IL-5 inhibiting 6-azauracil derivatives Number:6,894,046 from the United States Patent and Trademark Office (PTO) owispatent The present invention is concerned with the compounds of formula ##STR1## the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p is 0 to 4; X is O, S, NR5 or a direct bond; Y is O, S, NR5 or S(O)2; R1 independently is C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or substituted C1-4alkyl; R2 is Het1, C3-7cycloalkyl or optionally substituted C1-6alkyl and if X is O, S or NR5, then R2 may also represent aminocarbonyl, aminothiocarbonyl, C1-4alkylcarbonyl, C1-4alkylthiocarbonyl, arylcarbonyl, arylthiocarbonyl, Het1carbonyl or Het1thiocarbonyl; R3 and R4 independently are hydrogen, C1-6alkyl or C3-7cycloalkyl; R3 and R4 form a C2-6alkanediyl; R5 is hydrogen or C1-4alkyl; R6 is a sulfonyl or sulfinyl derivative; R7 and R8 are independently hydrogen, optionally substituted C1-4alkyl, aryl, a carbonyl containing moiety, C3-7cycloalkyl, —Y—C1-4alkanediyl-C(═O)—O—R14, Het3, Het4 and R6; R11 is hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C1-4alkyloxy, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(═O)NR7R8, C1-4alkanediyl-C(═O)—O derivatives, inhibiting, IL, 5, inhibiting, 6, azauracil, derivativ, 6894046.html, Patent, pto, 6894046

Title: IL-5 inhibiting 6-azauracil derivatives

Abstract: The present invention is concerned with the compounds of formula ##STR1##
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p is 0 to 4; X is O, S, NR⁵or a direct bond; Y is O, S, NR⁵or S(O)₂; R¹independently is C_1-6alkyl, halo, polyhaloC_1-6alkyl, hydroxy, mercapto, C_1-6alkyloxy, C_1-6alkylthio, C_1-6alkylcarbonyloxy, aryl, cyano, nitro, Het³, R⁶, NR⁷R⁸or substituted C_1-4alkyl; R²is Het¹, C_3-7cycloalkyl or optionally substituted C_1-6alkyl and if X is O, S or NR⁵, then R²may also represent aminocarbonyl, aminothiocarbonyl, C_1-4alkylcarbonyl, C_1-4alkylthiocarbonyl, arylcarbonyl, arylthiocarbonyl, Het¹carbonyl or Het¹thiocarbonyl; R³and R⁴independently are hydrogen, C_1-6alkyl or C_3-7cycloalkyl; R³and R⁴form a C_2-6alkanediyl; R⁵is hydrogen or C_1-4alkyl; R⁶is a sulfonyl or sulfinyl derivative; R⁷and R⁸are independently hydrogen, optionally substituted C_1-4alkyl, aryl, a carbonyl containing moiety, C_3-7cycloalkyl, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶; R¹¹is hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C_1-4alkyloxy, formyl, trihaloC_1-4alkylsulfonyloxy, R⁶, NR⁷R⁸, C(═O)NR⁷R⁸, C_1-4alkanediyl-C(═O)—O

Patent Number: 6,894,046 Issued on 05/17/2005 to Freyne, et al.

Inventors: Freyne; Eddy Jean Edgard (Rumst, BE); Lacrampe; Jean Fernand Armand (Le Mesnil-Esnard, FR); Deroose; Frederik Dirk (Drongen, BE); Venet; Marc Gaston (Le Mesnil-Esnard, FR)

Assignee: Janssen Pharmaceutica N.V. (BE)

Appl. No.: 812731

Filed: March 19, 2001

Foreign Application Priority Data

Sep 18, 1998[EP]

98203148

Current U.S. Class: 514/242; 514/227.8; 514/236.2; 544/58.6; 544/112; 544/182

Intern'l Class: A61K 031/53; C07D253/07

Field of Search: 544/182,112,586 514/242,236.2,227.8

References Cited [Referenced By]

U.S. Patent Documents

4631278	Dec., 1986	Boeckx et al.
4767760	Aug., 1988	Boeckx et al.
Foreign Patent Documents
0170316	Feb., 1986	EP.
0232932	Aug., 1987	EP.
0737672	Oct., 1996	EP.
0831088	Mar., 1998	EP.
WO 9902504	Jan., 1999	WO.
WO 9902505	Jan., 1999	WO.
WO 0017195	Mar., 2000	WO.

