Resumen
Compounds of formula (I): wherein: X represents CH=CH-, -CH=CR-, -CR=CR-, -CO-, -O-, -NH-, -NR-, -S-, -SO-, -SO2-, -CH=N-, -CR=N-, -CH=N(O)-, -CR=N(O)- or any other atom or groug of atoms capable of forming a S- or 6- membered heterocyclic ring; Y1, Y2 and Y3 independently represent hydrogen or halogen; R1, R2 and R3 are independently represent hydrogen, halogen, hydrocarbyl (-R), hydroxyl (-OH), hydrocarbyloxy (-O-R), mercapto (-SH), hydrocarbylthio (-S-R), hydrocarbylsulfinyl (-SO-R), hydrocarbylsulfonyl (-SO2-R), nitro (-NO2), amino (-NH2), hydrocarbylamino (-NHR), bis(hydrocarbyl)amino (-NR2), hydrocarbylcarbonylamino (-NH-CO-R), cyano (-CN), carbamoyl (-CONH2), hydrocarbylcarbamoyl (-CONHR), bis(hydrocarbyl)carbamoyl (-CONR2), carboxyl (-CO2H), hydrocarbyloxycarbonyl (-CO2R), formyl (-CHO), hydrocarbylcarbonyl (-COR), hydrocarbylcarbonyloxy (-OCOR), optionally substituted heteroaryl or optionally substituted hetereocyclic; and the hydrocarbyl group R is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl, which may optionally be subtituted by one or more substituents, selected from those defined above in relation to R1, R2, and R3] ; are of use in the manufacture of a medicament for the treatment including prophylaxis of disease mediated by the activation of GSK-3.
Reivindicaciones
CLAIMS 1. The use of a compound of formula I : Ri R CO-CY R3/X I [wherein: X represents-CH=CH-,-CH=CR-,-CR=CR-,-CO-,-O-,-NH-,-NR-,- S-,-SO-,-S02-,-CH=N-,-CR=N-,-CH=N (O)-,-CR=N (O)- or any other atom or group of atoms capable of forming a S-or 6- membered heterocyclic ring; yl, y2 and Y3 independently represent hydrogen or halogen; R1, R2 and R3 are independently represent hydrogen, halogen, hydrocarbyl (-R), hydroxyl (-OH), hydrocarbyloxy (-0-R), mercapto (-SH), hydrocarbylthio (-S-R), hydrocarbylsulfinyl (-SO- R), hydrocarbylsulfonyl (-SO2-R), nitro (-NO2), amino (-NH2), hydrocarbylamino (-NHR), bis (hydrocarbyl) amino (-NR2), hydrocarbylcarbonylamino (-NH-CO-R), cyano (-CN), carbamoyl (-CONH2), hydrocarbylcarbamoyl (-CONHR), bis (hydrocarbyl) carbamoyl (-CONR2), carboxyl (-C02H), hydrocarbyloxycarbonyl (-CO2R), formyl (-CHO), hydrocarbylcarbonyl (-COR), hydrocarbylcarbonyloxy (-OCOR), optionally substituted heteroaryl or optionally substituted heterocyclic; and the hydrocarbyl group R is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl, which may optionally be substituted by one or more substituents, selected from those defined above in relation to Ri, R2 and R3]; in the manufacture of a medicament for the treatment of a disease mediated by the activation of GSK-3. <Desc/Clms Page number 38> 2. A use according to claim 1, wherein X is selected from-CH=CH-,- CH=CR-,-CR=CR-,-CH=N-,-CR=N-,-O-,-NH-,-NR-, and-S- (the group R representing C1-6 alkyl or C 6-10 aryl). 