected
15 from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality; or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
- or an NRaOSO2Rb, where Ra and Rb are a linear or branched alkyl group
containing
2o from 1 to 10 carbon atoms atoms optionally substituted with at least one
heteroatom (for
example a halogen) and / or bearing a pendant basic nitrogen functionality; Ra
can also
be a hydrogen; a cycloalkyl, an aryl or heteroaryl group optionally
substituted with at
least one heteroatom, notably a halogen selected from I, Cl, Br and F, and /
or bearing a
pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
25 substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group
optionally substituted
with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality;
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41
- or a -S02-R group wherein R is an alkyl, cycloallcyl, aryl or heteroaryl
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR'
group,
wherein R and R' are independently chosen from H, an alkyl, a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with at least one heteroatom, notably
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality.
Ra, Rb, Rd, Re can also be halogen such as Cl, F, Br, I or trifluoromethyl;
l0 R4 is hydrogen, halogen or a linear or branched allcyl group containing
from 1 to 10
carbon atoms, trifluoromethyl or alkoxy;
R6 is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
at any one ring position, of one or more substituents such as halogen, alkyl
groups
containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
any combination of one or more substituents such as halogen, alkyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;
(iii) a five-membered ring aromatic heterocyclic group such as for example 2-
thienyl, 3-
2o thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear
any
combination of one or more substituents such as halogen, an alkyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or S02-R, wherein R is
a linear
or branched alkyl goup containing one or more group such as 1 to 10 carbon
atoms, and
optionally substituted with at least one heteroatom, notably a halogen
selected from I, Cl,
Br and F, and / or bearing a pendant basic nitrogen functionality.
Examples
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42
004 . 4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-
3-(4-
pyridin-4-yl-thiazol-2-ylamino)-benzamide
H
II N ~ ~ CF3
N / , N~
// O N \ ~ ~lN~
NJ H
1H NMR (MeOH-d4) ~ = 2.41 (s, 6H, NCH3+ArCH3); 2.50-2.70 (m, 4H, pyperazine-
H);
2.90 (m, 4H, pyperazine-H); 3.68 (br s, 2H, CH2-piperazine); 7.38 (d, 1H, J =
7.9Hz,
Ar-H); 7.50 (m, 1H, thiazol-H) ; 7.60 (m, 1H, Ar-H); 7.76 (d, 1H, J = 8.3Hz,
Ar-H) ;
7.90 (m, 2H, pyridyl-H); 8.00 (m, 1H, Ar-H); 8.12 (m, 1H, Ar-H) ; 8.46 (m, 2H,
pyridyl
to H); 8.90 (m, 1H, Ar-H).
005 . 4-Methyl-N-~4-[1-(4-methyl-piperazin-1-yl)-ethyl]-phenyl]-3-(4-pyridin-3-
yl-
thiazol-2-ylamino)-benzamide
H
\ YN ~ w
N / , N~
/ O N ~ ~ ~ IN ~
H
Among compounds of formula II, the invention is particularly embodied by the
compounds wherein X is a -aryl-substituted group, corresponding to the 3-
Disubstituted-
amino-N-[3-(thiazol-2-ylamino)-phenyl]-benzamide family and the following
formula
II-5:
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43
R6 R4 /
N H Ra
~ \ ~ N \ Rb
S! 'N
1 O I /
Re Rc
Rg~N~Rf
FORMULA II-5
wherein Ra, Rb, Rc, Re, Rf, Rg are independently chosen from H or an organic
group
that can be selected for example from a linear or branched alkyl group
containing from 1
to 10 carbon atoms optionally substituted with at least one heteroatom and /
or bearing a
pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl
group optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
a pendant basic nitrogen functionality; or a cycloallcyl, an aryl or
heteroaryl group
optionally substituted with a cycloalkyl, an aryl or heteroaryl group
optionally
to substituted with an heteroatom, notably a halogen selected from I, Cl, Br
and F or
bearing a pendant basic nitrogen functionality;
- or a NRR' group where R and R' are H or a linear or branched alkyl group
containing
from 1 to 10 carbon atoms optionally substituted with at least one heteroatom
and / or
bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with a heteroatom, notably a halogen selected from I,
Cl, Br and F
or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or
heteroaryl
group optionally substituted with a cycloalkyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality;
- or an OR group where R is H or a linear or branched alkyl group containing
from 1 to
10 carbon atoms optionally substituted with at least one heteroatom and / or
bearing a
pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl
group optionally
substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F
or bearing
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44
a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
optionally substituted with a cycloalkyl, an aryl or heteroaryl group
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality; a -S02-R' group wherein R' is
an alkyl,
s cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom,
notably a halogen
selected from I, Cl, Br and F or bearing a pendant basic nitrogen
functionality;
- or a NRaCORb group where Ra and Rb are H or a linear or branched alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
to group optionally substituted with a heteroatom, notably a halogen selected
from I, Cl, Br
and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
F or bearing a pendant basic nitrogen functionality;
15 - or a NRaCONRbRc group where Ra and Rb are H or a linear or branched
allcyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with a heteroatom, notably a halogen selected
from I, Cl, Br
and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an
