DK1618098T3 - 1,2,4-oxadiazolbenzoesyreforbindelser og deres anvendelse til nonsens-bekæmpelse og behandling af en sygdom - Google Patents

1,2,4-oxadiazolbenzoesyreforbindelser og deres anvendelse til nonsens-bekæmpelse og behandling af en sygdom Download PDF

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DK1618098T3
DK1618098T3 DK04759404.9T DK04759404T DK1618098T3 DK 1618098 T3 DK1618098 T3 DK 1618098T3 DK 04759404 T DK04759404 T DK 04759404T DK 1618098 T3 DK1618098 T3 DK 1618098T3
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phenyl
oxadiazol
benzoic acid
fluoro
disease
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Gary Mitchell Karp
Seongwoo Hwang
Guangming Chen
Neil Gregory Almstead
Young-Choon Moon
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Ptc Therapeutics Inc
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Claims (30)

1
1. Forbindelse med formel (I):
hvor: Z er substitueret aryl med undtagelse af 4-cyanophenyl, substitueret eller usubstitueret heteroaryl udvalgt fra triazolyl, tetrazolyl, oxadiazolyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothi-azolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazi-nyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl eller acridinyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret heterocyklus udvalgt fra morpholinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl eller tetrahy-drothiopyranyl, substitueret eller usubstitueret arylalkyl; eller Z er p-tolyl; (4-chlormethyl-phenyl); (4-ethyl-phenyl); o-tolyl; (3-methyl-thiophen-2-yl); (4-tert-butyl-phenyl); m-tolyl; (2,5-dimethyl-furan-3-yl); (4-pyrrol-1-yl-phenyl); (4-nitrophenyl); (4-isobutyl-phenyl); [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl]; R1 er hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret heterocycloalkyl, substitueret eller usubstitueret aryl, substitueret eller usubstitueret heteroaryl eller -(CH2CH20)nR6; R2, R3, R4 og R5 uafhængigt er hydrogen, alkoxy eller halogen; R6 er hydrogen eller alkyl; n er et helt tal fra 1 til 7; og 2 termen "substitueret" betyder en gruppe, som er substitueret med en til fire substituenter, udvalgt fra halogen, trifluormethyl, trifluormethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, alkylcarbonyl, cycloal-kyl, aryl, aryloxy, aralkyl, alkanoyloxy, cyano, azido, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino eller mono og disubstitueret amino, hvori den ene eller to substituenter på aminogruppen er udvalgt fra alkyl; hvor sådanne yderligere substituenter, når selve substituen-terne er yderligere substitueret, er udvalgt fra gruppen bestående af halogen, al kyl, alkoxy, aryl og aralkyl; eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
2. Forbindelse
ifølge krav 1 med formel II: (ii) hvor: Z er substitueret aryl med undtagelse af 4-cyanophenyl, substitueret eller usubstitueret heteroaryl udvalgt fra triazolyl, tetrazolyl, oxadiazolyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothi-azolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazi-nyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl eller acridinyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret heterocyklus udvalgt fra morpholinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl eller tetrahy-drothiopyranyl, substitueret eller usubstitueret arylalkyl; eller Z er p-tolyl; (4-chlormethyl-phenyl); (4-ethyl-phenyl); o-tolyl; (3-methyl-thiophen-2-yl); (4-tert-butyl-phenyl); m-tolyl; (2,5-dimethyl-furan-3-yl); (4-pyrrol-1 -yl-phenyl); (4-nitrophenyl); (4-isobutyl-phenyl); [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl]; og 3 R er hydrogen eller halogen; eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
3. Forbindelse ifølge krav 1 eller 2, hvor Z er p-tolyl; (4-chlormethyl-phenyl); (2-fluor-phenyl); (3,4-difluor-phenyl); (4-methoxy-phenyl); benzo[1,3]dioxol-5-yl; (4-ethyl-phenyl); o-tolyl; (2-chlor-phenyl); (3-methyl-thiophen-2-yl); ben-zo[b]thiophen-2-yl; (3-fluor-phenyl); (4-tert-butyl-phenyl); (2-methoxy-phenyl); (2,5-difluor-phenyl); thiophen-2-yl; (2,4-difluor-phenyl); (3-chlor-phenyl); m-tolyl; (4-trifluormethyl-phenyl); (4-fluor-phenyl); (3-methoxy-phenyl); (2,6-difluor-phenyl); (2,5-dimethyl-furan-3-yl); (4-pyrrol-1 -yl-phenyl); (3-dimethylamino-phenyl); biphenyl-4-yl; (4-dimethylamino-phenyl); ben-zo[c][1,2,5]oxadiazol-5-yl; (2-trifluormethyl-phenyl); furan-2-yl; (4-nitrophenyl); (3,4-dimethoxy-phenyl); (3-trifluormethoxy-phenyl); cyclohexyl; cyclopentyl; cyclopropyl; (4-pentyloxy-phenyl); (3,4,5-trimethoxy-phenyl); (4-isobutyl-phenyl); cyclobutyl; (1 -acetyl-piperidin-4-yl); isoxazol-5-yl; [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4- yi]-
4. Forbindelse ifølge krav 3, hvor Z er (2-fluor-phenyl); (3,4-difluor-phenyl); (2-chlor-phenyl); (3-fluor-phenyl); (2,5-difluor-phenyl); (2,4-difluor-phenyl); (3-chlor-phenyl); (4-fluor-phenyl); eller (2,6-difluor-phenyl).