3. A use according to claim 1, wherein X is selected from-CH=CH-,- CH=CR-, -CR=CR-, --O- and -S- (the group R representing Ci-6 alkyl). 4. A use according to claim 1, wherein X is selected from-CH=CH-and -S-. 5. A use according to any one of claims 1 to 4, wherein one or two of yl y2 and Y3 are halogen, and the other two or one are hydrogen. 6. A use according to any one of claims 1 to 4, wherein one of Yl, Y2 and Y3 is halogen, and the other two are hydrogen. 7. A use according to any one of claims 1 to 4, wherein one of Y1, Y2, and Y3 is chlorine, bromine or iodine, and the other two are hydrogen. 8. A use according to any one of claims 1 to 7, wherein Rl, R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6 alkoxy and cyano), C6-lo aryl, optionally substituted C7-16 aralkyl, hydroxy, C16 alkoxy, C610 aryloxy, C7-16 aralkyloxy, C16 alkylthio, C6-10 arylthio, C7-16 aralkylthio, C16 alkylsulfinyl, C6-10 arylsulfinyl, C7-16 aralkylsulfinyl, C1-6 alkylsulfonyl, C6-lo arylsulfonyl, C7-16 aralkylsulfonyl, cyano, carboxyl, C16 alkyloxycarbonyl, C7-11 aryloxycarbonyl, C8-16 <Desc/Clms Page number 39> aralkyloxycarbonyl, heteroaryl and Ci-so aliphatic acyl (which may be optionally substituted with a halogen atom). 9. A use according to any one of claims 1 to 7, wherein Rl, R2 and R3 are independently selected from hydrogen, halogen, Cl-6 alkyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy and Cl 6 alkoxy), Cl 6 alkoxy C6 lu aryl, heteroaryl, nitro, amino and Cl-2o aliphatic acyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy and Cl-6 alkoxy and cyano). 10. A use according to any one of claims 1 to 7, wherein Rl, R2 and R3 are independently selected from hydrogen, halogen, Cl-4 alkyl (which may be optionally substituted with one or more halogen atoms), Cl-4 alkoxy, C6-lo aryl, heteroaryl, nitro, amino and C2-6 aliphatic acyl (which may be optionally substituted with one or more halogen atoms), provided that at least one of R1, R2 and R3 are other than hydrogen. 11. A use according to any one of claims 1 to 7, wherein Rl, R2 and R3 are independently selected from hydrogen, chorine, bromine, methyl, ethyl, methoxy, ethoxy, acetyl, chloroacetyl, phenyl, morpholino, nitro, amino, and bromoacetyl, provided that at least one of R1, R2 and R3 is other than hydrogen. 12. A use according to any one of claims 1 to 7, wherein Rl, R2 and R3 are independently selected from hydrogen, chloro, bromo, iodo, methyl, methoxy, acetyl, phenyl, morpholino, nitro, amino, and chloroacetyl, provided that at least one of R1, R2 and R3 is other than hydrogen. <Desc/Clms Page number 40> 13. A use according to any one of claims 1 to 12, selected from the following table : <img class="EMIRef" id="dd45b283-49e4-48e6-9b8a-5d329728a322-IMG00400001" /> <tb> <tb> comp. <SEP> -X- <SEP> COCY1Y2Y3 <SEP> Rl <SEP> R2 <SEP> R3 <tb> <SEP> 1 <SEP> -S- <SEP> 3-COCH2Cl <SEP> 2-Br <SEP> 4-Cl <SEP> 5-Cl <tb> <tb> <SEP> 2 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 4-Cl <SEP> 5-Cl <SEP> H <tb> <tb> <SEP> 3-S-2-COCH2Cl <SEP> 4-Br <SEP> H <SEP> H <tb> <tb> <SEP> 4 <SEP> -S- <SEP> 3-COCH2Cl <SEP> 4-Cl <SEP> H <SEP> H <tb> <tb> <SEP> 5-S-3-COCH2C <SEP> 2-Br <SEP> 4-Br <SEP> 5-Br <tb> <tb> <SEP> 6 <SEP> -S- <SEP> 3-COCH2Cl <SEP> 2-Cl <SEP> 5-Cl <SEP> H <tb> <tb> <SEP> 7 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 5-Cl <SEP> H <SEP> H <tb> <tb> <SEP> 8 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 5-Br <SEP> H <SEP> H <tb> <tb> <SEP> 9-S-2-COCH2Cl <SEP> 4-COCH2Cl <SEP> H <SEP> H <tb> <tb> <SEP> 10 <SEP> -S- <SEP> 2-COCH2Cl <SEP> H <SEP> H <SEP> H <tb> <tb> <SEP> 11 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 4-COCH2Cl <SEP> 5-CH3 <SEP> H <tb> <tb> <SEP> 12 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 5-CH3 <SEP> H <SEP> H <tb> <tb> <SEP> 13 <SEP> -S- <SEP> 3-COCH2Cl <SEP> 2-CH3 <SEP> 5-CH3 <SEP> H <tb> <tb> <SEP> 14-S-2-COCH2Cl <SEP> 4-Br <SEP> 5-Br <SEP> H <tb> <tb> <SEP> 15 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 3-Br <SEP> 4-Br <SEP> H <tb> <tb> <tb> <SEP> 16 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 3-CH3 <SEP> 4- <SEP> H <tb> <SEP> COCH2Cl <tb> <tb> <SEP> 17 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 4-CH3 <SEP> H <SEP> H <tb> <tb> <SEP> 18 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 3-CH3 <SEP> H <SEP> H <tb> <tb> <SEP> 19 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 5-COCH3 <SEP> H <SEP> H <tb> <tb> <SEP> 20 <SEP> -S- <SEP> 2-COCH2Cl <SEP> 4-COCH3 <SEP> H <tb> <tb> <SEP> 21 <SEP> -2- <SEP> 2- <SEP> 3-Br <SEP> 4-Br <SEP> H <tb> <tb> <SEP> COCH2Br <tb> <tb> <SEP> 22-S-2-4-Br <SEP> 5-Br <SEP> H <tb> <tb> <SEP> COCH2Br <tb> <tb> <SEP> 23-S-5-Br <SEP> H <SEP> H <tb> <Desc/Clms Page number 41> <img class="EMIRef" id="dd45b283-49e4-48e6-9b8a-5d329728a322-IMG00410001" /> <tb> <SEP> COCH2Br <tb> <tb> <SEP> 24-CH=CH-COCH2Cl <SEP> 4-Cl <SEP> H <tb> <tb> <SEP> 25 <SEP> -CH=CH- <SEP> COCH2Cl <SEP> H <SEP> H <SEP> H <tb> <tb> <SEP> 26-CH=CH-COCH2Br <SEP> 2-Br <SEP> 4-Br <SEP> 6-Br <tb> <tb> <SEP> 27-CH=CH-COCH2Br <SEP> 3-Br <SEP> 4-Br <SEP> H <tb> <tb> <SEP> 28-CH=CH-COCH2Br <SEP> 4-Br <SEP> H <SEP> H <tb> <tb> <SEP> 29 <SEP> -CH=CH- <SEP> COCH2Br <SEP> 4-Cl <SEP> H <SEP> H <tb> <tb> <SEP> 30-CH=CH-COCH2Br <SEP> H <SEP> H <SEP> H <tb> <tb> <SEP> 31-CH=CH-COCH2Br <SEP> 4-CH3 <SEP> H <tb> <tb> <SEP> 32-CH=CH-COCH2Br <SEP> 4-OCH3 <SEP> H <tb> <tb> <SEP> 33-CH=CH-COCH2Br <SEP> 4-Ph <SEP> H <SEP> H <tb> <tb> <SEP> 34 <SEP> -CH=CH- <SEP> COCHBrCl <SEP> 4-Cl <SEP> H <SEP> H <tb> <tb> <SEP> 35-CH=CH-COCHBrCl <SEP> H <SEP> H <SEP> H <tb> <tb> <SEP> 36-CH=CH-COCHBr2 <SEP> H <tb> <tb> <SEP> 37 <SEP> -CH=CH- <SEP> COCHBr2 <SEP> 4-Br <SEP> H <SEP> H <tb> <tb> <SEP> 38-CH=CH-COCH2Br <SEP> 