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Triazolopyrazinones as PDE1 inhibitors

A technology of triazolo and pyrazine, which is applied in the field of triazolopyrazinone as a PDE1 inhibitor, and can solve problems such as not disclosing it

Active Publication Date: 2017-05-24
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Two compounds, 7-[(4-chlorophenyl)methyl]-3-methyl-1,2,4-triazolo[4,3-a]pyrazin-8(7H)-one ( CAS registry number: 946270-18-4) and 7-[(4-chlorophenyl)methyl]-3-propyl-1,2,4-triazolo[4,3-a]pyrazine-8 (7H)-Kone (CAS registry number: 946237-23-6) is known in the art, but it has not been disclosed as a PDE1 inhibitor or as a medicament

Method used

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  • Triazolopyrazinones as PDE1 inhibitors
  • Triazolopyrazinones as PDE1 inhibitors
  • Triazolopyrazinones as PDE1 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

no. 1 example E1

[0031] In a first embodiment E1, the invention relates to a compound (compound I) of formula (I):

[0032]

[0033] Compound (I)

[0034] in

[0035] n is 0 or 1;

[0036] R 1 selected from the group consisting of: linear or branched C 1 -C 8 Alkyl, such as C 1 to C 3 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and saturated monocyclic C 3 -C 8 Cycloalkyl; or

[0037] R 1 selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, saturated monocyclic C 3 -C 8 Cycloalkyl, and substituted by fluorine one or more times, preferably once, twice or three times, straight or branched chain C 1 -C 8 alkyl; and

[0038] R 2 selected from the group consisting of: linear or branched C 1 -C 8 Alkyl, phenyl, saturated monocyclic C 3 -C 8 Cycloalkyl, saturated bicyclic C 4 -C 10 Cycloalkyl, saturated tricyclic C 7 -C 10 Cycloalkyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; or

[0039] R 2 is selected from the group con...

example 1

[0175] Intermediate 1:

[0176]

[0177] 3-Propyl-[1,2,4]triazolo[4,3-a]pyrazin-8(7H)-one:

[0178] To a solution of commercially available 2-chloro-3-hydrazinopyrazine (28 g, 0.19 mol) in dichloromethane (200 mL) was added butyraldehyde (14.7 g, 0.20 mol) and the reaction was allowed to cool before cooling to 0 °C. Stir at 50°C for 2 hours. Diacetoxyiodobenzene (71.8 g, 0.223 mol) was added at 0°C. The cooling was removed and the mixture was stirred at 20 °C for 2 hours. Na 2 CO 3 (80 mL) of saturated aqueous solution was slowly poured into the reaction, and the mixture was stirred for 10 min. The organic phase was separated, washed with brine (3×50 mL), washed with Na 2 SO 4 Dry and concentrate under vacuum. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and petroleum ether to give 8-chloro-3-propyl-[1,2,4]triazolo[4,3-a]pyridine Azine 20 g (53%).

[0179] Dioxane (120mL) and H 2 A mixture of 8-chloro-3-propyl-[...

example 2

[0181]

[0182] 3-Propyl-7-((tetrahydro-2H-pyran-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazine-8(7H)- ketone:

[0183] Step 1: To a solution of (tetrahydro-2H-pyran-3-yl)methanol (300 mg, 2.58 mmol) and TEA (522 mg, 5.17 mmol) in dichloromethane (10 mL) was added methanesulfonate at 0 °C Acid chloride (355 mg, 3.10 mmol) and the reaction was allowed to warm to 20°C and stir for 1 hour. The solution was washed with saturated NaHCO 3 Aqueous solution (2mL), H 2 O (3 x 2 mL), washed with brine (1 mL), dried and concentrated to give (tetrahydro-2H-pyran-3-yl)methyl mesylate (500 mg), which was used directly in the next step .

[0184] Step 2: Dissolve (tetrahydro-2H-pyran-3-yl)methyl mesylate (500 mg, 2.58 mmol) and 3-propyl-[1,2,4]triazole in DMF (30 mL) And[4,3-a]pyrazin-8(7H)-one (413mg, 2.32mmol) was added K 2 CO 3 (534 mg, 3.87 mmol). The mixture was stirred at 60°C for 4 hours. The reaction was cooled to RT and diluted with DCM (100 mL). Wash the organic phase wit...

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Abstract

The present invention provides triazolopyrazinones as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

Description

[0001] field of invention [0002] The present invention provides compounds as PDE1 enzyme inhibitors and their use as medicaments, especially for the treatment of neurodegenerative diseases and mental diseases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating disorders using the compounds of the invention. [0003] Background of the invention [0004] Throughout this application, various publications are cited in their entirety. The disclosures of these publications are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. [0005] The second messengers cyclic nucleotides (cN), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play important roles in intracellular signal transduction cascades, which are controlled by the regulation of cN-dependent protein kinase ( PKA and PKG), EPAC (exc...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61P25/14A61P25/18A61P25/28A61P25/24A61P25/16
CPCC07D487/04A61P25/00A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P43/00A61K31/4196A61K31/4985
Inventor J·凯勒L·K·拉斯马森M·杰森
Owner H LUNDBECK AS
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