5. Forbindelse ifølge krav 1 udvalgt fra gruppen bestående af: 3-((5-p-tolyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-chlormethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3,4-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzo[1,3]dioxol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-ethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-o-tolyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(2-chlor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzo[b]thiophen-2-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(3-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-tert-butyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 4 3-[5-(2,5-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-thiophen-2-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-thiophen-2-ylmethyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(2,4-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-chlor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-m-tolyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-trifluormethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,6-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,5-dimethyl-furan-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-pyrrol-1-yl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-dimethylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-biphenyl-4-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-dimethylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzo[c][1,2,5]oxadiazol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(2-trifluormethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-furan-2-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-nitrogen-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3,4-dimethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-trifluormethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-cyclohexyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-cyclopentyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-pentyloxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3,4,5-trimethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-cyclobutyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-( 1 -acetyl-pi peridi n-4-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-isoxazol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-{5-[3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]-[1,2,4]oxadiazol-3-yl}-benzoesyre; 3-((5-isopropyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-tert-butyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-butyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-propenyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-chlor-benzyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-chlor-phenoxymethyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-methoxymethyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(1 -phenyl-propyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-fluor-benzyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-chlor-phenoxymethyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-cyclopentylmethyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-methoxy-benzyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,3-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-fluor-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3- [5-(2,2-difluor-benzo[1,3]dioxol-5-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 4- fluor-3-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 2- fluor-5-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3- [5-(4-chlor-2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-bromo-2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-fluor-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3- {5-[3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl)-[1,2,4]oxadiazol-3-yl}- benzoesyre; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyrenatriumsalt; 3-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyremethylester; 5- [5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-2-methoxy-benzoesyre; 3-[5-(2-fluor-6-hydroxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyremethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre- 2-methoxy-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-(2-methoxy-ethoxy)-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-[2-(2 methoxy- ethoxy)-ethoxy]-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-{2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy}-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-[2-(2-{2-[2-(2- hydroxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethylester; 3-[5-(4-amino-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-azido-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; og 3-[5-(4-benzyloxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre og farmaceutisk acceptable salte, hydrater og solvater deraf.
6. Forbindelse ifølae krav 2 med formlen:
hvor: Z er (2-fluor-phenyl), o-tolyl, (2-chlor-phenyl), (2-methoxyphenyl) eller (2-trifluormethyl-phenyl); eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
7. Forbindelse ifølge krav 6 udvalgt fra 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol- ^-x/n-honTneicx/rci morH ctri ilfti ιτοη;
eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
8. Farmaceutisk sammensætning omfattende forbindelsen ifølge et af kravene 1 til 7 og en farmaceutisk acceptabel bærer, excipiens eller fortyndingsmiddel.