aryl or
2o heteroaryl group optionally substituted with a cycloalkyl, an aryl or
heteroaryl group
optionally substituted with an heteroatom, notably a halogen selected from I,
Cl, Br and
F or bearing a pendant basic nitrogen functionality;
- or a COOR, where R is a linear or branched alkyl group containing from 1 to
10 carbon
atoms atoms optionally substituted with at least one heteroatom (for example a
halogen)
25 and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an
aryl or heteroaryl
group optionally substituted with at least one heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
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heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
- or a CONRaRb, where Ra and Rb are a hydrogen or a linear or branched allcyl
group
containing from 1 to 10 carbon atoms atoms optionally substituted with at
least one
5 heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen
functionality; a cycloalkyl, an aryl or heteroaryl group optionally
substituted with at least
one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally
substituted
to with an heteroatom, notably a halogen selected from I, Cl, Br and F, and /
or bearing a
pendant basic nitrogen functionality;
- or an NHCOOR, where R is a linear or branched alkyl group containing from 1
to 10
carbon atoms atoms optionally substituted with at least one heteroatom (for
example a
halogen) and / or bearing a pendant basic nitrogen functionality; a
cycloalkyl, an aryl or
15 heteroaryl group optionally substituted with at least one heteroatom,
notably a halogen
selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen
functionality; or a
cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl,
an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
20 - an OS02R, where R is a linear or branched alkyl group containing from 1
to 10 carbon
atoms atoms optionally substituted with at least one heteroatom (for example a
halogen)
and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl
or heteroaryl
group optionally substituted with at least one heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
or a
25 cycloallcyl, an aryl or heteroaryl group substituted by an alkyl, a
cycloallcyl, an aryl or
heteroaryl group optionally substituted with an heteroatom, notably a halogen
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;
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46
or an NRaOS02Rb, where Ra and Rb are a linear or branched alkyl group
containing
from 1 to 10 carbon atoms atoms optionally substituted with at least one
heteroatom (for
example a halogen) and / or bearing a pendant basic nitrogen functionality; Ra
can also
be a hydrogen; a cycloalkyl, an aryl or heteroaryl group optionally
substituted with at
least one heteroatom, notably a halogen selected from I, Cl, Br and F, and /
or bearing a
pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl
group
substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally
substituted
with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or
bearing a
pendant basic nitrogen functionality;
1o - or a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl
optionally
substituted with an heteroatom, notably a halogen selected from I, Cl, Br and
F or
bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR'
group,
wherein R and R' are independently chosen from H, an alkyl, a cycloalkyl, an
aryl or
heteroaryl group optionally substituted with at least one heteroatom, notably
selected
from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality.
Ra, Rb, Rc, Re can also be halogen such as Cl, F, Br, I or trifluoromethyl;
R4 is hydrogen, halogen or a linear or branched allcyl group containing from 1
to 10
2o carbon atoms, trifluoromethyl or alkoxy;
R6 is one of the following:
(i) an aryl group such as phenyl or a substituted variant thereof bearing any
combination,
at any one ring position, of one or more substituents such as halogen, alkyl
groups
containing from 1 to 10 carbon atoms, trifluoromethyl, and allcoxy;
(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may
additionally bear
any combination of one or more substituents such as halogen, allcyl groups
containing
from 1 to 10 carbon atoms, trifluoromethyl and allcoxy;
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47
(iii) a five-membered ring aromatic heterocyclic group such as for example 2-
thienyl, 3-
thienyl, 2-thiazolyl, 4-thiazolyl, 5-thia,zolyl, which may additionally bear
any
combination of one or more substituents such as halogen, an alkyl group
containing from
1 to 10 carbon atoms, trifluoromethyl, and alkoxy;
iv) H, a halogen selected from I, F, Cl or Br; NH2, N02 or S02-R, wherein R is
a linear
or branched alkyl goup containing one or more group such as 1 to 10 carbon
atoms, and
optionally substituted with at least one heteroatom, notably a halogen
selected from I, Cl,
Br and F, and / or bearing a pendant basic nitrogen functionality.
1 o Examples
089: N-(3-Dimethylamino-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-
benzamide
H
\ YN I w ~N~
N
O H
N
1s 1H NMR (DMSO-d6) 8 = 2.36 (s, 3H, ArCH3); 2.88 (s, 6H, 2xCH3); 6.50 (d, 1H,
J =
7.9Hz, Ar-H); 7.10-7.30 (m, 3 H, Ar-H); 7.38 (d, 1H, J = 7.9Hz, Ar-H); 7.62
(dd, 1H, J
= 7.9, l.SHz, Ar-H) ; 7.70 (s, 1H, thiazol-H) ; 7.85 (d, 2H, J = 6.4Hz,
pyridyl-H) ; 8.54
(d, 1 H, J = 6.4Hz, pyridyl-H) ; 8.78 (br s, 1 H, Ar-H) ; 9.63 (s, 1 H, NH),
10.04 (s, 1 H,
090: N-(3-Dimethylamino-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-
benzamide
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48
H
N I W wNi
N
I
p
N
In a second embodiment, the invention is directed to a process for
manufacturing a
compound of formula I depicted above. This entails the condensation of a
substrate of
general formula 10 with a thiourea of the type 11.
