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1. IL213996 - SULFAMOYL-PHENYL-UREIDO-BENZAMIDINE DERIVATIVES, COMPOSITIONS COMPRISING THE SAME AND USES THEREOF

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[ EN ]
79 213,996/4
WHAT   IS CLAIMED IS:
1. A compound of the formula (I) or a physiologically acceptable salt thereof, or a mono-, di-, tri- or tetrahydrate of said compound or said salt,
formula (I)
wherein
R a                                   is hydrogen;
R b  and R c together form a 5- or 6-membered saturated heterocycloalkyl ring, which contains one or more ring heteroatoms each selected from the group consisting of O, S and N, and which
has 0 or 1 substituents R”, and which is optionally substituted by 1 or 2 oxo;
R’                      independently represents hydrogen, -C0 2R’ ’ , -CONHR’ ’ , -CR”0, -S0 2N(R’ ’) 2,
-S0 2NHR”, -NR’ ’ -CO-haloalkyl, -N0 2, -NR”-S0 2-haloalkyl, -NR”-S0 2-alkyl, -S0 2-alkyl, -NR”-CO-alkyl, -CN, alkyl, cycloalkyl, amino, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, haloaryl, haloarylalkyl, arylalkyl, heterocyclyl or heteroaryl;
R”                      independently represents hydrogen, -(CH 2) mR’, -C0 2R’, -CON(R’) 2, -CR’O, -S0 2N(R’) 2,
-NR’ -CO-haloalkyl, -N0 2, -NR’-S0 2-haloalkyl, -NR’-S0 2-alkyl, -NR’-S0 2-aryl, -NR’-S0 2-heteroaryl, -S0 2-alkyl, -S0 2-aryl, -S0 2-heteroaryl, -NR’-CO-alkyl, -NR’-CO-aryl, -NR’-CO-heteroaryl, -NR’-CO-N(R’) 2, -CN, alkyl, amino, aminoalkyl, alkylamino, alkoxy, alkoxyalkyl, hydroxyl, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, or haloalkoxy;
wherein  the longest chain allowed in each group consisting of Rb and Rc are three coupled substituents
R’ and R”.
R 1  and R 2 represent hydrogen;
m                       is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
X                       is N,
R 3                      is hydrogen; and
R 4                                   is arylalkyl or aryl, which is optionally substituted with R”.
2.          A  compound   according   to  claim  1,  wherein  R is phenyl  or  benzyl. 
80 213,996/3
3. A compound according to claim 1, wherein R 4 is phenyl or benzyl substituted with S0 2NH 2.
4. A compound according to claim 1, wherein R 4 is benzyl substituted with S0 2NH 2.
5. A compound according to claim 1, wherein R b and R c together form a heterocyclic ring, which has 0 or 1 substituents R”, which heterocyclic ring is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiazolidinyl, thiomorpholinyl, piperidin-4-one-1-yl, S, S - d i o x o - 1 h i o - m o p h o 1 i n y 1 , and piperazin-3-one-l-yl.
6. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
7. Use of an effective amount of a compound according to claim 1 in the manufacture of a medicament for treating or preventing or ameliorating malaria in a subject.
8. A use according to claim 7, which is for treating malaria.
9. A use according to claim 7, wherein the malaria is caused by a strain of Plasmodium falciparum.
10. A use according to claim 7, wherein the compound of formula (I) is administrated in combination with another antimalaria compound.
11. A use according to claim 10, wherein the other antimalaria compound is selected from chloroquine, sulfadoxine/pyrimethamine, dapsone/pyrimethamine, halofantrine, amodiaquine, mefloquine, quinine, quinidine, doxycycline, lumefantrine, primaquine, proguanil, atovaquone, pyronaridine, chlorproguanyl, artemesinin, arteflene, artemether, artesunate or trimethoprim.
12. A use according to claim 9, wherein the compound of formula (I) is administrated in combination with another antimalaria compound.
13. A use according to claim 12, wherein the other antimalaria compound is selected from chloroquine, sulfadoxine/pyrimethamine, dapsone/pyrimethamine, halofantrine, amodiaquine, mefloquine, quinine, quinidine, doxycycline, lumefantrine, primaquine, proguanil, 81 213,996/4
atovaquone,   pyronaridine, chlorproguanyl, artemesinin, arteflene, artemether, artesunate or trimethoprim.
