DK2697246T3 - Selektive cysteinprotease-inhibitorer og anvendelser deraf - Google Patents

Selektive cysteinprotease-inhibitorer og anvendelser deraf Download PDF

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DK2697246T3
DK2697246T3 DK12770817.0T DK12770817T DK2697246T3 DK 2697246 T3 DK2697246 T3 DK 2697246T3 DK 12770817 T DK12770817 T DK 12770817T DK 2697246 T3 DK2697246 T3 DK 2697246T3
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Jan-Eric Ahlfors
Khalid Mekouar
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Genesis Tech Limited
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Claims (8)

1. Forbindelse med formel IIIIA 2a:
ΙΜΙΑ 2a hvor AA3 er sidekæden af en naturlig eller ikke-naturlig aminosyre; R1 og R2 kan enten være i cis-konfiguration eller trans-konfiguration; n er 0-3; Z er H, COR4, COR5, CN, OR9, OCOR9, OCO2R9, NO, N02, NR7R8, +NR7R8R9, NHSO2R9, NHCOR9, SO2R9, SOR9, SR9, halogen, NCOR9, SCOR9, en aminosyresidekæde, eller en mættet eller umættet heterocykel; W er H, alkyl, OH, OR9, NH2, NHR9, NHSOR9, halogen, COR4, COR9, CN, OCOR9, OCO2R9, NO, NO2, NR7R8, NHSO2R9, NHCOR9, SO2R9, SOR9, SR9; A er 1) H, 2) Ci-Ce alkyl, 3) a ry I, 4) heteroaryl, 5) heterocyclyl, 6) R3-C(0)-, 7) R3-0C(0)-, 8) R3-CH20C(0)-, 9) R3-C(0)0-, eller 10) R3-S(0)2-; 11) (4-amino-3-chlorbenzen)-C(0)- R1 er 1) aryl 2) heteroaryl, 3) heterocyclyl, 4) C2-Ce alken-R20, 5) S02R5, 6) SOsR5, 7) SOR5, 8) SONHR5, 9) S02NHR5, 10) CN, 11) C02R5, 12) COR5, 13) POsR5, 14) PO(OR5)2, eller 15) PO(OR5), hvor arylen, heteroarylen, eller heterocyclylen eventuelt er substitueret med én eller flere R30; R2 er 1) R1; eller 2) H, 3) halogen, 4) haloalkyl, 5) Ci-Ce alkyl, 6) C2-C6 alken, 7) C3-C7 cycloalkyl, 8) OR9, 9) SR9, 10) N+(R4)3' 11) OCOR6, 12) OCO2R6, 13) NR7R8, 14) NHSO2R6, 15) NHCOR6, 16) aryl, 17) heteroaryl, eller 18) heterocyclyl; R3 er 1) Ci-Ce alkyl, 2) aryl-Ci-Ce alkyl, 3) heteroaryl, eller 4) heterocyclyl; R4 er 1) OH, 2) OCi-Ce alkyl, 3) NHS02R9 4) alkyl, eller 5) heteroalkyl; R5 er 1) H, 2) Ci-Ce alkyl, 3) C2-C6 alken, 4) C3-C7 cycloalkyl, 5) haloalkyl, 6) a ry I, 7) heteroaryl, 8) heterocyclyl, 9) NHCH2C(0)0H, eller 10) (D) eller (L) naturlige eller ikke-naturlige a m i nosy rederi vater eventuelt beskyttet med en aminosyre-beskyttelsesgruppe; R6 er 1) hvilke som helst (D) eller (L) aminosyrerester, 2) Ci-Ce alkyl, 3) C3-C7 cycloalkyl, 4) a ry I, 5) heteroaryl, eller 6) heterocyclyl, hvor alkylen eller cycloalkylen eventuelt er substitueret med én eller flere R10 substituenter; og hvor arylen, heteroarylen eller heterocyclylen eventuelt er substitueret