Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-03
2003-01-14
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S307000, C514S300000, C514S340000, C548S235000, C544S353000, C544S060000, C544S132000
Reexamination Certificate
active
06506747
ABSTRACT:
BACKGROUND OF THE INVENTION
It has been well established that T-cells play an important role in regulating immune response (F. Powrie and R. L. Coffman,
Immunol. Today
, 14, p. 270 (1993)). Indeed, activation of T-cells is often the initiating event in many inflammatory and autoimmune diseases. IL-2 is an autocrine growth factor which plays an essential role in the regulation of T-cell activation and proliferation. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (T. A. Waldmann,
Immunol. Today
, 14, 270 (1993)). Accordingly, agents which inhibit IL-2 production are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
Previously, others have attempted to interfere with the activity of IL-2 by using cytokine antagonists, monoclonal antibodies, toxins and other biologics which seek to prevent IL-2 from binding to its receptor (G. Mazur and I. Frydecka,
Acta Haematol. Pol
., 24(4), p. 307 (1993)). More recently, others have attempted to inhibit IL-2 production at the T cell level, for example by blocking the expression of IL-2 mRNA with glucocorticoids or cyclosporin A. However, to date, the reported compounds suffer from several disadvantages such as low potency, poor in vivo activity, toxicity and poor oral bioavailability. Accordingly, a need exists for compounds that can effectively inhibit IL-2 production for preventing and treating immune disorders.
A number of 3,5-disubstituted-1-(4-substituted)phenypyrazoles are available commercially or are known in the literature. These include N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chlorobenzamide, N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-trifluoromethyoxybenzamid,e, N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-3,5-dimethylisoxazole-4-carboxamide, N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide, N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-N′-(3,5-dichlorophenyl)urea, N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-N′-(3,5-difluorophenyl)urea, and N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-N′-n-propylurea which are available commercially as chemical intermediates from Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall PL34 OHW, UK.
N-[4-(3,5-dimethylpyrazol-1-yl)phenyl]acetamide (Bouchet and Coquelet, Bull. Soc. Chim.
Fr. 1976, 195), N-[4-(3-methyl-5-chloropyrazol-1-yl)phenyl]acetamide (Michaelis and Behn, Chem. Ber. 1900, 33, 2602), N-[4-(3-methyl-5-(methylthio)pyrazol-1-yl)phenyl]acetamide (Michaelis, Justus Liebigs Ann. Chem., 1911, 378, 346), N-[4-(3-methyl-5-phenylpyrazol-1-yl)phenyl]benzamide (Barry et al., J. Chem. Soc. 1956, 4974), N-[4-(3-methyl-5-ethoxypyrazol-1-yl)phenyl]acetamide (Hoechster Farbw., DE 92990), N-[4-(3,5-dimethylpyrazol-1-yl)phenyl]-4-methoxybenzylamine, N-[4-(3,5-dimethylpyrazol-1-yl)phenyl]-4-nitrobenzylamine (Fernandes et al. J. Indian Chem. Soc. 1977, 54, 923), 4-(3,5-dimethylpyrazol-1-yl)-N-methylbenzamide (Wright et al., J. Med. Chem. 1964, 7, 102), 4-methoxy- and 4-nitro-alpha-{[4-(3,5-dimethylpyrazol-1-yl)phenyl]amino}benzeneacetonitrile and N-[4-(3,5-dimethylpyrazol-1-yl)phenyl]-4-methoxy-(and 4-nitro)-benzenemethaneamine (Fernandes et al., J. Indian Chem. Soc. 1977, 54, 923) are described in the chemical or patent literature. In no case is antiinflammatory activity or ability to inhibit IL-2 production associated with or described for any of these compounds.
1-(4-Methylaminophenyl)-5-(4-methylsulfonylphenyl)-3-trifluoromethylpyrazole, 1-(4-methylaminophenyl)-5-(4-methylsulfonylphenyl)-3-difluoromethylpyrazole (K. Tsuji et al., Chem. Pharm. Bull., 1997, 45, 1475) and 3-cyano-1-(4-methylaminophenyl)-5-(4-methylsulfonylphenyl)pyrazole and 3-cyano-1-(4-ethylaminophenyl)-5-(4-methylsulfonylphenyl)pyrazole (K. Tsuji et al., Chem Pharm. Bull. 1997, 45, 987) are among several compounds described as having antiinflammatory activity due to their ability to inhibit an isoform of cyclooxygenase referred to as COX-2. In neither case is the inhibition of IL-2 production mentioned.
