DK2948455T5 - N-acyl-(3-substituerede)-(8-substituerede)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyraziner som seleltive nk-3-receptorantagonister, farmaceutisk sammensætning, fremgangsmåder til anvendelse i nk-3 receptor-medierede forstyrrelser - Google Patents
N-acyl-(3-substituerede)-(8-substituerede)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyraziner som seleltive nk-3-receptorantagonister, farmaceutisk sammensætning, fremgangsmåder til anvendelse i nk-3 receptor-medierede forstyrrelser Download PDFInfo
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- DK2948455T5 DK2948455T5 DK14713844.0T DK14713844T DK2948455T5 DK 2948455 T5 DK2948455 T5 DK 2948455T5 DK 14713844 T DK14713844 T DK 14713844T DK 2948455 T5 DK2948455 T5 DK 2948455T5
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Claims (23)
1. Forbindelse med formlen I:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R1 er H, F eller methyl; R1’ er H; R2 er H, F, Cl eller methoxy; R2 er H eller F; R3 er H, F, Cl, methyl, trifluormethyl eller nitril; R4 er methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluormethyl, difluormethyl eller fluormethyl; R5 er methyl, ethyl, methoxymethyl, trifluormethyl, difluormethyl, fluormethyl, 1-fluorethyl, 1,1-difluorethyl eller 2,2,2-trifluorethyl; X1 er N og X2 er S eller O; eller X1 er S og X2 er N; - repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2; “ “ “ står for (R)-enantiomeren eller for racematet af forbindelsen med formlen I.
2. Forbindelse ifølge krav 1, med formlen Γ og I”:
eller et farmaceutisk acceptabelt solvat deraf, hvor R1, R1’, R2, R2’, R3, R4, R5, X1 og X2 er som defineret i krav 1; og — repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2.
3. Forbindelse ifølge krav 1 eller krav 2, med formlen la:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R1 er H, F eller methyl; R1’ erH; R2 er H, F, Cl eller methoxy; R2’ er H eller F; R3 er H, F, Cl, methyl, trifluormethyl eller nitril; R4 er methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluormethyl, difluormethyl eller fluormethyl; R5 er methyl, ethyl, methoxymethyl, trifluormethyl, difluormethyl eller fluormethyl; ~ ~ ~ står for (R)-enantiomeren eller for racematet af forbindelsen med formlen la.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, udvalgt fra formlerne la’ og la”:
eller et farmaceutisk acceptabelt solvat deraf, hvor R1, R1 R2, R2, R3, R4 og R5 er som defineret i krav 3.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, med formlen Ia-1:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R3 er H, F, Cl, methyl, trifluormethyl eller nitril; R4 er methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluormethyl, difluormethyl eller fluormethyl; R5 er methyl, ethyl, methoxymethyl, trifluormethyl, difluormethyl eller fluormethyl; - - - står for (R)-enantiomeren eller for racematet af forbindelsen med formlen Ia-1.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, med formlen Ia-2:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R1 er H, F eller methyl; R1’ er H; R2 er H, F, Cl eller methoxy; R2 er H eller F; R3 er H, F, Cl, methyl, trifluormethyl eller nitril; R5 er methyl, ethyl, methoxymethyl, trifluormethyl, difluormethyl eller fluormethyl; - - ~ står for (R)-enantiomeren eller for racematet af forbindelsen med formlen Ia-2.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, der har formlen Ia-3:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R1 er H, F eller methyl; R1 er H; R2 er H, F, Cl eller methoxy; R2 er H eller F; R3 er H, F, Cl, methyl, trifluormethyl eller nitril; R4 er methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluormethyl, difluormethyl eller fluormethyl; & står for (R)-enantiomeren eller for racematet af forbindelsen med formlen Ia-3.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, med formlen Ib:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R3 er F; R5 er methyl, ethyl, trifluormethyl, difluormethyl, fluormethyl, 1-fluorethyl, 1,1-difluorethyl eller 2,2,2-trifluorethyl; - - - står for (R)-enantiomeren eller for racematet af forbindelsen med formlen Ib.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8 med formlen Ib’:
eller et farmaceutisk acceptabelt solvat deraf, hvor R3 og R5 er som defineret i krav 8.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, med formlen le:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R!er H, F eller methyl; R*er H; R2er H, F, Cl eller methoxy; R2er H eller F; R3er H, F, Cl, methyl, trifluormethyl eller nitril; R4 er methyl, ethyl, n-propyl eller hydroxyethyl; R5 er methyl, ethyl eller trifluormethyl; ---står for (R)-enantiomeren eller for racematet af forbindelsen med formlen le.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10, med formlen le’:
eller et farmaceutisk acceptabelt solvat deraf, hvor: R1 er H, F eller methyl; R1’ erH; R2 er H, F, Cl eller methoxy; R2 er H eller F; R3 er H, F, Cl, methyl, trifluormethyl eller nitril; R4 er methyl, ethyl, n-propyl eller hydroxyethyl; R5 er methyl, ethyl eller trifluormethyl.
