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ME02513B - Deuterizovani 1-piperazino-3-fenil indani za tretiranje šizofrenije - Google Patents

Deuterizovani 1-piperazino-3-fenil indani za tretiranje šizofrenije

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Publication number
ME02513B
ME02513B MEP-2016-226A MEP2016226A ME02513B ME 02513 B ME02513 B ME 02513B ME P2016226 A MEP2016226 A ME P2016226A ME 02513 B ME02513 B ME 02513B
Authority
ME
Montenegro
Prior art keywords
compound
deuterium
atom
labeled
disorder
Prior art date
Application number
MEP-2016-226A
Other languages
German (de)
English (en)
French (fr)
Inventor
Morten Jorgensen
Peter Hongaard Andersen
Klaus Gjervig Jensen
Mette Graulund Hvenegaard
Lassina Badolo
Mikkel Fog Jacobsen
Original Assignee
H Lundbeck As
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by H Lundbeck As filed Critical H Lundbeck As
Publication of ME02513B publication Critical patent/ME02513B/me

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/454—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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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    • A61K31/55—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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    • A61K31/395—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
    • A61K31/554—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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    • 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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    • 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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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Claims (31)

1.Jedinjenje formule Y: u kojoj,R1 - R10 su nezavisno vodonik ili deuterijum, pri čemu su R6-R10 svaki deuterijum, i gde najmanje jedan od R1-R10 obuhvata najmanje oko 50% deuterijuma, ili njegova farmaceutski prihvatljiva adiciona so sa kiselinom.
2.  Jedinjenje prema zahtevu 1, u kojem su R3-R5 svaki vodonik.
3.  Jedinjenje prema zahtevu 1, u kojem su R3-R5 svaki deuterijum.
4.  Jedinjenje prema zahtevu 2, gde je jedinjenje
5.  Jedinjenje prema zahtevu 2, gde je jedinjenje
6.  Jedinjenje prema zahtevu 3, gde je jedinjenje
7.  Jedinjenje prema zahtevu 3, gde je jedinjenje
8.  Jedinjenje prema zahtevu 1, u kojem su R1 i R2 svaki deuterijum.
9.  Jedinjenje prema zahtevu 8, u kojem su R3-R5 svaki deuterijum.
10.  Jedinjenje prema zahtevu 8, u kojem su R3-R5 svaki vodonik.
11.  Jedinjenje prema bilo kom od zahteva 1-10, u kojem najmanje oko 85% jedinjenja ima atom deuterijuma na svakom položaju označenom kao deuterijum, a svaki atom koji nije označen kao deuterijum prisutan je otprilike u svojoj prirodnoj izotopskoj rasprostranjenosti.
12.  Jedinjenje prema bilo kom od zahteva 1-11, u kojem najmanje oko 90% jedinjenja ima atom deuterijuma na svakom položaju označenom kao deuterijum, a svaki atom koji nije označen kao deuterijum prisutan je otprilike u svojoj prirodnoj izotopskoj rasprostranjenosti.
13.  Jedinjenje prema zahtevu 1, gde je jedinjenje hidrogen tartaratna so
14.  Jedinjenje prema zahtevu 13, u kojem jedinjenje postoji u polimorfnom obliku koji ima XRPD difrakcioni obrazac kakav je prikazan na Fig. 18.
15.  Jedinjenje prema zahtevu 13, u kojem najmanje oko 85% jedinjenja ima atom deuterijuma na svakom položaju označenom kao deuterijum, a svaki atom koji nije označen kao deuterijum prisutan je otprilike u svojoj prirodnoj izotopskoj rasprostranjenosti.
16.  Farmaceutska kompozicija koja obuhvata jedinjenje prema bilo kom od zahteva 1 do 15 i jedan ili više farmaceutski prihvatljivih nosača, razblaživača ili ekscipijenasa.