R3
R4 / R2
R6
\ ~ ~B~ ~~R1
~N A B
H2N
R5 R7 L
l0 11 a 10
Substituent "L" in formula 10 is a nucleofugal leaving group in nucleophilic
substitution
reactions (for example, L can be selected from chloro, bromo, iodo,
toluenesulfonyloxy,
methanesulfonyloxy, trifluoromethanesulfonyloxy, etc., with L being
preferentially a
bromo group).
Group Rl in formula 1 la corresponds to an alkoxy group.
2o The reaction of 10 with 1 a-d leads to a thiozole-type product of formula
12a-d.
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49
R3
R6 R4 / R2
N
\ ~ ~B~ ~.R1
R7 S~N A B
R5
R8 12 a
Formula 12a is the same as formula I. Therefore, R1 in 12a corresponds to R1
in formula
I.
s
Examples of Compound s thesis
General: All chemicals used were commercial reagent grade products.
Dimethylformamide (DMF), methanol (MeOH) were of anhydrous commercial grade
and were used without further purification. Dichloromethane and
tetrahydrofuran (THF)
to were freshly distilled under a stream of argon before use. The progress of
the reactions
was monitored by thin layer chromatography using precoated silica gel 60F 254,
Fluka
TLC plates, which were visualized under UV light. Multiplicities in 1H NMR
spectra are
indicated as singlet (s), broad ringlet (br s), doublet (d), triplet (t),
quadruplet (q), and
multiplet (m) and the NMR spectrum were realized on a 300MHz Broker
spectrometer.
4-Bromoacetyl-pyridine, HBr salt
O
Br
N J .HBr
Dibromine (17.2g, 108 mmol) war added dropwise to a cold (0°C) solution
of 4-acetyl-
2o pyridine (12 g, 99 mmol) in acetic acid containing 33°f° of
HBr (165 mL) under
vigourous stirnng. The vigorously stirred mixture was warmed to 40°C
for 2h and then
to 75°C. After 2h at 75°C, the mixture was cooled and diluted
with ether (400 mL) to
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precipitate the product. which was recovered by filtration and washed with
ether and
acetone to give white crystals (100%). This material may be recrystallised
from
methanol and ether.
1H NMR (DMSO-d6) 8 = 5.09 (s, 2H, CH2Br) ; 8.62 (m, 2H, pyridyl-H) ; 9.07 (m,
2H,
5 pyridyl-H).
H
H2N ~ N
ISI
O O~
4-Methyl-3-thioureido-
l0 benzoic acid methyl ester
Benzoyl chloride (5.64 g, 80 mmol) was added dropwise to a well-stirred
solution of
ammonium thiocyanate (3.54 g, 88 mmol) in acetone (50 mL). The mixture was
refluxed
for 15 min, then, the 3-amino-4-methyl-benzoic acid methyl ester(13.2 g, 80
mmol) was
15 added slowly portionswise. After 1h, the reaction mixture was poured into
water (350
mL) and the bright yellow precipitate was isolated by filtration. This crude
solid was
stirred at room temperature with an excess anhydrous potassium carbonate in
200 mL of
methanol for 2 hours. Then, the solvent was removed under reduced pressure and
the
crude product wax extracted with ethyl acetate and washed with water. The
organic layer
20 was dried over Na2S04 and concentrated to give a white solid. The solid was
stirred in
ether for 15 min and filtered to give the final product as a white solid.
1H NMR (DMSO-d6) 8 = 2.22 (s, 3H, ArCH3) ; 3.81 (s, 3H, COZCH3) ; 7.38 (d, 1H,
J =
7.9Hz, Ar-H) ; 7.70 (dd, 1H, J = 7.9, l.SHz, Ar-H) ; 7.82 (d, 1H, J = l.BHz,
Ar-H).
4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoic acid methyl ester
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51
H
\ ~N ~ w
N
O O~
N
A mixture of 4-bromoacetyl-pyridine, HBr salt (0.40g, 1.43 mmol), 4-methyl-3-
thioureido-benzoic acid methyl ester (0.328, 1.43 mmol) and KHC03 (~0.4g) in
ethanol
(10 mL) was heated at 75°C for 20h. The mixture was cooled, filtered
(removal of
KHCO3) and evaporated under reduced pressure. The residue was dissolved in
CHC13
(40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution
and
with water. The organic layer was dried over Na2SO4 and concentrated. The
crude
product was triturated in small amount of ethyl acetate and filtered to give
the final
product as an orange solid.
1H NMR (DMSO-ds) 8 = 2.38 (s, 3H, ArCH3) ;
3.88 (s, 3H, C02CH3) ; 7.58 (dd, 1H, J = 7.9,
l.BHz, Ar-H) ; 7.75 (s, 1H, thiazol-H) ; 7.85 (d,
2H, J = 6.OHz, pyridyl-H) ; 8.62 (d, 1 H, J =
6.OHz, pyridyl-H) ; 9.12 (d, 1H, J = l.8Hz, Ar-
H) ; 9.63 (s, 1H, NH).