Other References

Miller et al., Chemical Abstracts, vol. 92:51708 (1980).*
Miller, My;Lari, Howes, Jr., Lynch, Lynch, Koch, Anticoccidial Derivatives of 6-Azauracil, 2, High Potency and Long Plasma Life of N1-Phenyl Structures, Journal of Medicinal Chemistry, Pfizer Medical Research Laboratories, Groton, CT, 1979, vol. 22, No. 12, 1483-1487.
PCT International Search Report dated Jan. 19, 2000 for PCT Appln. No. PCT/EP99/06776 which relates to U.S. Patent Appln. No. 09/812,731.
Castro, et al., "Reactifs De Couplage Pepidique IV (1)-L′Hexafluorophosphate De Benzotriazolyl N-Oxytrusdimethylamino Phosphonium (B.O.P)." Tetrahedron Letters, 1975, pp. 1219-1222, No. 14.
Baggiolini, et al., "CC Chemokines in Allergic Inflammation." Immunology Today, 1994, pp. 127-133, vol. 15, No. 3.
Carr et al., "Monocyte Chemoattractant Protein 1 Acts As A T-Lymphocyte Chemoattractant." Proc. Natl. Acad. Sci., USA, Immunology, 1994, pp. 3652-3656, vol. 91.

Primary Examiner: Raymond; Richard L.
Attorney, Agent or Firm: Lopez; Gabriel, Kriegeman; Alana G.

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of PCT/EP99/06776, filed Sep. 14, 1999 which application claims priority from EP 98203148.6, filed Sep. 18, 1998.

Claims

1. A compound having the formula ##STR71##

a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:

p represents an integer being 0, 1, 2, 3 or 4;

X represents O, S, NR⁵or a direct bond;

Y represents O, S, NR⁵, or S(O)₂;

each R¹independently represents C_1-6alkyl, halo, polyhaloC_1-6alkyl, hydroxy, mercapto, C_1-6alkyloxy, C_1-6alkylthio, C_1-6alkylcarbonyloxy, aryl, cyano, nitro, Het³, R⁶, NR⁷R⁸or C_1-4alkyl substituted with Het³, R⁶or NR⁷R⁸;

R²represents Het¹or C_1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C_1-4alkyl)amino, C_1-6alkyloxy, C_1-6alkylsulfonyloxy, C_1-6alkyloxycarbonyl, C_3-7cycloalkyl, aryl, aryloxy, arylthio, Het¹, Het¹oxy, and Het¹thio; and if X is O, S or NR⁵, then R²may also represent aminocarbonyl, aminothiocarbonyl, C_1-4alkylcarbonyl, C_1-4alkylthiocarbonyl, arylcarbonyl, arylthiocarbonyl, Het¹carbonyl or Het¹thiocarbonyl;

R³represents hydrogen, C_1-6alkyl or C_3-7cycloalkyl;

R⁴represents hydrogen, C_1-6alkyl or C_3-7cycloalkyl; or

R³and R⁴taken together form a C_2-6alkanediyl;

R⁵represents hydrogen or C_1-4alkyl;

each R⁶independently represents C_1-6alkylsulfonyl, aminosulfonyl, mono- or di(C_1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC_1-6alkylsulfonyl, C_1-6alkylsulfinyl, phenylC_1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C_1-4alkyl-N-piperidinylaminosulfonyl or mono-or di(C_1-4alkyl)aminoC_1-4alkylsulfonyl;

each R⁷and each R⁸are independently selected from the group consisting of: hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, aryl, arylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, arylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxy-C_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶;

