DK2928884T3 - Nye benzimidazolderivativer som ep4-antagonister - Google Patents

Nye benzimidazolderivativer som ep4-antagonister Download PDF

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DK2928884T3
DK2928884T3 DK13798684.0T DK13798684T DK2928884T3 DK 2928884 T3 DK2928884 T3 DK 2928884T3 DK 13798684 T DK13798684 T DK 13798684T DK 2928884 T3 DK2928884 T3 DK 2928884T3
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ethyl
carbazol
benzimidazole
carboxylic acid
methoxyethyl
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Olaf Peters
Nico Bräuer
Thorsten Blume
Laak Antonius Ter
Ludwig Zorn
Jens Nagel
Stefan Kaulfuss
Gernot Langer
Joachim Kuhnke
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Bayer Pharma AG
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Claims (13)

1. Forbindelser med den almene formel (I)
(i), hvori Rla, Rlb uafhængigt af hinanden repræsenterer H, Ci-Cs-alkyl, C2-C5-alkenyl, C2-C5-alkynyl, C3-C6-cycloalkyl- (CH2)m, C3-C6-heterocycloalkyl- (CH2)n, Ci-Cs-alkoxy-Ci-C3-alkyl, C3-C6-cycloalkoxy-Ci-C3_alkyl, amino -C1-C3- al kyl, Ci -Cs-al kyl amino -Ci-C3~alkyl, Ci-C5-dialkylamino-Ci-C3-alkyl eller cyano, hvor den eventuelt foreliggende heterocykliske enhed fortrinsvis er valgt fra gruppen bestående af oxetan, tetrahydrofuran, tetrahydropyran, 1,4-dioxan, morpholin, azetidin, pyrrolidin, piperazin og piperidin, og hvor eventuelt foreliggende alkyl-, cycloalkyl- eller heterocycloalkylradikaler kan være monoeller polysubstitueret, identisk eller forskellig, med halogen, Ci-Cs-alkyl, hydroxyl, carboxyl, carboxy-Ci-Cs-alkyl, Ci-Cs-alkoxycarbonyl-Ci-Cs-alkyl eller Ci-Cs-alkylsulfonyl, r4 repræsenterer H, F, Cl, Ci-C2-alkyl, C3-Cs-cycloalkyl, C1-C2- alkoxy eller C3-C4_cycloalkylmethyl, hvor den tilsvarende alkyl- eller cycloalkylenhed kan være mono- eller polysubstitueret, identisk eller forskellig, med halogen eller hydroxyl, A repræsenterer R0-C0(CH2)P, hvor R repræsenterer H eller C1-C2-alkyl, m er 0, 1, 2 eller 3, n er 0, 1, 2 eller 3, p er 0 og B er valgt blandt følgende strukturer,
R5 repræsenterer H, F, Cl, CH3, CF3 CH3O eller CF3O, R7, R8 i hvert tilfælde uafhængigt af hinanden repræsenterer H, F, Cl, cyano, SF5, Ci-C3-alkyl, C3-Cs-cycloalkyl, Ci-C2-alkoxy eller C3-C4-cycloalkylmethyl, hvor den tilsvarende alkyl- eller cycloalkylenhed kan være mono- eller polyhalogeneret, og r9 repræsenterer Ci-Cs-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3- Ce-cycloalkyl-(CH2) n, C3-C6-heterocycloalkyl-(CH2) n, eller C1-C7-alkoxy-C2-C5-alkyl, hvor den eventuelt foreliggende heterocykliske enhed er valgt fra gruppen bestående af oxetan, tetrahydrofuran, tetrahydropyran, morpholin, pyrrolidin og piperidin, og hvor de eventuelt foreliggende alkyl-, cycloalkyl- eller heterocycloalkylenheder kan være mono- eller polysubstituerede, identiske eller forskellige, med halogen , Ci-C2-alkyl, Ci-C2-alkoxy eller carboxyl, og deres isomerer, diastereomerer, enantiomerer, solvater og salte eller cyclodextrin-clathrater.
