MXPA01006154A - Il-5 inhibiting 6-azauracil derivatives - Google Patents

Il-5 inhibiting 6-azauracil derivatives

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Publication number
MXPA01006154A
MXPA01006154A MXPA/A/2001/006154A MXPA01006154A MXPA01006154A MX PA01006154 A MXPA01006154 A MX PA01006154A MX PA01006154 A MXPA01006154 A MX PA01006154A MX PA01006154 A MXPA01006154 A MX PA01006154A
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Mexico
Prior art keywords
alkyl
formula
optionally substituted
het3
substituted
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MXPA/A/2001/006154A
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Spanish (es)
Inventor
Jean Edgard Freyne Eddy
Fernand Armand Lacrampe Jean
Dirk Deroose Frederik
Constant Johan Embrechts Werner
Michel Claude Fortin Jerome
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Janssen Pharmaceutica Nv*
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Publication of MXPA01006154A publication Critical patent/MXPA01006154A/en

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Abstract

The present invention is concerned with the compounds of formula (I), a i(N)-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein p is 0 to 4;q is 0 to 5;X is O, S, NR3 or a direct bond;or -X-R2 is CN;R1 is H, OH, halo, NH2, mono- or di(C1-4alkyl)NH2, C1-6alkyl, C1-6alkylO, C3-7cycloalkyl, aryl, arylC1-6alkyl, NH2C1-4alkyl, mono- or di(C1-4alkyl)NH2C1-4alkyl or mono- or di(C1-4alkyl)NH2C1-4alkylNH2;R2 is aryl, Het1, optionally substituted C3-7cycloalkyl, optionally substituted C1-6alkyl;R3 is H or C1-4alkyl;R4 and R5 are -C(=O)-Z-R14, C1-6alkyl, halo, polyhaloC1-6alkyl, OH, mercapto, C1-6alkylO, C1-6alkylthio, C1-6alkylC(=O)O, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with -C(=O)-Z-R14, Het3, R6 or NR7R8;Z is O, S, NH, -CH2-O- or -CH2-S-;R14 is H, C1-20acyl, optionally substituted C1-20alkyl, optionally substituted C3-20alkenyl, C3-20alkynyl, C3-7cycloalkyl, polyhaloC1-20alkyl, Het5, phenyl;or R14 is an oxygen containing radical;aryl is optionally substituted phenyl;Het1, Het2, Het3 and Het5 are optionally substituted heterocycles;Het4 is a monocyclic heterocycle;provided however that R2 is other than NH2C(=O), C1-6alkylOC(=O)C1-6alkyl;and R11 is other than COOH, C1-4alkylOC(=O), NH2C(=O), C1-4alkylNH2C(=O), OHC1-4alkylNH2C(=O), C1-4alkylC(=O)NH2C(=O), C3-7cycloalkylNH2C(=O);and R7, R8, R9, R10, R12, R13, R15 and R16 are other than C1-4alkylC(=O)OC1-4alkylC(=O), OHC1-4alkylC(=O);and Het3 is other than a monocyclic heterocycle susbstituted with COOH or C1-4alkylOC(=O);and the compounds of formula (I) contain at least one -C(=O)-Z-R14 moiety;to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.

Description

DERIVATIVES OF 6-AZAURACILO IL-5 INHIBITORS DESCRIPTIVE MEMORY The present invention relates to new IL-5 inhibitor 6-azauracil derivatives useful for treating inflammatory diseases dependent on eosinophil; to the procedures for their preparation and to the compositions comprising them. In addition, it refers to its use as a medicine. The eosinophilic influx, which produces subsequent damage to the tissue, is an important pathogenic event in bronchial asthma and allergic diseases. Cytokine interleukin-5 (L-5), produced mainly by lymphocytes t as a glycoprotein, induces the differentiation of eosinophils in the bone marrow and prepares eosinophils for activation in the peripheral blood and maintains their survival in the tissues . As such, IL-5 plays a major role in the eosinophilic inflammation procedure. Therefore, the possibility that inhibitors of IL-5 production reduce the production, activation and / or survival of eosinophils provides a therapeutic approach for the treatment of bronchial asthma and allergic diseases such as, for example, atopic dermatitis, allergic rhinitis , allergic conjunctivitis and also other inflammatory diseases dependent on eosinophil.
Steroids, which strongly inhibit the production of IL-5 in vitro, have been used as the only drugs that have outstanding efficacy for bronchial asthma and atopic dermatitis, but cause several serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be convenient to find non-steroidal compounds which have the ability to inhibit the production of IL-5 in human T cells and which have little or no adverse reaction. U.S. Patent No. 4,631,278 describes a-aryl-4- (4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 (3H) -yl) benzeneacetonitriles and US Patent No. 4,767,760 describes the 2- (substituted phenyl) -1, 2,4-triazine-3,5 (2H, 4H) -diones, all have an anti-protozoal activity, in particular, an anticoccidial activity . EP 831,088 discloses 1, 2,4-triazine-3,5-diones as anti-coccidial agents. The present invention provides compounds that have been described and that possess a prominent pharmacological activity as inhibitors of II-5 production. The present invention relates to the compounds of the formula: The N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and their stereochemically isomeric forms, wherein: p represents an integer that is 0, 1, 2, 3 or 4; q represents an integer that is 0, 1, 2, 3, 4, or 5; X represents O, S, NR3 or a direct link; or -X-R2 taken together may present cyano; R1 represents hydrogen, hydroxy, halo, amino, mono- or di (alkyl (CM) amino, alkyl C-? 6, alkyloxy Ci-e, cycloalkyl C3-, aryl, arylalkyl Cie), aminoalkyl C? -, mono or di (C 1-4 alkyl, mono or di (alkyl CM) aminoalkyl CM or mono-di (C 1-4 alkyl) amino-C 1-4 alkylamino, R 2 represents aryl, Het 1, C 3-7 cycloalkyl optionally substituted with -C (= 0) -Z-R14, C1-6alkyl or Ci-βalkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono or di (alkylC-?) Amino, -C (= O) -Z -R 14, C 1-6 alkyloxy, optionally substituted with -C (= O) -ZR 4, C 1-6 alkylsulfonyloxy, C 3-7 cycloalkyl optionally substituted with -C (= 0) -Z-R 14, aryl, aryloxy, arylthio, Het1, Het1oxi and Het1tio, and if X is O, S or NR3, then R2 can also represent -C (= 0) -Z-R14, aminothiocarbonium, C? -4 alkylcarbonyl optionally substituted with -C (= O) -Z -R 14, C 1-4 alkylthiocarbonyl optionally substituted with -C (= O) -Z-R 14, arylcarbonyl, aryllocarbonyl, Hetlcarbonyl or Het 1-thiocarbonyl; R3 represents hydrogen or C1-4 alkyl: Each R4 independently represents -C (= 0) -Z-R14, C-? -6 alkyl, halo, C-16 polyahaloalkyl, hydroxy, mercapto, C1-6 alkyloxy, C-16 alkylthio, C6-alkylcarbonyloxy, aryl , cyano, nitro, Het3, R6, NR7R8 or C1-4 alkyl substituted with -C (= O) -Z-R14, Het3, R6 or NR7R8; Each R5 independently represents -C (= 0) -Z-R14, alkyl C 1-6, halo, polyahaloalkyl Cie, 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-R14, Het3, R6 or NR7R8; Each R 6 independently represents C 1-6 alkylsulfonyl, aminosulfonyl, mono- or di- (C 1-4 alkyl) aminosulfonyl, mono- or di (benzyl) aminosulfonyl, polyahaloalkyl Ci-e-sulfonyl, alkylsulfinyl C 1-6, phenylalkylsulfonyl CM, piperazinylsulfonyl, piperidinyl-sulfonyl, aminopiperidinylsulfonyl, piperidinaminosulfonyl, N-C 1-4 alkyl-N-piperidinylaminosulfonyl or mono- or di (C 1-4 alkyl) amino-C 1-4 alkylsulfonyl; Each R7 and R8 is independently selected from hydrogen, C1-4alkylhydroxylalkyl C-, dihydroxyC1-4alkyl, aryl, arylalkylC1-4alkyl, alkyloxyCalkylC4alkylcarbonyl, arylcarbonyl, Het3carbonyl, -C (= O ) -Z-R14, mono-di (C 1 -alkylamino-C-alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het 3 -aminocarbonyl, Het 3 amino-ticarbonyl, C 3 -cycloalkyl, pyridinylalkyl-CM, alkanediyl-Y-alkanediyl-4-C (= 0) -Z-R14, Het3 and R6, or R7 and R8 taken together with the nitrogen atom to which they are attached form a radical of the formula R 9 and R 10 are independently selected from hydrogen, C-alkyl, C 4 -hydroxylalkyl, C 14 -hydroxylalkyl, phenyl, phenylalkyl, C-alkyloxy C-alkyl, CM-alkylcarbonyl, phenylcarbonyl, Het-3-carbonyl, -C (-O) -Z- R14, mono- or di (alkylC? _) AminoalkylCM, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3aminocarbonium, Het'aminocarbonyl, cycloalkyl C3- > pyridinylalkyl CM, alkanediyl CM-C (= O) -R14, -Y-alkanediyl CM-C (= 0) -Z-R14, Het3 and R6; or R9 and R0 taken together form the nitrogen atom to which they are attached form a radical of the formula: Each R 11 is independently selected from hydroxy, mercapto, cyano, nitro, halo, C (= 0) -Z-R 14 -Y-alkanediyl CM-C (= O) -Z-R 14, trihalomethyl, alkyloxy CM, optionally substituted with - C (= O) -Z-R14, formium, trihaloalkyl C-suifonyloxy, R6, NR7R8, C (= 0) NR15R16, aryl, aryloxy, arylcarbonyl, cycloalkyl3- optionally substituted with -C (= O) -ZR4, cycloalkyloxyC3 optionally substituted with -C (= 0) -Z-R14, phthalimide-2-yl, Het3, Het4 and C (= O) Het3; R12 and R13 are independently selected from hydrogen, CM alkyl, CM hydroxylalkyl, CM dihydroxylalkyl, phenyl, phenylalkyl CM, alkyloxy CM alkyl CM, alkylcarbonyl CM, phenylcarbonyl, -C (= 0) -Z-R14, mono- or di (alkyl) CM) aminoalkyl CM, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7 cycloalkyl, pyridinylalkyl C? -4 > alkanediyl CM-C (= 0) -Z-R14, -Y-alkanediyl C? -4-C (= O) -Z-R14 and R6; or R9 and R10 taken together with the nitrogen atom to which it is attached forms a radical of the formula: each Z independently represents O, S; NH, -CH2-0- or -CH2-S- where -CH2- is attached to the carbonyl group; each R14 independently represents hydrogen, C? -2 aco acyl (having a straight or branched hydrocarbon chain saturated or unsaturated with 1 to 20 carbon atoms), C? -2o alkyl, C3-2 alkenyl optionally substituted with phenyl, C3-20 alkynyl, C3-7 cycloalkyl, polyhaloalkyl C-γ-2o, Het5, phenyl or C---2o alkyl substituted with one or more substituents selected from hydroxy, NR17, R18, phenyl, mono- or di (C1-alkyl) -4) amino, cyano, Het5, alkyloxycarbonyl CM, phenylalkyl CM oxycarbonyl, and C3-7 cycloalkyl; or R14 represents a radical of the formula: (r) (s) (e) wherein n is 0 to 5; m is 1 to 4; s is zero to 4; r is 0 to 2; Ra, Rb, Rc, Rd Rβ and Rf are each independently hydrogen, C 1 -β alkyl, phenyl or C 3-7 cycloalkyl; or Ra and Rf taken together can form -CH2CH2-, CH2-CH2-CH2-0-CH2-CH2-CH2-CH2; R9, Rh and Rk are each independently hydrogen or C? -4 alkyl; Each R1 independently is alkyl CM; R 'is -0-Rb, C-? 6 alkyl, phenyl or C3-7 cycloalkyl, optionally substituted with alkyloxy CM; Rn is hydrogen, alkyl CM, phenyl, phenylalkyl CM, O cycloalkyl C3-7; Rm is hydrogen or C? -4 alkoxy; or -Z-R 4 taken together form a radical of the formula: (f) (g) R15 and R16 each, independently, are selected from hydrogen, alkyl CM; hydroxyalkyl CM, aryl, arylalkyl CM, alkyloxy C alkyl CM, -C (= O) -Z-R14, arylcarbonyl, mono- or di- (alkyl C? -) amino-alkyl CM, arylaminocarbonyl, arylaminothiocarbonyl, aminocarbonylmethylene, mono- or di (C14 alkyl-, arylaminocarbonyl, arylaminthiocarbonyl, aminocarbonylmethylene, mono- or di (alkyl CM) aminocarbonyl-methylene, Het3 aminocarbonyl, Het3aminothiocarbonyl, pyridinylalkyl CM, Het3 or R6 and R16 taken together with the nitrogen atom to which they are attached form a radical of the formula: R17 and R18 each independently selected from hydrogen, C alkyl, hydroxyalkyl CM, CM dihydroxyalkyl, phenyl, CM, CM alkyloxy C alkyl, CM alkyl carboniio, phenylcarbonyl, mono- or di (alkyl C? -4) aminoC, phenylamino-carbonyl, phenylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC CM, CM alkanediyl -C (= 0) -Z-alkyl C? -6, -C (= O) -Z-alkyl C? -6, Y-alkanediyl CM -C (= 0) -Zalkyl C? .6 and R6; Aryl represents phenyl optionally substituted with one, two or three each independently selected from nitro, azido, cyano, halo, hydroxy, CM alkyl, C3-7 cycloalkyl, CM alkyloxy, formyl, polyhaloC CM, NR9R10 - (= 0) - NR 9 R 10, -C (= 0) -Z-R 14, R 6, -O-R 6, phenyl, Het 3, and C 1 -C alkyl substituted with one or more substituents each independently selected from halo, hydroxy, alkyloxy CM, -C (= 0 ) -Z-R14, -Y-alkanoylyl CM-C (= O) -Z-R14, Het3 or NR9R10; Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazoinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienium, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trityanil, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, purinyl 1H-pyrazolo [3 , 4-d] pyrimidinyl, benzimidazoiilo, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazo [2,1-b] thiazolyl; wherein said heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2 and