R⁹and R¹⁰are each independently selected from the group consisting of: hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, phenyl, phenylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxyC_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶;

each R¹¹independently being selected from the group consisting of: hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C_1-4alkyloxy, formyl, trihaloC_1-4alkylsulfonyloxy, R⁶, NR⁷R⁸, C(═O)NR⁷R⁸, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, aryl, aryloxy, arylcarbonyl, C_3-7cycloalkyl, C_3-7cycloalkyloxy, phthalimide-2-yl, Het³and C(═O)Het³;

R¹²and R¹³are each independently selected from the group consisting of: hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, phenyl, phenylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, phenylcarbonyl, C_1-4alkylcarbonyloxyC_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴and R⁶;

each R¹⁴independently represents hydrogen, C_1-4alkyl, C_3-7cycloalkyl, aminocarbonylmethylene or mono-or di(C_1-4alkyl)aminocarbonylmethylene;

aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C_1-4alkyl, C_3-7cycloalkyl, C_1-4alkyloxy, formyl, polyhaloC_1-4alkyl, NR⁹R¹⁰, C(═O)NR⁹R¹⁰, C(═O)—O—R¹⁴, R⁶, —O—R⁶, phenyl, Het³, C(═O)Het³and C_1-4alkyl substituted with hydroxy, C_1-4alkyloxy, C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³or NR⁹R¹⁰;

Het¹represents a heterocycle selected from the group consisting of: 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, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with one or two substituents independently selected from Het²and R¹¹; provided Het¹is other than 2-substituted-pyridin-5-yl;

Het²represents a heterocycle selected from the group consisting of: 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, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het⁴, R¹¹and C_1-4alkyl optionally substituted with one or two substituents independently selected from Het⁴and R¹¹;

Het³represents a monocyclic heterocycle selected from the group consisting of: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C_1-4alkyl, C_1-4alkyloxy, C_1-4alkylcarbonyl, piperidinyl, NR¹²R¹³, C(═O)—O—R¹⁴, R⁶and C_1-4alkyl substituted with one or two substituents independently selected from hydroxy, C_1-4alkyloxy, phenyl, C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, R⁶and NR¹²R¹³;

Het⁴represents a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl.

2. A compound as claimed in claim 1 wherein:

each R⁷and each R⁸are independently selected from the group consisting of: hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, aryl, arylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, arylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxy-C_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³and R⁶;

R⁹and R¹⁰are each independently selected from the group consisting of: hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, phenyl, phenylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het³carbonyl, C_1-4alkycarbonyloxyC_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³and R⁶;

R¹¹is being selected from the group consisting of: hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C_1-4alkyloxy, formyl, trihaloC_1-4alkylsulfonyloxy, R⁶, NR⁷R⁸, C(═O)NR⁷R⁸, —C(═O)—O—R¹⁴, aryl, aryloxy, arylcarbonyl, C_3-7cycloalkyl, C_3-7cycloalkyloxy, phthalimide-2-yl, Het³, Het⁴and C(═O)Het³; and

Het²represents a heterocycle selected from the group consisting of: 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, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R¹¹and C_1-4alkyl optionally substituted with one or two substituents independently selected from R¹¹.

3. A compound of the formula:

2-[3,5-dichloro-4-[1-methyl-1-(4-phenyl-2-thiazolyl)ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-[4-(3-chlorophenyl)-5-methyl-2-thiazolyl]-1-methylethyl]-phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl]-1,2,4-triazine-3,5(2H,4)-dione;

2-[3,5-dichloro-4-[1-(4,5-diphenyl-2-thiazolyl)-1-methylethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl]-phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-(4-methyl-5-phenyl-2-thiazolyl)ethyl]phenyl]-1,2,4-triazine-3,5(2H,4)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[4-phenyl-5-(3-pyridinyl)-2-thiazolyl]ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[4-phenyl-5-(phenylmethyl)-2-thiazolyl]ethyl]-phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl]ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[4-(3-thienyl)-2-thiazolyl]ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-4-(2-furanyl)-2-thiazolyl]-1-methylethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[5-(3-pyridinyl)-1,2,4-oxadiazol-3-yl]ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione;