2. Forbindelser ifølge krav 1, hvor Rla repræsenterer H eller Ci-Cs-alkyl, Rib repræsenterer H, Ci-Cs-alkyl, C2-C5-alkenyl, C3-C6- cycloalkyl-(CH2) m, C3-C6-heterocycloalkyl-(CH2) n, Ci-Cs-alkoxy-Ci-C3-alkyl eller Ci-C5-dialkylamino-Ci-C3-alkyl, hvor den eventuelt foreliggende heterocykliske enhed fortrinsvis er valgt fra gruppen bestående af oxetan, tetrahydrofuran, 1,4-dioxan, morpholin og pyrrolidin, og hvor eventuelt foreliggende alkyl- eller cycloalkylradikaler kan være monoeller polysubstituerede, identiske eller forskellige, med Ci-C5_alkyl, hydroxyl eller Ci-Cs-alkylsulfonyl, r4 repræsenterer H, F, Cl, Ci-C2-alkyl eller Ci-C2-alkoxy, A repræsenterer R0-C0(CH2)P, hvor R repræsenterer H eller C1-C2-alkyl, m er 0 eller 1, n er 0 eller 1, p er 0 og B er valgt blandt følgende strukturer,
τ r6 repræsenterer H, F, CH3 eller CH3O, R7, R° i hvert tilfælde uafhængigt af hinanden repræsenterer H, F, Cl, Ci-C3-alkyl eller Ci-C2-alkoxy og r9 repræsenterer Ci-Cs-alkyl, C2-Cs-alkenyl, C2-Cs-alkynyl, C3- Cb-cycloalkyl-(CH2) 3 eller Ci-C7alkoxy-C2-C5-alkyl, og deres isomerer, diastereomerer, enantiomerer, solvater og salte eller cyclodextrin-clathrater.
3. Forbindelser ifølge krav 1, hvor Rla repræsenterer H eller methyl, Rlb repræsenterer H, Ci-C2_alkyl, vinyl, cyclopropyl-(CH2) m, C3-Cb-heterocycloalkyl-(CH2) n, methoxy-Ci-C2-alkyl, eller (N,N-dimethylamino)-methyl, hvor den eventuelt foreliggende heterocykliske enhed fortrinsvis er valgt fra gruppen bestående af oxetan, tetrahydrofuran, 1,4-dioxan, morpholin og pyrrolidin, og hvor eventuelt foreliggende alkyl- eller cycloalkylgrupper kan være mono- eller polysubstitueret, identiske eller forskellige, med methyl, hydroxyl eller methylsulfony1, R4 repræsenterer H, F, Cl, methyl eller methoxy, A repræsenterer R0-C0(CH2)P, hvor R repræsenterer H eller C1-C2-alkyl, m er 0 eller 1, n er 0 eller 1, p er 0 og B er valgt blandt følgende strukturer,
r r6 repræsenterer H, F, CHs eller CHsO, R7, R8 i hvert tilfælde uafhængigt af hinanden repræsenterer H, F, Cl, methyl eller methoxy og r9 repræsenterer Ci-C3-alkyl, allyl, propargyl, C3-C4-cycloalkyl-(CH2) n eller methoxyethyl, og deres isomerer, diastereomerer, enantiomerer, solvater og salte eller cyclodextrin-clathrater.
4. Forbindelser ifølge krav 1, hvor Ria repræsenterer H eller methyl, R1b repræsenterer H, Ci-C2~alkyl, vinyl, cyclopropyl-(CH2) m, C3-Ce-heterocycloalkyl-(CH2) n, methoxy-Ci-C2-alkyl, eller (N,N-dimethylamino) -methyl, hvor den eventuelt foreliggende heterocykliske enhed fortrinsvis er valgt fra gruppen bestående af oxetan, tetrahydrofuran, 1,4-dioxan, morpholin og pyrrolidin, og hvor eventuelt foreliggende alkyl- eller cycloalkylgrupper kan være mono- eller polysubstitueret, identiske eller forskellige med methyl, hydroxyl eller methylsulfony1, r4 repræsenterer H, F, Cl, methyl eller methoxy, A repræsenterer R0-C0(CH2)P, hvor R betegner H, m er 0 eller 1, n er 0 eller 1, p er 0 og B er valgt blandt følgende strukturer,
8 r R6 repræsenterer H, F, CH3 eller CH3O, R7, R8 i hvert tilfælde uafhængigt af hinanden repræsenterer H, F, Cl, methyl eller methoxy og r9 repræsenterer Ci-C3~alkyl, allyl, propargyl, C3-C4-cycloalkyl-(CH2) n eller methoxyethyl, og deres isomerer, diastereomerer, enantiomerer, solvater og salte eller cyclodextrin-clathrater.