Among a series of substituted pyrazoles having antiinflammatory activity described by M. Matsuo (EP 418845 A1) are 1-[4-(C
1
-C
6
alkylamino)phenyl]- and [4-(C
1
-C
6
acylamino)phenyl]pyrazoles substituted on the pyrazole on either the 3-,4-, or 5-position with CF
3
, halogen, dimethylaminomethyl, CN, C
1-6
alkylthio, or esterified carboxy and on another of the 3-, 4-, or 5-positions with a substituted aryl or heteroaryl ring. No mention is made of inhibition of IL-2 production.
BRIEF SUMMARY OF THE INVENTION
The compounds of this invention are 1-(4-aminophenyl)pyrazoles optionally substituted on the 3- and 5-positions of the pyrazole ring and on the amino group on the 4-position of the phenyl ring having antiinflammatory activity by virtue of their ability to inhibit IL-2 production in T-lymphocytes.
In its broadest generic aspect, the invention comprises 1(4-amninophenyl)pyrazoles of Formula I
wherein:
R
1
and R
3
are the same or different and each is CF
3
, halogen, CN, C
1-8
alkyl or branched alkyl or C
1-8
alkenyl or branched alkenyl or C
3-8
cycloalkyl optionally substituted with OH, CN or methoxy; C
1-8
alkoxy, C
1-4
alkyloxyalkyl, C
1-8
alkylthio, C
1-4
alkylthioalkyl, C
1-8
dialkylamino, C
1-4
dialkylaminoalkyl, CO
2
R
5
where R
5
is C
1-4
alkyl or C
1-4
alkenyl optionally substituted with carbocyclyl or heterocyclyl; aryl or heterocyclyl connected to the pyrazole in any position that makes a stable bond, optionally substituted with halogen, C
1-4
alkyl, C
1-4
alkenyl, CN, Me
2
N, CO
2
Me, OMe, aryl, heterocyclyl or R
5
.
R
2
is H, halogen, or methyl.
L is —NHC(O)—, —NHC(O)O—, —NHC(O)C(O)—, —NHC(S)—, —NH—, —NHC(O)NH, NHC(S)NH, NHCH
2
, —NHCH(R
6
)—, where R
6
is H, CN, C
1-6
alkyl, C
1-6
alkyloxyoalkyl C
1-6
alkythioalkyl, C
1-6
alkylsulfinylalkyl, C
1-6
alkysulfonylalkyl, C
3-6
cycloalkyl, or heterocyclyl or aryl optionally substituted with a halogen, C
1-4
alkyl, CN, Me
2
N, CO
2
Me or OMe, or —NHC(R
6
)— lower alkyl.
R
4
is C
1-8
alkyl, C
1-8
alkyloxy, C
1-8
alkylthio, C
1-8
alkylamino, C
1-4
alkoxyalkyl, C
1-4
alkylthioalkyl, C
1-4
alkylaminoalkyl, C
1-4
dialkylalkylaminoalkyl, carbocyclyl or heterocyclyl, optionally substituted with one or more halogen, —CN, —NO
2
, SO
2
NH
2
, or R
7
where R
7
is phenyl, heterocyclyl, C
3-6
cycloalkyl, C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkyloxyalkyl, C
1-6
alkylthioalkyl, C
1-6
alkylsulfinylalkyl, C
1-6
alkylsulfonylalkyl or C
2-6
alkynyl, optionally substituted with halogen, OH, alkyloxy, CN, COO-lower alkyl, —CONH-lower alkyl, —CON(lower alkyl)
2
, dialkylamino, phenyl or heterocylcyl; CO
2
R
7
, —N(R
7
)
2
, —NH(R
7
), —C(O)R
7
, —OR
7
, S(O)
n
R
7
where n is 0, 1 or 2, —SO
2
NHR
7
, —SO
2
N(R
7
)
2
.
DETAILED DESCRIPTION OF THE INVENTION
In order that the invention herein described may be more fully understood, the following detailed description is set forth. As used herein, the following abbreviations are used:
BOC or t-BOC is tertiary butoxycarbonyl
DMAP is 4-dimethylamino pyridine
Bu is butyl
DIBAL is diisobutylaluminum hydride
DMF is dimethylformamide
Et is ethyl
Me is methyl
Oxz is oxazole
Ph is phenyl
Pr is propyl
Py is pyridine
PyBOP is Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
Th is thiophene
THF is tetrahydrofuran
Thz is thiazole
Rt is room temperature
EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride.
Also, as used herein, each of the following terms, used alone or in conjunction with other terms, are defined as follows (except where noted to the contrary):
The term “alkyl” refers to a saturated aliphatic radical containing from one to ten carbon atoms. “Alkyl” refers to both b
Betageri Rajashekhar
Cywin Charles L.
Hargrave Karl
Hoermann Mary Ann
Kirrane Thomas M.
Boehringer Ingelheim Pharmaceuticals Inc.
Devlin Mary-Ellen M.
Raymond Robert P.
Robinson Binta
Rotman Alan L.
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