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1. WO2010086177 - SULFAMOYL- PHENYL-UREIDO BENZAMIDINE-DERIVATIVES AS ANTIMALARIAL AGENTS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]
Claims

1. A compound of the formula (I) or a physiologically acceptable salt or derivative thereof,

wherein
formula (I)

Ra is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, -OCOR', C(O)R', CONHR' or -CO2R';

Rb and Rc independently are alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, haloalkyl, cycloalkyl, aryl and heteroaryl, heterocyclyl or -C02R'; or

Rb forms together with Rc a 3-, 4-, 5- , 6- or 7-membered saturated, partially unsaturated or entirely unsaturated heterocyclic ring selected from the group consisting of cycloalkyl, aryl, heterocycloalkyl and heteroaryl which optionally has O, 1, 2 or 3 substituents R", where chemically appropriate, two R" taken together can form a group =0; this heterocyclic group is preferably selected from the group consisting of piperidinyl, piprazinyl, morpholinyl, pyrrolidinyl, thiazolidinyl, thiomorpholinyl, piperidin-4-one- 1 -yl, S.S'-dioxo-thio-morpholinyl, piperazin-3-one-l-yl, or azepanyl

R' independently represents hydrogen, -CO2R", -CONHR", -CR"O, -SO2N(R")2, -SO2NHR", -NR"-CO-haloalkyl, -NO2, -NR"-SO2-haloalkyl, -NR"-SO2-alkyl, -SO2-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, -(CH2)mR\ -CO2R', -C0N(R')2, -CR'O, - SO2N(R')2, -NR'-CO-haloalkyl, -NO2, -NR'-SO2-haloalkyl, -NR'-SO2-alkyl, - NR'-SO2-aryl, -NR'-SO2-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -NR'- CO-alkyl, -NR'-CO-aryl, -NR'-CO-heteroaryl, -NR'-CO-N(R')2, -CN, alkyl, amino, amide, cycloalkyl, aminoalkyl, alkylamino, alkoxy, alkoxyalky, hydroxyl, - SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl; where chemically appropriate, two R" taken together can form a group =0; wherein R' groups are as defined above and may be selected independently from each other;

R1 and R2 independently represent hydrogen, (CH2)mR\ -CO2R', -C0N(R')2, CR'O, -SO2N(R')2, -NR'-CO-haloalkyl, NO2, -NR'-SO2-haloalkyl, NR'-SO2-alkyl, -NR'-SO2-aryl, -NR'-SO2-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -NR' -CO-alkyl, -NR'-CO-aryl, -NR'-CO-heteroaryl, -NR' -CO-N(R' )2, -CN, alkyl, amino, amide, cycloalkyl, aminoalkyl, alkylamino, alkoxy, hydroxyl, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl wherein R' groups are as defined above and may be selected independently from each other; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, or 12; wherein if

X is CR5, then

R3 forms together with R4 an unsaturated or saturated cyclic group selected from the group consisting of cycloalkyl, aryl, heterocyclyl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R", and wherein if X is part of a double bond, R5 is absent;

R5 is H, OH, halogen, C,-C4-alkyl; or wherein if

X is N, then

R3 is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, or -CO2R';

R4 is hydrogen, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, cyanoalkyl, amino, alkyl, arylalkyl or a partially or entirely unsaturated or saturated cyclic group selected from the group consisting of cycloalkyl, aryl, arylalkyl, heterocyclyl, haloarylalkyl and heteroaryl which is optionally substituted with R" as defined herein; or wherein if

X is N, then R3 forms together with R4 a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated or entirely unsaturated heterocyclic ring consisting of cycloalkyl, aryl, heterocyclyl, heterocycloaryl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R' '

2. A compound according to claim 1, wherein

Ra is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, -OCOR', -C(O)R', -CONHR' or -CO2R';

Rb and Rc independently are alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, haloalkyl, cycloalkyl, aryl and heteroaryl, heterocyclyl or -CO2R';

R' independently represents hydrogen, -CO2R", -CONHR", -CR"0, -SO2N(R")2, -SO2NHR", -NR"-CO-haloalkyl, -NO2, -NR"-SO2-haloalkyl, -NR"-SO2-alkyl, -SO2-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" is independently hydrogen, -(CH2)mR\ -CO2R', -C0N(R')2, -CR'O, -SO2N(R')2, - NR'-CO-haloalkyl, -NO2, -NR'-SO2-haloalkyl, -NR'-SO2-alkyl, -NR'-SO2-aryl, - NR'-SO2-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -NR'-CO-alkyl, - NR'-CO-aryl, -NR'-CO-heteroaryl, -NR'-C0-N(R')2, -CN, alkyl, amino, amide, cycloalkyl, aminoalkyl, alkylamino, alkoxy, alkoxyalky, hydroxyl, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl; where chemically appropriate, two R" taken together can form a group =0; wherein R' groups are as defined above and may be selected independently from each other;

R1 and R2 independently represents hydrogen, (CH2)mR\ -CO2R', -C0N(R')2, -CR'O, -SO2N(R')2, -NR'-CO-haloalkyl, NO2, -NR'-SO2-haloalkyl, NR'-SO2-alkyl, -NR'-SO2-aryl, -NR'-SO2-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -NR'-CO-alkyl, -NR'-CO-aryl, -NR'-CO-heteroaryl, -NR' -CO-N(R' )2, -CN, alkyl, amino, amide, cycloalkyl, aminoalkyl, alkylamino, alkoxy, hydroxyl, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroarylwherein R' groups are as defined above and may be selected independently from each other; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; wherein if