12. Forbindelse ifølge et hvilket som helst af kravene 1 til 11, udvalgt fra gruppen bestående af:
og farmaceutisk acceptable solvater deraf.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 12, der er udvalgt fra gruppen bestående af: (R)-(3-(3-ethyl-l,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[l,2,4]triazol[4,3- a]pyrazin-7(8H)-yl)(4-fluorphenyl)methanon; (R)-(4-chlorphenyl)(8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon; (R)-(4-fhiorphenyl)(8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon; (4-fhiorphenyl)(8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon og (R)-(4-fhiorphenyl)(8-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon, og farmaceutisk acceptable solvater deraf.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 13, der er (R)-(4-fluorphenyl)(8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon, eller et farmaceutisk acceptabelt solvat deraf.
15. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 14, eller et farmaceutisk acceptabelt solvat deraf, og mindst én farmaceutisk acceptabel bærer, fortynder, excipiens og/eller adjuvans.
16. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 eller et farmaceutisk acceptabelt solvat deraf til anvendelse som et medikament.
17. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 eller et farmaceutisk acceptabelt solvat deraf til anvendelse i behandling og/eller forebyggelse af depression, angst, psykose, skizofreni, psykotiske forstyrrelser, bipolare forstyrrelser, kognitive forstyrrelser, Parkinsons sygdom, Alzheimers sygdom, attention deficit hyperactivity disorder (ADHD), smerte, konvulsion, fedme, inflammatoriske sygdomme, herunder irritabel tarmsyndrom (IBS) og inflammatoriske tarmforstyrrelser, emesis, præeklampsi, luftvejsrelaterede sygdomme, herunder kronisk obstruktiv lungesygdom, astma, luftvej shyperresponsivitet, bronchokonstriktion og hoste, urininkontinens, reproduktionsforstyrrelser, kontraception og kønshormonafhængige sygdomme, herunder, men ikke begrænset til, godartet prostatisk hyperplasi (BPH), prostatisk hyperplasi, metastatisk prostatisk karcinom, testikelcancer, brystcancer, ovariecancer, androgenafhængig akne, mandligt hårtab, endometriose, anormal pubertet, uterinfibrose, fibrøs uterustumor, uterint leiomyon, hormonafhængige cancere, hyperandrogenisme, hirsutisme, virilisering, polycystisk ovariesyndrom (PCOS), præmenstruel dysforisk sygdom (PMDD), HAIR-AN-syndrom (hyperandrogenisme, insulinresistens og acanthosis nigricans), ovariehyperthekose (HAIR-AN med hyperplasi af luteiniserende thecaceller i ovariestroma), andre manifestationer af høje androgene intraovariekoncentrationer (f.eks. standsning af follikelmodning, atresi, anovulation, dysmenoré, abnorm vaginalblødning, infertilitet), androgen-producerende tumor (viriliserende ovarietumor eller viriliserende adrenaltumor), menoragi og adenomyose.
18. Forbindelse til anvendelse ifølge krav 17, hvor forbindelsen er (R)-(4-fluorphenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon eller et farmaceutisk acceptabelt solvat deraf.
19. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 eller et farmaceutisk acceptabelt solvat deraf til anvendelse i behandling og/eller forebyggelse af hedeture.
20. Forbindelse til anvendelse ifølge krav 19, hvor forbindelsen er (R)-(4-fluorphenyl)(8-methyl-3 -(3 -methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1.2.4] triazol[4,3-a]pyrazin-7(8H)-yl)methanon eller et farmaceutisk acceptabelt solvat deraf.
21. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 eller et farmaceutisk acceptabelt solvat deraf til anvendelse som et sænkningsmiddel til de cirkulerende LH-niveauer.
22. Forbindelse til anvendelse ifølge krav 21, hvor forbindelsen er (R)-(4-fluorphenyl)(8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[1.2.4]triazol[4,3-a]pyrazin-7(8H)-yl)methanon eller et farmaceutisk acceptabelt solvat deraf.
23. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1 til 14 eller et farmaceutisk acceptabelt solvat deraf, kendetegnet ved, at den omfatter følgende trin: a) omsætning af en forbindelse med formlen (i)
hvor: PG repræsenterer en egnet beskyttelsesgruppe såsom for eksempel DMB, PMB, Boc, allyl, diphenyl-phosphinamid eller 2-trimethylsilylethansulfonyl; R4’ er R4 som defineret i krav 1 eller en reducerbar præcursor af hydroxyethyl og som følge heraf en yderligere præcursor af methoxyethyl; * står for (R)-enantiomeren eller for racematet; med en forbindelse med formlen (ii)
hvor: R5 er R5 som defineret i krav 1, H eller l-((tert-butyldiphenylsilyl)oxy)ethyl; X1 og X2 er som defineret i krav 1; repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2; for således at opnå en forbindelse med formlen (iii)
A hvor PG, R4 , R5’, X1 og X2 er som defineret ovenfor, står for (R)-enantiomeren eller for racematet og---repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2; b) afbeskyttelse af forbindelsen med formlen (iii) med et egnet afbeskyttelsesmiddel for at frembringe en forbindelse med formlen (iv)
hvor R4’, R5’, X1 og X2 er som defineret ovenfor, står for (R)-enantiomeren eller for racematet “ og repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2; c) når R5 ’ er H, introducering af en trifluormethyl- eller difluormethylgruppe ved direkte C-H trifluor- eller difluormethylering, der fører til en forbindelse med formlen (v)
hvor R4, X1 og X2 er som defineret ovenfor og R5 er trifluormethyl eller £ difluormethyl,---står for (R)-enantiomeren eller for racematet og repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2; d) N-acylerende forbindelse med formlen (iv) hvor R5’ ikke er H eller forbindelse med formlen (v), med en forbindelse med formlen (vi)
hvor RI, RI’, R2, R2’ og R3 er som defineret i krav 1; der fører til en forbindelse med formlen (vii)
hvor R1, R1’, R2, R2’, R3, R4’, X1 og X2 er som defineret ovenfor, ’it ----står for (R)-enantiomeren eller for racematet, repræsenterer en enkelt- eller en dobbeltbinding i forhold til X1 og X2; og R5” er R5 som defineret i krav 1 eller l-((tert-butyldiphenylsilyl)oxy)ethyl; e) eventuelt endvidere udførelse af ét eller begge af de to følgende trin e’) og e”): e’) når R4’ er en reducerbar præcursor af hydroxyethyl og som følge heraf en yderligere præcursor af ethoxyethyl, et trin med reduktion eventuelt efterfulgt af methyletherdannelse; e”) når R5 er l-((tert-butyldiphenylsilyl)oxy)ethyl, et trin med alkoholafbeskyttelse og efterfølgende fluorinering for at danne 1-fluorethyl R5-gruppe; eller et trin med alkoholafbeskyttelse, efterfulgt af et oxideringstrin og et efterfølgende fluorineringstrin for at frembringe 1,1-difluorethyl R5 gruppe; for at frembringe en forbindelse med formlen I ifølge et hvilket som helst af kravene 1 til 14.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13161863 | 2013-03-29 | ||
| EP13193025 | 2013-11-15 | ||
| EP14154303 | 2014-02-07 | ||
| PCT/EP2014/056367 WO2014154895A1 (en) | 2013-03-29 | 2014-03-28 | NOVEL N-ACYL-(3-SUBSTITUTED)-(8-SUBSTITUTED)-5,6-DIHYDRO- [1,2,4]TRIAZOLO[4,3-a]PYRAZINES AS SELECTIVE NK-3 RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITION, METHODS FOR USE IN NK-3 RECEPTOR-MEDIATED DISORDERS |
Publications (2)
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| DK2948455T3 DK2948455T3 (da) | 2017-11-20 |
| DK2948455T5 true DK2948455T5 (da) | 2018-03-19 |
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| CA2907814C (en) | 2013-03-29 | 2021-07-13 | Euroscreen Sa | Novel n-acyl-(3-substituted)-(8-methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, methods for use in nk-3 receptor-mediated disorders |
| AU2014242907B2 (en) * | 2013-03-29 | 2018-06-28 | Ogeda Sa | Novel N-acyl-(3-substituted)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor-mediated disorders |
| US10183948B2 (en) | 2013-03-29 | 2019-01-22 | Ogeda Sa | N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists |
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- 2014-03-28 DK DK14713844.0T patent/DK2948455T5/da active
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- 2014-03-28 EP EP14713844.0A patent/EP2948455B1/en active Active
- 2014-03-28 CN CN201480018469.6A patent/CN105229008B/zh active Active
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- 2014-03-28 JP JP2016504705A patent/JP6316932B2/ja active Active
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- 2014-03-28 KR KR1020217004563A patent/KR102364835B1/ko active Active
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- 2014-03-28 BR BR112015024907-8A patent/BR112015024907B1/pt active IP Right Grant
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- 2014-03-28 WO PCT/EP2014/056367 patent/WO2014154895A1/en not_active Ceased
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- 2014-03-28 KR KR1020157031249A patent/KR102218621B1/ko active Active
- 2014-03-28 EP EP17165576.4A patent/EP3219715A1/en not_active Withdrawn
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2015
- 2015-04-23 US US14/694,228 patent/US9422299B2/en active Active
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2016
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2018
- 2018-03-28 JP JP2018062649A patent/JP2018118988A/ja active Pending
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2024
- 2024-04-30 NL NL301272C patent/NL301272I2/nl unknown
- 2024-05-06 FR FR24C1020C patent/FR24C1020I2/fr active Active
- 2024-05-07 HU HUS2400012C patent/HUS2400012I1/hu unknown
- 2024-05-10 LT LTPA2024513C patent/LTC2948455I2/lt unknown
- 2024-05-14 LU LU00342C patent/LUC00342I2/fr unknown
- 2024-06-06 FI FIC20240019C patent/FIC20240019I1/fi unknown
- 2024-06-11 CY CY2024019C patent/CY2024019I2/el unknown
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