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Polymorphs of 1-(2-Methylpropyl)-1H-Imidazo[4,5-C][1,5]Naphthyridin-4-Amine Ethane-Sulfonate

a technology of ethanesulfonate and polymorphs, which is applied in the field of polymorphs of 1(2methylpropyl)1himidazo4, 5c1, 5naphthyridin4amine ethanesulfonate, can solve the problem that the manufacturing process may not be as reproducible as desired

Inactive Publication Date: 2009-05-14
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the discovery of different crystalline forms of a compound called 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate. These different forms have different internal crystal lattices and can have different properties, such as different stabilities and different levels of hydration. The patent aims to provide control over manufacturing and stability issues related to this compound by identifying and characterizing these different forms. The technical effect of this patent is to provide new methods for controlling the manufacturing and stability of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate.

Problems solved by technology

Because of the existence of polymorphs, manufacturing may not be as reproducible as desired unless significant controls are in place.

Method used

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  • Polymorphs of 1-(2-Methylpropyl)-1H-Imidazo[4,5-C][1,5]Naphthyridin-4-Amine Ethane-Sulfonate
  • Polymorphs of 1-(2-Methylpropyl)-1H-Imidazo[4,5-C][1,5]Naphthyridin-4-Amine Ethane-Sulfonate
  • Polymorphs of 1-(2-Methylpropyl)-1H-Imidazo[4,5-C][1,5]Naphthyridin-4-Amine Ethane-Sulfonate

Examples

Experimental program
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Effect test

example 1

Preparation of 1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine Ethanesulfonate Monohydrate—Form C

Part A

[0190]Under an argon atmosphere, 1,5-naphthyridin-4-ol (1.6 kilograms (kg), 11 moles (mol)) was added in portions of 160 grams (g) with continuous stirring to fuming nitric acid (16 liters (L)) while maintaining the reaction temperature at 45.5° C. or below. After the addition, the reaction was stirred for 23 minutes (min) at about 45° C., heated to reflux over a period of 2.25 hours, heated at reflux (90° C. to 95° C.) for five hours, and allowed to cool to room temperature overnight. The reaction mixture was then cooled to 7.5° C., and water (16 L) was slowly added while maintaining the reaction temperature below 25° C. The resulting mixture was cooled to 9° C., and ammonium hydroxide (20 L) was slowly added to adjust the mixture to pH 6.2 while maintaining the temperature below 15° C. The resulting mixture was stirred for ten minutes and cooled to 2.8° C. The resul...

example 2

Preparation of 1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine Ethanesulfonate Monohydrate—Form C

Part A

[0199]Under an argon atmosphere, a solution of 3-nitro[1,5]naphthyridin-4-ol (0.800 kg, 4.19 mol) in DMF (8 L) was cooled to 19° C. Phosphorous oxychloride (803.6 g, 5.24 mol) was added over a period of 70 minutes while maintaining the temperature at 19° C. to 20° C. A precipitate formed, and the reaction was stirred overnight at room temperature. The reaction mixture was divided in two, and each half was then added with stirring to ice water (13 to 15 L) while maintaining the temperature below 15° C. The resulting mixtures were stirred for 30 minutes, and the resulting solids were isolated by filtration, washed with cold water (2 L), and combined. The solid was then mixed with dichloromethane (about 9 L) and heated to 30° C. The organic fraction was removed, and the rest of the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed wi...

example 3

Preparation of 1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine Ethanesulfonate Monohydrate—Form C

[0206]1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine prepared in Example 1, Parts A through G was used as the starting material for this example. A mixture of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (2.0 g, 8.3 mmol) and 2% (v / v) deionized water / isopropyl alcohol (20 mL) was heated to reflux with moderate stirring, and ethanesulfonic acid (1.0 g, 9.1 mmol) was added followed by a 2% (v / v) deionized water / isopropyl alcohol (6 mL) rinse, and the resulting solution was heated at reflux for 15 minutes. The solution was stirred and allowed to cool at a rate of 0.5° C. / minute for one hour, 0.33° C. / minute during the second hour, and 0.1° C. / minute during the third hour. Stirring was continued for another 22 hours, with the temperature leveling at 20° C. The resulting solid was collected by vacuum filtration, washed with 2% (v / v) deionized wate...

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Abstract

The invention provides various crystalline forms of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate, pharmaceutical compositions, methods of making, and methods of use.

Description

RELATED APPLICATIONS[0001]The present invention claims priority to U.S. Provisional Application Ser. No. 60 / 641,129, filed on Dec. 30, 2004, and U.S. Provisional Application Ser. No. 60 / 708,679, filed on Aug. 16, 2005, both of which are incorporated herein by reference.BACKGROUND[0002]The compound 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine has been found to be a useful immune response modifier (IRM) due to its ability to induce cytokine biosynthesis (U.S. Pat. No. 6,194,425). However, formulating and manufacturing pharmaceutical products can present many unforeseen challenges.SUMMARY OF THE INVENTION[0003]It has now been found that the compound 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate can crystallize in more than one type of molecular packing with more than one type of internal crystal lattice. The respective resulting crystal structures can have, for example, different unit cells. This phenomenon of “identical chemical structu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4375C07D471/14A61P35/00
CPCC07D471/14A61P31/12A61P35/00A61P37/02A61P43/00
Inventor ACH, DAVIDMARTIN, HUGHESVAN, ANNAJACOBSON, JOEL R.WU, JUNSHI Y.LINDSTROM, KYLE J.TRAN, TAI T.BROSTROM, MYLES L.RICE, MICHAEL J.SKWIERCZYNSKI, RAYMOND D.
Owner TAKEDA PHARMA CO LTD