Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-14
2004-06-01
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S227800, C514S235800, C544S182000, C544S060000, C544S112000
Reexamination Certificate
active
06743792
ABSTRACT:
The present invention concerns the use of IL-5 inhibiting 6-azauracil derivatives in the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases. It further relates to certain novel 6-azauracil derivatives, to processes for their preparation and compositions comprising them.
Eosinophil influx, leading to subsequent tissue damage, is an important pathogenic event in bronchial asthma and allergic diseases. The cytokine interleukin-5 (IL-5), produced mainly by T lymphocytes as a glycoprotein, induces the differentiation of eosinophils in bone marrow and, primes eosinophils for activation in peripheral blood and sustains their survival in tissues. As such, IL-5 plays a critical role in the process of eosinophilic inflammation. Hence, the possibility that inhibitors of IL-5 production would reduce the production, activation and/or survival of eosinophils provides a therapeutic approach to the treatment of bronchial asthma and allergic diseases such as, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and also other eosinophil-dependent inflammatory diseases.
Steroids, which strongly inhibit IL-5 production in vitro, have long been used as the only drugs with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds having the ability to inhibit IL-5 production in human T-cells and which have little or no adverse reactions.
U.S. Pat. No. 4,631,278 discloses &agr;-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitriles and U.S. Pat. No. 4,767,760 discloses 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoal activity, in particular, anti-coccidial activity. Unexpectedly, the 6-azauracil derivatives of the present invention, including said art-known 1,2,4-triazinedione derivatives, prove to be potent inhibitors of the production of IL-5.
The present invention is concerned with the use of compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
p represents an integer being 0, 1, 2, 3 or 4;
q represents an integer being 0, 1, 2, 3, 4 or 5;
R
1
represents hydrogen, C
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyloxy, mercapto, C
1-6
alkylthio, C
3-7
cycloalkyl, aryl or C
1-6
alkyl substituted with mono- or di(C
1-6
alkyl)amino, C
1-6
alkyloxy, aryl or Het;
R
2
represents cyano or a radical of formula —C(═X)—Y—R
5
; wherein
X represents O or S;
Y represents O, S, NR
6
or a direct bond;
R
5
represents hydrogen; C
1-6
alkyl; C
3-7
cycloalkyl; aryl or C
1-6
alkyl substituted with aryl, hydroxy or Het; and where Y is a direct bond, R
5
may also be halo or Het;
R
6
represents hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or arylC
1-6
alkyl;
each R
3
independently represents halo, haloC
1-6
alkyl, C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, C
1-6
alkylcarbonyloxy, mercapto, C
1-6
alkylthio, C
1-6
alkylsulfonyl, C
1-6
alkylsulfinyl, haloC
1-6
alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di(C
1-6
alkyl)amino or (C
1-6
alkylcarbonyl)amino;
each R
4
independently represents halo, haloC
1-6
alkyl, C
1-6
alkyl, hydroxy, C
1-6
alkyloxy, C
1-6
alkylcarbonyloxy, mercapto, C
1-6
alkylthio, C
1-6
alkylsulfonyl, C
1-6
alkylsulfinyl, haloC
1-6
alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di(C
1-6
alkyl)amino or (C
1-6
alkylcarbonyl)amino;
aryl represents phenyl or phenyl substituted with one, two or three substituents selected from the group comprising halo, C
1-6
alkyl, C
1-6
alkyloxy, haloC
1-6
alkyl, hydroxy, mercapto, C
1-6
alkylthio, C
1-6
alkylsulfonyl, C
1-6
alkylsulfonyloxy, C
1-6
alkylsulfinyl, haloC
1-6
alkylsulfonyl, nitro, cyano, amino, mono- and di(C
1-6
alkyl)amino and C
1-6
alkylcarbonylamino; and
Het represents a heterocycle selected from pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl and thiazolopyridinyl; said heterocycles each independently may be substituted with one, two or three substituents selected from hydroxy, mercapto, C
1-4
alkyl, C
1-4
alkyloxy, cyano, amino, nitro, mono- or di(C
1-4
alkyl)amino, mono- or di(C
1-4
alkyl)aminocarbonyl, mono- or di(aryl)amino, halo, haloC
1-4
alkyl, C
1-4
alkyloxycarbonyl, aryl, furanyl, thienyl, pyridinyl, piperidinyl, C
1-4
alkylcarbonylpiperidinyl and C
1-4
alkyl substituted with hydroxy, C
1-4
alkyloxy, aryl, piperidinyl, amino, mono- or di(C
1-4
alkyl)amino or C
3-7
cycloalkyl;
in the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases.
