Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-27
2004-06-22
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S190000
Reexamination Certificate
active
06753340
ABSTRACT:
The present invention relates to (4,2-disubstituted-thiazol-5-yl)amine derivatives, a process for their preparation, and pharmaceutical compositions containing them. These new compounds are useful as phosphodiesterase 7 (PDE7) inhibitors. Further contained in this invention are pharmaceutical compositions containing these phosphodiesterase 7 inhibitors as active principle for the treatment of disease for which treatment by PDE7 inhibitor is relevant. These medicinal products are useful in particular for treating T-cell-related diseases, autoimmune diseases, visceral pain, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, cancer, acquired immune deficiency syndrome, allergy, fertility diseases or inflammatory bowel disease.
Phosphodiesterases (PDE) play an important role in various biological processes by hydrolysing the key second messengers adenosine and guanosine 3′,5′-cyclic monophosphates (cAMP and cGMP respectively) into their corresponding 5′-monophosphate nucleotides. Therefore, inhibition of PDE activity produces an increase of cAMP and cGMP intracellular levels that activate specific protein phosphorylation pathways involved in a variety of functional responses.
At least eleven isoenzymes of mammalian cyclic nucleotide phosphodiesterases, numbered PDE 1 through PDE 11, have been identified on the basis of primary structure, substrate specificity or sensitivity to cofactors or inhibitory drugs. Among these phosphodiesterases, PDE7 is a cAMP-specific PDE. The biochemical and pharmacological characterization showed a high-affinity cAMP-specific PDE (Km=0.2 &mgr;M), that is not affected by cGMP potent selective PDE isoenzyme inhibitors.
PDE7 activity or protein has been detected in T-cell lines, B-cell lines, airway epithelial (AE) cell lines and several foetal tissues.
Increasing cAMP levels by selective PDE7 inhibition appears to be a potentially promising approach to specifically block T-cell mediated immune responses. Further studies have demonstrated that elevation of intracellular cAMP levels can modulate inflammatory and immunological processes. This selective approach could presumably be devoid of the side effects associated with known selective PDE inhibitors (e.g. PDE3 or PDE4 selective inhibitors) and which limit their use.
A functional role of PDE7 in T-cell activation has also been disclosed; therefore selective PDE7 inhibitors would be candidates for the treatment of T-cell-related diseases. AE cells actively participate in inflammatory airway diseases by liberating mediators such as arachidonate metabolites and cytokines. Selective inhibition of PDE7 may be a useful anti-inflammatory approach for treating AE cells related diseases.
Thus, there is a need for selective PDE7 inhibitors, which are active at very low concentrations.
The applicant has identified novel (4,2-disubstituted-thiazol-5-yl)amine compounds that are phosphodiesterase inhibitors, and more specifically compounds that are selective PDE7 inhibitors.
More specifically, the present invention relates to compounds of formula (I):
wherein:
R
1a
represents a group selected from hydrogen, (C
1
-C
6
)alkyl, and aryl(C
1
-C
6
)alkyl,
R
1b
represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, those groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, trifluoromethyl, nitro, cyano, oxo, —NR
4
R
5
, —CO
2
R
4
, —CONR
4
R
5
, —OR
4
, —S(O)
n
R
4
, —S(O)
n
NR
4
R
5
, tetrazolyl, and (C
1
-C
6
)alkyl which is optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from —OR
4
, —NR
4
R
5
, and —CO
2
R
4
, wherein:
n is an integer from 0 to 2 inclusive,
R
4
and R
5
, identical or different, independently of each other, represent a hydrogen atom or a group of formula —X
1
—R
a
wherein:
X
1
represents a single bond or a (C
1
-C
6
)alkylene group,
R
a
represents a group selected from (C
1
-C
6
)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
R
2
represents a group selected from (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, aryl and cycloalkyl,
R
3
represents a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by one or more groups, identical or different, selected independently of each other from halogen, nitro, cyano, trifluoromethyl, oxo, (C
1
-C
6
)alkyl, —OR
6
, —NR
6
R
7
, —COR
6
, —CO
2
R
6
, —CONHOH, —CONR
6
R
7
, —S(O)
m
R
6
, —S(O)
m
—NR
6
R
7
, —NR
6
COR
7
, —NR
6
SO
2
R
7
, —N(SO
2
R
7
)
2
, —NR
6
—CO—NR
7
R
8
, C(═N—CN)NR
6
R
7
, NR
8
—C(═N—CN)NR
6
R
7
and tetrazolyl optionally substituted with a (C
1
-C
4
)alkyl, wherein:
m is an integer from 0 to 2 inclusive,
R
6
and R
7
, identical or different, independently of each other, represent a hydrogen atom or a group of formula —X
2
—R
b
wherein:
X
2
represents a single bond or a (C
1
-C
6
)alkylene group,
R
b
represents a group selected from (C
1
-C
6
)alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups being optionally substituted by 1 to 3 groups, identical or different, selected independently of each other from hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkyl, amino, mono(C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino (each alkyl being identical or different, independently of each other), carboxy, (C
1
-C
6
)alkoxycarbonyl, and benzyl,
R
8
represents a hydrogen atom or a (C
1
-C
6
)alkyl group, optionally the racemics forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable acid or base salts thereof.
