DK2872497T3 - Chromanyl-derivater til behandling af mitokondriel sygdom - Google Patents

Chromanyl-derivater til behandling af mitokondriel sygdom Download PDF

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DK2872497T3
DK2872497T3 DK13759838.9T DK13759838T DK2872497T3 DK 2872497 T3 DK2872497 T3 DK 2872497T3 DK 13759838 T DK13759838 T DK 13759838T DK 2872497 T3 DK2872497 T3 DK 2872497T3
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Ruben Gerardus George Leenders
Geert Jan Sterk
Pedro Harold Han Hermkens
Richard Hendrik Blaauw
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Khondrion Ip B V
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Claims (20)

1. Forbindelse af generel formel (I):
hvor - L er en linker omfattende 1 til 10 eventuelt substituerede backbone-atomer valgt fra kulstof, nitrogen og oxygen; og - R1 og R2 er hver uafhængigt valgt fra hydrogen og Ci - C6 alkyl, eller R1 og R2 er forbundet med hinanden for at danne en anden linker mellem amidnitrogen-atomet og det kationiske nitrogenatom, eller R1 er forbundet med et backbone-atom af linkeren L i en cyklisk struktur og/eller R2 er forbundet med et backbone-atom af linkeren L i en cyklisk struktur; og - R3 er valgt fra hydrogen og Ci - Ce alkyl, hvor alkyldelen kan substitueres med et eller flere halogenatomer eller (halo)alkoxydele, eller R3 er fraværende, når det kationiske nitrogenatom er del af en imindel; og - R4 er valgt fra hydrogen og Ci - C6 alkyl, hvor alkyldelen kan substitueres med et eller flere halogenatomer eller (halo)alkoxydele; og - X' er en farmaceutisk acceptabel anion, hvor forbindelsen ikke er: (i) forbindelsen af formel (I), hvor L = -(CH2)3-(L3), R1 = H, R2 = H, R3 = H, R4 = H og X = Cl; (ii) forbindelsen af formel (I), hvor L = -(CH2)2-CHR1'-CH2-NH-(CH2)4-, R1-R1’ = -(CH2)2-(L1), R2 = H, R3 = -(CH2)2-CH3, R4 = H og X = Cl; (iii) forbindelsen af formel (I), hvor L = -(CH2)3-(L3), R1 = H, R2 = H, R3 = H, R4 = Η; X = TFA, hvilken er i S-konfigurationen ved 2-positionen; (iv) l-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-4-[(3,4-dihydro-6-hydroxy- 2.5.7.8- tetramethyl-2F/-[l]-benzopyran-2-yl)carbonyl]-piperazin hydrochlorid; (v) l-[4-(2-amino-6-pyridinyl)-3-butynyl]-4-[(3,4-dihydro-6-hydroxy- 2.5.7.8- tetramethyl-2F/-[l]-benzopyran-2-yl)carbonyl]-piperazin hydrochlorid; eller (vi) /V-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxamid fumarat.
2. Forbindelse ifølge krav 1, hvor backbone-atomerne af L er repræsenteret af Cn-mNm, hvor n designerer det totale antal af atomer i backbone, og m antallet af nitrogenatomer i backbone, hvor n = 2-7 og m = 0 - 3.