2-[3,5-dichloro-4-[1-methyl-1-[5-(2-methyl-3-pyridinyl)-1,2,4-oxadiazol-3-yl]ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; or

2-[3,5-dichloro-4-[1-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)dione; or a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

4. A compound as claimed in claim 1 provided that in those compounds wherein X is a direct bond, at least one of R³and R⁴is hydrogen, and R²is 3-pyridinyl optionally substituted in the 6 position with an optionally substituted alkyl or acyl group are excluded.

5. A compound as claimed in claim 2 provided that in those compounds wherein X is a direct bond, at least one of R³and R⁴is hydrogen, and R²is 3-pyridinyl optionally substituted in the 6 position with an optionally substituted alkyl or acyl group re excluded.

6. A compound as claimed in claim 1 wherein the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

7. A compound as claimed in claim 2 wherein the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

8. A compound as claimed in claim 4 wherein the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

9. A compound as claimed in claim 5 wherein the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

10. A compound as claimed in claim 1 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently elected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

11. A compound as claimed in claim 2 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

12. A compound as claimed in claim 4 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

13. A compound as claimed in claim 5 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently elected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

14. A compound as claimed in claim 6 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently elected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

15. A compound as claimed in claim 7 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

16. A compound as claimed in claim 8 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

17. A compound as claimed in claim 9, wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently elected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

18. A compound as claimed in claim 1 wherein R³and R⁴are both methyl and —X—R²is Het¹.

19. A compound as claimed in claim 2 wherein R³and R⁴are both methyl and —X—R²is Het¹.

20. A compound as claimed in claim 4 wherein R³and R⁴are both methyl and —X—R²is Het¹.

21. A compound as claimed in claim 5 wherein R³and R⁴are both methyl and —X—R²is Het¹.

22. A compound as claimed in claim 6 wherein R³and R⁴are both methyl and —X—R²is Het¹.

23. A compound as claimed in claim 7 wherein R³and R⁴are both methyl and —X—R²is Het¹.

24. A compound as claimed in claim 8 wherein R³and R⁴are both methyl and —X—R²is Het¹.

25. A compound as claimed in claim 9 wherein R³and R⁴are both methyl and —X—R²is Het¹.

26. A compound as claimed in claim 10 wherein R³and R⁴are both methyl and —X—R²is Het¹.

27. A compound as claimed in claim 11 wherein R³and R⁴are both methyl and —X—R²is Het¹.

28. A compound as claimed in claim 12 wherein R³and R⁴are both methyl and —X—R²is Het¹.

29. A compound as claimed in claim 13 wherein R³and R⁴are both methyl and —X—R²is Het¹.

30. A compound as claimed in claim 14 wherein R³and R⁴are both methyl and —X—R²is Het¹.

31. A compound as claimed in claim 15 wherein R³and R⁴are both methyl and —X—R²is Het¹.

32. A compound as claimed in claim 16 wherein R³and R⁴are both methyl and —X—R²is Het¹.

33. A compound as claimed in claim 17 wherein R³and R⁴are both methyl and —X—R²is Het¹.

34. A compound as claimed in claim 1 wherein p is 1 or 2 and each R¹is chloro.

35. A compound as claimed in claim 2 wherein p is 1 or 2 and each R¹is chloro.

36. A compound as claimed in claim 4 wherein p is 1 or 2 and each R¹is chloro.

37. A compound as claimed in claim 5 wherein p is 1 or 2 and each R¹is chloro.

38. A compound as claimed in claim 6 wherein p is 1 or 2 and each R¹is chloro.

39. A compound as claimed in claim 7 wherein p is 1 or 2 and each R¹is chloro.

40. A compound as claimed in claim 8 wherein p is 1 or 2 and each R¹is chloro.

41. A compound as claimed in claim 9 wherein p is 1 or 2 and each R¹is chloro.

42. A compound as claimed in claim 10 wherein p is 1 or 2 and each R¹is chloro.

43. A compound as claimed in claim 11 wherein p is 1 or 2 and each R¹is chloro.

44. A compound as claimed in claim 12 wherein p is 1 or 2 and each R¹is chloro.

45. A compound as claimed in claim 13 wherein p is 1 or 2 and each R¹is chloro.

46. A compound as claimed in claim 14 wherein p is 1 or 2 and each R¹is chloro.

47. A compound as claimed in claim 15 wherein p is 1 or 2 and each R¹is chloro.

48. A compound as claimed in claim 16 wherein p is 1 or 2 and each R¹is chloro.

49. A compound as claimed in claim 15 wherein p is 1 or 2 and each R¹is chloro.

50. A compound as claimed in claim 1 wherein R³and R⁴are both methyl, —X—R²is optionally substituted 2-thiazolyl or 3-oxadiazolyl, the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents, and p is 2 whereby both R¹substituents are chloro positioned ortho relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

51. A compound as claimed in claim 2 wherein R³and R⁴are both methyl, —X—R²is optionally substituted 2-thiazolyl or 3-oxadiazolyl, the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents, and p is 2 whereby both R¹substituents are chloro positioned ortho relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

52. A compound having the formula ##STR72##

a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:

p represents an integer being 0, 1 or 2;

X represents O, S, NR⁵or direct bond;

Y represents O, S, NR⁵, or S(O)₂;

each R¹independently represents chloro or trifluoromethyl;

R²represents Het¹or C_1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C_1-4alkyl)amino, C_1-6alkyloxy, C_1-6alkylsulfonyloxy, C_1-6alkyloxycarbonyl, C_3-7cycloalkyl, aryl, aryloxy, arylthio, Het¹, Het¹oxy and Het¹thio; and if X is O, S or NR⁵, then R²may also represent aminocarbonyl, aminothiocarbonyl, C_1-4alkylcarbonyl, C_1-4alkylthiocarbonyl, arylcarbonyl, arylthiocarbonyl, Het¹carbonyl or Het¹thiocarbonyl;

R³represents hydrogen, C_1-6alkyl or C_3-7cycloalkyl;

R⁴represents hydrogen, C_1-6alkyl or C_3-7cycloalkyl; or R³and R⁴taken together form a C_2-6alkanediyl;

R⁵represents hydrogen or C_1-4alkyl;

each R⁶independently represents C_1-6alkylsulfonyl, aminosulfonyl, mono- or di(C_1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC_1-6alkylsulfonyl, C_1-6alkylsulfinyl, phenylC_1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C_1-4alkyl-N-piperidinylaminosulfonyl or mono-or di(C_1-4alkyl)aminoC_1-4alkylsulfonyl;

each R⁷and each R⁸are independently selected from hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, aryl arylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, arylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxy-C_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶;

R⁹and R¹⁰are each independently selected from hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, phenyl, phenylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxyC_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶;

each R¹¹independently being selected from hydroxy, cyano, nitro, halo, C_1-4alkyloxy, formyl, NR⁷R⁸, C(═O) NR⁷R⁸, —C(═O)—O—R¹⁴, aryl, arylcarbonyl, Het³and C(═O)Het³;

each R¹⁴independently represents hydrogen, C_1-4alkyl, C_3-7cycloalkyl, aminocarbonylmethylene or mono-or di(C_1-4alkyl)aminocarbonylmethylene;

aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C_1-4alkyl, C_3-7cycloalkyl, C_1-4alkyloxy, formyl, polyhaloC_1-4alkyl, NR⁹R¹⁰, C(═O)NR⁹R¹⁰, C(═O)—O—R¹⁴, R⁶, —O—R⁶phenyl, Het³, C(═O)Het³and C_1-4alkyl substituted with hydroxy, C_1-4alkyloxy, C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³or NR⁹R¹⁰;

