IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS

a technology of pyridazine and derivatives, which is applied in the field ofimidazo1, 2bpyridazine derivatives, can solve the problems of cognitive deficits in schizophrenic patients and impaired attention and memory

Inactive Publication Date: 2012-08-30
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, schizophrenic patients suffer from cognitive deficits, such as impaired attention and memory.

Method used

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  • IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS
  • IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS
  • IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS

Examples

Experimental program
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examples

Chemistry

[0468]Several methods for preparing the compounds of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0469]Hereinafter, the term “LCMS” means liquid chromatography / mass spectrometry, “HPLC” means high-performance liquid chromatography, “min.” means minutes, “h.” means hours, “Rt” means retention time (in minutes), “[M+H]+” means the protonated mass of the free base of the compound, “m.p.” means melting point.

[0470]Microwave assisted reactions were performed in a single-mode reactor: Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currently Biotage).

[0471]Thin layer chromatography (TLC) was carried out on silica gel 60 F254 plates (Merck) using reagent grade solvents. Open column chromatography was performed on silica gel, particle size 60 Å, mesh=230-400 (Merck) under standard techniques. Flash column chromatography was performe...

example a1

Preparation of intermediate 1: 4-Bromo-6-chloro-pyridazin-3-ylamine

[0486]

[0487]Bromine (7.9 ml, 154 3 mmol) was added to a stirred suspension of 6-chloro-pyridazin-3-ylamine (20 g, 154.3 mmol) and sodium hydrogencarbonate (25.9 g, 308.8 mol) in methanol (500 ml). The mixture was stirred at room temperature for 16 h, then filtered. The filtrate was diluted with ethyl acetate and washed with a saturated solution of sodium thiosulfate, water and a saturated solution of sodium carbonate. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield intermediate 1 (24.59 g, 64%) as a brown solid which was used in next step without further purification. LCMS: 208 [M+H]+; Rt: 0.59 min (method 5).

example a2

Preparation of intermediate 2: 6-Chloro-4-morpholin-4-yl-pyridazin-3-ylamine

[0488]

[0489]Morpholine (8.37 ml, 95.9 mmol) was added to a stirred solution of intermediate 1 (2 g, 9.6 mmol) in acetonitrile (5 ml). The mixture was stirred at 80° C. for 16 h., then diluted with dichloromethane and washed with a saturated solution of sodium hydrogen carbonate. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, methanol in dichloromethane 0 / 100 to 30 / 70). The desired fractions were collected and concentrated in vacuo to yield intermediate 2 (1.98 g, 92%) as a pale brown solid. LCMS: 215 [M+H]+; Rt: 0.56 min (method 5).

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Abstract

The present invention relates to novel imidazo[1,2-b]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.

Description

FIELD OF THE INVENTION[0001]The present invention relates to novel imidazo[1,2-b]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.DESCRIPTION OF THE INVENTIONBackground of the Invention[0002]Phosphodiesterases (PDEs) are a family of enzymes encoded by 21 genes and subdivided into 11 distinct families according to structural and functional properties. These enzymes metabolically inactivate widely occurring intracellular second messengers, 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377A61K31/5025A61P25/00A61P25/18A61P3/00A61P25/14A61P25/28A61P25/30A61P25/04C07D487/04A61P25/22
CPCC07D487/04A61P25/00A61P25/04A61P25/14A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P3/00A61K31/5025A61K31/519
Inventor PASTOR-FERNÁNDEZ, JOAQUINBARTOLOMÉ-NEBREDA, JOSÉ MANUELMACDONALD, GREGOR JAMESCONDE-CEIDE, SUSANADELGADO-GONZÁLEZ, ÓSCARVANHOOF, GRETA CONSTANTIA PETERVAN GOOL, MICHIEL LUC MARIAMARTÍN-MARTÍN, MARÍA LUZALONSO-DE DIEGO, SERGIO-ALVAR
Owner JANSSEN PHARMA NV
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