R11; Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxoyanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl. , pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, sobenzotienilo, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo [3,4-d] pirimidin¡ I, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo [2,1-b] thiazolyl; wherein said heterocycles each independently can be optionally substituted with one, or when possible, two or three substituents each independently selected from R 11 and C alkyl optionally substituted with one or two substituents each independently selected from R 11; Het3 represents a monocyclic heterocycle selected from azetinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently can optionally be substituted with, when possible, one, two, three or four substituents each independently selected from hydroxy, C-alkyl, alkyloxy >14 CM, -C (= O) -ZR alkylcarbonyl CM, phenylalkyl CM, piperidinyl, NR12R13, R6 and alkylCM, substituted each or two substituents each independently selected from hydroxy, alkyloxyCM, phenyl, -Y-alkanediyl C ? -4-C (= O) -Z-R14, R6 or NR12R13; Het4 represents 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; Het5 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazoyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl. , pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzo-thienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolinyl, purinyl, 1H -pyzozoo [3,4-d] pyrimidinyl, benzimidazolyl, quinolyl, isoquinolium, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo [2,1-b] thiazolyl; wherein said heterocycles each independently can be optionally substituted with one, or when possible, two, three or four substituents, each independently selected from hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, aiquiicarbonyl CM, piperidinyl, NR 17 R 18, C (= O) -Z-C1-6alkyl, R6, sulphonamido, and CM alkyl substituted with one or two substituents independently selected from hydroxy, alkyloxyCM, phenyl, C (= 0) -Z-alkylC-? -6 , -A-alkanediyl C? -6-C (= 0) -Z-alkyl C? -6, R6 and NR17R18; If each time R2 is different from aminocarbonyl, C1-6alkyloxycarbonylalkylC6-6; and • R11 is different from carboxyl, alkyloxycarbonyl CM aminocarbonyl, alkylaminocarbonyl CM, hydroxyalkyl C? -4-aminocarbonyl, alkylcarbonylaminocarbonyl, cycloalkylaminocarbonyl C-3-7; and • R7, R8, R9, R10, R12, R13, R15 and R16 are different from alkyl d. 4-carbonyloxyalkyl CMcarbonyl, hydroxyalkylC 4 -carbonyl; and • Het3 is different from a monocyclic heterocycle substituted by carboxyl or alkyloxycarbonyl C; and • The compounds of the formula (I) contain at least one portion -C (= O) -Z-R14. A special group of compounds are those of the formula (I) wherein R 2 represents aryl, Het 1, C 3-7 cycloalkyl optionally substituted with -C (= O) -Z-R 14, d-β alkyl or substituted C 1 -C 6 alkyl with one or two substituents selected from hydroxy, cyano, amino, mono- or di- (C 1-4 alkyl) amino, -C (= O) -Z-R 14, C-α-6 alkoxy, optionally substituted -C ( = 0) -Z-R14, alkylsulfonyloxy Cie, optionally substituted C3-7 cycloalkyl -C (= O) -Z-R14, aryl, aryloxy, arylthio, Het1, Hetoxi and Hetthio; and if x is O, S or NR3, then R2 can also represent -C (= 0) -Z-R14, aminothiocarbonium, alkylcarbonyl CM, aminothiocarbonium, alkylcarbonyl CM optionally with -C (= O) -Z-R14, alkylthiocarbonyl C optionally substituted with -C (= O) -Z-R14, arylcarbonyl, arylthiocarbonyl; Each R 6 independently represents C 1-6 alkylsulfonyl, aminosuifonyl, mono- or di- (C 1-4 alkyl) aminosulfonyl, mono- or di (benzyl) aminosulfonyl, polyhaloalkyl Ci-sulfonyl, alkylsulfinyl C 1-6, phenylalkyl C 1-4 sulfonyl, piperazinylsulfonyl , aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-alkyl CM-N-piperidinylaminosulfoniio; Each R7 and each R8 are independently selected from hydrogen, CM alkyl, hydroxyalkyl CM, dihydroxyalkyl CM, aryl, arialkyl CM, alkyl CMOxyalkyl CM, alkylcarbonyl CM, arylcarbonyl, -C (= O) -Z-R14, mono- or di- (CM alkyl) arninoalkyl CM, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Heaminocarbonyl, C3 cycloalkyl. 7, pyridinylalkyl CM, Het3 and R6; R9 and R10 are each independently selected from hydrogen, CM alkyl, hydroxyalkyl CM, dihydroxyalkyl CM, phenyl, phenylalkyl CM, alkyloxy CM alkyl CM, alkylcarbonyl CM, phenylcarbonyl, -C (= O) -Z-R14, mono- or di- (CM alkyl) aminoalkyl CM, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7 cycloalkyl, pyridinylalkyl CM, Het3 and R6; each R 11 is independently selected from hydroxy, mercapto, cyano, nitro, halo, -C (= 0) -Z-R 14, trihalomethyl, C-alkyloxy optionally substituted by -C (= 0) -Z-R 14, formyl, trihaloalkyl C-sulfonyloxy , R6, NR7R8, -C (= O) -NR15R16 ,, aryl, aryloxy, arylcabonyl, C3-7 cycloalkyl optionally substituted with -C (= 0) -Z-R14, C3-7 cycloalkyloxy optionally substituted with -C (= 0) -Z-R14, phthalimide-2-yl, Het3 and C (= 0) Het3; R12 and R13 are each independently selected from hydrogen, CM alkyl, hydroxyalkyl CM, C1-4 hydroxy alkyl, phenyl, phenylalkyl CM, alkyl CM oxyalkyl CM, alkylcarbonyl CM, phenylcarbonyl, -C (= 0) -Z-R14, mono- or di (alkyl C) aminoalkyl CM, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7 cycloalkyl, pyridinylalkyl C and R6; each R 14 independently represents hydrogen, C 2 -2 acyl (with a straight or branched hydrocarbon chain, saturated or unsaturated having between 1 and 20 carbon atoms), C 2 -2 alkyl, C 3 cycloalkyl, polyalkyl C 1 - twenty; or R 4 represents a radical of the formula: (a) (b) R a, R b, R c, R d, Re and R f are each independently hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl; or Re and Rf taken together can form -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-; R15 and R16 are each independently selected from dihydroxyalkyl C, aryl, arylalkyl CM, alkyloxy CM alkyl CM, -C (= 0) -Z-R14, arylcarbonyl, mono- or di (alkyl CM) -aminoalkyl CM, arylaminocarbonyl, arylaminothiocarbonyl , het3aminocarbonyl, Het3aminotiocarbonilo, plridinilalquil CM, Het3 or R6; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, alkylCM, alkyloxyCM, polyhaloalkylCM, NR9R10, -C (= 0) -Z-R14, phenyl, Het3 , and C? -4 alkyl, substituted with -C (= O) -Z-R 14 or NR 9 R 10; Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diozanyl, titianyl, trityanil, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzodioxanyl, indolll, isoindolyl, indonylyl, purinyl, 1H-pyrazolo [3 , 4-d-pyrimidinyl, benzimidazolyl, quinolyl, isoquinilyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazol [2,1-b] thiazolyl; wherein said heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and CM alkyl optionally substituted with Het2 and R11; Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazonyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanium, dithianyl, trityanil, triazinyl; wherein said heterocycles each independently may be optionally substituted with one, or when possible, two or three substituents each independently selected from R 11 and C alkyl optionally substituted with one or two substituents each independently selected from R 1; Het3 represents a monocyclic heterocycle selected from pyrrolidinyl piperidinyl, piperazinium, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently can optionally be substituted with, where possible, one, two, three or four substituents each independently selected from CM alkyl, alkyloxy CM, -C (= 0) -Z-R14, alkylcarbonyl CM, phenylalkyl C, piperidinyl, NR12R13, R6 and alkylCM substituted with -C (= O) -Z-R14, R6 or NR12R13. As used in the above and later definitions, halo is a generic for fluoro, chloro, bromo, iodo; C3-7 cycloalkyl is a generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C- alkyl defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methyl ethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; by alkyl Cie is meant to include CM alkyl and its major homologs having 5 or 6 carbon atoms, such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like, C1-20 alkyl includes C1-6 alkyl and its larger homologs having from 7 to 20 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl, nonadecyl eicosyl and the like, Cs-2 alkyl includes C? -2o alkyl except for CM alkyl; polyhaloalkyl CM is defined as polyhalosubstituted C-alkyl, in particular CM alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; polyhaloC 1-6 alkyl, more in particular difluoro- or trifluoromethyl; C1-6alkyl is defined as polyhalosubstituted C? _ alquiloalkyl, polyhaloalkyl C? -2oo is defined as polyhalosubstituted C-20-20 alquilo alquilo alquilo alquilo alquilo-20-20-20-20................................................................. The term alkanediyl CM defines straight or branched bivalent chain 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; C2-β alkanediyl defines bivalent straight or branched chain 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. The term C3-2 alkenyl defines straight or branched hydrocarbon radicals containing a double bond and between 3 and 20 carbon atoms such as, for example, 2-.propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl , 3-methyl-2-butenyl, 3-hexenyl and the like; and the carbon of said C3.2 alkenyl is connected to the rest of the molecule, preferably saturated; and the term C3-2 alkynyl defines the straight or branched chain hydrocarbon radicals containing a triple bond having between 3 and 20 carbon atoms such as, for example, 2-propinyl, 3-butinyl, 2-butinyl, 2-pentynyl , 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl and the like; and the carbon of said C3-2 alkynyl connected to the rest of the molecule is preferably saturated. Het1, Het2, Het3, Het4 and Het5 include all possible isomeric forms of the heterocycles mentioned in the definition of Het1, Het2, Het3, Het4 or Het5, for example, pyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl, and 1,4-triazolyl; Oxadiazolyl includes 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl and 1,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, 1, 2,5-thiadiazolyl and 1,4-thiadiazolyl; Pyranyl includes 2H-pyranyl and 4H-pyranyl. The heterocycles represented by Het1, Het2, Het3, Het4 and Het5, can be linked to the rest of the molecule of the formula (I) through any carbon or heteroatom of the appropriate ring. Thus, for example, when the heterocycle is imidazolyl, it can be a 1-imidazolyl, 2-imidazolium, 4-imidazoyl and 5-imidazolyl; when it is thiazolyl, it can be 2-thiazolyl, 4-tJazolyl and 5-thiazolyl; when it is trizolyl it can be 1,24-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 benztriazolyl, it can be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl. The acyl C? -2o is derived from: The pharmaceutically acceptable addition salts as mentioned hereinbefore are understood to comprise the therapeutically active, non-toxic acid addition salt forms which the compounds of the formula (I) are capable of forming. The latter can be conveniently obtained by treating the base form with suitable acids such as, for example, inorganic acids, for example, hydrohalic acids, for example, hydrochloric, hydrobromic acid 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 acid, 2-hydroxy-1,2,3-propanecarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzene sulphonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids . Conversely, the salt form can be converted by the treatment with an alkali into the free base form. The compounds of the formula (I) containing acidic protons can be converted to the therapeutically active non-toxic metal or amine addition salt form by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkali earth metals, for example, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example , 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, choline and the like. Conversely, the salt form can be converted by the acid treatment into the free acid form. The term addition salt also comprises the hydrates and solvent addition forms that the compounds of the formula (I) are capable of forming. Examples of these forms are, for example, hydrates, alcoholates and the like. The N-oxide forms of the compounds present are understood to comprise the compounds of the formula (I) wherein several nitrogen atoms are oxidized in the so-called N-oxide. For example, one or more nitrogen atoms of any of the heterocycles in the definition of Het1, Het2, Het3, Het4 and Het5, can be N-oxidized.
