Pyrimidine derivatives for the prevention of hiv infection

Abstract

This invention concerns the use of a compound for the manufacture of a medicament for the prevention of HIV infection via sexual intercourse and related intimate contact between partners, wherein the compound is a compound of formula (I) a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein the ring containing -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; and pharmaceutical compositions comprising them.

1 . A method for the prevention of HIV infection via sexual intercourse or related intimate contact between partners, said method comprising application to a contact site of a compound selected from the formula  
     
       
         
         
             
             
         
       
     
     a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein 
 -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula 
   —CH═CH—CH═CH—  (a-1); —N═CH—CH═CH—  (a-2); —N═CH—N═CH—  (a-3); —N═CH—CH═N—  (a-4); —N═N—CH═CH—  (a-5); 
 -b 1 =b 2 -b 3 =b 4 - represents a bivalent radical of formula 
   —CH═CH—CH═CH—  (b-1); —N═CH—CH═CH—  (b-2); —N═CH—N═CH—  (b-3); —N═CH—CH═N—  (b-4); —N═N—CH═CH—  (b-5); 
 n is 0, 1, 2, 3 or 4; and in case -a 1 =a 2 -a 3 =a 4 - is (a-1), then n may also be 5;  
 m is 1, 2, 3 and in case -b 1 =b 2 -b 3 =b 4 - is (b-1), then m may also be 4;  
 R 1  is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl substituted with formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy; C 1-6 alkyloxyC 1-6 alkylcarbonyl substituted with C 1-6 alkyloxycarbonyl;  
 each R 2  independently is hydroxy, halo, C 1-6 alkyl optionally substituted with cyano or —C(═O)R 6 , C 3-7 cycloalkyl, C 2-6 alkenyl optionally substituted with one or more halogen atoms or cyano, C 2-6 alkynyl optionally substituted with one or more halogen atoms or cyano, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or a radical of formula  
                     
  wherein each A 1  independently is N, CH or CR 6 ; and 
 A 2  is NH, O, S or NR 6 ;  
 
 X 1  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- or —C 1-4 alkanediyl-X 2 —;  
 X 2  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O) p —;  
 R 3  is NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 6 ; C 1-6 alkyl substituted with one or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyl substituted with one or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7  and wherein 2 hydrogen atoms bound at the same carbon atom are replaced by C 1-4 alkanediyl; C 1-6 alkyl substituted with hydroxy and a second substituent selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 1-6 alkyloxyC 1-6 alkyl optionally substituted with one or more substituents each independently selected from cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkenyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; C 2-6 alkynyl substituted with one or more substituents each independently selected from halo, cyano, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; —C(═N—O—R 8 )-C 1-4 alkyl; R 7  or —X 3 —R 7 ;  
 X 3  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl-, —C 1-4 alkanediyl-X 2a —, —C 1-4 alkanediyl-X 2b —C 1-4 alkanediyl, —C(═N—OR 8 )-C 1-4 alkanediyl-; 
 with X 2a  being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —; and  
 with X 2b  being —NH—NH—, —N═N—, —C(═O)—, —S—, —S(═O) p —;  
 
 R 4  is halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino or R 7 ;  
 R 5  is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl substituted with formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl or C 1-6 alkylcarbonyloxy; C 1-6 alkyloxyC 1-6 alkylcarbonyl substituted with C 1-6 alkyloxycarbonyl;  
 R 6  is C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino or polyhaloC 1-4 alkyl;  
 R 7  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 ), R 7a , —X 3 —R 7a  or R 7a —C 1-4 alkyl;  
 R 7a  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 );  
 R 8  is hydrogen, C 1-4 alkyl, aryl or arylC 1-4 alkyl;  
 R 9  and R 10  each independently are hydrogen; hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl; —CH(═NR 11 ) or R 7 , wherein each of the aforementioned C 1-6 alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, cyano, amino, imino, mono- or di(C 1-4 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6 , R 7 ; or  
 R 9  and R 10  may be taken together to form a bivalent or trivalent radical of formula 
   —CH 2 —CH 2 —CH 2 —CH 2 —  (d-1) —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —  (d-2) —CH 2 —CH 2 —O—CH 2 —CH 2 —  (d-3) —CH 2 —CH 2 —S—CH 2 —CH 2 —  (d-4) —CH 2 —CH 2 —NR 12 —CH 2 —CH 2 —  (d-5) —CH 2 —CH═CH—CH 2 —  (d-6) ═CH—CH═CH—CH═CH—  (d-7) 
 R 11  is cyano; C 1-4 alkyl optionally substituted with C 1-4 alkyloxy, cyano, amino, mono- or di(C 1-4 alkyl)amino or aininocarbonyl; C 1-4 alkylcarbonyl; C 1-4 alkyloxycarbonyl; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl;  
 R 12  is hydrogen or C 1-4 alkyl;  
 R 13  and R 14  each independently are C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, C 2-6 alkenyl optionally substituted with cyano or aminocarbonyl, C 2-6 alkynyl optionally substituted with cyano or aminocarbonyl;  
 R 15  is C 1-6 alkyl substituted with cyano or aminocarbonyl;  
 R 16  is C 1-6 alkyl optionally substituted with cyano or aminocarbonyl, or R 7 ;  
 p is 1 or 2;  
 aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C 1-6 malkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-16 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7  or —X 3 —R 7 .  
 