3. Forbindelse ifølge krav 1 eller 2, hvor X = Cl, I, TFA eller format.
4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor - L = -(CH2)2-(L1), R!-R2 = -(CH2)2-(L1), R3 = H, R4 = Η, X = Cl; eller - L = -(CHzML1), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)2NHC(0)CH2-(L2), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)2NHC(NH2)=(L4), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -(CH2)2NHC(0)CH2NHC(NH2)=(L5), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -(CHz)3NHC(NH2)=(L5), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -(CH2)3-(L3), R1 = H, R2 = Me, R3 = Me, R4 = Me; X = I; eller - L = -(CH2ML1), R1 = H, R2 = Me, R3 = Me, R4 = Me; X = I; eller - L = -(CH2)2l\IHC(Me) = (L7), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -(CH2)2l\IHC(0)CH2NHC(Me) = (L8), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -(CH2)3l\IHC(Me) = (L9), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -(CH2)2NR1'C(NH2) = (L10), Ri-R1’ = -(CHzML1), R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -C(C02H)(CH2)3-(Ln), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3NHC(NH2) = (L12), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -C(C02H)CH2-(L13), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)2-(L14), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3-(L15), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3-(Ln), R1 = H, R2 = Me, R3 = Me, R4 = Η; X = Cl; eller - L = -(CH2)4-(L16), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)5-(L17) R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)4-(L16), R1 = H, R2 = Me, R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2'C(0)-(L18), R1 = H, R2-R2’ = -(CH2)3-(L3), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2'CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = H, R4 = Η; X = Cl; eller - L = -CHR5CH2NR5’C(Me) = (L20), R1 = H, R2 = H, R5-R5’ = -(CH2)3-(L3), R3 = fraværende, R4 = Η; X = Cl; eller - L = -CHR2’(CH2)2-(L21), R1 = H, R2-R2' = -(CH2)2-(L1), R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)2CHR1’-(L22), R^R1’ = -(CH2)2-(L1), R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)2CHR1’NHC(0)C(Me)-(L23), R1-R1’ = -(ChteML1), R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -CH2CHR1’-(L24), R^R1’ = -(CH2)3-(L3), R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -CH2CHRrNHC(Me)=(L25), R^R1’ = -(CH2)3-(L3), R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -CHR5(CH2)2CHR5’-(L26), R1 = H, R2 = H, R5-R5’ = -(CFhML1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2' = -(CH2)2-(L1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2'(CH2)2-(L21), R1 = H, R2-R2' = -(ChteML1), R3 = Me, R4 = Η; X = Cl.
5. Forbindelse ifølge krav 4, hvor - L = -(CH2)2NHC(0)CH2NHC(NH2)=(L5), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -(CH2)2l\IHC(0)CH2NHC(Me) = (L8), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -Cta^HXChhML11), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3NHC(NH2) = (L12), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -(CH2)5-(L17) R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)4-(L16), R1 = H, R2 = Me, R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2’(CH2)2-(L21), R1 = H, R2-R2' = -(ChfcML1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR5(CH2)2CHR5’-(L26), R1 = H, R2 = H, R5-R5' = -(CH2)2-(L1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2’ = -(CH2)3-(L3), R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2’(CH2)2-(L21), R1 = H, R2-R2' = -(CHOHL1), R3 = Me, R4 = H; X=CI.
6. Forbindelse ifølge krav 4, hvor - L = -(CH2)3-(L3), R1 = H, R2 = Me, R3 = Me, R4 = Me; X = I; eller - L = -(CH2)2-(L1), R1 = H, R2 = Me, R3 = Me, R4 = Me; X = I.
7. Farmaceutisk eller kosmetisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1 - 6 og en fysiologisk acceptabel bærer.
8. Forbindelse ifølge et hvilket som helst af kravene 1-6, til anvendelse som et medikament.
9. Forbindelse ifølge et hvilket som helst af kravene 1-6, til anvendelse i modulering af mindst en af mitokondriel morfologi og ekspression af OXPHOS-enzymer.
10. Forbindelse til anvendelse i behandling, forebyggelse, eller undertrykkelse af symptomer associeret med en mitokondriel sygdom, hvor forbindelsen er en forbindelse af generel formel (I):
hvor - L er en linker omfattende 1 til 10 eventuelt substitueret backbone-atomer valgt fra kulstof, nitrogen og oxygen; og - R1 og R2 er hver uafhængigt valgt fra hydrogen og Ci - Ce alkyl, eller R1 og R2 er forbundet med hinanden for at danne en anden linker mellem amidnitrogen-atomet og det kationiske nitrogenatom, eller R1 er forbundet med et backbone-atom af linkeren L i en cyklisk struktur og/eller R2 er forbundet med et backbone-atom af linkeren L i en cyklisk struktur; og - R3 er valgt fra hydrogen og Ci - C6 alkyl, hvor alkyldelen kan substitueres med et eller flere halogenatomer eller (halo)alkoxydele, eller R3 er fraværende når det kationiske nitrogenatom er del af en imindel; og - R4 er valgt fra hydrogen og Ci - C6 alkyl, hvor alkyldelen kan substitueres med et eller flere halogenatomer eller (halo)alkoxydele; og - X- er en farmaceutisk acceptabel anion.
