[1,10]-phenanthroline derivatives for the treatment of neurodegenerative or haematological diseases
The present invention relates to a new family of [1,10]-phenantroline derivatives of formula (I), which are useful for the treatment or profilaxis of a neurodegenerative or haematological disease or condition, their use as a medicament, especially for treating a treatment neurodegenerative or haematological disease or condition, and a pharmaceutical composition comprising the compounds.
1. A compound of formula (I):
wherein R 1 is —S—R 3 ;
R 7 is selected from —CH═N—OR 8 or —CHO;
R 3 is selected from the group consisting of C 6 -C 15 aryl and heteroaryl, each of which is optionally substituted by C 1 -C 6 alkyl, C 6 -C 15 aryl, halogen, —(C═O)NR 5 R 6 , —(C═O)OR 5 , C 1 -C 6 alkoxy and/or —NR 5 R 6 ,
R 5 and R 6 being independently selected from hydrogen and C 1 -C 6 alkyl,
R 8 is selected from hydrogen and C 1 -C 6 alkyl;
or any salt or stereoisomer or tautomer thereof.
2. The compound according to claim 1 , wherein R 7 is —CH═N—OR 8 .
3. The compound according to claim 2 , wherein R 8 is hydrogen.
4. The compound according to claim 1 , wherein R 3 is selected from heteroaryl and heteroaryl substituted by C 1 -C 6 alkyl, C 6 -C 15 aryl, halogen, —(C═O)NR 5 R 6 , —(C═O)OR 5 , C 1 -C 6 alkoxy and/or —NR 5 R 6 .
5. The compound according to claim 4 , wherein the heteroaryl group is substituted by C 1 -C 3 alkyl.
6. The compound according to claim 1 , wherein the double bond of the oxime group —CH═NOR 8 presents an E conformation.
7. The compound according to claim 1 , wherein R 7 is —CH═N—OR 8 and R 1 is —S—R 3 .
8. The compound according to claim 1 , selected from
4-(Thiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime
4-(5-Methyl-thiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime
4-(5-Methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime
4-([1,3,4]Thiadiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime
and salts, stereoisomers and tautomers thereof.
9. A pharmaceutical composition comprising at least one compound according to claim 1 , and at least one pharmaceutically acceptable carrier.
10. A process for the preparation of the compound of claim 1 , comprising the steps of:
a) optionally reacting a compound of formula (III) with a sodium salt of the corresponding alkoxide or thiolate, to form a compound of formula (II);
wherein
X is an halogen;
R 1 is —S—R 3 ;
R 3 is selected from the group consisting of
C 6 -C 15 aryl and heteroaryl, each of which is optionally substituted by C 1 -C 6
alkyl, C 6 -C 15 aryl, halogen, —(C═O)NR 5 R 6 , —(C═O)OR 5 , C 1 -C 6 alkoxy and/or —NR 5 R 6 ;
b) oxidizing the methyl group of the compound of formula (II) with an oxidizing agent to form a compound of formula (I);
wherein R 1 is as defined in step a); and, optionally
c) converting the aldehyde group —CHO in the compound of formula (I) into an oxyme group —CH═N—OR 8 , wherein R 8 is selected from hydrogen and C 1 -C 6 alkyl, in the presence of hydroxylamine or O—(C 1 -C 6 )alkylhydroxylamine:
11. A biological assay method, comprising reacting the compound of claim 1 with a biological sample.
12. A method of inhibiting secretion of amyloid beta, which method comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound according to claim 1 .