N-(4-Cyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide
H
N N I / CN
O N
H
N
4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoic acid methyl ester
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52
A 2M solution of trimethyl aluminium in hexane ( 1.9 mL) was added dropwise to
a cold
(0° C) solution of 4-amino-benzonitrile (0.29 g, 2.46 mmol) in
anhydrous
dichloromethane (30 mL) under argon atmosphere. The mixture was warmed to room
temperature and stirred at room temperature for 30 min. A solution of 4-methyl-
3-(4-
pyridin-4-yl-thiazol-2-ylamino)-benzoic acid methyl ester (0.80 g, 2.46 mmol)
in
anhydrous dichloromethane (30 mL) and added slowly, and the resulting mixture
was
heated at reflux for Sh. The mixture was cooled to 0°C and quenched by
dropwise
addition of a 4N aqueous sodium hydroxide solution (3 mL). The mixture was
extracted
to with dichloromethane (3x20 mL). The combined organic layers were washed
with brine
(3x20 mL) and dried over anhydrous MgS04. N-(4-Cyano-phenyl)-4-methyl-3-(4-
pyridin-4-yl-thiazol-2-ylamino)-benzamide is obtained in 98% after trituration
of the
crude product in methanol.
1H NMR (CDCl3) b = 2.40 (s, 3H, ArCH3) ; 7.40 ( d, 1H, J = 7.9Hz, Ar-H) ; 7.63
(dd,
1H, J = 7.9, l.SHz, Ar-H) ; 7.72 (s, 1H, thiazole-H) ; 7.80-7.88 (m, 4H, Ar-
H); 8.10 (d,
2H, J = 8.6Hz, Ar-H) ; 8.56 ( m, 2H, Ar-H) ; 8.86 ( d, 1H, J = l.BHz, Ar-H ) ;
9.66 (br s,
1H, NH).
2o Examples
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53
N\ N
/ N / H I / N /
\ ~ N \ ~ \ ~ \
H ~ / N S H O ~ / N
~N~ ~N~
_N N
/
/ /
\ \ I N\/ ~ / ~ \ I ~ /
N
S~N S N O
H O H \
N
/ -N
\ ~ /
\ / /
S ~~
H '\~N ~ \ \ I N\/NJ
S~N
~Nw H O
_N _N
/ ~2 ~ /
/ I H ~N O / I H ~O
~S~N \ N\/NJ ~S~N \ N\/N
H O H O
_N _N
/ O ~ / N
/ H / H
\ I N ~~ \ I N
S N I~ S N II
H O H O
N- N-
\\
N / H N / H
~S~ \ ~ N \ ~ \ ~ N \
S
O I / H O
~N~ ~O
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In a third embodiment, the invention relates to a pharmaceutical composition
comprising
a compound as depicted above.
Such medicament can take the form of a pharmaceutical composition adapted for
oral
administration, which can be formulated using pharmaceutically acceptable
carriers well
known in the art in suitable dosages. Such carriers enable the pharmaceutical
compositions to be formulated as tablets, pills, dragees, capsules, liquids,
gels, syrups,
slurries, suspensions, and the like, for ingestion by the patient. In addition
to the active
ingredients, these pharmaceutical compositions may contain suitable
pharmaceutically
1o acceptable carriers comprising excipients and auxiliaries which facilitate
processing of
the active compounds into preparations which can be used pharmaceutically.
Further
details on techniques for formulation and administration may be found in the
latest
edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton,
Pa.).
The composition of the invention can also take the form of a pharmaceutical or
cosmetic
composition for topical administration.
Such compositions may be presented in the form of a gel, paste, ointment,
cream, lotion,
liquid suspension aqueous, aqueous-alcoholic or, oily solutions, or
dispersions of the
2o lotion or serum type, or anhydrous or lipophilic gels, or emulsions of
liquid or semi-solid
consistency of the milk type, obtained by dispersing a fatty phase in an
aqueous phase or
vice versa, or of suspensions or emulsions of soft, semi-solid consistency of
the cream or
gel type, or alternatively of microemulsions, of microcapsules, of
microparticles or of
vesicular dispersions to the ionic and/or nonionic type. These compositions
are prepared
according to standard methods.
The composition according to the invention comprises any ingredient commonly
used in
dermatology and cosmetic. It may comprise at least one ingredient selected
from
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hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active
agents,
preservatives, emollients, viscosity enhancing polymers, humectants,
surfactants,
preservatives, antioxidants, solvents, and fillers, antioxidants, solvents,
perfumes, fillers,
screening agents, bactericides, odor absorbers and coloring matter.
5
As oils which can be used in the invention, mineral oils (liquid paraffin),
vegetable oils
(liquid fraction of shea butter, sunflower oil), animal oils, synthetic oils,
silicone oils
(cyclomethicone) and fluorinated oils may be mentioned. Fatty alcohols, fatty
acids
(stearic acid) and waxes (paraffin, carnauba, beeswax) may also be used as
fatty
to substances.
As emulsifiers which can be used in the invention, glycerol stearate,
polysorbate 60 and
the PEG-6/PEG-32/glycol stearate mixture are contemplated.
