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Salts of 3-(3-amino-2-(r)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one

A technology of sulfates and compounds, which can be used in medical preparations containing active ingredients, metabolic diseases, drug combinations, etc., and can solve problems such as low affinity

Inactive Publication Date: 2013-05-29
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The ORL-1 G protein-coupled receptor binds opioid ligands with low affinity

Method used

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  • Salts of 3-(3-amino-2-(r)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
  • Salts of 3-(3-amino-2-(r)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
  • Salts of 3-(3-amino-2-(r)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Bis-2-oxo-L-gulonic acid salt of compound of crystalline formula (Is)

[0130] 3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1, 3,8-Triaza-spiro[4.5]decane-4-one (30g) was heated to dissolve in IPA (100mL), and the resulting mixture was maintained at 70-80°C with 2-oxo-L- A warm solution of gluconic acid (68.7 g, 0.235 mol) in IPA (250 g) was treated. The reaction mixture was maintained at this temperature for about 15-30 min, then cooled to 25 °C over about 1-2 h. The resulting solid was collected by vacuum filtration, washed with IPA (70 g) and dried in a vacuum oven at 60°C to afford the title compound as a solid.

Embodiment 2

[0132] Preparation of monosulfate salt of compound of formula (Is) directly from bis-2-oxo-L-gulonic acid salt of compound of formula (Is)

[0133] Will contain 3-(3-amino-2-(R)-hydroxyl-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1 , 3,8-Triaza-spiro[4.5]decane-4-one, bis-2-oxo-L-gulonic acid salt (10 g, 10 mmol) and sulfuric acid (1.1 g, 11 mmol) were heated in water to about 75-80°C and then treat the resulting solution with ethanol (60 g). A precipitate formed when cooled to 50°C. The reaction mixture was cooled to 20-25 °C over about 1.5-2 h, then stirred for about 10-12 h. The solid was filtered, washed with ethanol (30 g) and dried in a vacuum oven at 60°C to afford the title compound as a solid.

Embodiment 3

[0135] Recrystallization of the monosulfate salt of the compound of formula (Is)

[0136] Will contain 3-(3-amino-2-(R)-hydroxyl-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1 , 3,8-Triaza-spiro[4.5]decane-4-one, bis-2-oxo-L-gulonic acid salt (3.3 g, 5.74 mmol) in water (95 mL) was heated to 100 °C . The resulting solution was filtered hot and the filtrate was concentrated under reduced pressure and temperature (50 mbar, 60° C.) to remove approximately 80 g of water. While maintaining the reaction temperature between 60-70 °C, ethanol (34 mL) was added. After precipitation started, over a period of about 1.5-2 h, the reaction was cooled to 25 °C and stirring was continued for about 12-14 h. The solid was isolated by vacuum filtration, washed with water (2 x 7 mL) and ethanol (9 mL). The solid was dried in a vacuum oven at 60°C to give the title compound as a solid.

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Abstract

The present invention is directed to salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by NOP, for example depression, anxiety, alcohol abuse, etc. The present invention is further directed to process(es) for the preparation of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one and its corresponding salts.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Application Serial No. 60 / 861,378, filed November 28, 2006, which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)- Salts of 1,3,8-triaza-spiro[4.5]decan-4-one, pharmaceutical compositions comprising said salts and their use in the treatment of diseases and conditions modulated by NOP. The present invention further relates to the preparation of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl )-1,3,8-triaza-spiro[4.5]decane-4-one and 3-(3-amino-2-(R)-hydroxyl-propyl)-1-(4-fluoro-benzene base)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-4-one salt method. Background of the invention [0004] ORL-1 (orphan opioid receptor) G protein-coupled receptor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/10A61K31/438A61P25/00
CPCC07D471/10A61P1/00A61P1/04A61P11/00A61P11/06A61P13/00A61P25/00A61P25/04A61P25/06A61P25/08A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P3/04A61P43/00A61P5/38A61P9/06A61P9/12A61P3/10A61K31/438
Inventor S·J·梅尔曼A·勒斯勒R·费斯勒F·J·韦拉尼J·F·A·L·海吉
Owner JANSSEN PHARMA NV
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