Some of the compounds of the formula (I) may also exist in their tautomeric forms. These forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention. For example, a portion of hydroxy substituted triazine may also exist as the corresponding triazinone portion; a portion of hydroxy substituted pyrimidine may also exist as the corresponding pyrimidinone moiety. The term "stereochemically isomeric forms" as used hereinbefore defines all possible stereoisomeric forms in which the compounds of formula (I) may exist. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of basic molecular structure. More particularly, the stereogenic centers may have the R- or S- configuration, used here according to the nomenclature of Chemical Abstracts. The stereochemically isomeric forms of the compounds of the formula (!) Are obviously included within the scope of this invention. The compounds of the formula (I) and some of the intermediates in the present invention contain one or more asymmetric carbon atoms. The stereochemically pure and mixed forms of the compounds of the formula (I) are intended to be included within the scope of the present invention.
Each time it is used hereinafter, the term "compounds of the formula (I)" also includes the N-oxide forms, pharmaceutically acceptable addition salts, quaternary amines and their stereochemically isomeric forms. The numbering of the phenyl ring bearing the R4 substituent is given below and is used herein as indicated by the position of the substituents R4 on said phenyl ring, unless indicated otherwise.
The carbon atom carrying the two phenyl rings and the substituents R1 and -X-R2 will be referred to herein as the central carbon atom. An interesting group of compounds are those compounds of the formula (I) wherein the 6-azauracil moiety is attached to the phenyl ring in the para or meta position with respect to the central carbon atom; preferably, in the para position. Another interesting group contains those compounds of the formula (I) where one or more of the following restrictions apply: • p is 0, 1 or 2; • X is S; NR3, or a direct link; more particularly NH or a direct link; • Each R5 independently is halo, polyhaloalkyl CM, C-i-e alkyl, C-? 6 alkyloxy, alkyloxy or C1-6 aryl, preferably, chloro or trifluoromethyl, more preferably, chloro; • At least one portion -C (= O) -Z-R14 contained in the compound of the formula (I) arises from R2; • R2 is Het1 or C1-6alkyl, substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di (alkylCM) amino, C (= O) -Z-R14alkyloxyC-? -6, optionally substituted with C (= O) -Z-R14 alkylsuifonyloxy C-? -6, aminosilyl-sulphonyloxy C-? -6, cycloalkyl C3-7, optionally substituted with C (= O) -Z-R14, aryl, aryloxy, arylthio, Het1, Het1oxi, and Het1tio; and if X is O, S or NR3, then R2 may also represent aminothiocarbonyl, C 1 -C 4 alkylcarbonyl, optionally substituted with C (= O) -Z-R 14, alkylathiocarbonyl CM optionally substituted with C (= 0) -Z- R 14, arylcarbonyl, arylthiocarbonyl, Hetlcarbonyl or Hetthiocarbonyl; particularly R2 is Het1 or in the case where X is NH, R2 may also be aminothiocarbonium or Het1carbonyl; • R1 is hydrogen or methyl; preferably, methyl; • R1 is C-i-β or aminosulfonyl alkylsulfonyl; • R7 and R8 are each independently, alkyl CM, Het3 or R 6 °.
R and R > 10 are each independently hydrogen, alkyloxy C Ct 4 alkyl, C 1 alkylcarbonyl, aminocarbonyl, Hei carbonyl, Het 3 or R 6; • R > 11 e "s ~ c: ia ~" no ~, "n: i < t.-ro, has "l? ~ o, a"? lq ", u.; lcox"; i / C • M, M NDR7 RD8, C (= 0) NR15R16, -C (= 0) - Z-R14, aryl, arylcarbonyl, Het3, Het4 or C (= 0) Het3, more preferably, R11 is phenyl, -C (= 0) -OR14, -C (= O) -S-R14 O -C (= 0) -NH-R14; • R14 is dihydrofuranyl, C5-2alkyl, C3-2alkenyl, polyhaloalkyl C6-6, Het5 or C2-2alkyl substituted with one or more substituents selected from alkylamino phenyl CM, cyano, Het1, hydroxy and C3-7 cycloalkyl; • R17 and R18 are each independently hydrogen or phenyl; • Aryl is phenyle optionally substituted with one, two or three substituents each independently selected from nitro, halo, hydroxy, CM alkyl, C3-7 cycloalkyl, alkyloxy CM, formyl, polyhaloalkyl CM, NR9R10, C (= 0) NR9R10, C (= 0) -0-R14, -O-R6, phenyl, C (= 0) Het3 and alkyl CM, substituted with one or more substituents each independently selected from halo, alkyloxy CM, C (= O) -Z- R14, Het3 or NR9R10; • Het1 is monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tretrazolyl, furanyl, thienyl, oxazolyl, isoxazollol, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, in particular imidazolyl, oxadiazolyl , thiazolyl, pyrimidinyl or pyridinyl, wherein said monocyclic heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and alkylCM optionally substituted with Het2 or R11; preferably, Het1 is imidazolyl, oxadiazolyl, thiazolyl or pyridinyl each independently and optionally substituted with one, or when possible three substituents, each independently selected from Het2, R11 and optionally alkyl with Hef2 or R11; • Het2 is an aromatic heterocycle; more particularly furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently can optionally be substituted with one, or when possible two or three substituents, each independently selected from R 11 and C- alkyl; • Het3 is azetidinyl, piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, when possible, one, two, three or four substituents each independently selected from hydroxy, alkylCM, alkylcarbonylCM, piperidinyl and substitutedCM alkyl with one or two substituents independently selected from hydroxy, alkyloxy CM O phenyl; Het4 is thienyl; Het5 is piperidinyl or piperazinyl optionally substituted with C 1 O alkyl sulfonamido. Suitably, Het1 represents a heterocycle selected from imidazolyl, triazolyl, furanyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl benzothiazolyl, benzoxazolyl, purinyl, 1 H-pyrazolo- [ 3,4-d-pyrimidinyl, benzimidazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazo- [2,1-bjthiazolyl; wherein said heterocycles each independently can be optionally substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and alkylCM optionally substituted with Het2 or R1. Suitably, Het2 represents furanyl, thienyl or pyridinyl; wherein said monocyclic heterocycles each independently can be optionally substituted with alkyl CM- Suitably, Het3 represents pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently can optionally be substituted with, when possible, one, two or three substituents each independently selected from CM alkyl, alkyloxy CM, -C (= O) -Z-R14, alkylcarbonyl CM, phenylalkyl CM, piperidinyl, NR12R13 and alkylCM substituted with -C (= O) -Z-R14 or NR12R13. Particular compounds are those compounds of the formula (I) wherein R4 and R5 each independently are -C (= 0) -Z-R14, halo, polyhaloalkyl, C-? -6 alkyl optionally substituted with -C (= O ) -ZR 4, C 1-6 alkyloxy or aryl, more particularly, chloro or trifluoromethyl. Other particular compounds are those compounds of the formula wherein R 2 represents aryl, Het 1, C 3-7 cycloalkyl optionally substituted with -C (= O) -Z-R 14 or C 1-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di (Cp 4 alkyl) amino, C 1-6 alkyloxy, C 1-6 alkylsulfonyloxy, dyalkyloxycarbonyl, C 3-7 cycloalkyl, aryl, aryloxy, arylthiol, Het 1, Hetoxy and Hetthio; and if X is O, S or NR3, then, R2 may represent -C (= O) -Z-R14, amothiocarbonyl, C1-4 alkylcarbonyl, C1-4 alkylthiocarbonyl, arylcarbonyl or arylthiocarbonyl; more particularly R2 is oxadiazolyl, thiazolyl, primidinyl or pyridinyl; wherein said heterocycles can each independently and optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 © R11. Even other particular compounds are those compounds of the formula (I) wherein X is O, S, NH or a direct bond, more preferably, S or a direct bond, more preferably, a direct bond. Preferred compounds are those compounds of the formula (I) wherein q is 1 or 2 and a substituent R4, preferably chlorine, is in the 4-position. Other preferred compounds are those compounds of the formula (I) wherein p is 1 or 2 and the substituent (s) R5, preferably chlorine, are in the ortho position with respect to the central carbon atom. To simplify the structural representation of the compounds of the formula (I), the group from now on it will be represented with the symbol D.
The compounds of the formula (I) can be prepared generally by reacting an intermediate of the formula (II) wherein W1 is a suitable transfer group such as, for example, a halogen atom with a suitable reagent of the formula (III). (11) Said reaction can be carried out in a solvent inert to the reaction such as, for example, acetonitrile, N, N-dimethylformamide, acetic acid, tetrahydrofuran, ethanol or their mixtures. Alternatively, in case the reagent of the formula (II) acts as a solvent, no solvent is required inert to the additional reaction. The reaction is optionally carried out in the presence of a base such as, for example, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium bicarbonate, sodiomethane and the like. Suitable reaction temperatures are within a range between -70 ° C and the reflux temperature. In this and the following preparations, the reaction products of the reaction medium can be isolated and, if necessary, further purified in accordance with the methodologies generally known in the art, such as, for example, extraction, crystallization, distillation, crushing and chromatography.
Alternatively, the compounds of the formula (I) can be prepared generally by cycling with an intermediate of the formula (IV) where L is a suitable transfer group such as, for example, alkyloxy d-6 or halo, and E represents a group that attracts suitable electrons such as, for example, an ester, an amide, a cyanide, an alkylsulfonyloxy d-6 and similar groups; and eliminating the E group of the triazinedione obtained in this way from the formula (V). Said reaction procedure is analogous to that described in EP-A-0 170 316.
Some of the compounds and intermediates of the present invention can be prepared according to or analogous to the processes described in EP-A-0 170 316 and EP-A-0 232 932. For example, scheme 1 illustrates the route of the reaction for the preparation of the compounds of the formula (I) wherein R1 is hydrogen and X is a direct bond, said compounds are represented by the formula (la-1). A ketone of the formula (VI) can be reacted with a reagent of the formula (VII) where W2 is a suitable transfer group, for example, a halogen, in a reaction-inert solvent such as, for example, tetrahydrofuran, diethylether , and in the presence of a suitable base such as, for example, butyl lithium, thus forming an intermediate of the formula (VIII). The hydroxy group of the intermediates of the formula (VIII) can be removed using a suitable reagent such as, for example, formamide in acetic acid or triethylsilane in trifluoroacetic acid, thereby obtaining an intermediate of the formula (IX) of which, the nitro group it can subsequently be reduced to an amino group which, in turn, can be converted to the 6-azauracil group as described in EP-A-0 170 316, thereby obtaining the compounds of the formula (la-1).
SCHEME 1 (l-a-l) (IX) In addition to the procedure of the reaction illustrated in scheme 1, other compounds of the formula (I) can be prepared where X is a direct bond, starting from a centone of the formula (X) (scheme 2). By reacting said ketone of the formula (X) with an intermediate of the formula (III) wherein X is a direct bond, said intermediates represented by the formula (III-a), result in a compound of the formula (I) wherein R1 is hydroxy and X is a direct bond, said compounds are represented by the formula (la-2). Said reaction can be carried out in a reaction-inert solvent such as, for example, tetrahydrofuran, diethylether, diisopropylacetamide or mixtures thereof, in the presence of a base such as, for example, lithium butyl. Alternatively, the intermediate of the formula (III-a) can first be converted into a Grignard reagent, which can then be reacted with the ketone of the formula (X). Said compounds of the formula (la-2) can furthermore be converted to compounds of the formula (I) wherein R 1 is an alkyloxy d-β group represented by the formula (la-3) using the transformation reactions of groups known in the art. . The compounds of the formula (1-a-2) can also be converted to the compounds of the formula (I) wherein R 1 is halo, said compounds are represented by the formula (l-a-4). A convenient method is to convert the hydroxy group to a chlorine atom using a suitable reagent such as, for example, thionyl chloride. Said compounds of the formula (la-4) can furthermore be converted to compounds of the formula (I) wherein R 1 is amino, said compounds are represented by the formula (la-5), using ammonia or its functional derivative, in an inert solvent to the reaction as for example, tetrahydrofuran; or they can be converted to compounds of the formula (1-a-3) using the group transformation reactions known in the art.