9. Farmaceutisk sammensætning ifølge krav 8 omfattende 0,1 mg til 2000 mg af 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf. 7
10. Farmaceutisk sammensætning ifølge krav 9 omfattende 5 mg til 500 mg af 3-[5-(2-fluor-phenyl-[1,2,4]oxadiazol-3-yl]-benzoesyre eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
11. Farmaceutisk sammensætning ifølge et af kravene 8 til 10, som er fremstillet til oral, parenteral, mukosal, transdermal eller topisk indgivelse.
12. Farmaceutisk sammensætning ifølge krav 11, hvor sammensætningen er et pulver, en tablet, en kapsel eller en suspension, hvor suspensionen eventuelt er vandig.
13. Farmaceutisk sammensætning ifølge et af kravene 8 til 10, hvor sammensætningen er en steril fast eller en steril parenteral doseringsform.
14. Enkeltenhedsdoseringsform omfattende: forbindelsen ifølge et af kravene 1 til 7 og en farmaceutisk acceptabel bærer, excipiens eller fortyndingsmiddel; eller den farmaceutiske sammensætning ifølge et af kravene 8 til 13.
15. Forbindelse med formel (I):
eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf, hvor: Z er substitueret eller usubstitueret aryl, substitueret eller usubstitueret hete-roaryl udvalgt fra triazolyl, tetrazolyl, oxadiazolyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazi- nyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl eller acridinyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret heterocyklus udvalgt fra morpholinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl eller tetrahy-drothiopyranyl, substitueret eller usubstitueret arylalkyl; eller Z er p-tolyl; (4-chlormethyl-phenyl); (4-ethyl-phenyl); o-tolyl; (3-methyl-thiophen-2-yl); (4-tert-butyl-phenyl); m-tolyl; (2,5-dimethyl-furan-3-yl); (4-pyrrol-1 -yl-phenyl); (4-nitrophenyl); (4-isobutyl-phenyl); [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl]; R1 er hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret heterocycloalkyl, substitueret eller usubstitueret aryl, substitueret eller usubstitueret heteroaryl eller -(CH2CH20)nR6; R2, R3, R4 og R5 uafhængigt er hydrogen, alkoxy eller halogen; R6 er hydrogen eller alkyl; ner et helt tal fra 1 til 7; og termen "substitueret" betyder en gruppe, som er substitueret med en til fire substituenter, udvalgt fra halogen, trifluormethyl, trifluormethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, alkylcarbonyl, cycloalkyl, aryl, aryloxy, aralkyl, alkanoyloxy, cyano, azido, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino eller mono og disubstitueret amino, hvori den ene eller to substituenter på aminogruppen er udvalgt fra alkyl; hvor sådanne yderligere substituenter, når selve substituen-terne er yderligere substitueret, er udvalgt fra gruppen bestående af halogen, al kyl, alkoxy, aryl og aralkyl; til anvendelse i en fremgangsmåde til behandling eller forebyggelse af en sygdom associeret med en manglende ekspression af et gen, som er et resultat af en præmatur stopkodon, hvor sygdommen associeret med en manglende ekspression af et gen, som er et resultat af en præmatur stopkodon, er en lysosomal lagringssygdom, en kardiovaskulær sygdom, en lungesygdom, en hjertesygdom, en autoimmun sygdom, en blodsygdom, en kollagensyg-dom, diabetes, en inflammatorisk sygdom, en sygdom i centralnervesystemet, en nyresygdom, en muskeldystrofi, retinitis pigmentosa, amyloidose, kæmpevækst, dværgvækst, hypothyroidisme, hyperthyroidisme, ældning eller obesitet.
