US2005090495A1PendingUtilityA1

Novel IL-5 inhibiting 6-azauracil derivatives for marking and identifying receptors and imaging organs

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Priority: Jul 10, 1997Filed: Sep 25, 2003Published: Apr 28, 2005
Est. expiryJul 10, 2017(expired)· nominal 20-yr term from priority
Inventors:Jean Fernand Armand LacrampeEddy Jean Edgard FreyneMarc Gaston VenetGustaaf Maria Boeckx
C07D 413/10C07D 417/10C07D 417/14C07D 403/12C07D 413/14C07D 401/10C07D 403/10A61P 37/08
52
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Claims

Abstract

The present invention is concerned with the compounds of formula the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, p and q are 0, 1, 2, 3 or 4 and q is also 5; X is O, S, NR 3 or a direct bond; R 1 is hydrogen, hydroxy, halo, optionally substituted amino, optionally substituted C 1-6 alkyl, C 1-6 alkyloxy, C 3-7 cycloalkyl or aryl; R 2 is aryl, Het 1 , C 3-7 cycloalkyl, optionally substituted C 1-6 alkyl; and if X is O, S or NR 3 , then R 2 may also be a carbonyl or thiocarbonyl linked substituent; R 3 is hydrogen or C 1-4 allyl; R 4 and R 5 independently are optionally substituted C 1-6 alkyl, halo, hydroxy, mercapto, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylcarbonyloxy, aryl, cyano, nitro, Het 3 , R 6 or NR 7 R 8 ; R 6 is substituted sulfonyl or sulfinyl; R 7 and R 8 are hydrogen, optionally substituted C 1-4 alkyl, aryl, a carbonyl or thiocarbonyl linked substituent, C 3-7 cycloalkyl, Het 3 and R 6 ; R 9 and R 10 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, phenyl, a carbonyl or thiocarbonyl linked substituent, C 3-7 cycloalkyl, Het 3 and R 6 ; R 11 is hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl, trihaloC 1-4 alkylsulfonyloxy, R 6 , NR 7 R 8 , C(═O)NR 7 R 3 , aryl, aryloxy, arylcarbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, phthalimide-2-yl, Het 3 and C(═O)Het 3 ; R 12 and R 13 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, phenyl, a carbonyl or thiocarbonyl linked substituent, C 3-7 cycloalkyl and R 6 ; aryl is optionally substituted phenyl; Het 1 , Het 2 and Het 3 are optionally substituted heterocycles; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.

Claims

exact text as granted — not AI-modified
1 - 12 . (canceled)  
     
     
         13 . A method of marking or identifying a receptor comprising the steps of: 
 a) radiolabelling a compound of formula (I)                          a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:    p represents an integer being 0, 1, or 2;    q represents an integer being 0, 1, or 2;    X represents O, S, NR 3  or a direct bond;    R 1  represents hydrogen, hydroxy, halo, amino, C 1-6 alkyl, C 1-6 alkyloxy or mono- or di(C 1-4 alkyl)aminoC 1-4 alkylamino; in particular, hydrogen, methyl and hydroxy;    R 2  represents oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;    each R 4  independently represents C 1-6 alkyl, halo, polyhaloC 1-6 alkyl or C 1-6 alkyloxy;    each R 5  independently represents C 1-6 alkyl, halo or C 1-6 alkyloxy;    each R 6  independently represents C 1-6 alkylsulfonyl, aminosulfonyl or phenylC 1-4 alkylsulfonyl;    each R 7  and each R 8  are independently selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, dihydroxyC 1-4 alkyl, aryl, arylC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, C 3-7 cycloalkyl, pyridinylC 1-4 alkyl, Het 3  and R 6 ;    R 9  and R 10  are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyloxyC 1-4 alkylcarbonyl, hydroxyC 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonylcarbonyl, Het 3 aminothiocarbonyl and R 6 ;    each R 11  independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl, trihaloC 1-4 alkylsulfonyloxy, R 6 , NR 7 R 8 , C(═O)NR 7 R 8 , aryl, aryloxy, arylcarbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, phthalimide-2-yl, Het 3  and C(═O)Het 3 ;    R 12  and R 13  are each independently selected from hydrogen and C 1-4 alkyl; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, NR 9 R 10 , R 6 , phenyl, Het 3  and C 1-4 alkyl substituted with NR 9 R 10 ;    Het 1  represents a heterocycle selected from a heterocycle selected from imidazolyl, triazolyl, furanyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, benzothiazolyl, benzoxazolyl, purinyl, 1H-pyrazolo-[3,4-d]pyrimidinyl, benzimidazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazo-[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;    Het 2  represents furanyl, thienyl or pyridinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with C 1-4 alkyl;    Het 3  represents pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two or three substituents each independently selected from C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, phenylC 1-4 alkyl, piperidinyl, NR 12 R 13  and C 1-4 alkyl substituted with NR 12 R 13 ;    b) administering said radiolabelled compound to biological material; and    c) detecting the emissions from the radiolabelled compound.    
     
