Patent EA-004740-B1 (EA)
Title: Interleukin-5-inhibiting 6-azauracil derivatives
Inventor: LACRAMPE JEAN FERNAND ARMAND
IPC: A61K31/53
Filed: 2000-07-31
Abstract: 1. A compound having the formula: the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: p represents an integer being 0,1,2,3 or 4; X represents a direct bond; Y represents O, S, NR<5> or S (O)2; each R<1> independently represents chloro or trifluoromethyl; R<3> represents hydrogen, C1-6alkyl or C3-7cycloalkyl; R<4> represents hydrogen, C1-6alkyl or C3-7cycloalkyl; each R<6> independently represents aminosulfonyl, mono- or di(C1-4alkyl)aminosulfonyl, Het<6>sulfonyl; each R<11> independently is selected from phenyl, C (=O)-O-R<14>, C(=O)-S-R<14>ORC(=O)-NH-R<14>; each R<14> independently represents hydrogen; C1-20acyl or C1-20alkylC1-20acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms) optionally substituted with one or more substituents selected from hydroxy, halogen, mercapto, C1-4alkyloxyC1-4alkyloxy, mercaptoC1-4alkyl, NR<17>R<18>, aryl, mono- or di-(C1-4alkyl)amino, cyano, Het<5>, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, arylC1-4alkyloxy, arylC1-4alkylthiocarbonyl, arylC1-4alkylthio, Het<5> C1-4alkyloxy, arylC1-4alkylthio, C3-7cycloalkyl and Het<5>C1-4alkylthio, C3-20alkenyl optionally substituted with phenyl; C3-20alkynyl; C3-7cycloalkyl optionally substituted with one or more substituents selected from hydroxy, mercapto, halo, mercaptoC1-4alkyl and hydroxyC1-4alkyl; Het<5> or phenyl or R<14> represents a radical having any of the following formulae: wherein m is 1 to 4, n is 0 to 5, q is 0 to 2, r is 0 to 2 and s is 0 to 4; R<B> is selected from hydrogen, C1-6alkyl, phenyl, C3-7cycloalkyl, C1-4alkyloxyC1-6alkyl and C1-4alkyl-Y-C1-4alkyl; R<A>, R<B>, R<D>, R<E> and R are each independently selected from hydrogen, C1-4alkyl, phenyl and C3-7cycloalkyl, or R<E> and R taken together may form -CH2-CH2-, -CH2-CH2-CH2 or -CH2-CH2-CH2CH2-; Rg, Rh and Rk are each independently hydrogen or C1-4alkyl; Ri is selected from hydroxy, C3-7cycloalkyl and C1-4alkyl, or two Ri taken together may form - form -CH2-CH2-, -CH2-CH2-CH2 or -CH2-CH2-CH2CH2-; (thus building a spiro radical); Rj is selected from -O-Rb; C 1-6alkyl optionally substituted with phenyl or C3-7cycloalkyl; phenyl; C3-7cycloalkyl optionally substituted with C1-4alkyloxy and mono- or di(C1-4alkyl)amino; Rm is hydrogen or C1-4alkyloxy; Rn is hydrogen, C1-4alkyl, C3-7cycloalkyl, phenyl or phenylC1-4alkyl; and W represents O or S; each Z independently represents O or S; R<17> and R<18> are each independently selected from hydrogen, C1-6alkyl optionally substituted with one or more substituents independently selected from hydroxy, mercapto, aryl, mono- or di(C1-4alkyl) amino, C1-4alkyloxy and pyridinyl; C1-4alkyloxycarbonyl; aryl; C1-4alkylcarbonyl; C1-4lkylthiocarbonyl; arylcarbonyl; arylthiocarbonyl; arylaminocarbonyl; arylaminothiocarbonyl; C3-7cycloalkyl; C1-4alkanediyl-C(=O)-Z-C1-6alkyl; -C(=O)-Z-C1-6alkyl; -Y-C1-4alkanediyl-C(=O)-Z-C1-6alkyl and R<6>; aryl represents phenyl; Het<1> represents thiazolyl, pyridinyl, or oxadiazolyl, wherein each of said heterocycles is independently disubstituted with phenyl and/or i) R<11> or ii) C1-4alkyl, substituted with R<11>; wherein R<11> is a group -C((O)-O-R<14>; Het<5> represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may be substituted with, where possible, one, two, three or four substituents each independently selected from carbonyl, C1-4alkyl, -C ((O)-Z-C1-6alkyl and R<6> Het<6> represents pirrolydinyl; with the proviso that R<14> is other than hydrogen, C1-4alkyl, C3-7cycloalkyl, aminocarbonylmethylene in case if R<11> represents -C((O)-O-R<14>. 