阅读说明：本技术 甲酰胺晶体 (Formamide crystal ) 是由 刘培岩 左保燕 马建佳 陶秀梅 陈鹏 于 2019-09-30 设计创作，主要内容包括：本发明涉及1-(2,4-二氯苄基)-N-(2,6-二氟苯基)-1H-吲哚-3-甲酰胺晶型C以及制备和表征这些晶型的方法、含有这些多晶型物的组合物以及这些组合物的用途。本发明的药物晶型克服了以其它晶型存在的式I化合物由于引湿性等原因导致药物不稳定的问题,可局部给药、皮肤(皮内)给药或透皮给药于皮肤或粘膜。<Image he="697" wi="462" file="DDA0002223933420000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide form C and methods of preparing and characterizing these forms, compositions containing these polymorphs, and uses of these compositions. The medicine crystal form overcomes the problem that the compound of the formula I existing in other crystal forms causes unstable medicines due to hygroscopicity and the like, and can be locally administered, dermally (intracutaneously) administered or transdermally administered to skin or mucous membranes.)

1. Crystalline form C of the compound of formula I1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is an anhydrous crystalline form characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Ka radiation comprising main peaks at the 2 Θ:7.66,8.27,9.06,13.27,14.34,14.88,15.34,16.57,16.80,21.05,22.21,22.61,23.09,28.77 and 29.10 ° positions, wherein each peak has an error amplitude of +/-0.2 °.

2. Crystalline form C of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide according to claim 1, characterized by TGA/DSC, which in the thermal analysis shows an endothermic peak at 179.5 ℃ (onset temperature). Wherein the temperature has a margin of error of +/-1 ℃.

3. A preparation method of the crystal form of claim 1, which is characterized by comprising the steps of crystallizing a compound MCS-01 of the crystal form A or other crystal forms in an organic solvent for 2-48 hours at a controlled temperature, filtering and drying to obtain a crystal form C of the compound MCS-01.

4. The process for preparing the compound MCS-01, form C, according to claim 3, wherein the organic solvent comprises any one or a mixture of alcohols, ethyl acetate, isopropyl acetate, acetonitrile, acetone, methyl isobutyl ketone, dichloromethane, chloroform, methyl tert-butyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, toluene, n-heptane, or a mixture of an organic solvent and water, preferably any one or a mixture of ethanol, methanol, isopropanol, ethyl acetate, methyl tert-butyl ether, acetone, n-heptane, or a mixture of an organic solvent and water, particularly preferably any one or a mixture of methanol, ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, acetone, water.

5. The method for preparing the compound MCS-01 of crystal form C according to claim 4, wherein the amount of any one solvent or the mixed solvent thereof is 10 to 200 times of the weight of the compound MCS-01 of crystal form A or other crystal forms, preferably 20 to 100 times.

6. The process for the preparation of compound MCS-01, form C according to claim 4, characterized in that the ratio of any one of the mixed solvents is 49/1-1/19, preferably 19/1-1/9.

7. The process for the preparation of the compound MCS-01, form C according to claim 4, characterized in that the temperature is controlled at-20 to 50 ℃, preferably-10 to 30 ℃.

8. The process for the preparation of the compound MCS-01, form C according to claim 4, characterized in that the stirring time is 2 to 48h, preferably 16 to 24 h.

9. Process for the preparation of the compound MCS-01, form C according to claim 4, characterized in that the drying temperature is 10 to 80 ℃, preferably 40 to 60 ℃.

10. Use of the polymorphic form of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide according to claim 1 or 2 for the preparation of a medicament for mast cell stabilization.

11. Use of the polymorph of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide according to claim 1 or 2 for the preparation of a medicament for the treatment of various diseases, disorders or conditions associated with mast cells.

12. The use of a polymorph of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide according to claim 1 or 2 as a mast cell stabilizer, for medicaments comprising but not limited to delaying the onset of, reversing or reducing the risk of acquiring peripheral diabetic neuropathy (PN) in an individual in need thereof, and also for delaying the onset of, reducing the risk of developing or accelerating the healing of wounds in an individual suffering from diabetes.

13. Use of the polymorph of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide according to any of claims 1 or 2 for the preparation of a medicament for preventing the increase of matrix metallopeptidase 9(MMP-9) and for accelerating the healing of foot ulcers in individuals suffering from diabetes.

14. A pharmaceutical composition comprising the crystalline form of claim 1 or 2 and one or more pharmaceutically acceptable excipients.

Technical Field

The present invention relates to a compound of formula (I), 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide crystalline form C, as well as to methods for the preparation and characterization of these crystalline forms, to compositions containing these polymorphs, and to the use of these compositions.