16. Forbindelse til anvendelse ifølge krav 15, hvor forbindelsen er med formel II-
(II) eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf, hvor: Z er substitueret eller usubstitueret aryl, substitueret eller usubstitueret hete-roaryl udvalgt fra triazolyl, tetrazolyl, oxadiazolyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazi-nyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl eller acridinyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret heterocyklus udvalgt fra morpholinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl eller tetrahy-drothiopyranyl, substitueret eller usubstitueret arylalkyl; eller Z er p-tolyl; (4-chlormethyl-phenyl); (4-ethyl-phenyl); o-tolyl; (3-methyl-thiophen-2-yl); (4-tert-butyl-phenyl); m-tolyl; (2,5-dimethyl-furan-3-yl); (4-pyrrol-1-yl-phenyl); (4-nitrophenyl); (4-isobutyl-phenyl); [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl]; og R er hydrogen eller halogen;
17. Forbindelse udvalgt fra gruppen bestående af: 3-((5-p-tolyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-chlormethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3,4-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzo[1,3]dioxol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-ethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-o-tolyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(2-chlor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzo[b]thiophen-2-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(3-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-tert-butyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,5-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-thiophen-2-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-thiophen-2-ylmethyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(2,4-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-chlor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-m-tolyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-trifluormethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,6-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,5-dimethyl-furan-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-pyrrol-1-yl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-dimethylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-biphenyl-4-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-dimethylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzo[c][1,2,5]oxadiazol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(2-trifluormethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-furan-2-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-nitrogen-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3,4-dimethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-trifluormethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-cyclohexyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-cyclopentyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-pentyloxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3,4,5-trimethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-cyclobutyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(1-acetyl-piperidin-4-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-isoxazol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-{5-[3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]-[1,2,4]oxadiazol-3-yl}-benzoesyre; 3-((5-isopropyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-tert-butyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-butyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-propenyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-chlor-benzyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-chlor-phenoxymethyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-benzyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-((5-methoxymethyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(1 -phenyl-propyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-fluor-benzyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-chlor-phenoxymethyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-((5-cyclopentylmethyl-[1,2,4]oxadiazol-3-yl)-benzoesyre; 3-[5-(4-methoxy-benzyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2,3-difluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-fluor-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3- [5-(2,2-difluor-benzo[1,3]dioxol-5-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 4- fluor-3-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 2- fluor-5-[5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3- [5-(4-chlor-2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-bromo-2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(3-fluor-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3- {5-[3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl)-[1,2,4]oxadiazol-3-yl}- benzoesyre; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyrenatriumsalt; 3-[5-(4-fluor phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyremethylester; 5- [5-(4-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-2-methoxy-benzoesyre; 3-[5-(2-fluor-6-hydroxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyremethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre- 2-methoxy-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-(2-methoxy-ethoxy)-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-[2-(2 methoxy- ethoxy)-ethoxy]-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-{2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy}-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethylester; 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre 2-[2-(2-{2-[2-(2- hydroxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethylester; 3-[5-(4-amino-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; 3-[5-(4-azido-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre; og 3-[5-(4-benzyloxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre og farmaceutisk acceptable salte, hydrater og solvater deraf til anvendelse i en fremgangsmåde til behandling eller forebyggelse af en sygdom associeret med en manglende ekspression af et gen, som er et resultat af en præmatur stopkodon, hvor sygdommen associeret med en manglende ekspression af et gen, der er et resultat af en præmatur stopkodon, er en lysosomal lagringssygdom, en kardiovaskulær sygdom, en lungesygdom, en hjertesygdom, en autoimmun sygdom, en blodsygdom, en kollagensyg-dom, diabetes, en inflammatorisk sygdom, en sygdom i centralnervesystemet, en nyresygdom, en muskeldystrofi, retinitis pigmentosa, amyloidose, kæmpevækst, dværgvækst, hypothyroidisme, hyperthyroidisme, ældning eller obesitet.
