Il-5 inhibiting 6-azauracil derivatives

Details Il-5 inhibiting 6-azauracil derivatives Il-5 inhibiting 6-azauracil derivatives

2001-08-29

2004-10-12

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S182000

Reexamination Certificate

active

06803364

ABSTRACT:

The present invention concerns novel IL-5 inhibiting 6-azauracil derivatives useful for treating eosinophil-dependent inflammatory diseases; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.
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. EP 831,088 discloses 1,2,4-triazine-3,5-diones as anticoccidial agents.
The present invention provides compounds which have never been described hitherto and which possess a remarkable pharmacological activity as inhibitors of the production of IL-5.
The present invention is concerned with the compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines 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;
X represents O, S, NR
3
or a direct bond; or
—X—R
2
taken together may represent cyano;
R
1
represents hydrogen, hydroxy, halo, amino, mono- or di(C
1-4
alkyl)amino, C
1-6
alkyl, C
1-6
alkyloxy, C
3-7
cycloalkyl, aryl, arylC
1-6
alkyl, aminoC
1-4
alkyl, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl or mono- or di(C
1-4
alkyl)amino-C
1-4
alkylamino;
R
2
represents aryl, Het
1
, C
3-7
cycloalkyl optionally substituted with —C(═O)—Z—R
14
, C
1-6
alkyl or C
1-6
alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C
1-4
alkyl)amino, —C(═O)—Z—R
14
, C
1-6
alkyloxy optionally substituted with —C(═O)—Z—R
14
, C
1-6
alkylsulfonyloxy, C
3-7
cycloalkyl optionally substituted with —C═O)—Z—R
14
, aryl, aryloxy, arylthio, Het
1
, Het
1
oxy and Het
1
thio; and if X is O, S or NR
3
, then R
2
may also represent —C(═O)—Z—R
14
, aminothiocarbonyl, C
1-4
alkylcarbonyl optionally substituted with —C(═Q)—Z—R
14
, C
1-4
alkylthiocarbonyl optionally substituted with —C(═O)—Z—R
14
, arylcarbonyl, arylthiocarbonyl, Het
1
carbonyl or Het
1
thiocarbonyl;
R
3
represents hydrogen or C
1-4
alkyl;
each R
4
independently represents —C(═O)—Z—R
14
, C
1-6
alkyl, halo, polyhaloC
1-6
alkyl, hydroxy, mercapto, C
1-6
alkyloxy, C
1-6
alkylthio, C
1-6
alkylcarbonyloxy, aryl, cyano, nitro, Het
3
, R
6
, NR
7
R
8
or C
1-4
alkyl substituted with —C(═O)—Z—R
14
, Het
3
, R
6
or NR
7
R
8
;
each R
5
independently represents —C(═O)—Z—R
14
, C
1-6
alkyl, halo, polyhaloC
1-6
alkyl, hydroxy, mercapto, C
1-6
alkyloxy, C
1-6
alkylthio, C
1-6
alkylcarbonyloxy, aryl, cyano, nitro, Het
3
, R
6
, NR
7
R
8
or C
1-4
alkyl substituted with —C(═O)—Z—R
14
, Het
3
, R
6
or NR
7
R
8
;
each R
6
independently represents C
1-6
alkylsulfonyl, aminosulfonyl, mono- or di-(C
1-4
alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC
1-6
alkyl-sulfonyl, C
1-6
alkylsulfonyl, phenylC
1-4
alkylsulfonyl, piperazinylsulfonyl, piperidinyl-sulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C
1-4
alkyl-N-piperidinylaminosulfonyl or mono- or di(C
1-4
alkyl)aminoC
1-4
alkylsulfonyl;
each R
7
and each R
8
are independently selected from hydrogen, C
14
alkyl, hydroxy-C
1-4
alkyl, dihydroxyC
1-4
alkyl, aryl, arylC
1-4
alkyl, C
1-4
alkyloxyC
1-4
alkyl, C
1-4
alkyl-carbonyl, arylcarbonyl, Het
3
carbonyl, —C(═O)—Z—R
14
, mono- or di(C
1-4
alkyl)amino-C)
4
alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het
3
aminocarbonyl, Het
3
amino-thiocarbonyl, C
3-7
cycloalkyl, pyridinylC
1-4
alkyl, C
1-4
alkanediyl-C(═O)—Z—R
14
, —Y—C
1-4
alkanediyl-C(═O)—Z—R
14
, Het
3
and R
6
; or R
7
and R
8
taken together with the nitrogen atom to which they are attached form a radical of formula
R
9
and R
10
are each independently selected from hydrogen, C
1-4
alkyl, hydroxyC
1-4
alkyl, dihydroxyC
1-4
alkyl, phenyl, phenylC
1-4
alkyl, C
1-4
alkyloxyC
1-4
alkyl, C
1-4
alkyl-carbonyl, phenylcarbonyl, Het
3
carbonyl, —C(═O)—Z—R
14
, mono- or di(C
1-4
alkyl)amino-C
1-4
alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het
3
aminocarbonyl, Het
3
aminothiocarbonyl, C
3-7
cycloalkyl, pyridinylC
1-4
alkyl, C
1-4
alkanediyl-C(═O)—Z—R
14
, —Y—C
1-4
alkanediyl-C(═O)—Z—R
14
, Het
3
and R
6
; or R
9
and R
10
taken together with the nitrogen atom to which they are attached form a radical of formula
each R
11
independently being selected from hydroxy, mercapto, cyano, nitro, halo, —C(═O)—Z—R
14
, —Y—C
1-4
alkanediyl-C(═O)—Z—R
14
, trihalomethyl, C
1-4
alkyloxy optionally substituted with —C(═O)—Z—R
14
, formyl, trihaloC
1-4
alkylsulfonyloxy, R
6
, NR
7
R
8
, C(═O)NR
15
R
16
, aryl, aryloxy, arylcarbonyl, C
3-7
cycloalkyl optionally substituted with —C(═O)—Z—R
14
, C
3-7
cycloalkyloxy optionally substituted with —C(═O)—Z—R
14
, phthalimide-2-yl, Het
3
, Het
4
and C(═O)Het
3
;
R
12
and R
13
are each independently selected from hydrogen, C
1-4
alkyl, hydroxyC
1-4
alkyl, dihydroxyC
1-4
alkyl, phenyl, phenylC
1-4
alkyl, C
1-4
alkyloxyC
1-4
alkyl, C
1-4
alkyl-carbonyl, phenylcarbonyl, —C(═O)—Z—R
14
, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C
3-7
cycloalkyl, pyridinylC
1-4
alkyl, C
1-4
alkanediyl-C(═O)—Z—R
14
, —Y—C
1-4
alkanediyl-C(═O)—Z—R
14
and R
6
; or R
9
and R
10
taken together with the nitrogen atom to which they are attached form a radical of formula
 each Z independently represents O, S, NH, —CH
2
—O— —CH
2
—S— whereby —CH
2
— is attached to the carbonyl group;
each R
14
independently represents hydrogen, C
1-20
acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms), C
1-20
alkyl, C
3-20
alkenyl optionally substituted with phenyl, C
3-20
alkynyl, C
3-7
cycloalkyl, polyhaloC
1-20
alkyl, Het
5
, phenyl or C
1-20
alkyl substituted with one or more substituents selected from hydroxy, NR
17
, R
18
, phenyl, mono- or di(C
1-4
alkyl)amino, cyano, Het
5
, C
1-4
alkyloxycarbonyl, phenylC
1-4
alkyloxycarbonyl and C
3-7
cycloalkyl; or R
14
represents a radical of formula
wherein n is 0 to 5; m is 1 to 4; s is zero to 4; r is 0 to 2;
R
a
, R
b
, R
c
, R
d
, R
e
and R
f
are each independently hydrogen, or C
1-6
alkyl; phenyl or C
3-7
cycloalkyl; or
R
e
and R
f
taken together may form —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
— or —CH
2
—CH
2
——CH
2
—CH
2
—;
R
g
, R
h
and R
k
are each independently hydrogen or C
1-4
alkyl;
each R
j
independently is C
1-4
alkyl;
R
i
is —O—R
6
, C
1-6
alkyl, phenyl or C
3-7
cycloalkyl optionally substituted with C
1-4
alkyloxy;
R
n
is hydrogen, C
1-4
alkyl, phenyl, phenylC
1-4
alkyl or C
3-7
cycloalkyl;
R
m
is hydrogen or C
1-4
alkyloxy; or
—Z—R
1

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