Preferably, the present invention relates to compounds of formula (I)
wherein R
1a
, R
1b
, R
2
and R
3
are as defined above, with the exclusion of the following compounds:
(4-Methyl-2-phenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-(3-fluoro-phenyl)-amine,
(2,4-diphenyl-thiazol-5-yl)-(4-fluoro-phenyl)-amine,
(4-chloro-phenyl)-(2,4-diphenyl-thiazol-5-yl)-amine,
(2-chloro-phenyl)-(2,4-diphenyl-thiazol-5-yl)-amine,
(2,4-diphenyl-thiazol-5-yl)-p-tolyl-amine, and,
(2,4-diphenyl-thiazol-5-yl)-(4-methoxy-phenyl)-amine.
Preferably, the present invention relates to compounds of formula (I)
wherein R
1a
, R
1b
, R
2
and R
3
are as defined above, with the exclusion of the following compounds:
(4-Methyl-2-phenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-phenyl-amine,
(2,4-diphenyl-thiazol-5-yl)-(3-fluoro-phenyl)-amine,
(2,4-diphenyl-thiazol-5-yl)-(4-fluoro-phenyl)-amine,
(4-chloro-phenyl)-(2,4-diphenyl-thiazol-5-yl)-amine,
(2-chloro-phenyl)-(2,4-diphenyl-thiazol-5-yl)-amine,
(2,4-diphenyl-thiazol-5-yl)-p-tolyl-amine, and,
(2,4-diphenyl-thiazol-5-yl)-(4-methoxy-phenyl)-amine,
and with the proviso that R
1b
is other than a substituted pyrimidine or a substituted pyrimidine fused to one or several other cycles.
The substituent R
1a
that is preferred according to the invention is the hydrogen atom or a (C
1
-C
6
)alkyl group, and the substituent R
1b
that is preferred according to the invention is the group selected from cycloalkyl and aryl, each of those groups being optionally substituted by 1 to 3 groups selected from halogen, trifluoromethyl, —CO
2
R
4
, —OR
4
, and tetrazolyl, in which R
4
represents a hydrogen atom or a (C
1
-C
6
)alkyl group.
More particularly, the substituent R
1a
that is preferred according to the invention is the hydrogen atom, and the substituent R
1b
that is preferred according to the invention is the cyclohexyl group optionally substituted by one hydroxy group, or the phenyl group optionally substituted by one tetrazolyl group or one —CO
2
R
4
group in which R
4
represents a hydrogen atom or a (C
1
-C
6
)alkyl group.
The substituent R
2
that is preferred according to the invention is a (C
1
-C
6
)alkyl group.
More particularly, the substituent R
2
that is preferred according to the invention is the methyl group.
The substituent R
3
that is preferred accordin
Bernardelli Patrick
Ducrot Pierre
Lorthiois Edwige
Vergne Fabrice
Benson Gregg C.
Gerstl Robert
Richardson Peter C.
Ronau Robert T.
Warner-Lambert Company LLC
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