HRP20161348T1 - Deuterirani 1-piperazino-3-fenil indani za liječenje shizofrenije - Google Patents

Deuterirani 1-piperazino-3-fenil indani za liječenje shizofrenije Download PDF

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HRP20161348T1
HRP20161348T1 HRP20161348TT HRP20161348T HRP20161348T1 HR P20161348 T1 HRP20161348 T1 HR P20161348T1 HR P20161348T T HRP20161348T T HR P20161348TT HR P20161348 T HRP20161348 T HR P20161348T HR P20161348 T1 HRP20161348 T1 HR P20161348T1
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deuterium
image
atom
treatment
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HRP20161348TT
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Morten Jorgensen
Peter Hongaard Andersen
Klaus Gjervig Jensen
Mette Graulund Hvenegaard
Lassina Badolo
Mikkel Fog Jacobsen
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H. Lundbeck A/S
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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Claims (31)

1. Tvar formule Y [image] pri čemu R1-R10 su nezavisno vodik ili deuterij, pri čemu su R6-R10 svaki deuterij, pri čemu najmanje jedan od R1-R10 sadrži najmanje oko 50% deuterija, ili njena farmaceutski prihvatljiva sol dobivena adicijom kiseline.
2. Tvar iz patentnog zahtjeva 1, pri čemu je svaki od R3-R5 vodik.
3. Tvar iz patentnog zahtjeva 1, pri čemu je svaki od R3-R5 deuterij.
4. Tvar iz patentnog zahtjeva 2, pri čemu je tvar [image]
5. Tvar iz patentnog zahtjeva 2, pri čemu je tvar [image]
6. Tvar iz patentnog zahtjeva 3, pri čemu je tvar [image]
7. Tvar iz patentnog zahtjeva 3, pri čemu je tvar [image]
8. Tvar iz patentnog zahtjeva 1, pri čemu je svaki od R1 i R2deuterij.
9. Tvar iz patentnog zahtjeva 8, pri čemu je svaki od R3-R5 deuterij.
10. Tvar iz patentnog zahtjeva 8, pri čemu je svaki od R3-R5 vodik.
11. Tvar iz bilo kojeg od patentnih zahtjeva 1-10, pri čemu najmanje oko 85% tvari ima atom deuterija na svakoj poziciji predviđenoj za deuterij, a svaki je atom koji nije predodređen za deuterij prisutan kao svoj prirodno zastupljeni oblik izotopa.
12. Tvar iz bilo kojeg od patentnih zahtjeva 1-11, pri čemu najmanje oko 90% tvari ima atom deuterija na svakoj poziciji predviđenoj za deuterij, a svaki je atom koji nije predodređen za deuterij prisutan kao svoj prirodno zastupljeni oblik izotopa.
13. Tvar iz patentnog zahtjeva 1, pri čemu je tvar hidrogen tartaratna sol tvari [image]
14. Tvar iz patentnog zahtjeva 13, pri čemu tvar postoji u polimorfnom obliku i ima XRPD uzorak difrakcije kako je prikazano na Slici 18.
15. Tvar iz patentnog zahtjeva 13, pri čemu najmanje oko 85% tvari ima atom deuterija na svakoj poziciji predviđenoj za deuterij, a svaki je atom koji nije predodređen za deuterij prisutan kao svoj prirodno zastupljeni oblik izotopa.
16. Farmaceutski sastav obuhvaća tvar iz bilo kojeg od patentnih zahtjeva 1 do 15 i jedan ili više farmaceutski prihvatljivih nosača, diluenata, ili ekscipijenasa.
17. Farmaceutski sastav iz patentnog zahtjeva 16, pri čemu je tvar hidrogen tartaratna sol tvari [image]
18. Tvar iz patentnih zahtjeva 16 ili 17, pri čemu nosač sadrži hidroksipropil-β-ciklodekstrin u vodi i pri čemu najmanje oko 85% tvari ima atom deuterija na svakoj poziciji predviđenoj za deuterij, a svaki je atom koji nije predodređen za deuterij prisutan kao svoj prirodno zastupljeni oblik izotopa.