14. A compound according to claim 1, or a physiologically acceptable salt thereof.
15. Use of an effective amount of a compound according to claim 14 in the manufacture of a medicament for treating or preventing or ameliorating malaria in a subject,.
16. A compound according to claim 1, wherein R’ independently represents hydrogen, -CN, cycloalkyl, -OH, heterocyclyl or heteroaryl.
17. A compound according to claim 1, wherein R” independently represents hydrogen, -(CH 2) mR\ -C0 2R\ -CON(R’) 2, -S0 2N(R’) 2, -NR’-CO-alkyl, alkyl, alkylamino, alkoxyalkyl, hydroxyl, hydroxyalkyl, or halogen.
18. A compound according to claim 1, wherein R’ independently represents hydrogen, -N0 2, -S0 2-alkyl, -CN, alkyl, cycloalkyl, amino, aminoalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxy alkylamino, halogen, haloalkyl, haloalkoxy, aryl, haloaryl, haloarylalkyl, arylalkyl, heterocyclyl or heteroaryl.
19. A compound according to claim 1, or a physiologically acceptable salt thereof.
20. A compound, which is one of the following compounds or a physiologically acceptable salt thereof, or a mono-, di-, tri- or tetrahydrate of said compound or said salt,
4-(3-(3-((4-butylpiperazin-1-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide;
methyl  4-(imino(3-(3-(4-(N-(4-sulfamoylphenyl)sulfamoyl)phenyl)ureido)phenyl)methyl)piperazine-lcarboxylate;
4-(3-(3-(imino(morpholino)methyl)phenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide;
4-(3-(3-(imino(4-methylpiperazin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide;
4-(3-(3-(imino(4-oxopiperidin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide; 4-(3-(3-((4-(2-hydroxyethyl)piperazin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-((4-(hydroxymethyl)piperidin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-(imino(thiomorpholino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;  82 213,996/4
l-(imino(3-(3-(4-(N-(4-sulfamoylbenzyl)sulfamoyl)-phenyl)ureido)phenyl)methyl)piperidine-4-carboxamide;
4-(3-(3-((4-butylpiperazin-1-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-((4-butylpiperazin-l-yl)(imino)methyl)phenyl)ureido)-N-(2,3,6-trifluorobenzyl)benzenesulfonamide;
N-benzyl-4-(3-(3-((4-butylpiperazin-l-yl)(imino)methyl)phenyl)ureido)benzenesulfonamide;
4-(3-(3-((4-ethylpiperazin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3 -(3 -(imino(4-propylpiper azin- 1 -yl)methyl)phenyl)ureido) -N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-((4-allylpiperazin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide; 4-(3-(3-((4-butylpiperazin- 1 -yl)(imino)methyl)phenyl)ureido)-N-( 1 -(4-sulfamoylphenyl)ethyl)benzenesulfonamide;
4-(3-(3-(imino(morpholino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-((l,l-dioxidothiomorpholino)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-(imino(4-(pyridin-4-ylmethyl)piperazin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3 -(imino(pyrrolidin- 1 -yl)methyl)phenyl)ureido)-N -(4-sulfamoylbenzyl)benzenesulfonamide ; 4-(3-(3-((4-hydroxypiperidin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-((3-(dimethylamino)pyrrolidin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-(imino(2-(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
tert-butyl  4-(imino(3-(3-(4-(N-(4-sulfamoylbenzyl)sulfamoyl)phenyl)ureido)phenyl)methyl)piperazine-lcarboxylate;
4-(3-(3-(imino(piperazin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-(imino(4-methylpiperazin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-(imino(4-isopropylpiperazin-l-yl)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3 -(3 -(imino(4-pentylpiper azin- 1 -yl)methyl)phenyl)ureido) -N-(4-sulfamoylbenzyl)benzenesulfonamide;
4-(3-(3-((4-heptylpiperazin-l-yl)(imino)methyl)phenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide;