Patent EP-3345917-A1 (EP)
Inventor: AGNELLO STEFANO
IPC: C07K7/02
Filed: 2017-01-05
Abstract: The present invention relates to a compound of formula (I)
     
wherein 
--A-- represents a peptide chain, wherein said peptide chain consists of 5 to 7 amino acids, wherein said amino acids are selected from any amino acid, wherein at least two, preferably at least three of said 5 to 7 amino acids are α-aminoisobutyric acid (Aib), leucine (Leu) or alanine (Ala); 
R 1  is
     
wherein 
X is N or CH; 
R 5  is selected from H, C 1 -C 16 alkyl, C 1 -C 16 alkenyl, C(O)-C 1 -C 16 alkyl, C(O)-C 1 -C 16 alkenyl, (wherein said C 1 -C 16 alkyl, C 1 -C 16 alkenyl, C(O)-C 1 -C 16 alkyl, C(O)-C 1 -C 16 alkenyl are) independently optionally substituted with halogen, NR 11 R 12 , -[O-C 2 H 4 ] n -OCH 3  wherein n=2-20; C(O)-R 8 , C(O)-C 1 -C 3 alkylene-R 8 , N(H)C(O)-R 8 , or S(O) 2 -R 9 , wherein 
R 8  is independently at each occurrence selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally substituted with C 1 -C 4 alkyl, halogen, CF 3 , OR 10 , NR 11 R 12 , C 6 H 5  and C 6 H 5  substituted with halogen, C 1 -C 3 alkyl, OR 10 , NR 11 R 12 ; wherein R 10 , R 11 , R 12  are independently at each occurrence H, C 1 -C 3 alkyl; 
R 9  is independently at each occurrence selected from C 1 -C 4 alkyl, aryl, heteroaryl, each independently optionally substituted with C 1 -C 4 alkyl, halogen, CF 3 , OR 13 , NR 14 R 15 ; wherein R 13 , R 14,  R 15  are independently at each occurrence H, C 1 -C 3 alkyl; 
 
R 6,  R 7  are independently at each occurrence selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C(O)-C 1 -C 3 alkyl, C(O)-C 1 -C 4 alkenyl, (wherein said C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C(O)-C 1 -C 3 alkyl, C(O)-C 1 -C 4 alkenyl are) independently optionally substituted with halogen, NR 11 R 12 ; or R 6  and R 7  together with the X-C to which they are attached form independently at each occurrence an aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally ( further ) substituted with C 1 -C 4 alkyl, halogen, CF 3 , OR 10 , NR 11 R 12 , C 6 H 5  and C 6 H 5  substituted with halogen, C 1 -C 3 alkyl, OR 10 , NR 11 R 12 ; wherein R 10 , R 11 , R 12  are independently at each occurrence H, C 1 -C 3 alkyl; and wherein 
the arrow indicates the attachment to the NH-moiety depicted in formula (I); 
 
R 2  is selected from C 1 -C 14 alkyl, C 2 -C 14 alkyl optionally substituted with OH, C 2 -C 14 alkoxy, C 2 -C 14 alkenyl optionally substituted with OH; C 1 -C 8 alkylene-R 23 , wherein in alkylene one or two -CH 2 - moieties are optionally replaced by -CH(NR 24 R 25 )-,-CH(OH)-, -C(=O)-, -NR 24 R 25 - or -CH(CH 3 )- moieties, wherein there are no adjacent-C(=O)- moieties or adjacent -NR 24 R 25 - moieties, and wherein 
R 23  is independently at each occurrence selected from hydrogen; aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally substituted with C 1 -C 4 alkyl, OR 26 , NR 27 R 28 ; wherein R 26 , R 27 , R 28  are independently at each occurrence H, halogen, CF 3 , C 1 -C 3 alkyl; and wherein 
R 24  and R 25  are independently at each occurrence H, C 1 -C 3 alkyl; 
with the proviso that R 2  is not -CH 2 CH(CH 3 )CH 2 CH(OH)CH 2 C(O)C 2 H 5 , -CH 2 CH(CH 3 )CH 2 CH=CHC(O)C 2 H 5 , -CH 2 CH(CH 3 )CH 2 CH 2 CH 2 C(O)C 2 H 5 , -CH 2 CH(CH 3 )(CH 2 ) 3 CH(OH)C 2 H 5 , -CH 2 CH(CH 3 )CH 2 CH(OCH 3 )CH 2 C(O)C 2 H 5 ; 
R 3  is selected from C 2 -C 12 alkyl optionally substituted with OH, C 2 -C 12 alkoxy, C 2 -C 12 alkenyl optionally substituted with OH, C 1 -C 8 alkylene-R 29 , wherein in alkylene one or two -CH 2 - moieties are optionally replaced by -CH(NR 30 R 31 )-, -CH(OH)-, -C(=O)-, -NR 30 R 31 - or -CH(CH 3 )- moieties, wherein there are no adjacent -C(=O)- moieties or adjacent -NR 30 R 31 - moieties, and wherein 
R 29  is independently at each occurrence selected from hydrogen; aryl, heteroaryl, cycloalkyl, heterocyclyl, each independently optionally substituted with C 1 -C 4 alkyl, OR 32 , NR 33 R 34 ; wherein R 32 , R 33 , R 34  are independently at each occurrence H, halogen, CF 3 , C 1 -C 3 alkyl; and wherein 
R 30  and R 31  are independently at each occurrence H, C 1 -C 3 alkyl; 
 
R 4  is
     
wherein 
R 35  is independently selected from hydrogen and C 1 -C 3 -alkyl; 
R 36  is independently at each occurrence selected from -cycloalkyl-NR 41 R 42 , wherein said cycloalkyl moiety is optionally substituted by C 1 -C 4 alkyl, hydroxyl, halogen, OR 43 ; -C 3 -C 6 alkylene-NR 41 R 42 , wherein said C 3 -C 6 alkylene moiety is optionally substituted by hydroxyl, OR 43 , halogen; cycloalkyl optionally substituted with C 1 -C 4 alkyl, halogen, OR 43 ; or wherein R 35  and R 36  together with the nitrogen atom to which they are attached form independently at each occurrence a heteroaryl, a heterocyclyl or a heterocyclic spiranyl, each independently optionally substituted with C 1 -C 4 alkyl, halogen, OR 43 , NR 44 R 45 , wherein R 43 , R 44 , R 45  are independently at each occurrence H, C 1 -C 4 alkyl; and wherein 
R 37 , R 38 , R 39  and R 40  are independently at each occurrence H or C 1 -C 3 alkyl, preferably H or methyl, or independently at each occurrence two of said R 37 , R 38 , R 39  and R 40  together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring, preferably a carbocyclic ring, and wherein 
R 41  and R 42  are independently of each other H or C 1 -C 4 alkyl optionally substituted with halogen, hydroxyl or C 3 -C 6 cycloalkyl; or together with the nitrogen atoms to which they are attached form independently at each occurrence a heteroaryl or a heterocyclyl, each independently optionally substituted with halogen, C 1 -C 4 alkyl, OR 43 , NR 44 R 45 ; wherein 
the arrow indicates the attachment to the C(O)-moiety depicted in formula (I); and pharmaceutically acceptable salts of said compound of formula (I). 
  
 
     The present invention further relates to pharmaceutical compositions comprising said compounds and to the use of said compounds in a method of treatment of a protozoan disease, wherein preferably said protozoan disease is selected from malaria, human African trypanosomiasis, Chagas disease or leishmaniasis.