Crystalline substituted pyrazines as pgi2 receptor agonists

Patent metadata

Field	Value
Publication number	US-2023303500-A1
Application number	US-202318133666-A
Country	US
Kind code	A1
Filing date	Apr 12, 2023
Priority date	Sep 28, 2017
Publication date	Sep 28, 2023
Grant date	—

Abstract

A main object of the present invention is to provide a novel crystal of 2-{4-[N-(5, 6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (hereinafter referred to as “Compound B”).
A form-I crystal of Compound B, which shows peaks at diffraction angles (2θ) of 6.4°, 8.1°, 9.5°, 10.9°, 13.2°, 15.7°, 17.0°, 19.5°, 20.3°, 21.0°, and 22.8° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å) .
A form-II crystal of Compound B, which shows peaks at diffraction angles (2θ) of 9.6°, 11.4°, 11.7°, 16.3°, 17.5°, 18.5°, 18.7°, 19.9°, 20.1°, 21.0°, and 24.6° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å) .

First claim

1 - 9 . (canceled)

10 . A method for producing a form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the steps of:
dissolving 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in acetonitrile while heating the acetonitrile solution; and cooling the acetonitrile solution to produce a form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein the form-I crystal of 2-{4-{N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows diffraction peaks at diffraction angles (20) of 6.4°, 8.1°, 9.5°, 10.9°, 13.2°, 15.7°, 17.0°, 19.5°, 20.3°, 21.0°, and 22.8° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å).

11 . The method according to claim 10 , wherein the form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows absorption peaks at wavenumbers of 2874 cm -1 , 1736 cm -1 , 1558 cm -1 , 1375 cm -1 , 1126 cm -1 , and 696 cm -1 in an infrared absorption spectrum.

12 . The method according to claim 10 , wherein the form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 127° C. in differential scanning calorimetry.

13 . The method according to claim 11 , wherein the form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 127° C. in differential scanning calorimetry.

14 . A method for producing a form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the steps of:
dissolving 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in acetonitrile while heating the acetonitrile solution; and cooling the acetonitrile solution to produce a form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein the form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows absorption peaks at wavenumbers of 2874 cm -1 , 1736 cm -1 , 1558 cm -1 , 1375 cm -1 , 1126 cm -1 , and 696 cm -1 in an infrared absorption spectrum.

15 . A method for producing a form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the steps of:
dissolving 2- {4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in acetonitrile while heating the acetonitrile solution; and cooling the acetonitrile solution to produce a form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein the form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 127° C. in differential scanning calorimetry.

16 . A method for producing a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the steps of:
dissolving 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in a mixed solution of isopropyl alcohol and an aqueous sodium hydroxide solution while heating the mixed solution; cooling the mixed solution and adjusting a pH of the mixed solution to between 5 and 6; and further cooling the mixed solution to produce a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows diffraction peaks at diffraction angles (20) of 9.6°, 11.4°, 11.7°, 16.3°, 17.5°, 18.5°, 18.7°, 19.9°, 20.1°, 21.0°, and 24.6° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å).

17 . The method according to claim 16 , wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows absorption peaks at wavenumbers of 2867 cm -1 , 1749 cm -1 , 1568 cm -1 , 1382 cm -1 , 1131 cm -1 , and 701 cm -1 in an infrared absorption spectrum.

18 . The method according to claim 16 , wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 147° C. in differential scanning calorimetry.

19 . The method according to claim 17 , wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 147° C. in differential scanning calorimetry.

20 . A method for producing a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the steps of:
dissolving 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in a mixed solution of isopropyl alcohol and an aqueous sodium hydroxide solution while heating the mixed solution; cooling the mixed solution and adjusting a pH of the mixed solution to between 5 and 6; and further cooling the mixed solution to produce a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows absorption peaks at wavenumbers of 2867 cm -1 , 1749 cm -1 , 1568 cm -1 , 1382 cm -1 , 1131 cm -1 , and 701 cm -1 in an infrared absorption spectrum.

21 . A method for producing a form-II crystal of 2-14-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the steps of:
dissolving 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in a mixed solution of isopropyl alcohol and an aqueous sodium hydroxide solution while heating the mixed solution; cooling the mixed solution and adjusting a pH of the mixed solution to between 5 and 6; and further cooling the mixed solution to produce a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 147° C. in differential scanning calorimetry.

22 . A method for producing a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, the method comprising the step of:
heating a form-III crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid to convert the form-III crystal to a form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid; wherein
the form-III crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows diffraction peaks at diffraction angles (20) of 8.4°, 12.6°, 13.4°, 14.3°, 14.6°, 15.9°, 16.9°, 18.0°, 18.8°, and 19.4° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å), and
the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows diffraction peaks at diffraction angles (20) of 9.6°, 11.4°, 11.7°, 16.3°, 17.5°, 18.5°, 18.7°, 19.9°, 20.1°, 21.0°, and 24.6° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å).

23 . The method according to claim 22 , wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid shows absorption peaks at wavenumbers of 2867 cm -1 , 1749 cm -1 , 1568 cm -1 , 1382 cm -1 , 1131 cm -1 , and 701 cm -1 in an infrared absorption spectrum.

24 . The method according to claim 22 , wherein the form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid has an endothermic peak at 147° C.

Assignees

• Nippon Shinyaku Co Ltd

Inventors

• Fujiwara Toshio

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P11/14

  Antitussive agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title