med én eller flere R20 substituenter; R7 og R8 er uafhængigt valgt fra: 1) H, 2) Ci-Ce alkyl, 3) C3-C7 cycloalkyl, 4) haloalkyl, 5) a ry I, 6) heteroaryl, eller 7) heterocyclyl, hvor alkylen og cycloalkylen eventuelt er substitueret med én eller flere R10 substituenter, og arylen, heteroarylen og heterocyclylen eventuelt er substitueret med én eller flere R20 substituenter; R9 er 1) H, 2) Ci-Ce alkyl, 3) C3-C7 cycloalkyl, 4) a ry I, 5) heteroaryl, eller 6) heterocyclyl, hvor alkylen eller cycloalkylen eventuelt er substitueret med én eller flere R10 substituenter; og hvor arylen, heteroarylen eller heterocyclylen eventuelt er substitueret med én eller flere R20 substituenter; R10 er uafhængigt valgt fra: 1) halogen, 2) Ci-Ce alkyl, 3) C3-C7 cycloalkyl, 4) haloalkyl, 5) a ry I, 6) heteroaryl, 7) heterocyclyl, 8) OR9, 9) S(0)mR9, 10) NR7R8, 11) COR9, 12) C(0)0R9, 13) 0C(0)R9, 14) SC(0)R9, 15) CONR7R8, eller 16) S(0)2NR7R8, hvor m er et heltal på 0, 1, eller 2; R20 er uafhængigt valgt fra: 1) halogen, 2) N02, 3) CN, 4) Ci-Ce alkyl, 5) haloalkyl, 6) C3-C7 cycloalkyl, 7) OR7, 8) NR7R8, 9) SR7, 10) a ry I, 11) heteroaryl, 12) heterocyclyl, 13) SO2R5, 14) SO3R5, 15) SOR5, 16) SONHR5, 17) SO2NHR5, 18) PO3R5, 19) PO(OR5)2, 20) PO(OR5), 21) COR5, 22) COR7, 23) CO2R7, 24) S(0)mR7, 25) CONR7R8, eller 26) S(0)2NR7R8, hvor alkylen og cycloalkylen eventuelt er substitueret med én eller flere R6 substituenter; og hvor arylen, heteroarylen, eller heterocyclylen eventuelt er substitueret med én eller flere R30; hvor m er et heltal på 0, 1, eller 2; og R30 er 1) NO2, 2) C2-Ce alken-R20, 3) SO2R5, 4) SOR5, 5) SONHR5, 6) SO2NHR5, 7) CN, 8) CO2R5, 9) COR5, 10) PO3R5, 11) PO(OR5)2, eller 12) PO(OR5); eller et farmaceutisk acceptabelt salt, eller forbindelsen er mærket med en detekterbar markør eller et affinitets-tag deraf, hvor affinitets-tag'et er biotin eller polyhistidin, og hvor den detekterbare markør er en fluorescerende markør, en kemiluminescerende markør, en kolorimetrisk markør, en enzymatisk markør, eller en radioisotop.
2. Forbindelsen ifølge krav 1, hvor R4 betegner OH eller OC1-6 alkyl.
3. Forbindelsen ifølge krav 2, hvor n betegner 0, 1 eller 3.
4. Forbindelsen ifølge krav 2 eller krav 3, hvor n betegner 1.
5. Forbindelsen ifølge et hvilket som helst af kravene 1 to 4, hvor AA3 betegner aminosyresidekæden af t-Leu, CyclohexanGlycin, CyclopropylGlycin, Glu, Gin, Asp, Ala, Gly, Thr, Val eller Trp.
6. Forbindelsen ifølge et hvilket som helst af kravene 1 til 4, hvor AA3 betegner aminosyresidekæden af phenylglycin, Ala-(2'-quinolyl), eller indanylglycin.