2. A compound according to claim 1, wherein R<3> represents hydrogen, methyl, ethyl, propyl or cyclohexyl; R<4> represents hydrogen or methyl; each R<14> independently represents dihydrofuranyl, C5-20alkyl, C3-20alkenyl, polyhalogenC1-6alkyl, Het<5>, radical of formula (a) or C1-20alkyl substituted with one or more substituents selected from phenyl, C1-4alkylamino group, cyano group, Het<5>, hydroxy and C3-7cycloalkyl; each R<17> and R<18> independently represents hydrogen or phenyl; and Het<5> represents piperidinyl or piperazinyl optionally substituted with C1-4alkyl, sulfonamido or R<6>. 3. A compound according to claim 1 wherein the 6-azauracil moiety is in the para position relative to the carbon atom bearing the -X-R<2>, R<3> and R<4> substituents. 4. A compound according to claim 1 wherein Het<1> represents thiazolyl. 5. A compound according to claim 1 wherein R<3> and R<4> are both methyl and -X-R<2> is Het<1>. 6. A compound according to claim 1 wherein p is 1 or 2 and each R<1> represents chloro. 7. A compound according to claim 1 wherein R<3> and R<4> are both methyl, X-R<2> is optionally substituted 2-thiazolyl or 3-oxadiazolyl, the 6-azauracil moiety is in the para position relative to the carbon atom bearing the -X-R<2>, R<3> and R<4> substituents, and p is 2 whereby both R<1> substituents are chloro positioned ortho relative to the carbon atom bearing the -X-R<2>, R<3> and R<4> substituents. 8. A compound according to claim 7 wherein X-R<2> is di-substituted phenyl and either (i) R<11> where R<11> is a group of formula -C(=O)-Z-R<14> in which Z is O and R<14> is C1-20alkyl substituted with hydroxy or with Het<5> where Het<5> is piperazinyl substituted with Het<6> sulfonyl, or R<14> is a radical of formula (a) in which R<1> is C1-6alkyl and s is 2, or (ii) C1-4alkyl substituted with R<11> where R<11> is a group of formula -C(=O)-Z-R<14> in which Z is O and R<14> is a radical of formula (a) in which Rj is C1-6alkyl and s is 2. 9. A compound according to claim 1 selected from those of formulae (A), (B), (C) and (D) below: 10. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to claim 1. 11. A process for preparing a composition as claimed in claim 10, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to claim 1. 12. A compound as claimed in any one of claims 1 to 9 for use as a medicine. 13. Use of a compound according to any of claims 1 to 9 in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases. 14. A process for preparing a compound according to claim 1, comprising the step of: reacting an intermediate of formula (II) wherein W<1> is a suitable leaving group with an appropriate reagent of formula (III) optionally in a reaction inert solvent and optionally in the presence of a base at a temperature ranging between -70 degree C and reflux temperature; wherein R<1> R<2>, R<3>, R<4>, p and X are as defined in claim 1 and, if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active nontoxic acid addition salt by treatment with an acid, or into a therapeutically active nontoxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and also, if desired, preparing stereochemically isomeric forms or N oxide forms thereof. 15. A process for preparing a compound according to claim 1, comprising the step of: eliminating the group E of a triazinedione of formula (V) wherein E is an appropriate electron attracting group and R<1>, R<2>, R<3>, R<4>, X and p are as defined in claim 1 and, if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active nontoxic acid addition salt by treatment with an acid, or into a therapeutically active nontoxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and also, if desired, preparing stereochemically isomeric forms or N oxide forms thereof. 16. A process of marking a receptor comprising the steps of: a) radiolabelling a compound according to claim 1; b) administering said radiolabelled compound to biological material; c) detecting the emissions from the radiolabelled compound. 17. A process of imaging an organ, wherein administering a sufficient amount of a radiolabelled compound of formula (I) in an appropriate composition, and detecting the emissions from the radioactive compound.