Het¹represents a heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹; provided Het¹is other than 2-substituted-pyridin-5-yl;

Het²represents a heterocycle selected from furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het⁴, R¹¹and C_1-4alkyl optionally substituted with R¹¹;

Het³represents a monocyclic heterocycle selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C_1-4alkyl, C(═O)—O—R¹⁴, C_1-4alkylcarbonyl, R⁶, piperidinyl and C_1-4alkyl substituted with one or two substituents independently selected from hydroxy, C_1-4alkyloxy, C(═O)—O—R¹⁴and phenyl;

Het⁴represents a monocyclic heterocycle selected from thienyl or pyridinyl.

53. A compound a claimed in claim 52, wherein when X is a direct bond, at least one of R³and R⁴is hydrogen, and R²is 3-pyridinyl, then R²is not substituted in the 6 position with an optionally substituted alkyl or acyl group.

54. A compound a claimed in claim 52 wherein the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

55. A compound claimed in claim 52 wherein R²is a monocyclic heterocycle selected from the group consisting of: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with Het²or R¹¹.

56. A compound a claimed in claim 52 wherein R³and R⁴are both methyl and —X—R²is Het¹.

57. A compound a claimed in claim 52 wherein p is 1 or 2 and each R¹is chloro.

58. A compound a claimed in claim 52 wherein R³and R⁴are both methyl, —X—R²is optionally substituted 2-thiazolyl or 3-oxadiazolyl, the 6-azauracil moiety is in the para position relative to the carbon atom bearing the —X—R², R³and R⁴substituents, and p is 2 whereby both R¹substituents are chloro positioned ortho relative to the carbon atom bearing the —X—R², R³and R⁴substituents.

59. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim 1.

Description

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 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 α-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazine-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 and EP 737,672 discloses a method of preparing such compounds. Miller et al. (J. Med. Chem., 1979, 22(12), p1483-1487) disclose anticoccidial derivatives of 6-azauracil.

