Analogues of hydroxychloroquine (HCQ) without retinal toxicity
AssigneesInoviem Scientific, Universite De Strasbourg, Centre National de la Recherche Scientifique (CNRS), Centre International De Recherche Aux Frontieres De La Chime
InventorsAnne-Sophie Korganow, Pierre Eftekhari, Alain Wagner, Corinne Baehr
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Abstract
The present invention relates to hydroxychloroquine analogues having an activity superior to that of hydroxychloroquine but free from retinal cytotoxicity of formula (I), their pharmaceutically acceptable salts, solvates or hydrates: their method of preparation and their use in the treatment of lupus erythematosus.
Claims28
A compound of formula (I), its pharmaceutically acceptable salt, solvate, or hydrate, in the form of an enantiomer or a mixture of enantiomers:
- In which U represents:
- F, Cl, Br, CN, or N3;
- and V, W and Y independently represent:
- H;
- Cl, Br, CN, or N3;
- and X represents:
- H, provided that V, W, X and Y do not all simultaneously represent H;
- Cl, Br, CN, or N3;
- Si(Ra)(Rb)(Rc), where
- Ra, Rb, and Rc, which may be identical or different, represent a C1 to C6, alkyl group or unsubstituted aryl group;
- R1, where
- R1 represents a C1 to C6 alkyl group;
- a C1 to C6 perfluoroalkyl group;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- or
- unsubstituted heteroaryl;
- S(O)nR2, where
- n=0, 1, or 2,
- R2 represents a C1 to C6 alkyl group;
- unsubstituted aryl;
- unsubstituted aralkyl;
- or unsubstituted heteroaryl,
- NR3R4, where
- R3 represents H, a C1 to C6 alkyl group;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- or unsubstituted heteroaryl,
- R4 represents H;
- a C1 to C6 alkyl group;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- unsubstituted heteroaryl;
- C(O)—C1 to C6 alkyl;
- C(O)-cycloalkyl;
- C(O)-unsubstituted aryl;
- C(O)-unsubstituted aralkyl;
- C(O)-unsubstituted heteroaryl;
- SO2—C1 to C6-alkyl;
- SO2-cycloalkyl;
- SO2-unsubstituted aryl;
- SO2-unsubstituted heteroaryl;
- C(O)N(R5)2;
- where R5 is as defined for R3;
- C(O)OR6, where R6 represents a C1 to C6 alkyl group;
- or unsubstituted aralkyl;
- or R3 and R4 may be joined together to form a non-aromatic ring of 5 to 8 atoms or a 5- to 8-membered cyclic imide;
- SR5, where
- R5 represents a C1 to C6 alkyl group;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- or unsubstituted heteroaryl,
- C(O)R6, where
- R6 represents a C1 to C6, alkyl group;
- perfluorinated alkyl;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- unsubstituted heteroaryl;
- O—C1 to C6 alkyl;
- O-cycloalkyl;
- O-unsubstituted aryl;
- O-unsubstituted aralkyl;
- O-unsubstituted heteroaryl;
- or N(R7)(R8);
- with the proviso that when X represents C(O)R6, then R6 represents a C1 to C6 alkyl group;
- perfluorinated alkyl;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- unsubstituted heteroaryl;
- or N(R7)(R8);
- R7 and R8, which may be identical or different, represent H;
- a C1 to C6 alkyl group;
- cycloalkyl cyclopropyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- or unsubstituted heteroaryl;
- OR7, where
- R7 represents H;
- a C1 to C6 alkyl group;
- cycloalkyl;
- unsubstituted aryl;
- unsubstituted aralkyl;
- unsubstituted heteroaryl;
- C(O)—C1 to C6 alkyl;
- C(O)-cycloalkyl;
- C(O)-unsubstituted aryl;
- C(O)-unsubstituted aralkyl;
- C(O)-unsubstituted heteroaryl;
- C(O)O—C1 to C6 alkyl;
- C(O)O-cycloalkyl;
- C(O)O-unsubstituted aryl;
- C(O)O-unsubstituted aralkyl;
- C(O)O-unsubstituted heteroaryl;
- CH2)mCCR8;
- (CH2)pCH═CR8;
- where m=1 to 6 and p=1 to 6;
- or
- CH2OR7;
- CH2SR5;
- CH2NR3R4;
- or CH2N3,
- provided that at least two of V, W, or Y represent H.
A method for anti-inflammatory treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I′), its pharmaceutically acceptable salt, solvate or hydrate, in the form of an enantiomer or a mixture of enantiomers:
- in which U1 represents:
- F, Cl, Br, CN, CF3, or N3;
- and V1, W1, X1 and Y1 independently represent I, NO2 or H, provided that V1, W1, X1 and Y1 do not all simultaneously represent H.
A method for treating lupus erythematosus comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I″), its pharmaceutically acceptable salt, solvate or hydrate in the form of an enantiomer or a mixture of enantiomers:
- in which U2 represents:
- F, Cl, Br, CN, CF3, or N3;
- and V2, W2, X2 and Y2 independently represent H, with the proviso that V2, W2, X2 and Y2 do not all simultaneously represent H, or C(O)R6, where R6 represents O—C1-C6 alkyl;
- O-cycloalkyl;
- O-aryl, O-aralkyl;
- or O-heteroaryl.
Dependencies are inferred from the claim text.