   
   
       2 . The method of  claim 1  wherein the compound has the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 -a 1 =a 2 -a 3 =a 4 -, -b 1 =b 2 -b 3 =b 4 -, R 1 , R 2 , R 3 , R 4 , m and X 1  are as defined in  claim 1;   
 n′ is 0, 1, 2 or 3 and in case -a 1 =a 2 -a 3 =a 4 - is (a-1), then n′ may also be 4;  
 R 2′  is halo, C 1-6 alkyl, trihalomethyl, trihalomethyloxy, cyano, aminocarbonyl, C 1-6 alkyl substituted with cyano or aminocarbonyl;  
 provided that R 2′  is placed at the para position in respect of the NR 1  moiety.  
 
   
   
       3 . The method of  claim 1  wherein the compound has the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 -b 1 =b 2 -b 3 =b 4 -, R 1 , R 2 , R 3 , R 4 , m and X 1  are as defined in  claim 1;   
 n′ and R 2′  are as defined in  claim 3 .  
 
   
   
       4 . The method of  claim 1  wherein the compound has the formula  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1 , R 2 , R 3 , R 4  and X 1  are as defined in  claim 1;   
 n′ and R 2′  are as defined in  claim 3 .  
 
   
   
       5 . The method of  claim 1  wherein R 2′  is cyano, aminocarbonyl or C 1-6 alkyl substituted with cyano or aminocarbonyl.  
   
   
       6 . The method of  claim 1  wherein the compound is selected from 
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-benzonitrile;    4-[[4-[4-(2-cyanoethenyl)-2,6-dimethylphenoxy]-2-pyriridinyl]amino]benzonitrile; 
 4-[[4-[4-[2-cyanoethenyl]-2-methylphenoxy]-2-pyrimidinyl]amino]benzonitrile;  
   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.    
   
   
       7 . The method of  claim 1  wherein the compound is selected from 
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-benzonitrile (E); or    4-[[4-[4-(2-cyanoethenyl)-2,6-dimethylphenoxy]-2-pyrimidinyl]amino]benzonitrile (E); 4-[[4-[4-[2-cyanoethenyl]-2-methylphenoxy]-2-pyrimidinyl]amino]benzonitrile (E).    
   
   
       8 . The method of  claim 1  wherein the sexual intercourse is vaginal, anal or oral sex.  
   
   
       9 . The method of  claim 1  wherein the sexual intercourse is vaginal sex.  
   
   
       10 . (canceled)  
   
   
       11 . The method according to  claim 1 , wherein the contact site comprises a vagina, rectum, mouth or skin.  
   
   
       12 . The method according to  claim 1 , wherein the compound comprises a composition in the form of a gel, jelly, cream, ointment, film, sponge, foam, intravaginal ring, cervical cap, suppository for rectal or vaginal application, vaginal or rectal or buccal tablet, or mouthwash.  
   
   
       13 . The method according to  claim 1 , wherein the HIV infection is a multidrug resistant HIV infection.  
   
   
       14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to  claim 1 , wherein said pharmaceutical composition is bioadhesive to the contact site of application.  
   
   
       15 . A pharmaceutical composition as claimed in  claim 14  wherein the contact site of application is a vagina, rectum, mouth or skin.  
   
   
       16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as according to  claim 1 , wherein said pharmaceutical composition comprises a form adapted to be applied to vagina or mouth.  
   
   
       17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to  claim 1 , wherein said pharmaceutical composition comrises a gel, jelly, cream, film, sponge, foam, intravaginal ring, cervical cap, suppository for rectal or vaginal application, vaginal or rectal or buccal tablet, or mouthwash.  
   
   
       18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to  claim 1 , wherein said pharmaceutical composition comprises a gel comprising carbopol, hydroxypropyl cellulose, hydroxyethyl cellulose or pregelatinized starch.  
   
   
       19 . A pharmaceutical composition according to  claim 14 , further comprising one or more additional antiretroviral compounds.  
   
   
       20 . A pharmaceutical composition according to  claim 14 , further comprising one or more components selected from an antibody, a detergent or surfactant, a coating for the contact site of administration of the pharmaceutical composition, a peptide or a pH regulator.  
   
   
       21 . A pharmaceutical composition as claimed in  claim 14 , further comprising a spermicidal compound.  
   
   
       22 . The method of  claim 1 , wherein the compound is  
     
       
         
         
             
             
         
       
     
     a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.