11. Forbindelse til anvendelse ifølge krav 10, hvor - L = -(CH2)2l\HC(0)CH2NHC(NH2)=(L5), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -(CH2)2NHC(0)CH2l\IHC(Me) = (L8), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3-(Ln), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3l\IHC(NH2) = (L12), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -(CH2)5-(L17) R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)4-(L16)/ R1 = H, R2 = Me, R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2’(CH2)2-(L21), R1 = H, R2-R2' = -(CH2ML1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR5(CH2)2CHR5’-(L26), R1 = H, R2 = H, R5-R5’ = -(CH2)2-(L1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2'CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2'(CH2)2-(L21), R1 = H, R2-R2' = -(CH2ML1), R3 = Me, R4 = H; X=CI.
12. Forbindelse til anvendelse ifølge krav 10 eller 11, hvor den mitokondrielle sygdom er en sygdom valgt fra gruppen bestående af: Myoklon epilepsi; Myoklon epilepsi med Ragged Red Fibers (MERRF); Lebers Hereditære Synsnerveatrofi (LHON); neuropatisk ataksi og retinitis pigmentosa (NARP); Mitokondrie Myopati, encefalopati, Lactacidose, slagtilfælde (MELAS); Leigh-syndrom; Leigh-lignende syndrom; Dominant Synsnerveatrofi (DOA); Kearns-Sayre Syndrom (KSS); Maternally Inherited Diabetes og Deafness (MIDD); Alpers-Huttenlocher syndrom; Ataksi Neuropati spektrum; Chronic Progressive External Ophthalmoplegia (CPEO); Pearson syndrom; Mitochondria Neuro-Gastro-Intestinal Encephalopathy (MNGIE); Sengers syndrom; 3-methylglutakonisk aciduria, sensorineural døvhed, encefalopati og neuroradiologiske opdagelser af Leigh-lignende syndrom (MEGDEL); myopati; mitokondriemyopati; kardiomyopati; og encefalomyopati, SURFS1 (COX-defekt Leigh syndrom grundet kompleks IV surfeit proteinmangel) og isoleret eller kombineret OXPHOS-defekter med indtil videre uopklaret genetisk defekt inkluderende forstyrret pyruvat oxidation og ATP plus PCr-produktionshastig heder.
13. Forbindelse ifølge et hvilket som helst af kravene 4 eller 5, til anvendelse i behandling, forebyggelse, eller undertrykkelse af symptomer associeret med en tilstand associeret med mitokondriel dysfunktion, hvor, fortrinsvis forbindelsen er en forbindelse ifølge krav 5.
14. Forbindelse til anvendelse ifølge krav 13, hvor tilstanden associeret med mitokondriel dysfunktion er en tilstand valgt fra gruppen bestående af: Friedreichs Ataksi (FRDA); renal tubulær acidose; Parkinsons sygdom; Alzheimers sygdom; amyotrofisk lateral sklerose (ALS); Huntingtons sygdom; gennemgribende udviklingsforstyrrelser; høretab; døvhed; diabetes; aldring; og bivirkninger fra lægemidler der hæmmer mitokondriel funktion.
15. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 10 - 14, hvor en målbar klinisk markør anvendes til at vurdere effektiviteten af terapien under anvendelse af forbindelser af opfindelsen.
16. Forbindelse til anvendelse ifølge krav 15, hvor den kliniske markør er en eller flere markører valgt fra gruppen bestående af mælkesyre (laktat) -niveauer, enten i fuldblod, plasma, rygmarvsvæske, eller cerebral ventrikelvæske; pyrodruesyre (pyruvat) -niveauer, enten i fuldblod, plasma, rygmarvsvæske, eller cerebral ventrikelvæske; laktat-/pyruvatforhold, enten i fuldblod, plasma, rygmarvsvæske, eller cerebral ventrikelvæske; aminosyrer, i særdeleshed alanin, citrullin og prolin i fuldblod, plasma, eller rygmarvsvæske, organiske syrer i kropsvæsker; FGF21 i serum og skeletmuskel; phosphokreatinniveauer, NADH (NADH + H+) eller NADPH (NADPH + H+) -niveauer; NAD- eller NADP-niveauer; ATP-niveauer; anaerobisk grænseværdi; reduceret coenzym Q (CoQred) -niveauer; oxideret coenzym Q (CoQox -niveauer; total coenzym Q (CoQtot) -niveauer; oxideret cytochrom C-niveauer; reducerede cytochrom C-niveauer; oxideret cytochrom C/reduceret cytochrom C forhold; acetoacetat-niveauer, beta-hydroxy butyrat-niveauer, acetoacetat/betahydroxy butyrat-forhold, 8-hydroxy-2'-deoxyguanosin (8-OHdG) -niveauer; niveauer af reaktive oxygenarter; og niveauer af oxygenforbrug (V02), niveauer af kuldioxidoutput (VC02), og respiratorisk kvotient (VC02/V02).