The reduction of the ketone of the formula (X) in its corresponding hydroxy derivative of the formula (XI) using a suitable reducing agent such as, for example, sodiumborohydride in a reaction-inert solvent such as, for example, water, an alcohol, tetrahydrofuran or its mixtures; the subsequent conversion of said hydroxy group into a suitable transfer group W4 which is for example, a halogen obtained in this way an intermediate of the formula (XII), and finally by reacting said intermediate of the formula (XII) with an intermediate of the formula (III) in a suitable solvent such as, for example, tetrahydrofuran, N, N, -dimethyl-formamide, acetonitrile, acetic acid, ethanol or mixtures thereof, and optionally in the presence of a suitable base such as for example 1, 8- diazabicyclo [5.4.0] undec-7-ene or sodium bicarbonate, will result in the compound of the formula (I) wherein R1 is hydrogen, said compounds are represented by the formula (lb). Alternatively, the intermediates of the formula (XI) can be directly transformed into the compounds of the formula (lb) where X is S, said compounds are represented by the formula (lb-1), using a suitable mercapto-containing reagent of the formula R2-SH in a suitable solvent for the reaction such as, for example, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfuric acid or the like. Further, starting from the ketone of the formula (X), the compounds of the formula (I) can be prepared, wherein R1 is hydrogen and -X-R2 is -NH-C (= O) - (aryl or d-β-alkyl) ), said compounds are represented by the formula (Ic). To achieve this, a ketone of the formula (X) is reacted with formamide in formic acid or its functional derivative, at elevated temperatures. The resulting intermediate of the formula (XIII) is hydrolysed in the corresponding amine of the formula (XIV), which can then be reacted with an intermediate of the formula (XV) where W3 is a suitable transfer group, in the presence of a suitable base, such as, for example, pyridine, optionally in the presence of a solvent inert to the reaction such as, for example, dichloromethane.
SCHEME 2 C 1-6 alkyl) (la-5) The compounds of the formula (I) wherein X is a direct bond and R 2 is a heterocycle, said compounds are generally represented by the formula (ld), they can be conveniently prepared by means of the cycle formation of the appropriate intermediary. Procedures for the formation of nonmolecular cycles are possible and scheme 3 lists several examples. The starting point is the conversion of the cyano group of a compound of the formula (I) wherein -X-R2 is cyano, said compounds are represented by the formula (le), in a carboxyl group thus forming the intermediates of the formula ( XVII) using the techniques known in the art, for example, using a combination of sulfuric acid and acetic acid in water, which in turn, can then be reacted with the acyl halides of the formula (XVIII), for example, the acyl chloride derivative can be prepared using thionyl chloride.
SCHEME 3 The intermediate of the formula (XVIII) can be reacted with an intermediate of the formula (XlX-a) where Y is O, S or NR3, to form an intermediate of the formula (XX) in the presence of a base as per for example, pyridine, said intermediate of the formula (XX) can then be formed in cycles in a compound of the formula (I) wherein -X-R2 is a benzothiazole or optionally substituted benzoxazole, said compounds are represented by the formula (1-4). 1), in the presence of a suitable solvent, such as, for example, acetic acid, at an elevated temperature, preferably at reflux temperature. It may be convenient to prepare compounds of the formula (1-d-1) without isolating the intermediates of the formula (XX). Analogously, an intermediate of the formula (XlX-b) to form an intermediate of the formula (XXI) that is formed in cycles of a compound of the formula (I) wherein -X-R2 is a 1, Optionally 3-substituted 2,4-oxadiazole, said compounds are represented by the formula (1-d-2), in a solvent inert to the reaction such as, for example, toluene, at an elevated temperature, preferably the reflux temperature. In addition, in an analogous manner, an intermediate of the formula (XVIII) can be reacted with an intermediate of the formula (XXII) which is formed in cycles in a compound of the formula (I) wherein -X-R2 is a 1, 2,4-triazole, 1,4-triadiazole or 1,4-oxadiazole optionally substituted, said compounds are represented by the formula (ID-3), in a suitable solvent such as, for example, phosphorus oxychloride.
Furthermore, in an analogous manner, an intermediate of the formula (XVIII) can be reacted with an intermediate of the formula (XlX-d) where Y is O, S, or NR3, to form an intermediate of the formula (XXIII) which is formed in cycles in a compound of the formula (I) wherein -X-R2 is a 1,4-triazole, 1, 3,4-thiadiazole or 1,4-substituted-amino-substituted-aminoadiazole, said compounds are represented by the formula (ld-4) in a solvent inert to the reaction such as, for example, toluene and in the presence of an acid; or, which is formed in cycles in a compound of the formula (I) wherein -X-R2 is a disubstituted 1,4-triazole, said compounds are represented by the formula (I-d-5). The nitrile derivative of the formula (XVI) can also be reacted with hydroxylamine hydrochloride or its functional derivative, thus forming an intermediate of the formula (XXIV) which can be reacted with an intermediate of the formula (XXV) to form a compound of the formula (I) wherein -X-R2 is a 1, 2,4-triazole, 1, 2,4-thiadiazoI or 5-substituted-1,2,4-oxadiazole, said compounds being represented by the formula ( ld-6), in a solvent inert to the reaction such as, for example, methanol, butanol or their mixtures, in the presence of a base such as, for example, sodium methanoate. The compounds of the formula (ld) wherein the heterocycle is substituted 2-thiazolyl, said compounds are represented by the formula (ld-7), can be prepared by reacting an intermediate of the formula (XVI) with hydrogen sulfide or its functional derivative, in a solvent inert to the reaction such as, for example, pyridine optionally in the presence of a suitable base such as, for example, triethylamine, thus forming an intermediate of the formula (XXVI), which can be subsequently reacted with an intermediate of the formula (XXVII ) or its functional derivative, such as, for example, the ketal derivative, in a solvent inert to the reaction such as, for example, ethanol, and optionally in the presence of an acid, such as, for example, hydrogen chloride.
The compounds of the formula (1-d) wherein the heterocycle is substituted 5-thiazolyl and R 1 is hydrogen, said compounds are represented by the formula (1-d-8), they can be prepared following the reaction procedure illustrated in scheme 4.
SCHEME 4 (l-d-8) (XXXI) Initially, an intermediate of formula (XXVIII) wherein P is a protecting group, such as, for example, an alkylcarbonyl group d-β, is reacted with a thiazole derivative of formula (XXIX) in the presence of a suitable base as for example, butyl lithium, in a solvent inert to the reaction such as, for example, tetrahydrofuran, thus forming an intermediate of the formula (XXX). Conveniently said reaction can be carried out under an inert atmosphere at a lower temperature, preferably at about -70 ° C. The hydroxy group and the protecting group P of said intermediates (XXX) can be removed using the known methods such as, for example, stannous chloride and hydrochloric acid in acetic acid, thus forming an intermediate of the formula (XXXI), of which the amino group it can be converted to the 6-azauracil portion according to the process described in EP-A-0 170 316, thus forming a compound of the formula (ld-8). In addition, the compounds of the formula (1-d) wherein the heterocycle is 4-thiazolyl, said compounds are represented by the formula (1-d-9), can be prepared following the reaction procedure illustrated in scheme 5.
SCHEME 5 (W-?) An intermediate of the formula (XVIII) is reacted with a Grignard reagent of the formula RCH2MgBr or its functional derivative to form an intermediate of the formula (XXXII), which can be halogenated, preferably brominated, in the position -a using a reagent such as, for example, trimethylphenylammonium tribromide in tetrahydrofuran, thereby forming an intermediate of the formula (XXXIII). Said intermediate (XXXIII) can then be reacted with a thioamide of the formula (XXXIV) to form a compound of the formula (l-d-9), in a solvent inert to the reaction, such as, for example, ethanol, at an elevated temperature, preferably, the reflux temperature. The compounds of the formula (I) can also be converted to each other following the procedures known in the art for the transformation of the function group, examples of which were mentioned above. The compounds of the formula (I) can also be converted to the N-oxide forms following the known procedures for converting a trivalent nitrogen into its A -oxide form. Said N-oxidation reaction, generally, can be carried out by reacting the starting material of the formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaziridine or with a suitable organic or inorganic peroxide. Suitable organic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide.; suitable organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or substituted benzenecarboperoxoic acid halo, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkylhydroperoxides, for example, t-butyl hydroperoxide. Suitable solvents are for example, water, minor alkanols, for example, ethanol and the like, hydrocarbons, for example, toluene, ketones, for example, 2-butanone, halogenated hydrocarbons, for example dichloromethane and mixtures of these solvents. The stereochemically isomeric forms of the compounds of the formula (I) can be obtained by means of the application of the processes known in the art. The diastereomers can be separated by physical methods such as, for example, selective crystallization and chromatographic techniques, for example, countercurrent distribution, liquid chromatography and the like. Some of the compounds of the formula (I) and some of the intermediates of the present invention may contain an asymmetric carbon atom. The pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by means of the application of the procedures known in the art. For example, the diastereoisomers can be separated by physical methods such as, for example, selective crystallization or chromatographic techniques, for example, countercurrent distribution, liquid chromatography and similar methods. The enantiomers can be obtained from the racemic mixtures by first converting said re-organic mixtures with suitable solvent agents such as, for example, chiral acids, into mixtures of salts or diastereomeric compounds; then physically separating said mixtures of diastereomeric salts or compounds by means of, for example, selective crystallization or chromatographic techniques, for example, liquid chromatography and the like; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Stereochemically isomeric forms can also be obtained from the pure stereochemically isomeric forms of suitable intermediates and starting materials, if the intervening reactions occur stereospecifically. An alternative way to separate the enantiomeric forms of the compounds of the formula (I) and the intermediates include liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Some of the intermediates and starting materials as used in the aforementioned reaction procedures are known compounds and may be marketed or may be prepared according to procedures known in the art. IL-5, also known as eosinophil differentiating factor (EDF) or eosinophilic colony stimulating factor (Eo-CSF), is a major survival and differentiation factor for eosinophils, and, therefore, is thought to have a key role in the infiltration of eosinophilic tissue. There is ample evidence that the eosinophil influx is an important pathogenic event in bronchial asthma and allergic diseases such as chelitis, irritable bowel disease, eczema, urticaria, vasculitis, vulvitis, "feet of winter" atopic dermatitis, pollinosis, allergic rhinitis, and allergic conjunctivitis: and other inflammatory diseases, such as eosinophilic syndrome, allergic angitis, eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, idopathic eosinophilia, eosinophilic myalgia, Crohn's disease, ulcerative colitis and similar diseases. The present compounds also inhibit the production of other chemokines such as, for example, monocyte chemoattractant protein 1 and 3 (MCP-1 and MCP-3). It is known that MCP-1 attracts both T cells, where the production of IL-5 mainly occurs, as to monocytes, which are known to act synergistically with eosinophils (Carr et al., 1994, immunology (Immunology), 91, 3652-3656). MCP-3 also has a primary role in allergic inflammation as it is known to mobilize and activate basophilic and eosinophilic leukocytes (Baggiolini et al., 1994, Immunology Today, 15 (3), 127- 133). The present compounds have little or no effect on the production of other chemokines such as, for example, IL-1, IL-2, IL-3, IL-4, IL-6, 1L-10,? -interferon (IFN-?) and the stimulating factor of the granulocyte-macrophage colony (GM-CSF) indicating that the IL-5 inhibitors present do not act as broad spectrum immunosuppressants. The inhibitory effect of the selective chemokine of the present compounds can be demonstrated by in vitro chemokine measurements in human blood. In vivo observations such as, for example, the inhibition of eosinophilia in the mouse ear, the inhibition of blood eosinophilia in the mouse model Ascaris; the reduction of the production of the IL-5 protein in serum and the expression IL-5 splenic mRNA induced by the anti-CD3 antibody in mice and the inhibition of the pulmonary influx induced by allergen or Sephadex of eosinophils in guinea pigs, are indicative of the utility of the present compounds for the treatment of inflammatory diseases dependent on eosinophil. The present inhibitors of IL-5 production are particularly useful for administration by inhalation. The intermediaries of the formula (Xl-a) are interesting intermediaries. Not only do they have particular utility as intermediates in the preparation of the compounds of the formula (I), but they also have a valuable pharmacological activity. Taking into account the above pharmacological properties, the compounds of the formula (I) can be used as medicaments. In particular, the present compounds can be used in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases as mentioned above, more particularly, bronchial asthma, dermatitis, atopic, allergic rhinitis and allergic conjunctivitis. Taking into account the usefulness of the compounds of the formula (I), a method is provided for treating warm-blooded animals, including humans, suffering from inflammatory diseases dependent on eosinophil, in particular bronchial asthma, dermatitis atopic, allergic rhinitis and allergic conjunctivitis. Said method comprises the systemic or topical administration of an effective amount of a compound of the formula (I), an N-oxide form, a pharmaceutically acceptable addition salt or its possible stereoisomeric form, to warm-blooded animals, including humans. . The present invention further provides compositions for treating eosinophil-dependent inflammatory diseases comprising a therapeutically effective amount of a compound of the formula (I) and its pharmaceutically acceptable carrier or diluent. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, in the base or addition salt form, as the active ingredient, is combined by intimately mixing with a pharmaceutically acceptable carrier, which may have a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are convenient in the unit dosage form suitable, preferably, for systemic administration such as, for example, parenteral administration; or topical administration by means of inhalation, nose spraying or the like. The application of these compositions can be aerosolized, for example, with a propellant such as, for example, nitrogen, carbon dioxide, a freon, or without a propellant such as, for example, pump sprays, drops, lotions or a semi-solid such as example, a thick composition that can be applied by means of a gauze. In particular, semisolid compositions, such as balsam, creams, gels, ointments and the like, will be conveniently used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in the unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form as used in the specification and claims refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient calculated as to produce the desired therapeutic effect associated with the required pharmaceutical carrier. Examples of these unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, powder packets, disks, injectable solutions or suspensions, teaspoons of tea, and the like, and their manifolds. To increase the solubility and / or stability of the compounds of the formula (I) in the pharmaceutical compositions, the a-, β- or β-cyclodextrins or their derivatives can be advantageously used. Also co-solvents such as, for example, alcohols can improve the solubility and / or stability of the compounds of the formula (I) in the pharmaceutical compositions. In the preparation of the aqueous compositions, the addition salts of the objective compounds are obviously more suitable due to their increased solubility in water. Suitable cyclodextrins are α-, β-, β-cyclodextrins or mixed esters and esters, where one or more hydroxy groups of the ahydroglucose units of the cyclodextrin are substituted with d-Cß alkyl, particularly methyl, ethyl or sopropyl, for example, β-CD; hydroxyalkyl d- Ce, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl d-Cß, particularly carboxymethyl or carboxyethyl; D-C6 alkylcarbonyl, particularly acetyl; C 1 -C 6 alkylcarbonylalkyl C 1 -C 6 alkyl or C 1 -C 6 carboxy-alkyloxycarbonyloxyalkyl Ci-Ce, particularly carboxymethoxypropyl or carboxyethoxypropyl; alkyl d-Cβ alkylcarbonyloxy d-Cß, particularly 2-acetyoxypropyl. Specialized complexing and / or solubilizing agents are the randomly methylated ß-CD, β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD and (2- carboxymethoxy) propyl-β-CD, and in particular, 2-hydroxypropyl-β-CD (2-HP-β-CD). The term "mixed ether" denotes the cyclodextrin derivatives wherein at least two hydroxy cyclodextrin groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The MS value can be determined by means of several analytical techniques, preferably, measured by mass spectrometry, the MS intervals are between 0.125 and 10. The average substitution degree (SD) refers to the average number of hydroxyls substituted by anhydroglucose unit. The DS value can be determined by means of several analytical techniques, preferably measured by mass spectrometry, the DS intervals are between 0.125 and 3. Due to their high degree of selectivity as IL-5 inhibitors, the compounds of the formula (I) As we defined earlier, they are also useful for marking or identifying receivers. To this end, the compounds of the present invention need to be labeled, in particular by partially or completely replacing one or more atoms in the molecule by means of their radioactive isotopes. Examples of the interesting compounds labeled are those compounds having at least one halo which is a radioactive isotope of iodine, bromine or fluorine; or those compounds having at least one 1C atom or tritium atom. A particular group is formed by those compounds of the formula (I) wherein R4 and / or R5 are a radioactive halogen atom. In the beginning, any compound of formula (I) containing a halogen atom is capable of being radio-labeled by replacing the halogen atom by any suitable isotope. The radioisotopes of halogen for this purpose are radioactive iodides for example, 122l, 123l, 125l, 131l; radioactive bromides, for example. ^ Br ^ Br. ^ Br and 82Br, and radioactive fluorides, for example, 18F. The introduction of a radioactive halogen atom can be carried out by means of an appropriate exchange reaction or using any of the methods described hereinabove to prepare the halogen derivatives of the formula (I). Another interesting way to radiorotulate is by replacing a carbon atom with a 11C atom or by replacing a hydrogen atom with a tritium atom. Theref said radio-labeled compounds of the formula (I) can be used in a method for specifically labeling the receptor sites in the biological material. Said method comprises the steps of (a) radiolabelling a compound of the formula (I), (b) administering this radio-labeled compound to the biological material and subsequently (c) detecting the emissions of the radio-labeled compound. The term biological material intends to understand any type of material that has a biological origin. Mparticularly, this term refers to samples of tissue, plasma or body fluids but also refers to warm-blooded animals or parts of animals such as, for example, organs. The radiolabelled compounds of the formula (i) are also useful as agents for classifying whether the test compound has the ability to occupy or bind to a particular receptor site. The degree to which a test compound will displace a compound of formula (I) from that particular receptor site will show the ability of the test compound as much as an agonist, antagonist or mixed agonist / antagonist of said receptor. When used in in vivo assays, suitable radiolabeled compounds are administered to a suitable composition to an animal and the location of said radio-labeled compounds is detected using imaging techniques such as, for example, single photon emission computed tomography (SPECT) or positron emission tomography (PET) and the like. In this way, the distribution of the particular receptor sites in the body can be detected and the organs containing said receptor sites can be visualized by means of the imaging techniques mentioned hereinabove. This imaging procedure of an organ by administering a radio-labeled compound of the formula (I) and detecting the emissions of the radioactive compound also constitutes a part of the present invention. In general, it is contemplated that a daily therapeutically effective amount would be between 0.01 mg / kg to 50 mg / kg of body weight, in particular between 0.05 mg / kg to 10 mg / kg of body weight. A method for treatment may also include administering the active ingredient in a regimen between two to four intakes per day.
EXAMPLE A1 Experimental part A. Preparation of the compounds of the formula (I) Intermediary 1 Intermediary 2 Compound 1 a) A mixture of 2- [3,5-dichloro-4 [(4-chlorophenyl) hydroxymethyl] phenyl-1, 2,4-triazine-3,5 (2H, 4H) -dione (0.0063 mmol) was added in portions. ) and 1,2-dihydro-2-thioxo-3-pyridinecarboxylic acid to methanesulfonic acid (20 ml), was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice-water and ethyl acetate was added. The organic layer was separated, washed with brine, dried, filtered and the solvent was evaporated. The residue was stirred in boiling ethanol, filtered, washed with diisopropyl ether and dried, yielding 3.1 g (91%) of the intermediate (1). { MS (ES +) m / z 535 [MH +]} . b) Reaction under an atmosphere of N2. A solution of intermediate (1) (0.00187 moles) in N, N-dimethylformamide (20 ml) was treated with 1,1'-carbonylbis-1 H-imidazole (0.00373 moles) and the mixture was stirred for 12 hours at room temperature . H2S was bubbled through the mixture for 15 to 30 minutes. Then, the reaction mixture was stirred for 2 hours. The mixture was poured into ice water (brine) and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and the solvent was evaporated. The residue was co-evaporated 3 times with toluene, giving 1 g (100%) of the intermediate (2). { MS (ES +) m / z 551 [MH *]} . c) A solution of 3-bromodihydro-2- (3H) furanone (1 mmol) in N, N-dimethylformamide (2 ml) was added portionwise to an ice suspension of intermediate 2 (0.91 mmol) and NaHCOs (1 mmol) in N, N-dimethylformamide (5 ml). The reaction mixture was stirred for 15 minutes, and then partitioned between water (25 ml) and ethyl acetate (25 ml). The organic layer was separated, washed with water (2 x 25 ml), dried, filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane, gradient from 20-810 to 80-20% (v / v)). The pure fractions were collected in an evaporated solvent, 0.243 g (42%) of the compound. { MS (ES +) m / z 635 [MH *]} .
EXAMPLE A2 Intermediary 3 Intermediary 4 Intermediary 5 Intermediary 6 Intermediary 7 Compound 2 a) A mixture of intermediate 1 (0.075 mol) in SOCI2 (300 ml) was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated, yielding 41.6 g of intermediate 3. b) NaBH4 (0.495 mol) was added in portions over 90 minutes to a mixture of intermediate 3 (0.075 mol) in 1,4-dioxane ( 500 ml), was stirred at room temperature. The resulting mixture was stirred for 48 hours at room temperature, then cooled in an ice bath. HCl (2 N) was added in portions (up to pH = 2) and this mixture was extracted with CH 2 Cl 2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH2Cl2 / CH3? H 97/3). The pure fractions were collected and the solvent was evaporated, yielding 2.2 g of intermediate 4. c) A mixture of intermediate 4 (0.004 mol) and triethylamine (0.005 mol) in CH2Cl2 (40 ml) was stirred at 0-5 ° C. A solution of methylsulfonyl chloride (0.005 mole) in CH2Cl2 (10 ml) was added portionwise for 15 minutes at 0-5 ° C and the resulting reaction mixture was stirred for one hour at ± 5 ° C. Triethylamine (0.70 ml) was added and the resulting reaction mixture was stirred for one hour at 0 ° C, giving 2.4 g of intermediate 5. d) A solution of 1-acetyl-piperazine (0.3624 moles) in CH2Cl2 (30 ml ) was added in portions to a solution of intermediate 5 (0.0128 moles) and triethylamine (0.0302 moles) in CH2Cl2 (150 ml) was stirred at 0 ° C. the reaction mixture was stirred overnight at room temperature, then washed with a saturated NaHCO3 solution, with brine, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CHsOH gradient 98/2 to 95/5). The pure fractions were collected and the solvent was evaporated, then co-evaporated with ethyl acetate. The residue was stirred in 2-methoxy-2-methylpropane, filtered and dried to give 1.51 g (20%) of intermediate 6. e) Intermediate 6 (0.00321 mol) was dissolved in 1,4-dioxane (50 ml). 2N HCl (0.05 mole) was added and the reaction mixture was stirred and refluxed for 12 hours. The reaction mixture was cooled, poured slowly into a solution of saturated aqueous NaHCO3 (150 ml) + ice (100 g) and this mixture was extracted with CH2Cl2 / CHsOH (90/10). The combined organic layers were washed with brine, dried, filtered and the solvent was evaporated, then co-evaporated with ethyl acetate. When ethylacetate was added a second time, precipitation was caused. This precipitate was filtered, washed with diisoproii ether and dried, giving 1.39 g (74%) of intermediate 7. f) A mixture of the intermediate was stirred at room temperature. 7 (0.0034 mol) in CH3CN (60 ml). Triethylamine (1.47 ml) was added. Bromoacetic acid, ethyl ester (0.0034 mol) was added in portions and the resulting reaction mixture was stirred for 90 minutes at room temperature. The solvent was evaporated. The residue was taken in CH2Cl2. The organic solution was washed with water. The water layer was extracted with CH2Cl2 / CHsOH 90 / 10.2). The organic layer was washed with water, combined with the other organic layer, dried, filtered and the solvent was evaporated. It was purified by flash column chromatography on silica gel (eluent: CH2Cl2 / CH3? H 99/1). The pure fractions were collected and the solvent was evaporated. The residue was co-evaporated with ethyl acetate. The residue was stirred in diisopropyl ether, filtered, washed and dried to give 0.44 g of compound 2.