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 ##STR2##
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;
X represents O, S, NR⁵or a direct bond;
Y represents O, S, NR⁵, or S(O)₂;
each R¹independently represents C_1-6alkyl, halo, polyhaloC_1-6alkyl, hydroxy, mercapto, C_1-6alkyloxy, C_1-6alkylthio, C_1-6alkylcarbonyloxy, aryl, cyano, nitro, Het³, R⁶, NR⁷R⁸or C_1-4alkyl substituted with Het³, R⁶or NR⁷R⁸;
R²represents Het¹, C_3-7cycloalkyl, C_1-6alkyl or C_1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C_1-4alkyl)amino, C_1-6alkyloxy, C_1-6alkylsulfonyloxy, C_1-6alkyloxycarbonyl, C_3-7cycloalkyl, aryl, aryloxy, arylthio, Het¹, Het¹oxy and Het¹thio; and if X is O, S or NR⁵, then R²may also represent aminocarbonyl, aminothiocarbonyl, C_1-4alkylcarbonyl, C_1-4alkylthio-carbonyl, arylcarbonyl, arylthiocarbonyl, Het¹carbonyl or Het¹thiocarbonyl;
R³represents hydrogen, C_1-6alkyl or C_3-7Cycloalkyl;
R⁴represents hydrogen, C_1-6alkyl or C_3-7cycloalkyl; or
R³and R⁴taken together form a C_2-6alkanediyl;
R⁵represents hydrogen or C_1-4alkyl;
each R⁶independently represents C_1-6alkylsulfonyl, aminosulfonyl, mono- or di-(C_1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhalo-C_1-6alkylsulfonyl, C_1-6alkylsulfinyl, phenylC_1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C_1-4alkyl-N-piperidinylamino-sulfonyl or mono- or di(C_1-4alkyl)aminoC_1-4alkylsulfonyl;
each R⁷and each R⁸are independently selected from hydrogen, C_1-4alkyl, hydroxy-C_1-4alkyl, dihydroxyC_1-4alkyl, aryl, arylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkyl-carbonyl, aminocarbonyl, arylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxy-C_1-4alkyl-carbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het³amino-carbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶;
R⁹and R¹⁰are each independently selected from hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, phenyl, phenylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het³carbonyl, C_1-4alkylcarbonyloxyC_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)-aminoC_1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het³aminocarbonyl, Het³aminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³, Het⁴and R⁶;
each R¹¹independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C_1-4alkyloxy, formyl, trihaloC_1-4alkylsulfonyloxy, R⁶, NR⁷R⁸, C(═O)NR⁷R⁸, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, aryl, aryloxy, arylcarbonyl, C_3-7cycloalkyl, C_3-7cycloalkyloxy, phthalimide-2-yl, Het³and C(═O)Het³;
R¹²and R¹³are each independently selected from hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl, dihydroxyC_1-4alkyl, phenyl, phenylC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, C_1-4alkylcarbonyl, phenylcarbonyl, C_1-4alkylcarbonyloxyC_1-4alkylcarbonyl, hydroxyC_1-4alkylcarbonyl, C_1-4alkyloxycarbonylcarbonyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, phenylamino-carbonyl, carbonyl, phenylaminothiocarbonyl, C_3-7cycloalkyl, pyridinylC_1-4alkyl, C_1-4alkanediyl-C(═O)—O—R¹⁴, —C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴and R⁶;
each R¹⁴independently represents hydrogen, C_1-4alkyl, C_3-7cycloalkyl, aminocarbonylmethylene or mono- or di(C_1-4alkyl)aminocarbonylmethylene;
aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C_1-4alkyl, C_3-7cycloalkyl, C_1-4alkyloxy, formyl, polyhaloC_1-4alkyl, NR⁹R¹⁰, C(═O)NR⁹R¹⁰, C(═O)—O—R¹⁴, R⁶, —O—R⁶, phenyl, Het³, C(═O)Het³and C_1-4alkyl substituted with hydroxy, C_1-4alkyloxy, C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, Het³or NR⁹R¹⁰;
Het¹represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thioxanyl, 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, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het², R¹¹and C_1-4alkyl optionally substituted with one or two substituents independently selected from Het²and R¹¹;
Het²represents 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, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het⁴, R¹¹and C_1-4alkyl optionally substituted with one or two substituents independently selected from Het⁴and R¹¹;
Het³represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C_1-4alkyl, C_1-4alkyloxy, C_1-4alkylcarbonyl, piperidinyl, NR¹²R¹³, C(═O)—O—R¹⁴, R⁶and C_1-4alkyl substituted with one or two substituents independently selected from hydroxy, C_1-4alkyloxy, phenyl, C(═O)—O—R¹⁴, —Y—C_1-4alkanediyl-C(═O)—O—R¹⁴, R⁶and NR¹²R¹³;
Het⁴represents a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl.

As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C_3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C_1-4alkyl 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_1-6alkyl is meant to include C_1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; polyhaloC_1-4alkyl is defined as polyhalosubstituted C_1-4alkyl, in particular C_1-4alkyl substituted with 1 to 6 halogen atoms, more in particular bromomethyl, chloromethyl, difluoro- or trifluoromethyl; polyhaloC_1-6alkyl is defined as polyhalosubstituted C_1-6alkyl. The term C_1-4alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like: C_2-6alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 2 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like.

Het¹, Het², Het³and Het⁴are meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het¹, Het², Het³and Het⁴, for instance, pyrtolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.

The heterocycles represented by Het¹, Het², Het³and Het⁴may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl.

The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzene-sulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. For example, one or more nitrogen atoms of any of the heterocycles in the definition of Het¹, Het²and Het³may be N-oxidized.

Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, a hydroxy substituted triazine moiety may also exist as the corresponding triazinone; a hydroxy substituted pyrimidine moiety may also exist as the corresponding pyrimidinone.

The term "stereochemically isomeric forms" as used hereinbefore defines all t