17. Forbindelse til anvendelse i behandling, forebyggelse, eller undertrykkelse af symptomer associeret med en neoplastisk sygdom, hvor forbindelsen er en forbindelse af generel formel (I):
hvor - L = -(CH2)3-(L3), R1 = H, R2 = Me, R3 = Me, R4 = Me; X = I; eller - L = -(CH2)2- (L1), R1 = H, R2 = Me, R3 = Me, R4 = Me; X = I.
18. Forbindelse til anvendelse ifølge krav 17, hvor den neoplastiske sygdom er cancer, fortrinsvis en cancer valgt fra gruppen omfattende basalcelle carcinom, knoglecancer, tarmkræft, hjernecancer, brystcancer, livmoderhalskræft, leukæmi, levercancer, lungecancer, lymfom, melanom, æggestokscancer, kræft i bugspytkirtel, prostatacancer eller skjoldbruskkirtelkræft.
19. Kosmetisk fremgangsmåde til at behandle eller forsinke yderligere aldring af huden i et individ, hvilken fremgangsmåde omfatter trinnet at administrere til huden af individet en effektiv mængde af en sammensætning omfattende forbindelse af generel formel (I):
hvor - L er en linker omfattende 1 til 10 eventuelt substituerede backbone-atomer valgt fra kulstof, nitrogen og oxygen; og - R1 og R2 er hver uafhængigt valgt fra hydrogen og Ci - Ce alkyl, eller R1 og R2 er forbundet med hinanden for at danne en anden linker mellem amidnitrogen-atomet og det kationiske nitrogenatom, eller R1 er forbundet med et backbone-atom af linkeren L i en cyklisk struktur og/eller R2 er forbundet med et backbone-atom af linkeren L i en cyklisk struktur; og - R3 er valgt fra hydrogen og Ci - Ce alkyl, hvor alkyldelen kan substitueres med et eller flere halogenatomer eller (halo)alkoxydele, eller R3 er fraværende når det kationiske nitrogenatom er del afen imindel; og - R4 er valgt fra hydrogen og Ci - C6 alkyl, hvor alkyldelen kan substitueres med et eller flere halogenatomer eller (halo)alkoxydele; og - X' er en farmaceutisk acceptabel anion.
20. Fremgangsmåde ifølge krav 19, hvor - L = -(CH2)2NHC(0)CH2NHC(NH2)=(L5), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = TFA; eller - L = -(CH2)2NHC(0)CH2NHC(Me)=(L8), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3-(L11), R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -C(C02H)(CH2)3NHC(NH2) = (L12), R1 = H, R2 = H, R3 = fraværende, R4 = Η; X = Cl; eller - L = -(CH2)5-(L17) R1 = H, R2 = H, R3 = H, R4 = Η; X = Cl; eller - L = -(CH2)4-(L16), R1 = H, R2 = Me, R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2’(CH2)2-(L21), R1 = H, R2-R2' = -(C^ML1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR5(CH2)2CHR5’-(L26), R1 = H, R2 = H, R5-R5’ = -(CH^HL1), R3 = H, R4 = Η; X = Cl; eller - L = -CHR2’CH2-(L19), R1 = H, R2-R2' = -(CH2)3-(L3), R3 = Me, R4 = Η; X = Cl; eller - L = -CHR2’(CH2)2-(L21), R1 = H, R2-R2' = -(CH2)2-(L1), R3 = Me, R4 = Η; X = Cl.
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