Crystal forms of octahydropyrrolo[3,4-c]pyrrole derivatives

Abstract

The present invention relates to crystal forms of octahydropyrrolo[3,4-c]pyrrole derivatives. The present invention also relates to a pharmaceutical composition comprising the crystalline form, and the use of the crystalline form or the pharmaceutical composition in the manufacture of a medicament for preventing, treating or alleviating orexin receptor-related diseases.

Description

technical field

[0001] The invention belongs to the technical field of medicine, and relates to a crystal form of octahydropyrrolo[3,4-c]pyrrole derivatives, in particular to (5-(5-chlorobenzo[d]oxazol-2-yl)hexahydropyrrole) The crystalline form and The use thereof further relates to a pharmaceutical composition comprising the crystalline form. Background technique

[0002] Orexin, also known as hypocretin, orexin, which includes orexin A and orexin B (or hypocretin-1 and hypocretin-2), is a hormone secreted by the hypothalamus. Its main physiological functions are: 1. Regulating feeding, orexin can activate neurons that regulate feeding, significantly promote feeding, and has a dose-dependent response; 2. Participate in the regulation of energy metabolism, orexin can significantly increase metabolism 3. Participate in the regulation of sleep-awakening, orexin can inhibit rapid eye movement sleep, prolong the awakening time, and block the effect of orexin can promote sleep...

Examples

Embodiment 1

[0128] Embodiment 1 Crystal form I of the present invention

[0129] 1. Preparation of Form I

[0130] The compound represented by formula (I) (307 g) was prepared with reference to the method of Example 3 in International Application WO 2017088759 A1, which was dissolved in DMF (614 mL), heated to 80° C. and stirred for 0.5 h to dissolve, and then slowly cooled to room temperature , crystallization, suction filtration, the filter residue was washed with water (50 mL × 2), and air-dried at 70°C to obtain an off-white solid powder.

[0131] 2. Identification of Form I

[0132] (1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by the angle 2θ: 7.44°, 7.78°, 8.24°, 12.69°, 12.95°, 14.08°, 14.75 °,15.03°,17.75°,19.71°,20.12°,20.81°,21.30°,21.89°,22.18°,23.27°,25.49°,25.85°,26.08°,26.60°,27.21°,27.44°,27.70°, 28.53° with an error tolerance of ±0.2°.

[0133] (2) Identification ...

Embodiment 2

[0134] Example 2 Amorphous of the present invention

[0135] 1. Amorphous Preparation

[0136] The crystalline form I (500 mg) of the compound represented by the formula (I) was added to DCM (5.0 mL), dissolved at room temperature, followed by rotary evaporation under reduced pressure to precipitate a solid, which was dried to obtain an off-white solid powder.

[0137] 2. Identification of Amorphous

[0138] Identified by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with substantially as image 3 An X-ray powder diffraction (XRPD) pattern is shown.

Embodiment 3

[0139] Example 3 Crystal form II of the present invention

[0140] 1. Preparation of Form II

[0141] The crystal form I (200 mg) of the compound represented by the formula (I) was added to ethyl acetate (2.0 mL), heated to 75° C. under stirring for 24 h, and the reaction was stopped, suction filtration, and drying to obtain an off-white solid powder, the target crystal form.

[0142] 2. Identification of Form II

[0143] (1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angle 2θ: 10.43°, 12.31°, 13.08°, 14.49°, 15.18°, 15.92°, 16.00 °,16.61°,16.90°,17.90°,18.42°,20.52°,21.04°,21.45°,23.59°,24.00°,24.26°,24.75°,25.07°,26.26°,26.53°,26.83°,28.02°, 28.31°, 29.31°, 30.03°, 30.42°, 31.20°, 31.56°, 32.25°, 32.80°, 33.63°, 34.24°, 35.54°, 36.41°, 36.96°, 38.33°, 38.78°, with ±0.2° Error tolerance.

[0144] (2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC...

technical field

[0001] The invention belongs to the technical field of medicine, and relates to a crystal form of octahydropyrrolo[3,4-c]pyrrole derivatives, in particular to (5-(5-chlorobenzo[d]oxazol-2-yl)hexahydropyrrole) The crystalline form and The use thereof further relates to a pharmaceutical composition comprising the crystalline form. Background technique

[0002] Orexin, also known as hypocretin, orexin, which includes orexin A and orexin B (or hypocretin-1 and hypocretin-2), is a hormone secreted by the hypothalamus. Its main physiological functions are: 1. Regulating feeding, orexin can activate neurons that regulate feeding, significantly promote feeding, and has a dose-dependent response; 2. Participate in the regulation of energy metabolism, orexin can significantly increase metabolism 3. Participate in the regulation of sleep-awakening, orexin can inhibit rapid eye movement sleep, prolong the awakening time, and block the effect of orexin can promote sleep...

Examples

Embodiment 1

[0128] Embodiment 1 Crystal form I of the present invention

[0129] 1. Preparation of Form I

[0130] The compound represented by formula (I) (307 g) was prepared with reference to the method of Example 3 in International Application WO 2017088759 A1, which was dissolved in DMF (614 mL), heated to 80° C. and stirred for 0.5 h to dissolve, and then slowly cooled to room temperature , crystallization, suction filtration, the filter residue was washed with water (50 mL × 2), and air-dried at 70°C to obtain an off-white solid powder.

[0131] 2. Identification of Form I

[0132] (1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by the angle 2θ: 7.44°, 7.78°, 8.24°, 12.69°, 12.95°, 14.08°, 14.75 °,15.03°,17.75°,19.71°,20.12°,20.81°,21.30°,21.89°,22.18°,23.27°,25.49°,25.85°,26.08°,26.60°,27.21°,27.44°,27.70°, 28.53° with an error tolerance of ±0.2°.

[0133] (2) Identification ...

Embodiment 2

[0134] Example 2 Amorphous of the present invention

[0135] 1. Amorphous Preparation

[0136] The crystalline form I (500 mg) of the compound represented by the formula (I) was added to DCM (5.0 mL), dissolved at room temperature, followed by rotary evaporation under reduced pressure to precipitate a solid, which was dried to obtain an off-white solid powder.

[0137] 2. Identification of Amorphous

[0138] Identified by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with substantially as image 3 An X-ray powder diffraction (XRPD) pattern is shown.

Embodiment 3

[0139] Example 3 Crystal form II of the present invention

[0140] 1. Preparation of Form II

[0141] The crystal form I (200 mg) of the compound represented by the formula (I) was added to ethyl acetate (2.0 mL), heated to 75° C. under stirring for 24 h, and the reaction was stopped, suction filtration, and drying to obtain an off-white solid powder, the target crystal form.

[0142] 2. Identification of Form II

[0143] (1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angle 2θ: 10.43°, 12.31°, 13.08°, 14.49°, 15.18°, 15.92°, 16.00 °,16.61°,16.90°,17.90°,18.42°,20.52°,21.04°,21.45°,23.59°,24.00°,24.26°,24.75°,25.07°,26.26°,26.53°,26.83°,28.02°, 28.31°, 29.31°, 30.03°, 30.42°, 31.20°, 31.56°, 32.25°, 32.80°, 33.63°, 34.24°, 35.54°, 36.41°, 36.96°, 38.33°, 38.78°, with ±0.2° Error tolerance.

[0144] (2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC...

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