As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acrylic
copolymers
15 such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides
such as
hydroxypropylcellulose, clays and natural gums may be mentioned, and as
lipophilic
gelling agents, modified clays such as bentones, metal salts of fatty acids
such as
aluminum stearates and hydrophobic silica, or alternatively ethylcellulose and
polyethylene may be mentioned.
As hydrophilic active agents, proteins or protein hydrolysates, amino acids,
polyols,
urea, allantoin, sugars and sugar derivatives, vitamins, starch and plant
extracts, in
particular those of Aloe very may be used.
As lipophilic active, agents, retinol (vitamin A) and its derivatives,
tocopherol (vitamin
E) and its derivatives, essential fatty acids, ceramides and essential oils
may be used.
These agents add extra moisturizing or shin softening features when utilized.
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In addition, a surfactant can be included in the composition so as to provide
deeper
penetration of the compound capable of depleting mast cells, such as a
tyrosine kinase
inhibitor, preferably a c-kit inhibitor.
Among the contemplated ingredients, the invention embraces penetration
enhancing
agents selected for example from the group consisting of mineral oil, water,
ethanol,
triacetin, glycerin and propylene glycol; cohesion agents selected for example
from the
group consisting of polyisobutylene, polyvinyl acetate and polyvinyl alcohol,
and
thickening agents.
Chemical methods of enhancing topical absorption of drugs are well known in
the art.
For example, compounds with penetration enhancing properties include sodium
lauryl
sulfate (Dugard, P. H. and Sheuplein, R. J., "Effects of Ionic Surfactants on
the
Permeability of Human Epidermis: An Electrometric Study," J. Ivest. Dermatol.,
V.60,
is pp. 263-69, 1973), lauryl amine oxide (Johnson et. al., US 4,411,893),
atone
(Rajadhyaksha, US 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura,
D. L.
and Scala, J., "The Percutaneous Absorption of Alkylinethyl Sulfides,"
Pharmacology of
the Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) V. 12, pp. 257-
69,
1972). It has been observed that increasing the polarity of the head group in
amphoteric
2o molecules increases their penetration-enhancing properties but at the
expense of
increasing their skin irritating properties (Cooper, E. R. and Berner, B.,
"Interaction of
Surfactants with Epidermal Tissues: Physiochemical Aspects," Surfactant
Science
Series, V. 16, Reiger, M. M. ed. (Marcel Dekker, Inc.) pp. 195-210, 1987).
25 A second class of chemical enhancers are generally referred to as co-
solvents. These
materials are absorbed topically relatively easily, and, by a variety of
mechanisms,
achieve permeation enhancement for some drugs. Ethanol (Gale et. al., U.S.
Pat. No.
4,615,699 and Campbell et. al., U.S. Pat. Nos. 4,460,372 and 4,379,454),
dimethyl
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57
sulfoxide (IJS 3,740,420 and 3,743,727, and US 4,575,515), and glycerine
derivatives
(LTS 4,322,433) are a few examples of compounds which have shown an ability to
enhance the absorption of various compounds.
The pharmaceutical compositions of the invention can also be intended for
administration with aerosolized formulation to target areas of a patient's
respiratory tract.
Devices and methodologies for delivering aerosolized bursts of a formulation
of a drug
is disclosed in US 5,906,202. Formulations are preferably solutions, e.g.
aqueous
to solutions, ethanoic solutions, aqueouslethanoic solutions, saline
solutions, colloidal
suspensions and microcrystalline suspensions. For example aerosolized
particles
comprise the active ingredient mentioned above and a carrier, (e.g., a
pharmaceutically
active respiratory drug and carrier) which are formed upon forcing the
formulation
through a nozzle which nozzle is preferably in the form of a flexible porous
membrane.
The particles have a size which is sufficiently small such that when the
particles are
formed they remain suspended in the air for a sufficient amount of time such
that the
patient can inhale the particles into the patient's lungs.
The invention encompasses the systems described in US 5,556,611:
- liquid gas systems (a liquefied gas is used as propellent gas (e.g. low-
boiling FCHC or
2o propane, butane) in a pressure container,
- suspension aerosol (the active substance particles are suspended in solid
form in the
liquid propellent phase),
- pressurized gas system (a compressed gas such as nitrogen, carbon dioxide,
dinitrogen
monoxide, air is used.
Thus, according to the invention the pharmaceutical preparation is made in
that the
active substance is dissolved or dispersed in a suitable nontoxic medium and
said
solution or dispersion atomized to an aerosol, i.e. distributed extremely
finely in a carrier
gas. This is technically possible for example in the form of aerosol
propellent gas packs,
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58
pump aerosols or other devices known per se for liquid misting and solid
atomizing
which in particular permit an exact individual dosage.
Therefore, the invention is also directed to aerosol devices comprising the
compound as
defined above and such a formulation, preferably with metered dose valves.
The pharmaceutical compositions of the invention can also be intended for
intranasal
administration.
In this regard, pharmaceutically acceptable carriers for administering the
compound to
to the nasal mucosal surfaces will be readily appreciated by the ordinary
artisan. These
carriers are described in the Remington's Pharmaceutical Sciences" 16th
edition, 1980,
Ed. By Arthur Osol, the disclosure of which is incorporated herein by
reference.