4-CN <SEP> H <SEP> H <tb> <tb> <SEP> 39-CH=CH-COCHBr2 <SEP> 4-CN <SEP> H <SEP> H <tb> <tb> <SEP> 40-CH=CH-COCH2Br <SEP> 4-CF3 <SEP> H <SEP> H <tb> <tb> <SEP> 41 <SEP> -CH=CH- <SEP> COCHBr2 <SEP> 4-CF3 <SEP> H <SEP> H <tb> <tb> <SEP> 42-CH=CH-COCH2Br <SEP> 4-H <SEP> H <tb> <tb> <tb> <SEP> Morpholine <tb> <SEP> 43-CH=CH-COCH2Br <SEP> 3-CN <SEP> H <SEP> H <tb> <tb> <SEP> 44 <SEP> -CH=CH- <SEP> COCHBr2 <SEP> 3-CN <SEP> H <SEP> H <tb> <tb> <SEP> 45 <SEP> -CH=CH- <SEP> COCHBr2 <SEP> 4-I <SEP> H <SEP> H <tb> <tb> <SEP> 46 <SEP> -CH=CH- <SEP> COCH2Br <SEP> 4-NO2 <SEP> H <SEP> H <tb> <tb> <SEP> 47 <SEP> -CH=CH- <SEP> COCH2Br <SEP> 3-Br <SEP> 4-NH2 <SEP> 5-Br <tb> <tb> <tb> 48 <SEP> -CH=CH- <SEP> COCH2I <SEP> 4-Br <SEP> H <SEP> H <tb> 14. A use according to any preceding claim, wherein the disease is Aizheimer's disease. <Desc/Clms Page number 42> 15. A use according to any of claims 1 to 13, wherein the disease is non-dependent insulin diabetes mellitus. 16. A use according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of a hyperproliferative disease. 17. A use according to claim 16, wherein the hyperproliferative disease is selected from cancer, displasias and metaplasia of different tissues, psoriasis, arteriosclerosis and restenosis. 18. A compound of formula I : <img class="EMIRef" id="dd45b283-49e4-48e6-9b8a-5d329728a322-IMG00420001" /> I wherein: X represents-CH=CH-,-CH=CR-,-CR=CR-,-CO-,-O-,-NH-,-NR-,- S-,-SO-,-S02-,-CH=N-,-CR=N-,-CH=N (O)-,-CR=N (0)- or any other atom or group of atoms capable of forming a S-or 6- membered heterocyclic ring; yl, Y2 and Y3 independently represent hydrogen or halogen; R1, R2 and R3 are independently represent hydrogen, halogen, hydrocarbyl (-R), hydroxyl (-OH), hydrocarbyloxy (-0-R), mercapto (-SH), hydrocarbylthio (-S-R), hydrocarbylsulfinyl (-SO- R), hydrocarbylsulfonyl (-SO2-R), nitro (-NO2), amino (-NH2), hydrocarbylamino (-NHR), bis (hydrocarbyl) amino (-NR2), hydrocarbylcarbonylamino (-NH-CO-R), cyano (-CN), carbamoyl (-CONH2), hydrocarbylcarbamoyl (-CONHR), bis (hydrocarbyl) carbamoyl (-CONR2), carboxyl (-C02H), hydrocarbyloxycarbonyl (-CO2R), formyl (-CHO), hydrocarbylcarbonyl (-COR), hydrocarbylcarbonyloxy (-OCOR), <Desc/Clms Page number 43> optionally substituted heteroaryl or optionally substituted heterocyclic; and the hydrocarbyl group R is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl, which may optionally be substituted by one or more substituents, selected from those defined above in relation to R1, R2 and R3. 19. A pharmaceutical preparation containing as active ingredient a compound according to claim 18. 20. A compound according to claim 18 for use as a medicament. 21. A method of treatment of a disease mediated by the activation of GSK-3, the method comprising administering an effective amount of a compound according to claim 18.