5. Forbindelser ifølge krav 1, hvor Rla repræsenterer H, Rib repræsenterer methoxymethyl, r4 repræsenterer H, F, Cl, methyl eller methoxy, A repræsenterer R0-C0(CH2)P, hvor R betegner H, n er 0 eller 1, p er 0 og B er valgt blandt følgende strukturer,
r6 repræsenterer H, F, CH3 eller CH3O, R7, R8 i hvert tilfælde uafhængigt af hinanden repræsenterer H, F, Cl, methyl eller methoxy og r9 repræsenterer Ci-C3-alkyl, allyl, propargyl, C3-C4- cycloalkyl-(CH2) n eller methoxyethyl, og deres isomerer, diastereomerer, enantiomerer, solvater og salte eller cyclodextrin-clathrater.
6. Forbindelse ifølge krav 1, der er valgt fra en gruppe, som indeholder de følgende forbindelser: 1. methyl-1-allyl-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazol-5-carboxylat 2. l-allyl-2-(9-ethyl-9H-carbazol-3-yl)-lH-benzimidazol-5-carboxylsyre 3 . methyl-2-(9-ethyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-1H-benzimidazol-5-carboxylat 4 . 2-(9-ethyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-IH- benzimidazol-5-carboxylsyre 5. methyl-1-(cyclopropylmethyl)-2-( 9-ethyl-9H-carbazol-3-yl) -lH-benzimidazol-5-carboxylat 6. 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazol-5-carboxylsyre 7 . methyl-4-chlor-l-(cyclopropylmethyl)-2-(9-ethyl-9H- carbazol-3-yl)-lH-benzimidazol-5-carboxylat 8. 4-chlor-1-(cyclopropylmethyl) -2-( 9-ethyl-9H-carbazol-3-yl) -lH-benzimidazol-5-carboxylsyre 9. 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-4-methy1-lH-benzimidazol-5-carboxylsyre 10 . 2-(9-ethyl-7-fluor-9H-carbazol-3-yl)-1-(2-methoxyethyl)- lH-benzimidazol-5-carboxylsyre 11. 2 - ( 9-ethyl-5-fluor-9H-carbazol-3-yl)-1-(2-methoxyethyl)- lH-benzimidazol-5-carboxylsyre 12 . 2-(9-ethyl-8-fluor-9H-carbazol-3-yl)-1-(2-methoxyethyl)- lH-benzimidazol-5-carboxylsyre 13 . 1-(cyclopropylmethyl)-2-[9-(2-methoxyethyl)-9H-carbazol-3- yl]-lH-benzimidazol-5-carboxylsyre 14 . 1-(cyclopropylmethyl)-2-(9-ethyl-9H-pyrido[2,3—b]indol-3- yl)-lH-benzimidazol-5-carboxylsyre 15. 2-(9-ethyl-6-methoxy-9H-carbazol-3-yl)-1-(2-methoxyethyl)-lH-benzimidazol-5-carboxylsyre 16. 2 -(9-allyl-9H-carbazol-3-yl)-1-(cyclopropylmethyl)-lH-benzimidazol-5-carboxylsyre 17 . 1-(cyclopropylmethyl)-2-(9-methyl-9H-carbazol-3-yl)-1H- benzimidazol-5-carboxylsyre 18 . 1-(cyclopropylmethyl)-2-[9-(cyclopropylmethyl)-9H- carbazol-3-yl]-lH-benzimidazol-5-carboxylsyre 19. 2-[9-(cyclopropylmethyl)-9H-carbazol-3-yl]-1-(2- methoxyethyl)-lH-benzimidazol-5-carboxylsyre 0 . ethyl-2-(9-ethyl-9H-carbazol-3-yl)-1-[2-(pyrrolidin-1- yl)ethyl]-lH-benzimidazol-5-carboxylat 21. 