The selection of appropriate carriers depends upon the particular type of
administration
that is contemplated. For administration via the upper respiratory tract, the
composition
can be formulated into a solution, e.g., water or isotonic saline, buffered or
unbuffered,
or as a suspension, for intranasal administration as drops or as a spray.
Preferably, such
solutions or suspensions are isotonic relative to nasal secretions and of
about the same
pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7Ø
Buffers
2o should be physiologically compatible and include, simply by way of example,
phosphate
buffers. For example, a representative nasal decongestant is described as
being buffered
to a pH of about 6.2 (Remington's, Id. at page 1445). Of course, the ordinary
artisan can
readily determine a suitable saline content and pH for an innocuous aqueous
carrier for
nasal and/or upper respiratory administration.
Common intranasal carriers include nasal gels, creams, pastes or ointments
with a
viscosity of, e.g., from about 10 to about 3000 cps, or from about 2500 to
6500 cps, or
greater, may also be used to provide a more sustained contact with the nasal
mucosal
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59
surfaces. Such carrier viscous formulations may be based upon, simply by way
of
example, alkylcelluloses andlor other biocompatible carriers of high viscosity
well
l~nown to the art (see e.g., Remington's, cited supra. A preferred
alkylcellulose is, e.g.,
rnethylcellulose in a concentration ranging from about 5 to about 1000 or more
mg per
100 ml of carrier. A more preferred concentration of methyl cellulose is,
simply by way
of example, from about 25 to about mg per 100 ml of carrier.
Other ingredients, such as art known preservatives, colorants, lubricating or
viscous
mineral or vegetable oils, perfumes, natural or synthetic plant extracts such
as aromatic
1o oils, and humectants and viscosity enhancers such as, e.g., glycerol, can
also be included
to provide additional viscosity, moisture retention and a pleasant texture and
odor for the
formulation. For nasal administration of solutions or suspensions according to
the
invention, various devices are available in the art for the generation of
drops, droplets
and sprays.
A premeasured unit dosage dispenser including a dropper or spray device
containing a
solution or suspension for delivery as drops or as a spray is prepared
containing one or
more doses of the drug to be administered and is another object of the
invention. The
invention also includes a kit containing one or more unit dehydrated doses of
the
2o compound, together with any required salts and/or buffer agents,
preservatives, colorants
and the like, ready for preparation of a solution or suspension by the
addition of a
suitable amount of water.
Another aspect of the invention is directed to the use of said compound to
manufacture a
medicament. In other words, the invention embraces a method for treating a
disease
related to unregulated c-kit transduction comprising administering an
effective amount
of a compound as defined above to a mammal in need of such treatment.
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More particularly, the invention is aimed at a method for treating a disease
selected from
autoirmnune diseases, allergic diseases, bone loss, cancers such as leukemia
and GIST,
tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD),
interstitial cystitis, mastocytosis, infections diseases, metabolic disorders,
fibrosis,
5 diabetes and CNS disorders comprising administering an effective amount a
compound
depicted above to a mammal in need of such treatment.
The above described compounds are useful for manufacturing a medicament for
the
treatment of diseases related to unregulated c-kit transduction, including,
but not limited
1o to:
- neoplastic diseases such as mastocytosis, canine mastocytoma, human
gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small
cell
lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia,
myelodysplastic syndrome, chronic myelogenous leukemia, colorectal
15 carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular
cancers, glioblastomas, solid tumors and astrocytomas.
- tumor angiogenesis.
- metabolic diseases such as diabetes mellitus and its chronic complications;
obesity; diabete type II; hyperlipidemias and dyslipidemias; atherosclerosis;
2o hypertension; and cardiovascular disease.
- allergic diseases such as astlnna, allergic rhinitis, allergic sinusitis,
anaphylactic
syndrome, urticaria, angioedema, atopic dermatitis, allergic contact
dermatitis,
erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and
insect bite skin inflammation and blood sucking parasitic infestation.
25 - interstitial cystitis.
- bone loss (osteoporosis).
- inflammatory diseases such as rheumatoid arthritis, conjunctivitis,
rheumatoid
spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.
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- autoimmune diseases such as multiple sclerosis, psoriasis, intestine
inflammatory
disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and
polyarthritis,
local and systemic scleroderma, systemic lupus erythematosus, discoid lupus
erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's
syndrome, nodular panarteritis, autoimmune enteropathy, as well as
proliferative
glomerulonephritis.
graft-versus-host disease or graft rejection in any organ transplantation
including
kidney, pancreas, liver, heart, lung, and bone marrow.
- Other autoimmune diseases embraced by the invention active chronic hepatitis
1 o and chronic fatigue syndrome.
- subepidermal blistering disorders such as pemphigus.
- Vasculitis.
- melanocyte dysfunction associated diseases such as hypermelanosis resulting
from melanocyte dysfunction and including lentigines, solar and senile
lentigo,
~ Dubreuilh melanosis, moles as well as malignant melanomas. In this regard,
the
invention embraces the use of the compounds defined above to manufacture a
medicament or a cosmetic composition for whitening human skin.