     
         14 . The method of  claim 13  wherein the 6-azauracil moiety of said compound according to  claim 13  is in the para position relative to the central carbon atom.  
     
     
         15 . The method of  claim 13  wherein the 6-azauracil moiety of said compound according to  claim 13  is in the para position relative to the central carbon atom; q is 1 or 2 and one R 4  substituent is in the 4 position; and p is 1 or 2 and the one or two R 5  substituents are in the ortho position relative to the central carbon atom.  
     
     
         16 . The method of  claim 13  wherein one or more atoms in the compound are replaced by radioactive isotopes.  
     
     
         17 . The method of  claim 13  wherein the compound comprises at least one halo which is a radioactive isotope of iodine, bromine, or fluorine.  
     
     
         18 . The method of  claim 13  wherein the compound comprises at least one  11 C-atom or tritium atom.  
     
     
         19 . The method of  claim 13  wherein R 3  and/or R 4  are a radioactive halogen atom.  
     
     
         20 . A method of imaging an organ comprising the steps of: 
 a) radiolabelling a compound of formula (I)                          a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:    p represents an integer being 0, 1, or 2;    q represents an integer being 0, 1, or 2;    X represents O, S, NR 3  or a direct bond;    R 1  represents hydrogen, hydroxy, halo, amino, C 1-6 alkyl, C 1-6 alkyloxy or mono- or di(C 1-4 alkyl)aminoC 1-4 alkylamino; in particular, hydrogen, methyl and hydroxy;    R 2  represents oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;    each R 4  independently represents C 1-6 alkyl, halo, polyhaloC 1-6 alkyl or C 1-6 alkyloxy;    each R 5  independently represents C 1-6 alkyl, halo or C 1-6 alkyloxy;    each R 6  independently represents C 1-6 alkylsulfonyl, aminosulfonyl or phenylC 1-4 alkylsulfonyl;    each R 7  and each R 8  are independently selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, dihydroxyC 1-4 alkyl, aryl, arylC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, C 3-7 cycloalkyl, pyridinylC 1-4 alkyl, Het 3  and R 6 ;    R 9  and R 10  are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyloxyC 1-4 alkylcarbonyl, hydroxyC 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonylcarbonyl, Het 3 aminothiocarbonyl and R 6 ;    each R 11  independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl, trihaloC 1-4 alkylsulfonyloxy, R 6 , NR 7 R 8 , C(═O)NR 7 R 8 , aryl, aryloxy, arylcarbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, phthalimide-2-yl, Het 3  and C(═O)Het 3 ;    R 12  and R 13  are each independently selected from hydrogen and C 1-4 alkyl; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, NR 9 R 10 , R 6 , phenyl, Het 3  and C 1-4 alkyl substituted with NR 9 R 10 ;    Het 1  represents a heterocycle selected from a heterocycle selected from imidazolyl, triazolyl, furanyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, benzothiazolyl, benzoxazolyl, purinyl, 1H-pyrazolo-[3,4-d]pyrimidinyl, benzimidazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazo-[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;    Het 2  represents furanyl, thienyl or pyridinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with C 1-4 alkyl;    Het 3  represents pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two or three substituents each independently selected from C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, phenylC 1-4 alkyl, piperidinyl, NR 12 R 13  and C 1-4 alkyl substituted with NR 12 R 13 ;    b) administering a sufficient amount of said radiolabelled compound in an appropriate composition to an animal; and    c) detecting the location of said radiolabelled compound.    
     
     
         21 . The method of  claim 20  wherein the 6-azauracil moiety of said compound according to  claim 20  is in the para position relative to the central carbon atom.  
     
     
         22 . The method of  claim 20  wherein the 6-azauracil moiety of said compound according to  claim 20  is in the para position relative to the central carbon atom; q is 1 or 2 and one R 4  substituent is in the 4 position; and p is 1 or 2 and the one or two R 5  substituents are in the ortho position relative to the central carbon atom.  
     
     
         23 . The method of  claim 20  wherein one or more atoms in the compound are replaced by radioactive isotopes.  
     
     
         24 . The method of  claim 20  wherein the compound comprises at least one halo which is a radioactive isotope of iodine, bromine, or fluorine.  
     
     
         25 . The method of  claim 20  wherein the compound comprises at least one  11 C-atom or tritium atom.  
     
     
         26 . The method of  claim 20  wherein R 3  and/or R 4  are a radioactive halogen atom.  
     
     
         27 . The method of  claim 20  wherein the location of said radiolabelled compounds is detected using imaging techniques.  
     
     
         28 . The method of  claim 27  wherein said imaging techniques comprises positron emission tomography.  
     
     
         29 . The method of  claim 27  wherein said imaging techniques comprises single photon emission computerized tomography.  
     
     
         30 . The method of  claim 13  wherein said biological material comprises an animal.  
     
     
         31 . The method of  claim 13 , wherein said biological material comprises a human being.  
     
     
         32 . The method of  claim 13 , wherein said biological material comprises a tissue sample.  
     
     
         33 . The method of  claim 13  wherein the emissions of said radiolabelled compounds is detected using imaging techniques.  
     
     
         34 . The method of  claim 33  wherein said imaging techniques comprises positron emission tomography.  
     
     
         35 . The method of  claim 33  wherein said imaging techniques comprises single photon emission computerized tomography.  
     
     
         36 . A method of evaluating receptor binding ability of a test compound, comprising the steps of: 
 a) radiolabelling a compound of formula (I)                          a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:    p represents an integer being 0, 1, or 2;    q represents an integer being 0, 1, or 2;    X represents O, S, NR 3  or a direct bond;    R 1  represents hydrogen, hydroxy, halo, amino, C 1-6 alkyl, C 1-6 alkyloxy or mono- or di(C 1-4 alkyl)aminoC 1-4 alkylamino; in particular, hydrogen, methyl and hydroxy;    R 2  represents oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;    each R 4  independently represents C 1-6 alkyl, halo, polyhaloC 1-6 alkyl or C 1-6 alkyloxy;    each R 5  independently represents C 1-6 alkyl, halo or C 1-6 alkyloxy;    each R 6  independently represents C 1-6 alkylsulfonyl, aminosulfonyl or phenylC 1-4 alkylsulfonyl;    each R 7  and each R 8  are independently selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, dihydroxyC 1-4 alkyl, aryl, arylC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylaminocarbonyl, arylaminothiocarbonyl, C 3-7 cycloalkyl, pyridinylC 1-4 alkyl, Het 3  and R 6 ;    R 9  and R 10  are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkylcarbonyloxyC 1-4 alkylcarbonyl, hydroxyC 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonylcarbonyl, Het 3 aminothiocarbonyl and R 6 ;    each R 11  independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C 1-4 alkyloxy, carboxyl, C 1-4 alkyloxycarbonyl, trihaloC 1-4 alkylsulfonyloxy, R 6 , NR 7 R 8 , C(═O)NR 7 R 8 , aryl, aryloxy, arylcarbonyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, phthalimide-2-yl, Het 3  and C(═O)Het 3 ;    R 12  and R 13  are each independently selected from hydrogen and C 1-4 alkyl; aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, NR 9 R 10 , R 6 , phenyl, Het 3  and C 1-4 alkyl substituted with NR 9 R 10 ;    Het 1  represents a heterocycle selected from a heterocycle selected from imidazolyl, triazolyl, furanyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, benzothiazolyl, benzoxazolyl, purinyl, 1H-pyrazolo-[3,4-d]pyrimidinyl, benzimidazolyl, thiazolopyridinyl, oxazolopyridinyl, imidazo-[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het 2 , R 11  and C 1-4 alkyl optionally substituted with Het 2  or R 11 ;    Het 2  represents furanyl, thienyl or pyridinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with C 1-4 alkyl;    Het 3  represents pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two or three substituents each independently selected from C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, phenylC 1-4 alkyl, piperidinyl, NR 12 R 13  and C 1-4 alkyl substituted with NR 12 R 13 ;    b) administering said radiolabelled compound to biological material; and    c) detecting displacement of said compound of formula (I) by said test compound.    
     
     
         37 . The method of  claim 36  wherein the 6-azauracil moiety of said compound according to  claim 36  is in the para position relative to the central carbon atom.  
     
     
         38 . The method of  claim 36  wherein the 6-azauracil moiety of said compound according to  claim 20  is in the para position relative to the central carbon atom; q is 1 or 2 and one R 4  substituent is in the 4 position; and p is 1 or 2 and the one or two R 5  substituents are in the ortho position relative to the central carbon atom.  
     
     
         39 . The method of  claim 36  wherein one or more atoms in the compound are replaced by radioactive isotopes.  
     
     
         40 . The method of  claim 36  wherein the compound comprises at least one halo which is a radioactive isotope of iodine, bromine, or fluorine.  
     
     
         41 . The method of  claim 36  wherein the compound comprises at least one  11 C-atom or tritium atom.  
     
     
         42 . The method of  claim 36 , wherein R 3  and/or R 4  are a radioactive halogen atom.

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