2-(9-ethyl-9H-carbazol-3-yl)-1-[2 - (pyrrolidin-l-yl)ethyl]- lH-benzimidazol-5-carboxylsyre 22 . 2-(5-ethyl-5H-pyrido[3,2-b]indol-2-yl)-1-(2-methoxyethyl)- lH-benzimidazol-5-carboxylsyre 23 . 1-(cyclopropylmethyl)-2-(9-ethyl-6-methoxy-9H-carbazol-3- yl)-lH-benzimidazol-5-carboxylsyre 2 4. 2-(9-ethyl-9H-carbazol-3-yl)-1-[2-(morpholin-4-yl) ethyl]- ΙΗ-benzimidazol-5-carboxylsyre 5 . ethyl-1-[2-(dimethylamino)ethyl]-2-(9-ethyl-9H-carbazol-3-yl)-lH-benzimidazol-5-carboxylat 2 6. 1-[2-(dimethylamino)ethyl]-2-(9-ethyl-9H-carbazol-3-yl) - ΙΗ-benzimidazol-5-carboxylsyre 27 . 2-( 9-ethyl-9H-carbazol-3-yl)-1-(2-hydroxyethyl)-1H- benzimidazol-5-carboxylsyre 8 . ethyl-2-(9-ethyl-9H-carbazol-3-yl)-1-isopropyl-lH- benzimidazol-5-carboxylat 29. 2- ( 9-ethyl-9H-carbazol-3-yl)-1-isopropyl-lH-benzimidazol-5-carboxylsyre 30. 2-( 9-ethyl-9H-carbazol-3-yl)-1-methyl-ΙΗ-benzimidazol-5-carboxylsyre 31. methyl-1-ethyl-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazol-5-carboxylat 32. 2-(9-allyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-1H-benzimidazol-5-carboxylsyre 33 . ethyll-(2-methoxyethyl)-2-[9-(2-methoxyethyl)-9H-carbazol-3-yl]-lH-benzimidazol-5-carboxylat 34 . 1-(2-methoxyethyl)-2-[9-(2-methoxyethyl)-9H-carbazol-3- yl]-ΙΗ-benzimidazol-5-carboxylsyre 35 . ethyl-2-(9-ethyl-9H-carbazol-3-yl)-1-(3-methoxypropyl)-1H-benzimidazol-5-carboxylat 36. 2-(9-ethyl-9H-carbazol-3-yl)-1-(3-methoxypropyl)-1H- benzimidazol-5-carboxylsyre 37 . 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-6- methoxy-lH-benzimidazol-5-carboxylsyre 38 . 2-(9-ethyl-9H-carbazol-3-yl)-6-methoxy-l-(2-methoxyethyl)- ΙΗ-benzimidazol-5-carboxylsyre 39 . 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-4- methoxy-lH-benzimidazol-5-carboxylsyre 40 . 2-( 9-ethyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-4-methyl- lH-benzimidazol-5-carboxylsyre 41 . 1-(cyclopropylmethyl)-2-( 9-ethyl-9H-pyrido[2,3-b]indol-3-yl)-4-methyl-ΙΗ-benzimidazol-5-carboxylsyre 42 . 1-(cyclopropylmethyl)-2-(9-ethyl-9H-beta-carbolin-6-yl)- lH-benzimidazol-5-carboxylsyre 43 . 1-(eye1opropylmethyl)-2-(5-ethyl-5H-pyrido[4,3—b]indol-8-yl)-lH-benzimidazol-5-carboxylsyre 44 . 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-6- methy1-lH-benzimidazol-5-carboxylsyre 45 . 2-(9-ethyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-6-methyl- lH-benzimidazol-5-carboxylsyre 4 6. 2 -(9-ethyl-9H-carbazol-3-yl)-6-fluor-l-(2-methoxyethyl)-lH-benzimidazol-5-carboxylsyre 47. 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-6- fluor-lH-benzimidazol-5-carboxylsyre 48 . 