- CNS disorders such as psychiatric disorders, migraine, pain, memory loss and
nerve cells degeneracy. More particularly, the method according to the
invention
2o is useful for the treatment of the following disorders: Depression
including
dysthymic disorder, cyclothyrnic disorder, bipolar depression, severe or
"melancholic" depression, atypical depression, refractory depression, seasonal
depression, anorexia, bulimia, premenstrual syndrome, post-menopause
syndrome, other syndromes such as mental slowing and loss of concentration,
pessimistic worry, agitation, self deprecation, decreased libido, pain
including,
acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain,
neuropathic pain, psychogenic pain syndromes, anxiety disorders including
anxiety associated with hyperventilation and cardiac arrhythmias, phobic
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disorders, obsessive-compulsive disorder, posttraumatic stress disorder, acute
stress disorder, generalized anxiety disorder, psychiatric emergencies such as
panic attacks, including psychosis, delusional disorders, conversion
disorders,
phobias, mania, delirium, dissociative episodes including dissociative
amnesia,
dissociative fugue and dissociative identity disorder, depersonalization,
catatonia,
seizures, severe psychiatric emergencies including suicidal behaviour, self
neglect, violent or aggressive behaviour, trauma, borderline personality, and
acute psychosis, schizophrenia including paranoid schizophrenia, disorganized
schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia,
- neurodegenerative diseases including Alzheimer's disease , Parkinson's
disease,
Huntington's disease, the prion diseases, Motor Neurone Disease (MND), and
Amyotrophic Lateral Sclerosis (ALS).
- substance use disorders as referred herein include but are not limited to
drug
addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome
and overdose.
- Cerebral ischemia
- Fibrosis
- Duchenne muscular dystrophy
Regarding mastocytosis, the invention contemplates the use of the compounds as
defined
above for treating the different categories which can be classified as
follows:
The category I is composed by two sub-categories (IA and IB). Category IA is
made by
diseases in which mast cell infiltration is strictly localized to the skin.
This category
represents the most frequent form of the disease and includes : i) urticaria
pigmentosa,
the most common form of cutaneous mastocytosis, particularly encountered in
children,
ii) diffuse cutaneous mastocytosis, iii) solitary mastocytoma and iv) some
rare subtypes
like bullous, erythrodermic and teleangiectatic mastocytosis. These forms are
characterized by their excellent prognosis with spontaneous remissions in
children and a
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63
very indolent course in adults. Long term survival of this form of disease is
generally
comparable to that of the normal population and the translation into another
form of
mastocytosis is rare. Category IB is represented by indolent systemic disease
(SM) with
or without cutaneous involvement. These forms are much more usual in adults
than in
children. The course of the disease is often indolent, but sometimes signs of
aggressive
or malignant mastocytosis can occur, leading to progressive impaired organ
function.
The category II includes mastocytosis with an associated hematological
disorder, such
as a myeloproliferative or myelodysplastic syndrome, or acute leukemia. These
to malignant mastocytosis does not usually involve the skin. The progression
of the disease
depends generally on the type of associated hematological disorder that
conditiones the
prognosis.
The category III is represented by aggressive systemic mastocytosis in which
massive
infiltration of multiple organs by abnormal mast cells is common. In patients
who pursue
this kind of aggressive clinical course, peripheral blood features suggestive
of a
myeloproliferative disorder are more prominent. The progression of the disease
can be
very rapid, similar to acute leukemia, or some patients can show a longer
survival time.
2o Finally, the category IV of mastocytosis includes the mast cell leukemia,
characterized
by the presence of circulating mast cells and mast cell progenitors
representing more
than 10% of the white blood cells. This entity represents probably the rarest
type of
leukemia in humans, and has a very poor prognosis, similar to the rapidly
progressing
variant of malignant mastocytosis. Mast cell leukemia can occur either de novo
or as the
terminal phase of urticaria pigmentosa or systemic mastocytosis.
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64
The invention also contemplates the method as depicted for the treatment of
recurrent
bacterial infections, resurging infections after asymptomatic periods such as
bacterial
cystitis. More particularly, the invention can be practiced for treating FimH
expressing
bacteria infections such as Gram-negative enterobacteria including E. coli,
Klebsiella
pneumoniae, Ser°oatia ma~cescehs, Cit~obactor fi°eudii and
Salmo~zella typhimurium.
In this method for treating bacterial infection, separate, sequential or
concomitant
administration of at least one antibiotic selected bacitracin, the
cephalosporins, the
penicillins, the aminoglycosides, the tetracyclines, the streptomycins and the
macrolide
antibiotics such as erythromycin; the fluoroquinolones, actinomycin, the
sulfonamides
and trimethoprim, is of interest.
In one preferred embodiment, the invention is directed to a method for
treating
neoplastic diseases such as mastocytosis, canine mastocytoma, human
gastrointestinal
stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer,
acute
myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome,
chronic
myelogenous leukemia, colorectal carcinomas, gastric carcinomas,
gastrointestinal
stromal tumors, testicular cancers, glioblastomas, and astrocytomas comprising
administering a compound as defined herein to a human or mammal, especially
dogs and
cats, in need of such treatment.