The compounds of formula (I) are deemed novel, provided that the &agr;-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitriles published in U.S. Pat. No. 4,631,278 and the 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones published in U.S. Pat. No. 4,767,760 are excluded therefrom.
Thus, the invention also concerns novel compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p, q, R
1
, R
2
, R
3
and R
4
are as defined in the compounds of formula (I), provided that the following conditions apply to the variables R
3a
, R
3b
, R
3c
, R
4a
, R
4b
, R
4c
, R
1
and R
2
in the compounds with general structure:
a) if R
3a
, R
3b
are chloro; R
4a
is 4-chloro; and R
1
, R
3c
, R
4b
and R
4c
are hydrogen; then R
2
is other than aminocarbonyl, carboxyl, chlorocarbonyl, 1-piperidinylcarbonyl, methoxycarbonyl, methylaminocarbonyl, 1-pyrrolidinylcarbonyl, 4-methyl-1-piperazinylcarbonyl, methylcarbonyl, NH
2
—C(═S)—, phenylcarbonyl; and
b) if R
3a
is chloro; R
4a
is 4-chloro; and R
1
, R
3b
, R
3c
, R
4b
and R
4c
are hydrogen; then R
2
is other than aminocarbonyl, carboxyl, NH
2
—C(═S)—, chlorocarbonyl, methylaminocarbonyl, (4-methylcarbonyl-1-piperazinyl)carbonyl, (4-phenylmethyl-1-piperazinyl)carbonyl or methyloxycarbonyl; and
c) if the combination of R
1
, R
3a
, R
3b
, R
3c
, R
4a
, R
4b
and R
4c
is one of the following
R
1
R
3a
R
3b
R
3c
R
4a
R
4b
R
4c
4-chlorophenyl
Cl
H
H
H
4-Cl
H
1-propyl
Cl
H
H
H
4-Cl
H
1-butyl
Cl
H
H
H
4-Cl
H
CH
3
Cl
H
H
H
4-Cl
H
CH
3
H
H
H
H
4-H
H
CH
3
H
Cl
H
H
4-F
H
CH
3
CF
3
H
H
H
4-Cl
H
CH
3
Cl
H
H
3-CF
3
4-Cl
H
CH
3
Cl
Cl
H
H
4-Cl
H
CH
3
Cl
CH
3
H
H
4-Cl
H
CH
3
F
H
H
H
4-F
H
H
Cl
CH
3
H
H
4-Cl
H
H
Cl
H
H
H
4-F
H
H
Cl
H
H
H
4-CH
3
H
H
Cl
Cl
H
H
4-F
H
H
Cl
CH
3
H
H
4-F
H
H
CH
3
CH
3
H
H
4-F
H
H
CH
3
CH
3
H
H
4-Cl
H
H
Cl
Cl
H
H
4-Cl
H
H
Cl
H
H
H
4-Cl
H
H
Cl
H
H
2-Cl
4-Cl
H
H
Cl
H
H
2-Cl
4-Cl
6-Cl
H
Cl
H
H
H
4-Br
H
H
Cl
Cl
H
H
4-Br
H
H
Cl
Cl
H
H
4-CH
3
C(═O)O
H
H
Cl
Cl
H
H
4-OH
H
H
OH
H
H
H
4-Cl
H
H
Cl
H
H
H
4-CH
3
S
H
H
Cl
Cl
H
H
4-CH
3
S
H
H
CH
3
CH
3
H
H
4-CH
3
S
H
H
Cl
H
H
3-CH
3
4-CH
3
S
H
H
Cl
Cl
H
3-CH
3
4-CH
3
S
H
H
Cl
H
H
H
4-CH
3
SO
H
H
Cl
Cl
H
H
4-CH
3
SO
H
H
Cl
H
H
H
4-CH
3
S(O)
2
H
H
Cl
Cl
H
H
4-CH
3
S(O)
2
H
H
Cl
H
H
H
4-SH
H
H
Cl
Cl
H
H
4-SH
H
CH
3
Cl
H
CH
3
4-Cl
H
H
H
H
H
OCH
3
4-Cl
H
H
then R
2
is other than cyano.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
3-7
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C
1-6
alkyl is me
Boeckx Gustaaf Maria
Diels Gaston Stanislas Marcella
Freyne Eddy Jean Edgard
Van Wauwe Jean Pierre Frans
Balasubramanian Venkataraman
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Kriegsman Alana G.
Raymond Richard L.
LandOfFree
6-azauracil derivatives as IL-5 inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 6-azauracil derivatives as IL-5 inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 6-azauracil derivatives as IL-5 inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3353543