EXAMPLE A3 Compound 3 Intermediary 10 a) CH2Cl2 (20 ml) was stirred at room temperature. HCl (gas) was bubbled through the solution for 15 minutes. This solution was added in the form of drops to a solution of intermediate 4 (0.01 mol) in CH2CI2 (50 ml). The HCl salt precipitated. SOCI2 (0.05 mol) was added and the mixture was stirred and refluxed for 2 hours. SOCl2 (3.6 ml) was added and The reaction mixture was stirred and refluxed for 2 hours. The mixture was cooled. The precipitate was filtered. The solid and the precipitate were recombined. The solvent was evaporated. More CH2Cl2 (70 mL) and SOCI2 (3.6 mL) were added and the reaction mixture was stirred and refluxed for 3 hours, then cooled and the resulting precipitate was filtered, washed with diisopropyl ether and dried, giving 4 g of intermediate 8. b) A solution of 4-methylamino-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.02244 mol) in CH3CN (20 ml) was added to a solution of intermediate 8 (0.00748 mol) in CH3CN ( 60 ml) and the resulting reaction mixture was stirred for 3 hours at 60 ° C, then overnight at room temperature. The solvent was evaporated. The residue was stirred in boiling ethyl acetate, then filtered and taken up in CH 2 Cl 2 / CH 3 OH 95/5. The solution was washed with brine, dried, filtered and the solvent was evaporated. The residue was purified by HPLC on silica (eluent: CH 2 Cl 2 / CH 3 OH 90/10) / CH 3 OH (0 min) 100/0/0, (34 min) 65/35/0, (40 minutes) 50/0/50, (43 min) 0/0/100, (46.6-60 min) 100/0/0). The pure fractions were collected and the solvent was evaporated. The residue was stirred in diisopropyl ether, filtered and dried to give 3.42 g (64%) of intermediate 9. c) A mixture of intermediate 0 (0.00409 mol) in methanol (30 ml) was stirred overnight at room temperature. and HCl / 2-propanol (4 ml). More HCl / 2-propanol (2 ml) was added and stirring was continued for 2 hours. The reaction mixture was poured into water (300 ml) and CH 2 Cl 2 / CH 3 OH 90/10 (400 ml) was added. The reaction mixture was neutralized by the portionwise addition of a saturated aqueous NaHC 3 solution. The layers separated. The water layer was extracted with CH2Cl2 / CH3? H 90/10. The combined organic layers were dried, filtered and the solvent was evaporated. Ethyl acetate was added and azeotroped on a rotary evaporator. The residue was stirred in boiling CH3CN, cooled, filtered, washed with diisopropyl ether and dried, giving 2.27 g (90%) of intermediate 10. d) Triethylamine (1.42 ml) was added to intermediate 10 (0.00304 moles) in dimethyl sulfoxide (100 ml). The mixture was stirred at 60 ° C. Then, bromoacetic acid, ethyl ester (0.00304 mole) was added and the resulting solution was allowed to cool to room temperature, stirred overnight. The reaction mixture was poured into water (300 ml) and this mixture was extracted with toluene. The toluene layers were combined, dried, filtered and the solvent was evaporated. The residue was purified by HPLC on silica gel (eluent: gradient CH2Cl2 / CH3OH). The two pure fraction groups were collected and their solvent was evaporated. The desired fraction was dissolved in ethyl acetate, filtered through a folded paper filter and the solvent. The residue was stirred in n-hexane, filtered and dried, giving 0.87 g (41%) of compound 3.
EXAMPLE A4 Intermediary 11 Intermediary 12 Intermediary 13 Intermediary 14 Compound 4 a) A mixture of 2- [3,5-dichloro-4 [(4-chlorophenyl) hydroxymethyl] methyl] phenyl] -1, 2,4-triazine-3, 5 (2H, 4H) -dione (0.05 moles) [CAS 219981-46-1] and 6-mercapto-3-piperidinecarboxylic acid (0.05 mole) was added in portions over 1 hour to the methane sulfonic acid (100 ml), stirred at room temperature. The reaction was stirred overnight at room temperature, then poured into ice-water and this mixture was extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 26.8 g of intermediate 11. b) A mixture of intermediate 11 (0.05 mol) in SQCI2 (250 ml) was stirred and refluxed for 2 hours . The solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated, yielding 27.7 g of intermediate 12. c) NaBH4 (0.33 mol) was added in portions over 60 minutes to a mixture of intermediate 12 (0.05 mol) in 1,4-dioxane ( 350 ml), was stirred at room temperature. The resulting reaction mixture was stirred for 2 hours at room temperature, then cooled on an ice bath. HCl (concentrated) was added in the form of droplets until acidic. Water was added and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH 2 Cl 2 / CH 3 OH from 98/2 to 97/3). The pure fractions were collected and the solvent was evaporated, yielding 10.4 g of intermediate 13. d) A mixture of SOCI2 (0.2375 moles) in CH2Cl2 (200 ml) was stirred at room temperature. A mixture of intermediate 13 (0.0475 mol) in CH2Cl2 (50 ml) was added as drops. The reaction mixture was stirred for 2 hours at room temperature. The solvent was evaporated. The residue was stirred in diisoproyl ether, filtered and dried to give 23.8 g of intermediate 14. e) Triethylamine (0.001388 mmole) was added to a solution of intermediate 14 (0.000347 mmole) and 3-azetidinylcarboxylic acid (0.000381 mmole) in CH3CN (4 ml). The reaction mixture was stirred for 12 hours at 60 ° C. The desired compound was isolated and purified by HPLC (eluent gradient: CH3CN / H20). The desired fractions were collected and the solvent was evaporated, yielding 0.009 g (5%) of compound 4.
EXAMPLE A5 H Compound 5 A mixture of intermediate 5 (0.004 mole), glycine, ethyl ester hydrochloride (0.0044 mole) and triethylamine (0.016 mole) in CH3CN (50 ml) was stirred for 24 hours at 50 ° C. The solvent was evaporated. The residue was stirred in water and extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (eluent: CH 2 Cl 2 / CHsOH from 99.5 / 0.5 to 98/2). The desired fractions were collected and the solvent was evaporated. The residue was purified by HPLC (eluent: collected and the solvent was evaporated.) The residue was dried, giving 0.11 g (4.5%) of compound 5.
EXAMPLE A6 Compound 6 A solution of 4- (bromometii) -5-metii-1,3-dioxol-2-one (0.0062 mol) in N, N-dimethylformamide (5 ml) was added in portions to a solution of intermediate 1 (0.00373 moles) and 1H-imidazole (0.007 moles) in N, N-dimethylformamide (25 ml). The mixture was stirred at 60 ° C overnight. The solvent was evaporated there. The residue was taken up in ethyl acetate, washed with H2O and a saturated NaCl solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent hexane / ethylacetate 75/25). The desired fractions were collected and the solvent was evaporated. The residue was purified once more on silica gel on a glass filter (eluent: hexane / ethyl acetate 75/25 to 50/50). The pure fractions were collected and the solvent was evaporated. The residue was stirred in diisopropyl ether. The precipitate was filtered, washed with diisopropyl ether and dried, yielding 0.595 g (25%) of compound 6.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS
1. - A compound of the formula an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or its stereochemically isomeric form, wherein p represents an integer that is 0, 1, 2, 3 or 4; q represents an integer that is 0, 1, 2, 3, 4 or 5; X represents O, S, NR3 or a direct link; or -X-R2 taken together can represent cyano; R 1 represents hydrogen, hydroxy, halo, amino, mono- or di (alkyl d-4) amino C 1-6 alkyl, C 1-6 alkyloxy, C 3-7 cycloalkyl, aryl, arylalkyl C-? 6, aminoalkyl d- 4, mono or di (C1-alkyl, mono- or di (alkyl d-4) aminoalkyl CM O mono- or di (alkyl d-4) amino-a! -cylamino CM; R2 represents aryl, Het1, optionally substituted C3-7 cycloalkyl with -C (= O) -Z-R14, d-β alkyl or C-16 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di (alkyl CM) amino, -C (= O) ) -Z- R14, C alquilo--βalkyloxy, optionally substituted with -C (= 0) -Z-R 14, C alqu-C alqu alkylsulfonyloxy, C 3-7 cycloalkyl optionally substituted with -C (= 0) -Z-R 14 , aryl, aryloxy, arylthio, Het1, Hephoxy and Hetthio, and if X is O, S or NR3, then R2 can also represent -C (= 0) -Z-R14, aminothiocarbonyl, alkylcarbonyl CM optionally substituted with -C (= O) -Z-R14, alkylthiocarbonyl C optionally substituted with -C (= 0) -Z-R14, arylcarbonyl, arylthiocarbonyl, Het1carbonyl or Hetlthiocarbonyl; represents hydrogen or alkyl d-; each R4 independently represents -C (= 0) -Z-R14, alkyl d-β, halo, polyhaloalkyl C6-6, hydroxy, mercapto, alkyloxy d-β, alkylthio d-β, alkylcarbonyloxy Ci-β, aryl, cyano , nitro, Het3, R6, NR7R8 or substituted alkyl with -C (= O) -Z-R14, Het3, R6 or NR7R8; each R 5 independently represents -C (= O) -Z-R 14, d-β alkyl, halo, C 6 -haloalkyl, hydroxy, mercapto, C 6 -alkyloxy, alkylthio Ci-e, alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or alkylCM substituted with -C (= O) -Z-R14, Het3, R6 or NR7R8; each R6 independently represents C1-6 alkylsulfonyl, aminosulfonyl, mono- or di- (alkyl CM) aminosulfonyl, mono- or di (benzyl) aminosulfonyl, polyhaloalkyl d-6, sulfonyl, alkylsulfinyl C-? 6, phenylalkylsulfonyl C1-4 , piperazinylsulfonyl, piperidinylsulphonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-alkyl d-4-N-piperidinylaminosulfoniio or mono- or di (alkyl d-4) aminoalkyl C? -4Sulfonyl; each R7 and each R8 is independently selected from hydrogen, C-alkyl, hydroxyalkyl CM, dihydroxyalkyl, CMaryl, arylalkyl, CM, alkyloxy, C-alkyl, CM alkyl, carbonyl, arylcarbonyl, Het3, carbonyl, -C (= O) -Z-R14, mono- or di (alkyl Ci-4) amino-alkyl CM, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3 amino-thiocarbonyl, C3-7 cycloalkyl, pyridinylalkyl CM, alkanediyl CM, -C (= O) -Z-R14, -Y-alkanediyl d-4-C (= O) -Z-R14, Het3 and R6; or R7 and R8 taken together with the nitrogen atom to which it is attached form a radical of the formula R9 and R10 are independently selected from hydrogen, CM alkyl, hydroxyalkyl CM, dihydroxyalkyl CM, phenyl, phenylalkyl CM, alkyloxy CM, alkyl CM, alkylcarbonyl CM, phenylcarbonyl, Het3 carbonyl, -C (= 0) -Z-R14, mono- or di (alkyl CM) amino-alkyl CM, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3 aminocarbonyl, Het3 aminocarbonyl, cycloaikyl C3-7, pyridinylalkyl CM, alkanediyl CM-C (= 0) -Z-R14, Het3 and R6; or R9 and R10 taken together form the nitrogen atom to which they are attached form a radical of the formula: Each R 11 is independently selected from hydroxy, mercapto, cyano, nitro, halo, -C (= O) -Z-R 14, y-alkanediyl d-4-C (= O) -Z-R 14, trihalomethyl, alkyloxy CM, optionally substituted with -C (= 0) -Z-R14, formyl, trihaloalkyl d-4-sulfonyloxy, R6, NR7R8, C (= 0) NR15R16, aryl, aryloxy, arylcarbonyl, C3-7 cycloaicil, optionally substituted with -C (= O ) -Z-R14, C3-7 cycloalkyloxy optionally substituted with -C (= O) -Z-R14, phthalimide-2-yl, Het3, Het4 and C (= O) Het3; R12 and R13 are independently selected from hydrogen, CM alkyl, CM hydroxylalkyl, CM dihydroxyalkyl, phenyl, phenylalkyl CM, alkyloxy CM, alkylCM, alkyiChemylCM, phenylcarbonyl, -C (= 0) -Z-R14, mono- or di ( CM alkyl) aminoalkyl CM, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7 cycloalkyl, pyridinylalkyl CM, alkanediyl d-4-C (= O) -Z-R14, -Y-alkanediyl CM-C (= O) -Z-R14 and R6; or R9 and R0 taken together with the nitrogen