In one other preferred embodiment, the invention is directed to a method for
treating
allergic diseases such as asthma, allergic rhinitis, allergic sinusitis,
anaphylactic
syndrome, urticaria, angioedema, atopic dermatitis, allergic contact
dermatitis, erythema
nodosum, er5rthema multiforme, cutaneous necrotizing venulitis and insect bite
skin
inflammation and blood suclcing parasitic infestation comprising administering
a
compound as defined herein to a human or mammal, especially dogs and cats, in
need of
such treatment.
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In still another preferred embodiment, the invention is directed to a method
for treating
inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid
spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
comprising
administering a compound as defined herein to a human in need of such
treatment.
5
In still another preferred embodiment, the invention is directed to a method
for treating
autoimmune diseases such as multiple sclerosis, psoriasis, intestine
inflammatory
disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and
polyarthritis, local
and systemic scleroderma7 systemic lupus erythematosus, discoid lupus
erythematosus,
to cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular
panarteritis, autoimmune enteropathy, as well as proliferative
glomerulonephritis
comprising administering a compound as defined herein to a human in need of
such
treatment.
15 In still another preferred embodiment, the invention is directed to a
method for treating
graft-versus-host disease or graft rejection in any organ transplantation
including kidney,
pancreas, liver, heart, lung, and bone marrow comprising administering a
compound as
defined herein to a human in need of such treatment.
2o Example 1 : in vitro TK inhibition assays
~ Procedure
Experiments were performed using purified intracellular domain of c-kit
expressed in
baculovirus. Estimation of the kinase activity was assessed by the
phosphorylation of
tyrosine containing target peptide estimated by established ELISA assay.
~ Experimental results on tested compounds
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66
Result in Table 1 shows the potent inhibitory action of the catalytic activity
of c-kit with
an IC50 <10 ~,M. Further experiments (not shown) indicates that at least one
compound
acts as perfect competitive inhibitors of ATP.
Example 2 : ex vivo TK inhibition assays
~ Procedures
o C-Kit WT and mutated C-Kit (JM1 assay
Proliferation assays
Cells were washed two times in PBS before plating at 5 x 104 cells per well of
96-well
to plates in triplicate and stimulated either with hematopoietic growth
factors (HGF) or
without. After 2 days of culture, 37 Bq (1.78 Tbq/mmol) of [3H] thymidine
(Amersham
Life Science, UK) was added for 6 hours. Cells were harvested and filtered
through glass
fiber filters and [3H] thymidine incorporation was measured in a scintillation
counter.
For proliferation assay, all drugs were prepared as 20mM stock solutions in
DMSO and
conserved at -80°C. Fresh dilutions in PBS were made before each
experiment. DMSO
dissolved drugs were added at the beginning of the culture. Control cultures
were done
with corresponding DMSO dilutions. Results are represented in percentage by
taking the
proliferation without inhibitor as 100%.
Cells
2o Ba/F3 marine kit and human kit, BalF3 mkitD27 (juxtamembrane deletion) are
derived
from the marine IL-3 dependent Ba/F3 proB lymphoid cells. The FMA3 and P815
cell
lines are mastocytoma cells expressing endogenous mutated forms of I~it, i.e.,
frame
deletion in the marine juxtamembrane coding region of the receptor-codons 573
to 579.
The human leukaemic MC line HMC-1 expresses mutations JM-V560G;
Immunoprecipitation assays and western blotting analysis
For each assay, 5.106 Ba/F3 cells and Ba/F3-derived cells with various c-kit
mutations
were lysed and immunoprecipitated as described (Beslu et al., 1996), excepted
that cells
were stimulated with 250 ng / ml of rmKL. Cell lysates were immunoprecipitated
with a
CA 02554925 2006-07-28
WO 2005/073225 PCT/IB2005/000401
67
rabbit immunsenun anti marine KIT, directed against the KIT cytoplasmic domain
(Rottapel et al., 1991). Western blot was hybridized either with the 4610 anti-
phosphotyrosine antibody (UBI) or with the rabbit immunserum anti-marine KTT
or with
different antibodies (described in antibodies paragraph). The membrane was
then
incubated either with HRP-conjugated goat anti mouse IgG antibody or with HRP-
conjugated goat anti rabbit IgG antibody (Immunotech), Proteins of interest
were then
visualized by incubation with ECL reagent (Amersham).
~ Experimental results
to The experimental results for various compounds according to the invention
using above-
described protocols are set forth at Table 2:
Table 2:
Target IC50 (mM) Compounds
c-Kit IC50 < 10 001; 002; 003; 004; 005; 028; 029; 030;
WT mM 031; 032; 033;
034; 35; 036; 038; 039; 040; 041; 042;
043; 044; 045;
046; 047; 048; 049; 050; 051; 052; 053;
054; 055; 056;
057; 058; 059; 060; 061; 062; 0.65;
089; 090; 092; 093;
094; 096; 099; 100; 101; 102; 105; 106
c-Kit IC50 < 1
JM mM
D27