18. Forbindelse til anvendelse ifølge et af kravene 15 til 17, hvor den lysosomale lagringssygdom er tuberøs sklerose, mukopolysakkaridose type INA, mukopolysakkaridose type VI, mukopolysakkaridose type VII, metakromatisk leukodystrofi Niemann Picks sygdom eller Sandhoff-sygdom; eller hvor den autoimmune sygdom er en immundeficiens, reumatoid artritis eller graft-versus-host-sygdom; eller hvor den inflammatoriske sygdom er artritis; eller hvor sygdommen i centralnervesystemet er multipel sklerose, sen infantil neuronal ceroid lipofuscinose, Alzheimers sygdom, Tay Sachs sygdom, en neurodegenerativ sygdom eller Parkinsons sygdom; eller hvor blodsygdommen er hæmofili, Von Willebrand-sygdom, ataxia-telangiectasia eller b-thalassemia; eller hvor nyresygdommen er nyresten; eller hvor kollagensygdommen er osteogenese imperfecta, Marfan-syndrom eller cirrose; eller hvor lungesygdommen er cystisk fibrose; eller hvor muskeldystrofien er Duchenne muskeldystrofi; eller hvor den kardiovaskulære sygdom er familiær hyperkolesterolæmi eller ate- rosklerose.
19. Forbindelse med formel (I):
eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf, hvor: Z er substitueret eller usubstitueret aryl, substitueret eller usubstitueret hete-roaryl udvalgt fra triazolyl, tetrazolyl, oxadiazolyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazi-nyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl eller acridinyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret alkenyl, substitueret eller usubstitueret heterocyklus udvalgt fra morpholinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl eller tetrahy-drothiopyranyl, substitueret eller usubstitueret arylalkyl; eller Z er p-tolyl; (4-chlormethyl-phenyl); (4-ethyl-phenyl); o-tolyl; (3-methyl-thiophen-2-yl); (4-tert-butyl-phenyl); m-tolyl; (2,5-dimethyl-furan-3-yl); (4-pyrrol-1 -yl-phenyl); (4-nitrophenyl); (4-isobutyl-phenyl); [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl]; R1 er hydrogen, substitueret eller usubstitueret alkyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret heterocycloalkyl, substitu- 14 eret eller usubstitueret aryl, substitueret eller usubstitueret heteroaryl eller -(CH2CH20)nR6; R2, R3, R4 og R5 uafhængigt er hydrogen, alkoxy eller halogen; R6 er hydrogen eller alkyl; n er et helt tal fra 1 til 7; og termen "substitueret" betyder en gruppe, som er substitueret med en til fire substituenter, udvalgt fra halogen, trifluormethyl, trifluormethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, alkylcarbonyl, cycloal-kyl, aryl, aryloxy, aralkyl, alkanoyloxy, cyano, azido, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino eller mono og disubstitueret amino, hvori den ene eller to substituenter på aminogruppen er udvalgt fra alkyl; hvor sådanne yderligere substituenter, når selve substituen-terne er yderligere substitueret, er udvalgt fra gruppen bestående af halogen, al kyl, alkoxy, aryl og aralkyl; til anvendelse i en fremgangsmåde til behandling, forebyggelse eller lindring af kræft eller en eller flere symptomer associeret med eller former for kræft.
20. Forbindelse til anvendelse ifølge krav 19, hvor forbindelsen er med formel II-
(II) eller et farmaceutisk acceptabelt salt, solvat eller hydrater deraf, hvor: Z er substitueret eller usubstitueret aryl, substitueret eller usubstitueret heteroaryl udvalgt fra triazolyl, tetrazolyl, oxadiazolyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazi-nyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl eller acridinyl, substitueret eller usubstitueret cycloalkyl, substitueret eller usubstitueret al- 15 kenyl, substitueret eller usubstitueret heterocyklus udvalgt fra morpholinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl eller tetrahy-drothiopyranyl, substitueret eller usubstitueret arylalkyl; eller Z er p-tolyl; (4-chlormethyl-phenyl); (4-ethyl-phenyl); o-tolyl; (3-methyl-thiophen-2-yl); (4-tert-butyl-phenyl); m-tolyl; (2,5-dimethyl-furan-3-yl); (4-pyrrol-1 -yl-phenyl); (4-nitrophenyl); (4-isobutyl-phenyl); [3-(2-chlor-6-fluor-phenyl)-5-methyl-isoxazol-4-yl]; eller [3-(2-chlor-phenyl)-5-methyl-isoxazol-4-yl]; og R er hydrogen eller halogen;
21. Forbindelse til anvendelse ifølge krav 20, hvor forbindelsen er 3-[5-(2-fluor-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoesyre med strukturen:
eller et farmaceutisk acceptabelt salt, solvat eller hydrat deraf.