2-(9-ethyl-9H-carbazol-3-yl)-4-fluor-l-(2-methoxyethyl)- lH-benzimidazol-5-carboxylsyre 49. 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl) - 4 - fluor-lH-benzimidazol-5-carboxylsyre 50 . 1-(cyclopropylmethyl)-2-(9-ethyl-9H-pyrido[2,3—b]indol-6- yl)-lH-benzimidazol-5-carboxylsyre 51 . 1-(2-cyclopropylethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H- benzimidazol-5-carboxylsyre 52 . 1-(2-methoxyethyl)-2-(9-propyl-9H-carbazol-3-yl)-1H- benzimidazol-5-carboxylsyre 53 . 1-(2-methoxyethyl)-2-[9-(prop-2-yn-l-yl)-9H-carbazol-3- yl]-lH-benzimidazol-5-carboxylsyre 54 . 1-(cyclopropylmethyl)-2-(9-propyl-9H-carbazol-3-yl)-1H- benzimidazol-5-carboxylsyre 55 . 1-[(2,2-dimethylcyclopropy1)methyl]-2-(9-ethyl-9H- carbazol-3-yl)-lH-benzimidazol-5-carboxylsyre 6 . ethyl-2-(9-ethyl-9H-carbazol-3-yl)-1-(oxetan-3-ylmethyl)-lH-benzimidazol-5-carboxylat 57 . 2-(9-ethyl-9H-carbazol-3-yl)-1-(oxetan-3-ylmethyl)-1H- benzimidazol-5-carboxylsyre 58. 2-[9-(cyclobutylmethyl)-9H-carbazol-3-yl]-1-(2-methoxyethyl)-lH-benzimidazol-5-carboxylsyre 59. 2-[9-(cyclobutylmethyl)-9H-carbazol-3-yl] -1-(cyclopropylmethyl)-lH-benzimidazol-5-carboxylsyre 60 . 2-(9-ethyl-9H-carbazol-3-yl)-1-[2-(trifluormethoxy)ethyl]- lH-benzimidazol-5-carboxylsyre 61. 1-(cyclopropylmethyl)-2-(9-ethyl-l-methyl-9H-beta- carbolin-3-yl)-lH-benzimidazol-5-carboxylsyre 62 . 2-(9-ethyl-9H-carbazol-3-yl)-1-(oxetan-2-ylmethyl)-1H- benzimidazol-5-carboxylsyre 63. 2-(9-ethyl-9H-carbazol-3-yl)-1-(tetrahydrofuran-2- ylmethyl)-lH-benzimidazol-5-carboxylsyre 64 . 2-(9-ethyl-9H-carbazol-3-yl)-1-[ (2R)-2-hydroxy-3- methoxypropyl]-lH-benzimidazol-5-carboxylsyre 65 . 2-(9-ethyl-9H-carbazol-3-yl)-1-[ (2S)-2-hydroxy-3- methoxypropyl]-lH-benzimidazol-5-carboxylsyre 66 . 2 - ( 9-ethyl-9H-carbazol-3-yl)-1-[2-(methylsulfony1) ethyl]- lH-benzimidazol-5-carboxylsyre 67 . 1-(2-cyclopropyl-2-hydroxyethyl)-2-(9-ethyl-9H-carbazol-3- yl)-lH-benzimidazol-5-carboxylsyre 68. 1-[ (2 S)-2,3-dihydroxypropyl]-2-(9-ethyl-9H-carbazol-3-yl)- lH-benzimidazol-5-carboxylsyre 69 . 1-(1,4-dioxan-2-ylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-lH- benzimidazol-5-carboxylsyre 7 0. 1-(1,4-dioxan-2-ylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-lH- benzimidazol-5-carboxylsyre 71. 2-(9-ethyl-6-methyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)- 4-methyl-lH-benzimidazol-5-carboxylsyre 72 . 2-(6-chlor-9-ethyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-4- methy1-lH-benzimidazol-5-carboxylsyre 7 3. 2 -(8-chlor-9-ethyl-9H-carbazol-3-yl)-1-(2-methoxyethyl) - 4 - methyl-lH-benzimidazol-5-carboxylsyre
