DK2384753T3 - Hydantoinderivater som inhibitorer for cellenekrose - Google Patents

Hydantoinderivater som inhibitorer for cellenekrose Download PDF

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DK2384753T3
DK2384753T3 DK10011481.8T DK10011481T DK2384753T3 DK 2384753 T3 DK2384753 T3 DK 2384753T3 DK 10011481 T DK10011481 T DK 10011481T DK 2384753 T3 DK2384753 T3 DK 2384753T3
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carbon atoms
alkyl
compound
virus
compounds
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Junying Yuan
Prakash Jagtap
Alexei Degterev
Gregory D Cuny
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Brigham & Womens Hospital
Harvard College
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Claims (15)

1. Forbindelse af formlen:
en stereoisomer form deraf, et farmaceutisk acceptabelt syre- eller baseadditionssalt deraf, hvor X repræsenterer O; Y repræsenterer NH; Ri, R2 og R3 repræsenterer uafhængigt H, ORe, F, Cl, Br, I, N(Re)2, CO2R8, NO2, NHC(0)Re, alkyl med 1 til 10 kulstofatomer, eller substitueret alkyl med 1 til 10 kulstofatomer; R4 repræsenterer O Re, F, Cl, Br, I, N(Re)2, CO2R8, NO2, NHC(0)R8, methoxyl, alkyl med 1 til 10 kulstofatomer, eller substitueret alkyl med 1 til 10 kulstofatomer; R5 og R7 repræsenterer uafhængigt H eller alkyl med 1 til 10 kulstofatomer; R6 repræsenterer alkyl med 1 til 10 kulstofatomer; Re repræsenterer H, alkyl med 1 til 10 kulstofatomer, substitueret alkyl med 1 til 10 kulstofatomer, alkenyl med færre end 12 kulstofatomer, eller alkynyl med færre end 12 kulstofatomer; Rg, R10, R9', Rio' repræsenterer uafhængigt H, F, Cl, Br, I, alkyl med 1 til 10 kulstofatomer, substitueret alkyl med 1 til 10 kulstofatomer, eller tre- til seks-leddet cycloalkyl eller substitueret cycloalkyl, som inkluderer Cn og/eller Cn'; og n og n' er lig med et heltal fra nul til fem; og hvor substituerede grupper omfatter én eller flere substituenter valgt fra halogen, alkyl med 1 til 10 kulstofatomer, alkenyl med færre end 12 kulstofatomer, alkynyl med færre end 12 kulstofatomer, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonat, phosphinat, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, keton, aldehyd, ester, heterocyclyl, -CF3 og -CN.
2. Forbindelse ifølge krav 1, hvor R6 repræsenterer en methylgruppe.
3. Forbindelse ifølge krav 1 eller 2, hvor R4 repræsenterer et halogen, en methyl eller en methoxyl.
4. Forbindelse ifølge krav 3, hvor R4 repræsenterer Cl eller F.
5. Farmaceutisk præparation omfattende en forbindelse ifølge ethvert af kravene 1-4 og en farmaceutisk acceptabel bærer.
6. Farmaceutisk præparation ifølge krav 5, hvor i) den farmaceutisk acceptable bærer vælges fra et fortyndingsmiddel, et fast fyldstof, og et opløsningsmiddel indkapslende materiale; eller ii) den farmaceutisk acceptable bærer vælges fra sukker, stivelse, cellulose, pulverformet tragacanth, malt, gelatine, talk, et excipiens, en olie, en glycol, en polyol, en ester, en agar, et puffermiddel, alginsyre, pyrogenfrit vand, isotonisk saltopløsning, Ringer's opløsning, ethylalkohol, en pH-pufret opløsning, en polyester, et polyanhydrid og en polycarbonat.
7. Forbindelse til anvendelse ved en fremgangsmåde til behandling af nekrotisk cellelidelse, omfattende indgivelse til et subjekt med en nekrotisk cellelidelse af en forbindelse af formlen:
en stereoisomer form deraf, et farmaceutisk acceptabelt syre- eller baseadditionssalt deraf, hvor X repræsenterer O; Y repræsenterer ΝΗ; Ri, R2 og R3 repræsenterer uafhængigt H, ORe, F, Cl, Br, I, N(Re)2, CO2R8, NO2, NHC(0)R8, alkyl med 1 til 10 kulstofatomer, eller substitueret alkyl med 1 til 10 kulstofatomer; R4 repræsenterer O Re, F, Cl, Br, I, N(Re)2, CO2R8, NO2, NHC(0)R8, methoxyl, alkyl med 1 til 10 kulstofatomer, eller substitueret alkyl med 1 til 10 kulstofatomer; R5 og R7 repræsenterer uafhængigt H eller alkyl med 1 til 10 kulstofatomer; R6 repræsenterer alkyl med 1 til 10 kulstofatomer; Re repræsenterer H, alkyl med 1 til 10 kulstofatomer, substitueret alkyl med 1 til 10 kulstofatomer, alkenyl med færre end 12 kulstofatomer, eller alkynyl med færre end 12 kulstofatomer; Rg, R10, R9, Rio' repræsenterer uafhængigt H, F, Cl, Br, I, alkyl med 1 til 10 kulstofatomer, substitueret alkyl med 1 til 10 kulstofatomer, eller tre- til seks-leddet cycloalkyl eller substitueret cycloalkyl, som inkluderer Cn og/eller Cn'm, n og n' er lig med et heltal fra nul til fem; hvor substituerede grupper omfatter én eller flere substituenter valgt fra halogen, alkyl med 1 til 10 kulstofatomer, alkenyl med færre end 12 kulstofatomer, alkynyl med færre end 12 kulstofatomer, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonat, phosphinat, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, keton, aldehyd, ester, heterocyclyl, -CF3 og -CN; og hvor forbindelsen indgives i en mængde, som er effektiv til at behandle den nekrotiske cellelidelse.