22. Forbindelse til anvendelse ifølge et af kravene 19 til 21, hvor kræften er hoved-halskræft, kræft i øjet, hudkræft, kræft i munden, halskræft, spiserørs-kræft, kræft i brystkassen, knoglekræft, lungekræft, tarmkræft, sigmoid-kræft, kræft i endetarmen, mavekræft, prostatakræft, brystkræft, æggestokkræft, nyrekræft, leverkræft, bugspytkirtelkræft, kræft i hjernen, tarmkræft, kræft i hjertet eller binyrer, hvor kræften er en fast tumor udvalgt fra sarkom, karci-nom, fibrosarkom, myxosarkom, liposarkom, kondrosarkom, osteogent sarkom, chordom, angiosarkom, endotheliosarkom, lymphangiosarkom, lymp-hangioendotheliosarkom, synovialom, mesothelioma, Ewings tumor, leiomy-osarkom, rhabdomyosarkom, pladecellekarcinom, basal cellekarcinom, adenokarcinom, svedkirtelkarcinom, talgkirtelkarcinom, papillært karcinom, papilllære adenokarcinomer, cystadenokarcinom, medullært karcinom, bron-chogen karcinom, nyrecellekarcinom, hepatom, galdevejskarcinom, chori-okarcinom, seminom, embryonalt karcinom, Wilms tumor, livmoderhalskræft, testikulær tumor, lungekarcinom, småcellet lungekarcinom, blærekarcinom, epithelt karcinom, gliom, astrocytom, medulloblastom, kraniofaryngeom, ependymom, Kaposis sarkom, pinealom, hemangioblastom, akustisk neu-rom, oligodendrogliom, menangiom, melanom, neuroblastom, retinoblastom, en blodbåren tumor, akut lymfoblastisk leukæmi, akut lymfoblastisk B-celle-leukæmi, akut lymfoblastisk T-celle-leukæmi, akut myeloblastisk leukæmi, akut promyelocytisk leukæmi, akut monoblastisk leukæmi, akut erythro-leukæmisk leukæmi, akut megakaryoblastisk leukæmi, akut myelomonocy-tisk leukæmi, akut ikke-lymfocyctisk leukæmi, akut udifferentieret leukæmi, kronisk myelocytisk leukæmi, kronisk lymfocytisk leukæmi, hårcelleleukæmi eller myelomatose.
23. Forbindelse til anvendelse ifølge et af kravene 15 til 22, hvor patienten er et pattedyr.
24. Forbindelse til anvendelse ifølge et af kravene 15 til 22, hvor forbindelsen er til parenteral, transdermal, mukosal, nasal, bukkal, sublingual eller oral indgivelse.
25. Forbindelse til anvendelse ifølge krav 24, hvor forbindelsen er til oral indgivelse.
26. Forbindelse til anvendelse ifølge krav 25, hvor forbindelsen er til oral indgivelse i en tablet-, flydende eller kapselform.
27. Forbindelse ifølge et af kravene 15 til 22, hvor forbindelsen er til indgivelse i en terapeutisk eller profylaktisk virksom mængde fra 1 mg til 2000 mg om dagen.
28. Forbindelse til anvendelse ifølge krav 27, hvor forbindelsen er til indgivelse i en terapeutisk eller profylaktisk virksom mængde fra 5 mg til 500 mg om dagen.
29. Forbindelse til anvendelse ifølge krav 28, hvor forbindelsen er til indgivelse i en terapeutisk eller profylaktisk virksom mængde fra 10 mg til 200 mg om dagen.
30. Forbindelse ifølge et af kravene 1 til 6, hvor R1 er H, og forbindelsen er en fri syre.
DK04759404.9T 2003-04-11 2004-04-09 1,2,4-oxadiazolbenzoesyreforbindelser og deres anvendelse til nonsens-bekæmpelse og behandling af en sygdom DK1618098T3 (da)

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