atom to which it is attached forms a radical of the formula: each Z independently represents O, S; NH, -CH2-O- or -CH2-S- where -CH2- is attached to the carbonyl group; each R 4 independently represents hydrogen, C? -2 aco acyl (having a straight or branched hydrocarbon chain, saturated or unsaturated with 1 to 20 carbon atoms), C alquilo? - alquilo alkyl, optionally substituted alkenyl 03-20 with phenyl, alkyl 03-20, C3-7 cycloalkyl, polyhaloalkyl C2_2o, Het5, phenyl or C1_2alkyl substituted with one or more substituents selected from hydroxy, NR17, R18, phenyl, mono- or di (alkyl CM) amino, cyano, Het5, alkyloxycarbonyl-4, phenylalkyl d-4-oxycarbonyl, and C3-7 cycloalkyl; or R14 represents a radical of the formula: (r) (s) (e) wherein n is 0 to 5; m is 1 to 4; s is zero to 4; r is 0 to 2; Ra, Rb, Rc, Rd, Re and Rf are each independently hydrogen, C 1 -β alkyl, phenyl or C 3-7 cycloalkyl; or Re and Rf taken together can form -CH2-CH2-, -CH2-CH2-, -CH2 or CH2-CH2-CH2-CH2-; R9, Rh and Rk are each independently hydrogen or alkyl CM; R !, is -O-Rb, C 1-6 alkyl, phenyl or C 3-7 cycloalkyl, optionally substituted with alkyloxy d-; Rn is hydrogen, alkyl d-, phenyl, phenylalkyl C? -4, or C3-7 cycloalkyl; Rm is hydrogen or alkyloxy CM; O -Z-R taken together form a radical of the formula: (0 (g) R15 and R16 each independently are selected from hydrogen, CM alkyl, hydroxyalkyl CM, dihydroxyalkyl CM, aryl, arylalkyl CM, alkyloxy CM, alkyl CM, -C (= O) -Z-R14, arylcarbonyl, mono - or di- (alkyl d-4) amino-alkyl d-4, arylaminocarbonyl, arylaminothiocarbonyl aminocarbonylmethylene, mono- or dl (alkyl CM), arylaminocarbonyl, arylaminothiocarbonyl, aminocarbonylmethylene, mono- or di (alkyl d-4) aminocarbonyl-methylene , Het3 aminocarbonyl, Het3 aminothiocarbonyl, pyridinylalkyl CM, Het3 or R6, or R15 and R16 taken together with the nitrogen atom to which they are attached form a radical of the formula: R »17 and R > 18 are each independently selected from hydrogen, CM alkyl, hydroxyalkyl d-4, dihydroxyalkyl CM, phenyl, phenylalkyl CM, alkoloxl CM, alkylCM, alkylcarboniumCM, phenylcarbonyl, mono- or di (C1-4alkyl) aminoalkyl d-4, phenylaminocarbonyl, phenylaminothiocarbonyl, C 3-7 cycloalkyl, pyridinylalkyl CM, alkanediyl CM-C (= 0) -Z-C 1-6 alkyl, -C (= 0) -Z-C 1-6 alkyl, Y-alkanediyl d -4-C (= 0) -Z-C6-alkyl and R6; aryl represents phenyl optionally substituted with one, two or three substituents each, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, alkylCM, C3-7 cycloalkyl, alkyloxyCM, formyl, polyhaloalkylCM, NR 9 R 10, - (= 0) -NR 9 R 10, -C (= 0) -Z-R 14 R 6, -O-R 6, phenyl, Het 3, and C 4 -4 alkyl substituted with one or more substituents each independently selected from halo, hydroxy , alkyloxy d-4, -C (= 0) -ZR 4, -Y-alkanediyl C -C (= 0) -Z-R14, Het3 or NR9R10; Het1 represents a selected from pyrrolyl heterocycle, pyrrolinyl, imidazoiilo, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazoiilo, thiazolyl, thiazolinyl, sotiazolilo, thiadiazolyl, oxadiazoliio, pyridinyl , pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trityanil, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indonilyl, purinyl, 1H -pyrazolo [3,4-d] pyrimidinyl, benzimidazolyl, quinolyl, soquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazole [2,1-b] thiazolium; wherein said heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2 and R11; Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazoliniio, isoxazolyl, thiazolyl, thiazoylin, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioaxanyl, dithianyl , trityanil, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolium, indolinyl, purinyl, 1H-pyrazolo [3,4-d] pyrimidinyl, benzimidazolyl, quinoxy, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazol [2,1-b] thiazolyl; wherein said heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from R11 and optionally substituted alkyl with one or two substituents each independently selected from R11; Het3 represents a monocyclic heterocycle selected from azetidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and tetrahydropyranyl; wherein said monocyclic heterocycles each independently can optionally be substituted with, when possible, one, two, three or four substituents each independently selected from hydroxy, alkylCM, alkyloxyCM, -C (= O) -Z-R14, alkylcarbonylC , phenylalkyl CM, piperidinyl, NR12R13, R6 and C-alkyl substituted with one or two substituents each independently selected from hydroxy, C-alkyloxy, phenyl, -Y-alkanediyl CM, -C (= O) -Z-R14, -C ( = O) -Z-R14, R6 or NR12R13; Het4 represents a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pipazonyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl; Het5 represents a heterocycle selected from pyrrolyl, pyrroiinyl, imidazolyl, imidazo-linyl, pyrazolyl, pyrazolinyl, triazoyl, tetrazoyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazoyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tiomorfoliniio, tetrahydropyranyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indoiilo, isoindolyl, indoniiilo, purinyl, 1H-pyrazolo [3,4-d-pyrimidinyl, benzimidazolyl, quinolyl, isoqulnolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo [2,1-b] thiazolyl; wherein said heterocycles each independently can optionally be substituted with one, or when possible, two, three or four substituents, each independently selected from hydroxy, CM alkyl, alkyloxy CM, alkylcarbonyl CM, piperidinyl, NR17R18, C (= O) - Z-Alkyl d-6, R 6, sulfonamido and C 1 -alkyl, substituted with one or two substituted with one or two substituents independently selected from hydroxy, Ci-4 alkyloxy, phenyl, C (= O) -Z-alkyl d-6, -A-C6-alkanediyl -6-C (= O) -Z-C6-alkyl, R6 or NR 7R18; If each time R2 is different from aminocarbonyl, d-β-oxoxycarbonylalkyl Ci-β and R11 is different from carboxyl, dyalkyloxycarbonyl d-4, aminocarbonyl, alkylaminocarbonyl CM, hydroxyC1-4alkylaminocarbonyl, alkyl d4carbonylaminocarbonyl, cycloalkylaminocarnyl C3 -7; and R7, R8, R9, R10, R12, R13, R15 and R16 are different from alkyl d. 4-carbonyloxyalkyl d-4-carbonyl, hydroxyalkylcarbonyl; and Het3 is different from a monocyclic heterocycle substituted with carboxyl or alkyloxycarbonyl CM; and the compounds of the formula (I) contain at least one portion -C (= O) -Z-R14.
2. A compound according to claim 1, wherein: R2 represents aryl, Het1, C3 cycloaicyl-optionally substituted with -C (= 0) -Z-R14, d-6 alkyl or C6-6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di (alkyl d-4) amino, -C (= 0) -Z-R14, Ci-e alkyloxy, optionally substituted with -C (= O) -Z-R14, alkylsulfonyloxy d-6, optionally substituted C3-7 cycloalkyl with -C (= O) -Z-R14, aryl, aryloxy, arylthio, Het1, Hetoxi and Hetthio; and if X is O, S or NR3, then R2 may also represent -C (= 0) -Z-R14, aminothiocarbonyl, C1-4 alkylcarbonyl, aminothiocarbonyl, alkylcarbonyl CM optionally substituted with -C (= O) -Z-R14 , alkylthiocarbonyl d-4 optionally substituted with -C (= O) -ZR 4, arylcarbonyl, arylthiocarbonyl; each R6 independently represents C6-6 alkylsulfonyl, aminosulfonyl, mono- or di- (C-14 alkyl) aminosulfonyl, mono- or di (benzyl) aminosulfonyl, polyhaloalkyl d -sulfonyl, C1-6 alkylsulfinyl, phenylalkyl C? -4Sulfon? it, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-alkyl C? -4-N-piperidinylaminosulfonyl; each R7 and each R8 are independently selected from hydrogen, CM alkyl, C4 hydroxyalkyl, CM dihydroxyalkyl, aryl, arylalkyl CM, alkylCM oxyalkyl C, alkylcarbonyl CM, arylcarbonyl, -C (= O) -Z-R14, mono- or di (methiquil d- ^ aminoalkyl CM, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminocarbonyl, C3-7 cycloalkyl, pyridinylalkyl CM, Het3 and R6; R9 and R10 are each independently selected from hydrogen, CM alkyl, hydroxyalkyl CM, dihydroxyalkyl CM, phenyl, phenylalkyl CM, alkyloxy CM alkylCalkyl, alkylcarbonylCM, phenylcarbonyl, -C (= 0) -Z-R14, mono- or di (alkylCM) aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, cycloalkyl C3-7, pyridinylalkyl CM, Het3 and R6, each R1 is independently selected from hydroxy, mercapto, cyano, nitro, halo, -C (= O) -Z-R14, trihalomethyl, C1-4alkyl optionally substituted with -C (= 0) -Z-R14, formyl, trihaloalkium CM sulfonyloxy, R6 , NR7R8, C (= O) -NR15R16, aryl, aryloxy, arylcarbonyl, C3-7 cycloalkyl optionally substituted with -C (= O) -Z-R14, C3-7 cycloalkyloxy optionally substituted with -C (= O) Z- R14, phthalimide-2-yl, Het3 and C (= 0) Het3; R12 and R13 are each independently selected from hydrogen, CM alkyl, hydroxyalkyl CM, dihydroxyalkyl CM, phenyl, phenylalkyl CM, alkyl C-oxyalkyl CM, phenylaminocarbonyl, phenylaminothiocarbonyl, C3.7 cycloalkyl, pyridinylalkyl d-4 and R6; each R14 independently represents hydrogen, C1-20 acyl (with a straight or branched, saturated or unsaturated hydrocarbon chain having between 1 and 20 carbon atoms), C1-20 alkyl, C3-7 cycloalkyl, phaloalkyl d-2o; or R14 represents a radical of the formula: (a) (b) Ra, Rb, Rc, Rd and Rf are each independently hydrogen, C6-6 alkyl or C3-7 cycloalkyl; or Re and Rf taken together can form -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-; R15 and R16 are each independently selected from dihydroxyalkyl CM, aryl, arylalkyl CM, alkyloxy CM alkyl C -C (= 0) -Z-R14, arylcarbonyl, mono- or di (alkylC? -4) -aminoaikyl C -4, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, pyridinylalkyl d-4, Het3 or R6; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido halo, hydroxy, alkylCM, alkyloxyCM, polyhaloC1-4alkyl, NR9R10; Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazoyl, imidazolinyl, pyrazoyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxalanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trityanil , triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indonylyl, purinyl, 1-pyrazolo [3,4-d] pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazoinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl, imidazole [2,1] thiazolyl: wherein said heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and alkylCM optionally substituted with Het2 and R11; Het2 represents a heterocycle selected from pyrrolyl, pyrroiinyl, imidazolyl, imidazonyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrodfuranyl, thienyl, thiolanium, dioxalanyl oxazolyl, oxazoliniio, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl. , pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trityanil, triazinyl; wherein said heterocycles each independently can be optionally substituted with one, or when possible, two or three substituents each independently selected from R 11 and C 1-4 alkyl optionally substituted with one or two substituents each independently selected from R 11; Het3 represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently can optionally be substituted with, where possible, one, two, three or four substituents each independently selected from CM alkyl, alkyloxy CM, -C (= 0) -Z-R14, alkylcarbonyl CM, phenylalkyl CM, piperidinyl, NR12R13, R6 and alkylCM substituted with -C (= 0) -Z-R14, R6 or NR12R1
3. 3. A compound according to claim 1 or 2, wherein the 6-azauracil moiety is in the para position with respect to the central carbon atom.