17.  Farmaceutska kompozicija prema zahtevu 16, gde je jedinjenje hidrogen tartaratna so
18.  Kompozicija prema zahtevima 16 ili 17, u kojoj nosač obuhvata hidroksipropil-β-ciklodekstrin u vodi, i u kojoj najmanje oko 85% jedinjenja ima atom deuterijuma na svakom položaju označenom kao deuterijum, a svaki atom koji nije označen kao deuterijum prisutan je otprilike u svojoj prirodnoj izotopskoj rasprostranjenosti.
19.  Upotreba jedinjenja prema bilo kom od zahteva 1-15, ili kompozicija prema bilo kom od zahteva 16-18 za proizvodnju leka za tretiranje psihoze, ostalih bolesti koje uključuju psihotične simptome, psihotičnih poremećaja ili bolesti koje su prisutne sa psihotičnim simptomima.
20.  Upotreba prema zahtevu 19, pri čemu je psihoza ili bolest koja uključuje psihotične simptome šizofrenija, šizofreniformni poremećaj, šizoafektivni poremećaj, deluzioni poremećaj, kratkotrajni psihotični poremećaj, podeljeni psihotični poremećaj, bipolarni poremećaj ili manija u bipolarnom poremećaju.
21.  Upotreba prema bilo kom od zahteva 19-20, koja dalje obuhvata jedinjenje odabrano iz grupe koja se sastoji od sertindola, olanzapina, risperidona, kvetiapina, aripiprazola, haloperidola, klozapina, ziprasidona i osanetanta.
22.  Upotreba prema bilo kom od zahteva 19-20, gde je psihoza ili bolest koja uključuje psihotične simptome šizofrenija.
23.  Upotreba prema bilo kom od zahteva 19-20, gde je psihoza ili bolest koja uključuje psihotične simptome šizofrenija, pri čemu farmaceutska kompozicija obuhvata efektivnu količinu hidrogen tartaratne soli i hidroksipropil-β-ciklodekstrin u vodi, i gde najmanje oko 85% (IV) ima atom deuterijuma na svakom položaju označenom kao deuterijum, a svaki atom koji nije označen kao deuterijum prisutan je otprilike u svojoj prirodnoj izotopskoj rasprostranjenosti.
24.  Jedinjenje formule
25.  Postupak za pripremanje jedinjenja koji obuhvata tretiranje jedinjenja (XIV) sa [(S)-BINAP]Rh(I)BF4.
26.  Postupak prema zahtevu 25, u kojem se [(S)-BINAP]Rh(I)BF4 primenjuje u katalitičkoj količini.
27.  Postupak za pripremanje jedinjenja (XIV) koji obuhvata a) tretiranje bis(pinakolato) diboronom, i b) tretiranje 2-bromo-5-hlorobenzaldehidom.
28.  Postupak prema zahtevu 27, u kojem tretiranje bis(pinakolato) diboronom dalje obuhvata dodavanje Pd(II).
29.  Postupak prema zahtevu 28, u kojem tretiranje 2-bromo-5-hlorobenzaldehidom dalje obuhvata dodavanje Pd(0).
30.  Postupak za pripremanje jedinjenja (1R,3S)-(IV) tartarat, koji obuhvata tretiranje racemskog trans-1-(6-hloro-3-fenil(d5)-indan-1-il)-1(d3), 2, 2-trimetil-piperazina L-(+)-vinskom kiselinom.
31.  Postupak prema zahtevu 30, u kojem se racemski trans-1-(6-hloro-3-fenil(d5)-indan-1-il)-1(d3), 2, 2-trimetil-piperazin generiše iz njegove odgovarajuće sukcinatne soli.
MEP-2016-226A 2011-06-20 2012-06-19 Deuterizovani 1-piperazino-3-fenil indani za tretiranje šizofrenije ME02513B (me)

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

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DK3135656T3 (en) 2011-06-20 2019-04-23 H Lundbeck As DEUTERATED 1-PIPERAZINO-3-PHENYL INDANES FOR TREATMENT OF schizophrenia
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
EP3873885A1 (en) * 2018-10-29 2021-09-08 H. Lundbeck A/S Amorphous compounds of formula (i) and amorphous compounds of formula (i) salts
WO2020114853A1 (en) 2018-12-03 2020-06-11 H. Lundbeck A/S Prodrugs of 4-((1r,3s)-6-chloro-3-phenyl-2,3-dihydro-1h-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1/r,3s)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1h-inden-1-yl)-2,2-dimethy-1-(methyl-d3)piperazine
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