X is CR5, then

R3 forms together with R4 an unsaturated or saturated cyclic group selected from the group consisting of cycloalkyl, aryl, heterocyclyl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R", and wherein if X is part of a double bond, R5 is absent;

R5 is H, OH, halogen, C1 -C4-alkyl; or wherein if

X is N, then

R3 is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, or -CO2R';

R4 is hydrogen, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, cyanoalkyl, amino, alkyl, arylalkyl or a partially or entirely unsaturated or saturated cyclic group selected from the group consisting of cycloalkyl, aryl, arylalkyl, heterocyclyl, haloarylalkyl and heteroaryl which is optionally substituted with R" as defined herein; or wherein if

X is N, then or R3 forms together with R4 a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated or entirely unsaturated heterocyclic ring consisting of cycloalkyl, aryl, heterocyclyl, heterocycloaryl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R' '

3. A compound according to claim 1, wherein

Ra is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, -OCOR', -C(O)R', -CONHR' or -CO2R';

Rb forms together with Rc a 3-, 4-, 5- , 6- or 7-membered saturated, partially unsaturated or entirely unsaturated heterocyclic ring selected from the group consisting of cycloalkyl, aryl, heterocycloalkyl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R", where chemically appropriate, two R" taken together can form a group =0; this heterocyclic group is preferably selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiazolidinyl, thiomorpholinyl, piperidin-4-one-l-yl, S.S-dioxo-thio-morpholinyl, piperazin-3-one-l-yl, or azepanyl

R' independently represents hydrogen, -CO2R", -CONHR", -CR"O, -SO2N(R")2, -SO2NHR", -NR"-CO-haloalkyl, -NO2, -NR"-SO2-haloalkyl, -NR"-SO2-alkyl, -SO2-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 hydrogen, -(CH2)mR\ -CO2R', -C0N(R')2, -CR'O, -SO2N(R')2, - NR'-CO-haloalkyl, -NO2, -NR'-SO2-haloalkyl, -NR'-SO2-alkyl, -NR'-SO2-aryl, - NR'-SO2-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -NR'-CO-alkyl, - NR'-CO-aryl, -NR'-CO-heteroaryl, -NR'-C0-N(R')2, -CN, alkyl, amino, amide, cycloalkyl, aminoalkyl, alkylamino, alkoxy, alkoxyalky, hydroxyl, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl; where chemically appropriate, two R" taken together can form a group =0; wherein R' groups are as defined above and may be selected independently from each other;

R1 and R2 independently represents hydrogen, (CH2)mR\ -CO2R', -C0N(R')2, -CR'O, -SO2N(R')2, -NR'-CO-haloalkyl, NO2, -NR'-SO2-haloalkyl, NR'-SO2-alkyl, -NR'-SO2-aryl, -NR'-SO2-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -NR'-CO-alkyl, -NR'-CO-aryl, -NR'-CO-heteroaryl, -NR' -CO-N(R' )2, -CN, alkyl, amino, amide, cycloalkyl, aminoalkyl, alkylamino, alkoxy, hydroxyl, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl wherein R' groups are as defined above and may be selected independently from each other; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; wherein if

X is CR5, then

R3 forms together with R4 an unsaturated or saturated cyclic group selected from the group consisting of cycloalkyl, aryl, heterocyclyl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R", and wherein if X is part of a double bond, R5 is absent;

R5 is H, OH, halogen, Ci-C4-alkyl; or wherein if X is N, then R3 is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, or -CO2R';

R4 is hydrogen, hydroxyalkyl, haloalkyl, aminoalkyl, alkoxy, cyanoalkyl, amino, alkyl, arylalkyl or a partially or entirely unsaturated or saturated cyclic group selected from the group consisting of cycloalkyl, aryl, arylalkyl, heterocyclyl, haloarylalkyl and heteroaryl which is optionally substituted with R" as defined herein; or wherein if

X is N, then

R3 forms together with R4 a 3-, A-, 5-, 6- or 7-membered saturated or partially unsaturated or entirely unsaturated heterocyclic ring consisting of cycloalkyl, aryl, heterocyclyl, heterocycloaryl and heteroaryl which optionally has 0, 1, 2 or 3 substituents R' '

4. A compound according to claim 1, wherein R3 = H, R4 = alkylaryl, Ra = H, and Rb forms together with Rc a 6-membered saturated heterocyclic ring which optionally has 0, 1, 2 or 3 substituents R".

5. A compound according to claim 1, wherein R3 = H, R4 = aryl, Ra = H, and Rb forms together with Rc a 6-membered saturated heterocyclic ring which optionally has 0, 1, 2 or 3 substituents R".

6. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

7. A method of treating or preventing or ameliorating a disease or condition in a subject comprising the administration of a compound according to claim 1.

8. A method according to claim 7, wherein the disease or condition is malaria.

9. A method according to claim 7, wherein the disease or condition is malaria, caused by a strain of Plasmodium falciparum.

10. A method according to claims 6 to 9, wherein the compound is administrated in combination with another antimalaria compound.

11. A method according to claim 10, wherein the other antimalaria compound is selected from chloroquine, sulfadoxine/pyrimethamine, dapsone/pyrimethamine, sulfonamides, halofantrine, amodiaquine, mefloquine, quinine, quinidine, doxycycline, lumefantrine, primaquine, proguanil, atovaquone, pyronaridine, chlorproguanyl, artemesinin, arteflene, artemether, artesunate or trimethoprim.