4. A compound according to any of claims 1 to 3 wherein one of the following restrictions applies: p is 0, 1 or 2; X is S; NR3, or a direct link, more particularly NH or a direct link; each R 5 independently is halo, polyhaloalkyl CM, C 1-6 alkyl, C 1-6 alkyl, alkyloxy or C 1-6 aryl, preferably, chloro or trifluoromethyl, more preferably chloro; at least one portion -C (= 0) -Z-R14 contained in the compound of the formula (I) arises from R2; R 2 is Het 1 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 (= 0) -Z-R 14 optionally substituted C 1-6 alkyloxy with C (= O) -Z-R14, C1-6 alkylsulfonyloxy, C3 cycloalkyl- optionally substituted with C (= O) -Z-R14, aryl, aryloxy, arylthio, Het1, Hetoxi and Hetthio; and if X is O, S or NR3, then R2 may also represent aminothiocarbonyl, C-alkylcarbonyl optionally substituted with C (= 0) -Z-R14, alkylthiocarbonyl CM optionally substituted with C (= O) -Z-R14, arylcarbonyl, arylthiocarbonyl , Hethylcarbonyl or ethylcarbonyl; particularly R2 is Het1 or in the case where X is NH, R2 may also be aminothiocarbonyl or Hefcarbonyl; R1 is hydrogen or methyl; preferably methyl; R6 is C1-6 alkylsulfonyl or aminosulfonyl; R7 and R8 are each independently hydrogen, alkylCM, Het3 or R6; R9 and R10 are each independently hydrogen, alkyloxy C, alkyl CM, alkylcarbonyl C, aminocarbonyl, Het3 carbonyl, Het3 or R6; R11 is cyano, nitro, halo, alkyloxy CM, formyl, NR7R8, C (= 0) NR15R16, -C (= 0) -Z-R14, ary, arylcarbonyl, Het3, Het4 or C (= 0) Het3, more preferably R11 is phenyl, -C (= 0) -OR14, -C (= 0) -S-R14 or -C (= 0) -NH-R14; R14 is dihydrofuranyl, C5-20 alkyl, C3-20 alkenyl, polyhaloC-C6 alkyl, Het5 or C1-20 alkyl substituted with one or more substituents selected from alkylamino phenyl CM, cyano, Het1, hydroxy and C3-7 cycloalkyl; R17 and R18 are each independently hydrogen or phenyl; aryl is phenyl optionally substituted with one, two or three substituents each independently selected from nitro, halo, hydroxy, alkylCM, C3-7 cycloalkyl, alkyloxyCM, formyl, polyhaloalkyl CM, NR9R10, C (= 0) NR9R10, C ( = 0) -0-R14, -O-R6, phenyl, C (= 0) Het3 and C? -4 alkyl substituted with one or more substituents each independently selected from halo, hydroxy, alkyloxy CM, C (= 0 ) -Z-R14, Het3 or NR9R10; Het1 is monocyclic heterocycle selected from pyrrolyl, midazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolium, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, in particular imidazolyl, oxadiazolyl , thiazolyl, pyrimidinyl or pyridyl, wherein said monocyclic heterocycles each independently can optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and C-alkyl optionally substituted with Het2 or R11; preferably, Het1 is imidazoiyl, oxadiazoiyl, thiazoiiio or pyridinyl each independently and optionally substituted with one or, when possible, two or three substituents each independently selected from Het2, R11 and CM alkyl optionally substituted with Het2 or R11; Het2 is an aromatic heterocycle, more particularly furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently may optionally be substituted with one, or when possible, two or three substituents, each independently selected from R11 and CM alkyl.; Het3 is azetidinyl, piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, when possible, one, two, three or four substituents, each independently selected from hydroxy, CM alkyl, alkylcarbonyl CM, piperidinyl and C substituted with one or two substituents independently selected from hydroxy, alkyloxy CM O phenyl Het 4 is thienyl; Het5 is piperidinyl or piperazinyl optionally substituted with CM O sulfonamido alkyl.
5. A compound according to any of claims 1 to 4, wherein R2 represents aryl, Het1, C3-7 cycloalkyl optionally with -C (= O) -Z-R14 or C6_6 alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or (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 , Het1oxi and Het1tio; and if X is O, S or NR3, then, R2 may represent -C (= O) -Z-R14, aminothiocarbonyl, alkylcarbonyl CM, alkylthiocarbonyl CM, arylcarbonyl or arylthiocarbonyl; wherein each of the heterocycles can independently and optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and optionally substituted alkyl with Het2 or R11.
6. A compound according to any of claims 1 to 5, wherein R2 is oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl; each may optionally be substituted with one, or when possible, two or three substituents each independently selected from Het2, R11 and C1-6 alkyl optionally substituted with Het2 or R11.
7. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as claimed in claims 1 or 6.
8. The use of a compound as claimed in claims 1 or 6 in the manufacture of a medicament for treating bronchial asthma.
9. A process for preparing a compound as claimed in claim 1, characterized in that: a) reacting an intermediate of the formula (II) wherein W1 is a suitable transfer group with a suitable reagent of the formula ( III) optionally in a solvent inert to the reaction and in the presence of a base; (ll) where R1, R2, R4, X and q are as defined in claim 1, and D represents: wherein R5 and p are as defined in claim 1; b) eliminate the E group of a triazinedione of the formula (V) wherein R1, R2, R4, R5, X and q are as defined in claim 1; c) reacting a ketone of the formula (X) with an intermediate of the formula (III-a) in the presence of a base and in a solvent inert to the reaction thus obtaining a compound of the formula (l-a-2); (l-a-2) where R, R and q are as defined in claim 1 and D is defined as in claim 1 a); d) converting a compound of the formula (1-a-2) to a compound of the formula (1-a-3) using the group transformation reactions known in the art; (l-a-2) (l-a-3) wherein R2, R4 and q are as defined in claim 1 and D is as defined in claim 7a); e) converting a compound of the formula (1-a-2) to a compound of the formula (1-a-4) using the group transformation reactions known in the art; (l-a-2) (l-a-4) wherein R2, R4 and q are as defined in claim 1 and D is as defined in claim 7a); f) converting a compound of the formula (l-to-4) to a compound of the formula (l-to-5) using the group transformation reactions known in the art; (l-a-4) (l-a-5) wherein R2, R4 and q are as defined in claim 1 and D is as defined in claim 7a); g) reacting an intermediate of the formula (XII) wherein W4 is a suitable transfer group with an intermediate of the formula (III) optionally in the presence of a suitable base; thereby obtaining a compound of the formula (l-b); where R2, R4, X and q are as defined in claim 1 and D is as defined in claim 7a); h) reacting an intermediate of the formula (XIV) with an intermediate of the formula (XV) wherein W3 is a suitable transfer group, in the presence of a suitable base and optionally in the presence of a solvent inert to the reaction; thus obtaining a compound of the formula (I-c); alkyl of C ^ .6 (l-c) wherein R4 and q are as defined in claim 1 and D is as defined in claim 7a); i) forming cycles with an intermediate of the formula (XX) wherein Y is O, S or NR3, in a compound of the formula (l-d-1), before the present of a suitable solvent at an elevated temperature; (XX) where R, R1, R4 and q are as defined in claim 1 and D is as defined in claim 7a); j form cycles of an intermediary of the formula (XX!) In a compound of the formula (l-d-2) in a solvent inert to the reaction at an elevated temperature, where R, R1, R4 and q are as defined in claim 1 and D is as defined in claim 7a); k) forming cycles with an intermediate of the formula (XXI i) where Y is O, S or NR3, in a compound of the formula (l-d-3), in a suitable solvent, where R, R1, R4 and q are as defined in claim 1 and D is defined as in claim 7a); I) forming cycles of an intermediate of the formula (XXIII) where Y is O, S or NR3, in a compound of the formula (l-d-4), in a solvent inert to the reaction and in the presence of an acid, where R, R1, R4 and q are as defined in claim 1 and D is as defined in claim 7a); m) forming cycles of an intermediate of the formula (XXIII) where Y is O, S or NR3 in a compound of the formula (l-d-5), in a solvent inert to the reaction and in the presence of an acid, where R, R1, R4 and q are as defined in claim 1 and D is as defined in claim 7a); n) reacting an intermediate of the formula (XXIV) with an intermediate of the formula (XXV) where Y is O, S or NR3, and W5 is a suitable assignment group; thus forming a compound of the formula (1-d-6) in a solvent inert to the reaction and in the presence of a base, where R, R1, R4 and q are as defined in claim 1 and D is as defined in claim 7a); o) reacting an intermediate of the formula (XXVI) with an intermediate of the formula (XXVII) where W6 is a suitable assignment group; thus forming a compound of the formula (1-d-7), in a solvent inert to the reaction and in the presence of an acid; (l-d -7) where R, R1, R4, and q are as defined in claim 1 and D is as defined in claim 7a); p) reacting an intermediate of the formula (XXXI 11) with a thioamide of the formula (XXXIV); thereby forming a compound of the formula (1-d-9) in a solvent inert to the reaction at an elevated temperature; (XXXIII) (XXXIV) (l-d-9) where R, R1, R4 and q are as defined in claim 1 and D is as defined in claim 7a); and if desired, converting the compounds of the formula (I) into each of the following transformations known in the art, and even more, if desired, converting the compounds of the formula (I) into an acid addition salt therapeutically. active, non-toxic by treatment of an acid, or in a therapeutically active, non-toxic base addition salt by means of treatment with a base, or conversely, converting the acid addition form to a free base by means of treatment with an alkali, or converting the base addition salt to a free acid by means of treatment with an acid; and also, if desired, preparing the stereochemically isomeric forms or their N-oxide forms.
10. An in vitro method for labeling a receptor comprising the steps of; a) radio-labeling a compound as defined in claim 1; b) administering said radiorotouted compound in a biological material; c) detecting the emissions of the radio-labeled compound. SUMMARY OF THE INVENTION The present invention relates to the compounds of the formula (i), an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or its stereochemically isomeric form, where p is from 0 to 4: q is from 0 to 5; X is O, S; NR3 or a direct link; or -X-R2 is CN; R1 is H, OH, halo, NH2, mono- or di (C? -4 alkyl) NH2, C1-6 alkyl, alkyl d-6O, C3-7 cycloalkyl, aryl, arylalkyl d-?, NH2alkyl C? -, mono or di (C 4 alkyl) NH 2 aC 4 alkyl or mono- or di (C alkyl) NH 2 alkyl CMNH 2; R2 is aryl, Het1, optionally substituted C3-7 cycloalkyl, optionally substituted C1-6alkyl; R3 is H or alkyl CM; R 4 and R 5 are -C (= 0) -Z-R 14, C 1-6 alkyl, halo, polyhaloC 1-6 alkyl, OH, mercapto, Ci-eO alkyl, Cilt-6 alkylthio, C C-C6 alkyl (= O ) Or, aryl, cyano nitro, Het3, R6, NR7R8 or d_4 alkyl substituted with -C (= O) -Z-R14, Het3, R6 or NR7, R8 or substituted alkyl with -C (= 0) -Z- R14, Het3, R6 or NR7, R8; Z is O, S, NH, -CH2-0- or -CH2-S-; R 14 is H, C 2 -2 acyl, optionally substituted C 20 alkyl, optionally substituted C 3-20 alkenyl, C 3-2 alkynyl, C 3-7 cycloalkyl, C 1-20 polyhaloalkyl, Het 5, phenyl; or R14 is a radical containing oxygen; aryl is optionally substituted phenyl; Het1, Het2, Het3 and Het5 are optionally substituted heterocycles; Het4 is a monocyclic heterocycle; if R2 is different from NH2C (= 0), alkyl d-6OC (= 0) C6-C6 alkyl; and R11 is different from COOH, alkyl d.4OC (= 0), NH2C (= 0), alkyl CMNH2C (= 0), OHalkyl d.4NH2C (= 0), alkyl C? .4C (= 0) NH2C (= O), C3-7NH2C cycloalkyl (= 0); and R7, R8, R9, R10, R12, R13, R15 and R16 are different from C? -4C alkyl (= 0), CMC OHalkyl (= 0); and Het3 is different from a monocyclic heterocycle substituted with COOH or alkyl CMOC (= 0); and the compounds of the formula (I) contain at least one portion -C (= 0) -Z-R14; to the procedures for their preparation and compositions comprising them; also, it refers to its use as a medicine. JANSSEN / ET / all P01 / 825F
MXPA/A/2001/006154A 1998-12-18 2001-06-15 Il-5 inhibiting 6-azauracil derivatives MXPA01006154A (en)

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EP98204336.6 1998-12-18

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MXPA01006154A true MXPA01006154A (en) 2001-12-13

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