IL-5 inhibiting 6-azauracil derivatives

Details IL-5 inhibiting 6-azauracil derivatives IL-5 inhibiting 6-azauracil derivatives

2001-05-22

2002-10-22

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C514S242000, C544S182000, C544S060000, C544S112000

Reexamination Certificate

active

06469001

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C. 371 of PCT/EP99/09155 filed Nov. 22, 1999, which claims priority from EP 98.203.930.7, filed Nov. 23, 1998.
The present invention concerns 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 ill 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. Unexpectedly, the 6-azauracil derivatives of the present invention prove to be potent 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 and the stereochemically isomeric forms thereof, wherein:
p represents an integer being 0, 1, 2 or 3;
q represents an integer being 0, 1, 2, 3, 4 or 5;
—A—B— represents —(CH
2
)
r
—, —(CH
2
)
t
—O—, —(CH
2
)
t
—S(═O)
u
— or —(CH
2
)
t
—NR
3
—;
r represents 2, 3 or 4;
each t independently represents 1, 2 or 3;
u represents 0, 1 or 2;
X
1
represents O, S, NR
3
or a direct bond;
each R
1
independently represents 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 Het
3
, R
6
or NR
7
R
8
;
R
2
represents aryl, Het
1
, C
3-7
cycloalkyl, cyano, C
1-6
alkyl, —C(═Q)—X
2
—R
15
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
1-6
alkyloxy, C
1-6
alkylsulfonyloxy, C
1-6
alkyloxycarbonyl, C
3-7
cycloalkyl, aryl, aryloxy, arylthio, Het
1
, Het
1
Het
1
thio and —C(═Q)—X
2
—R
15
;
R
3
represents hydrogen or C
1-4
alkyl;
each R
4
independently represents 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 Het
3
, R
6
or NR
7
R
8
;
each R
15
independently represents hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, aryl or C
1-6
alkyl substituted with aryl, halo, hydroxy or Het
1
;
where X
2
is a direct bond, R
15
may also be halo or Het
1
;
where X
2
is NR
5
, R
15
may also be hydroxy;
where X
2
is C(═O)—NH—NH or NH—NH—C(═O), R
15
may be replaced by R
11
; R
5
represents hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or arylC
1-6
alkyl;
each Q independently represents O, S or NR
3
;
each X
2
independently represents O, S, NR
5
, C(═O)—NH—NH, NH—NH—C(═O) or a direct bond;
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
alkylsulfonyl, C
1-6
alkylsulfinyl, phenylC
1-4
alkylsulfonyl, piperazinylsulfonyl, 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
1-4
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
alkylcarbonyl, aminocarbonyl, arylcarbonyl, Het
3
carbonyl, C
1-4
alkylcarbonyloxy-C
1-4
alkylcarbonyl, hydroxyC
1-4
alkylcarbonyl, C
1-4
alkyloxycarbonylcarbonyl, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het
3
aminocarbonyl, Het
3
aminothiocarbonyl, C
3-7
cycloalkyl, pyridinylC
1-4
alkyl, C
1-4
alkanediyl-C(═O)—O—R
14
, —C(═O)—O—R
14
, —Y—C
1-4
alkanediyl-C(═O)—O—R
14
, Het
3
and R
6
;
Y represents O, S, NR
3
, or S(O)
2
;
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
alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het
3
carbonyl, C
1-4
alkylcarbonyloxy-C
1-4
alkylcarbonyl, hydroxyC
1-4
alkylcarbonyl, C
1-4
alkyloxycarbonylcarbonyl, mono-or di(C
1-4
alkyl)aminoC
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)—O—R
14
, —C(═O)—O—R
14
, —Y—C
1-4
alkanediyl—C(═O)—O—R
14
, Het
3
and R
6
;
each R
11
independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C
1-4
alkyloxy, formyl, trihaloC
1-4
alkylsulfonyloxy, R
6
, NR
7
R
8
, C(═O)NR
7
R
8
, —C(═O)—O—R
14
, —Y—C
1-4
alkanediyl—C(═O)—O—R
14
, aryl, aryloxy, arylcarbonyl, C
3-7
cycloalkyl, C
3-7
cycloalkyloxy, phthalimide-2-yl, Het
3
, Het
4
and C(═O)Het
3
;
R
1
and R
2
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
alkylcarbonyl, phenylcarbonyl, C
1-4
alkylcarbonyloxyC
1-4
alkylcarbonyl, hydroxyC
1-4
alkylcarbonyl, C
1-4
alkyloxycarbonylcarbonyl, 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)—O—R
14
, —C(═O)—O—R
14
, —Y—C
1-4
alkanediyl-C(═O)—O—R
14
and R
6
;
each R
14
independently represents hydrogen, C
1-4
alkyl, C
3-7
cycloalkyl, aminocarbonylmethylene, mono-or di(C
1-4
alkyl)aminocarbonylmethylene, mono-or di(C
3-7
cycloalkyl)aminocarbonylmethylene, azetidin-1-ylcarbonylmethylene, pyrrolidin-1-yl-carbonylmethylene, piperidin-1-ylcarbonylmethylene or homopiperidin-1-ylcarbonylmethylene;
aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C
1-4
alkyl, C
3-7
cyclo-alkyl, C
1-4
alkyloxy, formyl, polyhaloC
1-4
alkyl, NR
9
R
10
, C(═O)NR
9
R
10
, C(═O)—O—R
14
, R
6
, —O—R
6
, phenyl, Het
3
, C(═O)Het
3
and C
1-4
alkyl substituted with hydroxy, C
1-4
alkyloxy, C(═O)—O—R
14
, —Y—C
1-4
alkanediyl-C(═O)—O—R
14
, Het
3
or NR
9
R
10
;
Het
1
represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl

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