Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-23
2003-09-30
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S256000, C514S399000, C548S338100
Reexamination Certificate
active
06627647
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, 1993, 14, 270). 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, 1993, 14, 264). 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., 1993, 24, 307). 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.
U.S. application Ser. No. 09/324,933 discloses substituted 1-(4-aminophenyl)pyrazoles as anti-inflammatory agents. WO9919303 describes substituted phenyl-, heteroaryl- and heterocyclyl-substituted pyrazoles as useful in the treatment of allergy, inflammatory and autoimmune diseases. WO9951580 describes substituted pyrazoles as inhibitors of cytokine production.
BRIEF SUMMARY OF THE INVENTION
The compounds of this invention are 1-(4-aminophenyl)imidazoles optionally substituted on the imidazole 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-aminophenyl)imidazoles of Formulas Ia and Ib
wherein:
R
1
and R
2,
which may be the same or different, are CF
3
; halogen; CN; branched or unbranched C
1-8
alkyl; branched or unbranched C
1-8
alkenyl; 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
4
where R
4
is C
1-4
alkyl or C
1-4
alkenyl optionally substituted with carbocyclyl or heterocyclyl; aryl or heterocyclyl connected to the imidazole in any position that makes a stable bond which aryl or heterocyclyl may be optionally substituted with halogen, C
1-4
alkyl, C
1-4
alkenyl, CN, Me
2
N, CO
2
Me, OMe, aryl, heterocyclyl or R
4
;
L is —NHC(O)—; —NHC(O)O—; —NHC(O)C(O)—; —NHC(S)—; —NH—; —NHC(O)NH—; —NHC(S)NH—; —NHCH—
2
; —NHCH(R
5
)— where R
5
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, heterocyclyl or aryl optionally substituted with a halogen, C
1-4
alkyl, CN, Me
2
N, CO
2
Me or OMe; or L is —NHC(R
5
)-lower alkyl;
R
3
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, which carbocyclyl or heterocyclyl may optionally be substituted with one or more of the following: halogen, —CN, —NO
2
, —SO
2
NH
2
or R
6
(where R
6
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) and R
6
may be optionally substituted with halogen, —OH, alkyloxy, —CN, —COO-lower alkyl, —CONH-lower alkyl, —CON (lower alkyl)
2
, dialkylamino, phenyl or heterocylcyl; or R
3
is —CO
2
R
6
; —N(R
2
); —NH(R
6
); —C(O)R
6
; —OR
6
; S(O)
n
R
6
where n is O, 1 or 2; —SO
2
NHR
6
; or —SO
2
N(R
6
)
2
; or a pharmaceutically acceptable derivative thereof.
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:
DMAP is 4-dimethylamino pyridine;
DMF is dimethylformamide;
DMSO is dimethylsulfoxide;
Et is ethyl;
EtOAc is ethyl acetate;
Me is methyl;
MeOH is methanol; and
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 branched and unbranched alkyl groups. Preferred alkyl groups are straight chain alkyl groups containing from one to eight carbon atoms and branched alkyl groups containing from three to eight carbon atoms. More preferred alkyl groups are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. “Alkyl”, as used herein, includes unsubstituted alkyl radicals, those radicals that are partially or fully halogenated and those radicals substituted with one to four, preferably one or two, substituents selected from amino, cyano, nitro, methoxy, ethoxy and hydroxy. The term “cycloalkyl” refers to the cyclic analog of an alkyl group, as defined above. Preferred cycloalkyl groups are saturated cycloalkyl groups containing from three to eight carbon atoms, and more preferably three to six carbon atoms. “Alkyl” and “cycloalkyl”, as used herein, include unsubstituted alkyl and cycloalkyl radicals, those radicals that are partially or fully halogenated and those radicals substituted with one to four, preferably one or two, substituents selected from halo, amino, cyano, nitro, methoxy, ethoxy and hydroxy. It should be understood that any combination term using an “alk” or “alkyl” prefix refers to analogs according to the above definition of “alkyl”. For example, terms such as “alkoxy”, “alkythio” refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
The terms “alkenyl” and “alkynyl” refer to a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms, containing at least one double or triple bond, respectively. “Alkenyl” and “alkynyl” refer to both branched and unbranched alkenyl and alkynyl groups. Preferred alkenyl and alkynyl groups are straight chain alkenyl or alkynyl groups containing from two to eight carbon atoms and branched alkenyl or alkynyl groups containing from five to ten carbon atoms. More preferred alkenyl and alkynyl groups are straight chain alkenyl or alkynyl groups containing from two to six carbon atoms and branched alkenyl or alkynyl groups containing from five to eight carbon atoms. “Alkenyl” and “alkynyl”, as used herein, include unsubstituted alkenyl or alkynyl radicals, those radicals that are partially or fully halogenated and those radicals substituted with one to four, preferably one or two, substituents selected from halo, amino, cyano, nitro, methoxy, ethoxy and hydroxy.
The term “aryl” refers to phenyl and naphthyl, phenyl and naphthyl that are partially or fully halogenated and phenyl and naphthyl substituted with halo, alkyl, hydroxy, nitro, —COOH, —CO(lower alkoxy), —CO(lower alkyl), amino, alkylamino, dialkylamino, alkoxy, —NCOH, —NCO(lower alkyl), —NSO
2
-Ph(halo)
0-3
, Ph, —O-Ph; naphthyl, —O-naphthyl, pyrrolyl, pyrrolyl substituted with lower alkyl, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.
The term “halo” refers to a halogen radical selected from fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term “carbocyclyl” refers to a stable 3-8 membered (but preferably, 5 or 6 me
Boehringer Ingelheim Pharmaceuticals Inc.
Bottino Anthony P.
Morris Patricia L.
Raymond Robert P.
Witkowski Timothy X.
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