19. Uporaba tvari iz bilo kojeg od patentnih zahtjeva 1-15, ili sastava iz bilo kojeg od patentnih zahtjeva 16-18 za proizvodnju lijeka za liječenje psihoza, drugih bolesti koje uključuju psihotične simptome, psihotičke poremećaje ili bolesti koje se manifestiraju psihotičnim simptomima.
20. Uporaba u skladu s patentnim zahtjevom 19, pri čemu su psihoze ili bolesti koje uključuju psihotične simptome shizofrenija, shizofrenoformni poremećaj, shizoafektivni poremećaj, diluzijski poremećaj, kratkotrajni psihotički poremećaj, grupni psihotički poremećaj, bipolarni poremećaj, ili manija u bipolarnom poremećaju.
21. Uporaba u skladu s bilo kojim od patentnih zahtjeva 19-20, nadalje obuhvaća tvar odabranu iz grupe koja sadrži sertindol, olanzapin, risperidon, kvetiapin, aripiprazol, haloperidol, klozapin, ziprasidon i osanetant.
22. Uporaba u skladu s bilo kojim od patentnih zahtjeva 19-20, pri čemu je psihoza ili bolest koja uključuje psihotične simptome shizofrenija.
23. Uporaba u skladu s bilo kojim od patentnih zahtjeva 19-20, pri čemu je psihoza ili bolest koja uključuje psihotične simptome shizofrenija, pri čemu farmaceutski sastav sadrži učinkovitu količinu hidrogen tartaratne soli tvari [image] i hidroksipropil-β-ciklodekstrin u vodi i pri čemu najmanje oko 85% tvari (IV) ima atom deuterija na svakoj poziciji predviđenoj za deuterij, a svaki je atom koji nije predodređen za deuterij prisutan kao svoj prirodno zastupljeni oblik izotopa.
24. Tvar formule [image]
25. Postupak za pripravu tvari [image] obuhvaća tretiranje tvari (XIV) sa [(S)-BINAP]Rh(I)BF4. [image]
26. Postupak iz patentnog zahtjeva 25, pri čemu se [(S)-BINAP]Rh(I)BF4 koristi u katalitičkoj količini.
27. Postupak za pripravu tvari (XIV) obuhvaća a) tretiranje [image] s bis(pinakolato)diboronom, i b) tretiranje s 2-bromo-5-klorobenzaldehidom.
28. Postupak iz patentnog zahtjeva 27, pri čemu tretiranje tvari [image] s bis(pinakolato)diboronom nadalje uključuje dodavanje Pd(II).
29. Postupak iz patentnog zahtjeva 28, pri čemu tretiranje s 2-bromo-5-klorobenzaldehidom nadalje uključuje dodavanje Pd(0).
30. Postupak priprave tvari (1R, 3S)-(IV) tartarata obuhvaća tretiranje racemičnog trans-1-(6-kloro-3-fenil(d5)-indan-1-il)-1(d3),2,2-trimetil-piperazina s L-(+)-vinskom kiselinom.
31. Postupak iz patentnog zahtjeva 30, pri čemu se racemični trans-1-(6-kloro-3-fenil(d5)-indan-1-il)-1(d3),2,2-trimetil-piperazin stvara iz njegove odgovarajuće sukcinatne soli.
HRP20161348TT 2011-06-20 2016-10-17 Deuterirani 1-piperazino-3-fenil indani za liječenje shizofrenije HRP20161348T1 (hr)

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US201161498651P 2011-06-20 2011-06-20
US201161537103P 2011-09-21 2011-09-21
EP12748046.5A EP2720989B1 (en) 2011-06-20 2012-06-19 Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia
PCT/IB2012/001386 WO2012176066A1 (en) 2011-06-20 2012-06-19 Deuterated 1-piperazino-3-phenyl indanes for treatment of schizophrenia

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HRP20190593TT HRP20190593T1 (hr) 2011-06-20 2019-03-27 Deuterirani 1-piperazino-3-fenil indani za liječenje shizofrenije

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JP5668177B2 (ja) 2011-06-20 2015-02-12 ハー・ルンドベック・アクチエゼルスカベット 統合失調症の治療のための重水素化１−ピペラジノ−３−フェニルインダン
AR094054A1 (es) * 2012-12-19 2015-07-08 H Lundbeck As 6-cloro-3-(fenil-d₅)-inden-1-ona y uso de la misma
WO2019049918A1 (en) 2017-09-07 2019-03-14 Otsuka Pharmaceutical Co., Ltd. INDUSTRIAL PROCESS FOR MONOALKYLATION OF PIPERIDINE NITROGEN IN PIPERIDINE DERIVATIVES WITH DEUTERATED ALKYL
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