Background

Mast cells can cause allergy or anaphylactic reactions by releasing allergic mediators, and are also involved in acquired and innate immunity and autoimmunity as well as in bacterial infection immunity. In addition, studies have shown that mast cells are associated with inflammatory diseases caused by central nervous system diseases, the occurrence of some tumors, and metabolic disorders and non-allergy, in addition to allergic inflammation, such as bronchial asthma, allergic rhinitis and conjunctivitis, eczema, keratosis, and the like. Inflammation is an important factor leading to complications such as dyslipidemia and neuropathy of a diabetic patient. Therefore, the mast cell stabilizer has certain effects on preventing and relieving diabetes-related diseases.

WO2017/123826 describes mast cell stabilizers with pharmacological properties. One example of a mast cell stabilizer disclosed therein is 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide. However, the starting material of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide which is not recrystallized is extremely hygroscopic, resulting in instability of the starting material. Also, it is difficult to make an effective topical formulation because solubility and particle uniformity do not reach the required concentration to exert an effective dose in the preparation of a topical formulation.

Disclosure of Invention

Based on the above-mentioned drawbacks of the prior art, and the need for a pharmaceutically stable and topically administrable formulation, the present invention provides crystalline form C of compound 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide of formula I as an anhydrous crystalline form, characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Ka radiation, comprising main peaks at positions 2 θ:7.66,8.27,9.06,13.27,14.34,14.88,15.34,16.57,16.80,21.05,22.21,22.61,23.09,28.77 and 29.10 °, wherein each peak has an error amplitude of +/-0.2 °.

Preferably, said crystalline form C of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is characterized by TGA/DSC and exhibits an endothermic peak at 179.5 ℃ (onset temperature) in this thermal analysis. Wherein the temperature has a margin of error of +/-1 ℃.

The invention further provides a preparation method of the crystal form of the compound in claim 1, which is characterized by comprising the steps of carrying out temperature-controlled crystallization on the compound MCS-01 of the crystal form A or other crystal forms in an organic solvent for 2-48 h, filtering and drying to obtain the crystal form C of the compound MCS-01.

Preferably, the compound MCS-01 crystal form C is prepared by a method, wherein the organic solvent comprises any one of alcohol, ethyl acetate, isopropyl acetate, acetonitrile, acetone, methyl isobutyl ketone, dichloromethane, chloroform, methyl tert-butyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, toluene and n-heptane or a mixed solvent thereof, or a mixed solvent of the organic solvent and water, preferably any one of ethanol, methanol, isopropanol, ethyl acetate, methyl tert-butyl ether, acetone and n-heptane or a mixed solvent thereof, or a mixed solvent of the organic solvent and water, particularly preferably any one of methanol, ethanol, isopropanol, ethyl acetate, methyl tert-butyl ether, acetone and water or a mixed solvent thereof.

Preferably, the preparation method of the compound MCS-01 crystal form C is characterized in that the amount of any one solvent or the mixed solvent thereof is 10-200 times of the weight of the compound MCS-01 of the crystal form A or other crystal forms, preferably 20-100 times.

More preferably, the preparation method of the compound MCS-01 crystal form C is characterized in that the proportion of any one mixed solvent is 49/1-1/19, preferably 19/1-1/9.

Further preferably, the preparation method of the compound MCS-01 crystal form C is characterized in that the temperature is controlled to be-20-50 ℃, and preferably-10-30 ℃.

Still more preferably, the preparation method of the compound MCS-01 crystal form C is characterized in that the stirring time is 2-48 h, preferably 16-24 h.

Further preferably, the preparation method of the compound MCS-01 crystal form C is characterized in that the drying temperature is 10-80 ℃, preferably 40-60 ℃.

The invention also provides the use of said polymorphic form of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide in the manufacture of a medicament for use as a mast cell stabilizer.

Further, the use of said polymorphic form of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide in the manufacture of a medicament for the treatment of various diseases, disorders or conditions associated with mast cells.

Further, the use of said polymorphic form of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide as a mast cell stabilizer drug is useful in applications including, but not limited to, delaying the onset of, reversing or reducing the risk of acquiring peripheral diabetic neuropathy (PN) in a subject in need thereof, and also in delaying the onset of, reducing the risk of developing, or accelerating the healing of a wound in a subject with diabetes.

Further, the 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide polymorph is used for preparing a medicament for preventing increase of matrix metallopeptidase 9(MMP-9) and accelerating healing of foot ulcers in individuals with diabetes.

The present invention provides a pharmaceutical composition comprising the crystalline form of any one of claims 1-3 and one or more pharmaceutically acceptable excipients.

The invention has the beneficial effects that:

the medicine crystal form of the invention overcomes the problem that the compound of the formula I existing in other crystal forms causes unstable medicine due to hygroscopicity and the like.

The pharmaceutical crystalline forms of the present invention may be administered topically, dermally (intradermally), or transdermally to the skin or mucosa. Typical dosage forms for this purpose include colloids, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol.

Drawings

Figure 1 is an XRPD pattern of anhydrous crystalline form C of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide provided by the present invention.

FIG. 2 is a TGA/DSC thermogram spectrum of anhydrous crystal form C of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide provided by the invention.

Figure 3 is a PLM of anhydrous crystalline form C of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide provided by the invention.

Detailed Description