Amorphous, crystalline, preparation methods, and uses of dioxopiperidine compounds or their medicinal salts.

Abstract

This disclosure relates to amorphous materials, crystals, preparation methods, and uses of dioxopiperidine compounds or medicinal salts thereof. Specifically, this disclosure relates to amorphous materials and crystals of the compound represented by formula I or medicinal salts thereof, which have good physicochemical properties. [Formula 1] JPEG2026518634000036.jpg35139

Claims

1. The amorphous form of the compound shown in formula I. 【Chemistry 1】

2. The XRPD spectrum of the amorphous material is characterized by the absence of sharp peaks, and preferably by the presence of non-sharp peaks. The amorphous material according to claim 1.

3. A medicinal salt of the compound shown in formula I, wherein the medicinal salt is selected from succinate, mandelate, oxalate, phosphate, hydrochloride, maleate, fumarate, hydrobromide, citrate, sulfate, mesylate, hippurate, benzoate, malate, and acetate, preferably succinate and mandelate, and more preferably succinate and D-mandelate. A medicinal salt of the compound shown in formula I. 【Chemistry 2】

4. The chemical mixing ratio of the compound represented by formula I to the acid molecule or acid group is 2:0.5 to 1:3, preferably selected from 2:1 to 1:3, and more preferably selected from 1:0.5, 1:1, 1:1.5, or 1:

2. A medicinal salt of the compound represented by formula I as described in claim 3.

5. A succinate salt of the compound represented by formula I, wherein the chemical ratio of the compound of formula I to the succinic acid group or succinic acid is about 2:1 to 1:3, preferably 1:1 or 1:

2. The succinate salt of the compound shown in formula I.

6. A succinate type B crystal of the compound shown in formula I, wherein the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.402, 9.400, 15.728, 17.957, and 19.070, preferably at 6.402, 9.400, 15.728, 17.957, 19.070, and 21.589, and more preferably, the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is shown in Figure 3. succinate type B crystal. 【Transformation 3】

7. A method for preparing a crystal type according to claim 6, comprising mixing a compound represented by formula I with a solvent and succinic acid, crystallizing it to obtain succinate type B crystals, wherein the solvent is selected from ketone solvents, and preferably the ketone solvent is acetone. Preparation method.

8. A D-mandelate salt of the compound shown in formula I, wherein the chemical ratio of the compound of formula I to the mandelic acid group or mandelic acid is approximately 1:

1. D-mandelate.

9. A type A crystal of D-mandelate of the compound shown in formula I, wherein the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 10.554, 13.168, 15.728, 17.944, and 19.784, preferably at 6.159, 8.371, 10.554, 13.168, 15.728, 17.944, 19.784, and 20.381, and more preferably at 6.159, 8.371, 10.554, 13.168, 15.728, 17.944, 19.784, 20.381, 21.121, and 21.

434. More preferably, the powder X-ray diffraction pattern represented by the diffraction angle 2θ is shown in Figure 6. D-mandelate type A crystal. 【Chemistry 4】

10. A method for preparing a crystal type according to claim 9, comprising mixing a compound represented by formula I with a solvent and D-mandelic acid, crystallizing it to obtain D-mandelate type A crystals, wherein the solvent is one or more selected from isopropanol, ethanol, and ethyl acetate, and preferably the solvent is selected from isopropanol / ethyl acetate, ethanol / ethyl acetate, and ethyl acetate. Preparation method.

11. A pharmaceutical composition comprising an amorphous substance according to any one of claims 1 to 2, a pharmaceutically acceptable salt according to claims 3 to 5, 8, a crystalline form according to any one of claims 6, 9 or a crystalline form prepared by the preparation method according to any one of claims 7, 10, and an optional pharmaceutically acceptable excipient. Pharmaceutical composition.

12. A method for preparing the pharmaceutical composition according to claim 11, comprising the step of mixing an amorphous substance according to any one of claims 1 to 2, a pharmaceutically acceptable salt according to claims 3 to 5, 8, a crystalline form according to any one of claims 6, 9, or a crystalline form prepared by the preparation method according to any one of claims 7, 10, with a pharmaceutically acceptable excipient. Preparation method.

13. Use of the amorphous substance according to any one of claims 1 to 2, the medicinal salt according to claims 3 to 5, 8, the crystalline form according to any one of claims 6, 9, the crystalline form prepared by the preparation method according to any one of claims 7, 10, or the pharmaceutical composition according to claim 11 in the preparation of a drug for regulating the ubiquitination and degradation of androgen receptor (AR) proteins.

14. Use of an amorphous substance according to any one of claims 1 to 2, a medicinal salt according to claims 3 to 5, 8, a crystalline form according to any one of claims 6, 9, a crystalline form prepared by the preparation method according to any one of claims 7, 10, or a pharmaceutical composition according to claim 11 in the preparation of a drug for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions, wherein the androgen receptor-mediated or dependent diseases or conditions are preferably selected from tumors, male sexual dysfunction and Kennedy disease. use.

15. Androgen receptor-mediated or dependent diseases or conditions are selected from prostate cancer, benign prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy disease, and AIDS, preferably prostate cancer, and more preferably hormone-sensitive prostate cancer or hormone-refractory prostate cancer. The use described in claim 14.

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