7. Forbindelsen ifølge et hvilket som helst af kravene 1 til 6, hvor forbindelsen er valgt fra gruppen bestående af: (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-Asp methyl-vinyl-sulfon (forbindelse 14), 2-quinolincarbonyl-t-Leu-Pro-Asp methyl-vinyl-sulfon (forbindelse 6), (l,5-naphthyridin-2-carbonyl)-t-Leu-Pro-Asp-methyl-vinyl-sulfon (forbindelse 8), quinolin-6-carbonyl-t-Leu-Pro-Asp-methyl-vinyl-sulfon (forbindelse 10), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-p-cyano-Ala-methyl-vinyl-sulfon (forbindelse 90), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-p-cyano-Ala-a-chlorvinyl methyl-vinyl-sulfon (forbindelse 91), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-(p-lH-tetrazol-Ala)-methyl-vinyl-sulfon (forbindelse 92), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-(p-lH tetrazol-Ala)-a-chlorvinyl methyl-vinyl-sulfon (forbindelse 93), 2-quinolincarbonyl-t-Leu-Pro-p-cyano-Ala-methyl-vinyl-sulfon (forbindelse 94), 2-quinolincarbonyl-t-Leu-Pro-(p-cyano-Ala)-a-chlorvinyl-methyl-vinyl-sulfon (forbindelse 95), 2-quinolincarbonyl-i--Leu-Pro-^-lH tetrazol-Ala)-methyl-vinyl-sulfon (forbindelse 96), 2-quinolincarbonyl-t-Leu-Pro-(p-lH tetrazol-Ala)-a-chlorvinyl-methyl-vinyl-sulfon (forbindelse 97), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-(p-lH tetrazol-Ala)-a-chlorvinyl-ethyl-vinyl-ester (forbindelse 113), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-(β-lH tetrazol-Ala)-ethyl-vinyl-ester (forbindelse 112), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-Asp-a-chlorvinyl-ethyl-vinyl-ester (forbindelse 117), 2-quinolincarbonyl-f--Leu-Pro-^-lHtetrazol-Ala)-ethyl-vinyl-ester (forbindelse 114), 2-quinolincarbonyl-t-Leu-Pro-(p-lH tetrazol-Ala)-a-chlorvinyl-ethyl-vinyl-ester (forbindelse 115), (4-amino-3-chlorbenzencarbonyl)-t-Leu-Pro-Asp-ethyl-vinyl-ester (forbindelse 116), 2-quinolincarbonyl-t-Leu-Pro-Asp-ethyl-vinyl-ester (forbindelse 118), og 2-quinolincarbonyl-t-Leu-Pro-Asp-a-chlorvinyl-ethyl-vinyl-ester (forbindelse 119).
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7 til anvendelse i forebyggelse og/eller behandling afen caspase-medieret sygdom eller en cysteinprotease-medieret sygdom, hvor sygdommen er valgt fra gruppen bestående af: apoptose-medierede sygdomme, IL-l-medierede sygdomme, inflammatoriske sygdomme, autoimmun sygdomme, autoinflammatoriske sygdomme, proliferative sygdomme, infektiøse sygdomme, degenerative sygdomme, nethindelidelser, inflammatorisk peritonitis, osteoarthritis, pancreatitis, astma, respiratorisk distress syndrom, rheumatoid arthritis, systemisk lupus erythematous, scleroderma, Grave's sygdom, autoimmun gastritis, diabetes, autoimmun hæmolytisk anæmi, autoimmun neutropeni, thrombocytopeni, hepatitis, inflammatorisk tarmsygdom, Crohn's sygdom, psoriasis, dermatitis, Graft vs. host sygdom, organtransplantat-afstødning, osteoporose, leukemier og beslægtede lidelser, multipel myelom-beslægtede sygdomme, cancer, metastatisk cancer, lungecancer, metastatiske melanomer, Kaposi's sarcom, sepsis, septisk chok, Alzheimer's sygdom, Parkinson's sygdom, Huntington's sygdom, cerebral iskæmi, epilepsi, myocardial iskæmi, akut og kronisk hjertesygdom, myocardial infarkt, kongestiv hjertefejl, atherosclerose, spinal muskelatrofi, amyotrofisk lateral sclerose, multipel sclerose, HIV-beslægtet encephalitis, aldring, neurologisk skade på grund af slagtilfælde, ulcerativ colitis, traumatisk hjerneskade, rygmarvsskade, hepatitis-B, hepatitis-C, hepatitis-G, lever-beslægtede sygdomme, nyresygdom, og HIV-infektion.
DK12770817.0T 2011-04-15 2012-04-15 Selektive cysteinprotease-inhibitorer og anvendelser deraf DK2697246T3 (da)

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CA2833082A1 (en) 2012-10-18
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WO2012140500A9 (en) 2013-10-24
US10975119B2 (en) 2021-04-13
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US9944674B2 (en) 2018-04-17
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