8. Forbindelse til anvendelse ifølge krav 7, hvor R6 repræsenterer en methylgruppe.
9. Forbindelse til anvendelse ifølge krav 7 eller 8, hvor R4 er halogen, methyl eller methoxyl.
10. Forbindelse til anvendelse ifølge krav 9, hvor R4 repræsenterer Cl eller F.
11. Forbindelse til anvendelse ifølge ethvert af kravene 7-10, hvor i) den nekrotiske cellelidelse vælges fra gruppen bestående af trauma, iskæmi, slagtilfælde, hjerteinfarkt, infektion og sepsis; ii) den nekrotiske cellelidelse er en neurodegenerativ lidelse valgt fra Parkinson's syge, Alzheimer's syge, amyotrofisk lateral sclerose, Huntington's syge, og HIV-associeret demens; iii) forbindelsen indgives via en rute valgt fra oral, parenteral, topisk, okular, transdermal og nasale ruter; iv) forbindelsen indgives ved subkutan, intramuskulær, intravenøs eller epidural injektion; v) forbindelsen indgives i kombination med en farmaceutisk acceptabel bærer, eller vi) forbindelsen indgives i kombination med en anden forbindelse, især når forbindelsen vælges fra listen bestående af apoptoseinhibitorer, PARP-inhibitorer, Src-inhibitorer, midler til behandling af slagtilfælde, midler til behandling af kardiovaskulære lidelser og antimikrobielle midler.
12. Forbindelse af formlen:
en stereoisomer form deraf, et farmaceutisk acceptabelt syre- eller baseadditionssalt deraf, hvor X repræsenterer O; Y repræsenterer NRe; G repræsentererO eller NR7; Ri, R2, og R3 repræsenterer uafhængigt H, OH, ORe, F, Cl, Br, I, N(Re)2, COOH, CO2R8, NO2, NHC(0)Re, alkyl med 1 til 10 kulstofatomer, eller substitueret alkyl med 1 til 10 kulstofatomer; R4 repræsenterer OH, ORe, F, Cl, Br, I, N(Re)2, COOH, CO2R8, NO2, NHC(0)Re, methoxyl, alkyl med 1 til 10 kulstofatomer eller substitueret alkyl med 1 til 10 kulstofatomer; R5 og R7 repræsenterer uafhængigt H eller alkyl med 1 til 10 kulstofatomer; R6 repræsenterer alkyl med 1 til 10 kulstofatomer; Re repræsenterer alkyl med 1 til 10 kulstofatomer, substitueret alkyl med 1 til 10 kulstofatomer, alkenyl med færre end 12 kulstofatomer, eller alkynyl med færre end 12 kulstofatomer; Rg, Rio, R9', Rio' repræsenterer uafhængigt H, F, Cl, Br, I, alkyl med 1 til 10 kulstofatomer, substitueret alkyl med 1 til 10 kulstofatomer, eller en tre- til seks-leddet cycloalkyl eller substitueret cycloalkyl, som inkluderer Cn og/eller Cog n og n' er lig med et heltal fra nul til fem; hvor substituerede grupper omfatter én eller flere substituenter valgt fra halogen, alkyl med 1 til 10 kulstofatomer, alkenyl med færre end 12 kulstofatomer, alkynyl med færre end 12 kulstofatomer, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonat, phosphinat, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, keton, aldehyd, ester, heterocyclyl, -CF3, og -CN.
13. Farmaceutisk præparation omfattende en forbindelse ifølge krav 12 eller 15, og en farmaceutisk acceptabel bærer.
14. Forbindelse ifølge ethvert af kravene 1-4, 12 eller 15 til anvendelse ved en fremgangsmåde til behandling af nekrotisk cellelidelse omfattende indgivelse af den nævnte forbindelse til et subjekt, som har en nekrotisk cellelidelse, hvor forbindelsen indgives i en mængde, som er effektiv til at behandle den nekrotiske cellelidelse.
15. Forbindelse af formlen
en stereoisomer form - især en (R)- eller (S)-enantiomer deraf, eller et farmaceutisk acceptabelt syre- eller baseadditionssalt deraf.
DK10011481.8T 2003-08-29 2004-08-30 Hydantoinderivater som inhibitorer for cellenekrose DK2384753T3 (da)

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US49888203P 2003-08-29 2003-08-29
EP04821344A EP1663184A2 (en) 2003-08-29 2004-08-30 Hydantoin derivatives as inhibitors of cellular necrosis

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US (3) US7491743B2 (da)
EP (3) EP2384753B1 (da)
JP (2) JP2007504171A (da)
AU (1) AU2004315596B2 (da)
CA (1) CA2536622C (da)
DK (1) DK2384753T3 (da)
ES (1) ES2567135T3 (da)
HU (1) HUE027546T2 (da)
PL (1) PL2384753T3 (da)
SI (1) SI2384753T1 (da)
WO (1) WO2005077344A2 (da)

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