7. Forbindelse med formlen (I) som defineret i et af kravene 1 til 6 til behandling og/eller profylakse af sygdomme.
8. Forbindelse med formlen (I) som defineret i et af kravene 1 til 6 til anvendelse i en fremgangsmåde til behandling og/eller profylakse af endometriose, af livmoderledomyomer, af livmoderblødningsforstyrrelser, hvor blødningsforstyrrelserne kan være svære og langvarige blødninger, tidsmæssigt uregelmæssige blødninger og smerte, dysmenorré, kræft, hvor kræft kan være lunge, tarm, bryst, hud, prostata, øsofageal cancer og leukæmi, af arteriosklerose og af polycystiske nyresygdomme.
9. Anvendelse af en forbindelse ifølge krav 1, 2, 3, 4, 5 eller 6 til fremstilling af et medikament til behandling og/eller profylakse af sygdomme.
10. Anvendelse af en forbindelse som defineret i et af kravene 1 til 6 til fremstilling af et medikament til behandling og/eller profylakse af endometriose, af livmoderledomyomer, af livmoderblødningsforstyrrelser, hvor blødningsforstyrrelserne kan være svære og langvarige blødninger, tidsmæssigt uregelmæssige blødninger og smerte, dysmenorré, kræft, hvor kræft kan være lunge, tarm, bryst, hud, prostata, øsofageal cancer og leukæmi, af arteriosklerose og af polycystiske nyresygdomme.
11. Lægemiddel indeholdende en forbindelse som defineret i et af kravene 1 til 6 i kombination med et eller flere yderligere aktive stoffer, især med selektive østrogenreceptor-modulatorer (SERM'er), østrogenreceptor (ER)-antagonister, aromatase-inhibitorer, 17β-HSDl-inhibitorer, steroidsulfatase (STS)-inhibitorer, GnRH-agonister og -antagonister, kisspeptin-receptor (KISSR)-antagonister, selektive androgenreceptor-modulatorer (SARMs), androgener, 5a-reduktaseinhibitorer, selektive progesteronreceptor-modulatorer (SPRM'er), gestagener, antigestagener, orale præventionsmidler, inhibitorer af mitogen-aktiveret protein (MAP)-kinaser og inhibitorer af MAP kinaser (Mkk3/6, Mekl/2, Erkl/2), inhibitorer af proteinkinaser B (ΡΚΒα/β/γ, Aktl/2/3), inhibitorer af phosphoinositid-3-kinaser (PI3K), inhibitorer af cyclinafhængig kinase (CDKl/2), inhibitorer af den hypoxi-inducerede signalvej (HIFlalpha inhibitorer, aktivatorer af prolylhydroxylaser), histon-deacetylase (HDAC)-inhibitorer, prostaglandin-F-receptor (FP) (PTGFR) -antagonister, neurokinin 1 receptorantagonister, paracetamol, selektive COX2-inhibitorer og/eller ikke-selektive COX1/COX2-inhibitorer.
12. Lægemiddel indeholdende en forbindelse med formlen (I) som defineret i et af kravene 1 til 6 i kombination med et inert, ikke-toksisk, farmaceutisk egnet excipiens.
13. Lægemiddel ifølge krav 11 eller 12 til behandling og/eller profylakse af endometriose, af livmoderledomyomer, af livmoderblødningsforstyrrelser, hvor blødningsforstyrrelserne kan være alvorlige og langvarige blødninger, tidsmæssigt uregelmæssige blødninger og smerte af dysmenorré af kræft, hvor kræften kan være lunge, tarm, bryst, hud, prostata, øsofageal cancer og leukæmi, af arteriosklerose og af polycystiske nyresygdomme.
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