CN110885308A - Formamide crystal - Google Patents
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- CN110885308A CN110885308A CN201910945108.0A CN201910945108A CN110885308A CN 110885308 A CN110885308 A CN 110885308A CN 201910945108 A CN201910945108 A CN 201910945108A CN 110885308 A CN110885308 A CN 110885308A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
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.
Description
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
Example 1:
adding 200mL of methanol into 10g of a compound 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide, heating to 50 ℃, stirring for 0.5H, filtering, cooling a filtrate to 5 ℃, preserving heat, stirring, crystallizing for 18H, filtering, and vacuum-drying at 50 ℃ for 6H to obtain 8.84g of a crystal form C product, wherein the yield is 88.4%.
Example 2:
adding 10g of the compound 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide into 600mL of ethanol, heating to 70 ℃, stirring for 0.5H, filtering, cooling the filtrate to 5 ℃, preserving heat, stirring, crystallizing for 18H, filtering, and vacuum drying at 50 ℃ for 8H to obtain 8.82g of a crystal form C product, wherein the yield is 88.2%.
Example 3:
adding 10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide into 800mL of ethanol, heating to 70 ℃, stirring for 0.5H, filtering, cooling the filtrate to-10 ℃, preserving heat, stirring, crystallizing for 16H, filtering, and vacuum drying at 60 ℃ for 6H to obtain 8.90g of a crystal form C product, wherein the yield is 89.0%.
Example 4:
adding 10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide into 800mL of ethanol, heating to 70 ℃, stirring for 0.5H, filtering, cooling the filtrate to 20 ℃, preserving heat, stirring, crystallizing for 24H, filtering, and vacuum drying at 60 ℃ for 6H to obtain 8.74g of a crystal form C product, wherein the yield is 87.4%.
Example 5:
adding 10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide into 1000mL of isopropanol, heating to 80 ℃, stirring for 0.5H, filtering, cooling the filtrate to 5 ℃, preserving heat, stirring, crystallizing for 24H, filtering, and vacuum drying at 60 ℃ for 8H to obtain 9.02g of a crystal form C product, wherein the yield is 90.2%.
Example 6:
10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is added to 250mL of ethyl acetate, stirred at 70 ℃ for 0.5H, filtered, the filtrate stirred at 25 ℃ for 24H, filtered and the filter cake vacuum dried at 50 ℃ to give 8.80g of product form C, yield 88.0%.
Example 7:
10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is added with 200mL of methanol, heated to 50 ℃ and stirred for 0.5H, filtered, 10mL of water is added dropwise to the filtrate, kept at 25 ℃ and stirred for crystallization for 24H, filtered, and vacuum-dried at 50 ℃ for 6H to obtain 8.96g of a crystal form C product with a yield of 89.6%.
Example 8:
adding 10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide into 600mL of ethanol, heating to 70 ℃, stirring for 0.5H, filtering, dropwise adding 30mL of water into the filtrate, keeping the temperature at 25 ℃, stirring, crystallizing for 24H, filtering, and vacuum drying at 50 ℃ for 6H to obtain 8.93g of a crystal form C product, wherein the yield is 89.3%.
Example 9:
10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is added to 200mL of ethyl acetate, stirred at 70 ℃ for 0.5H, filtered, 200mL of N-heptane is added dropwise to the filtrate, the filtrate is stirred at 25 ℃ for 24H, filtered and the filter cake is dried under vacuum at 60 ℃ to give 8.79g of the product of crystalline form C with a yield of 87.9%.
Example 10:
10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is suspended in 200mL of methanol, heated and dissolved at 60 ℃ for 0.5H, filtered, 800mL of methyl tert-butyl ether is added dropwise to the filtrate, stirred at room temperature for 48H, filtered, and the filter cake is dried under vacuum at 60 ℃ to give 9.16g of the product of crystalline form C in 91.6% yield.
Example 11:
10g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is suspended in 200mL of acetone, dissolved by heating at 60 ℃ for 0.5H, filtered, 800mL of methyl tert-butyl ether is added dropwise to the filtrate, stirred at room temperature for 48H, filtered and the filter cake is dried under vacuum at 50 ℃ to give 9.04g of the product of crystalline form C in 90.4% yield.
Example 12:
10g of 1- (2, 4-dichlorobenzyl) N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide was suspended in 250mL of ethyl acetate/ethanol (1/19, v/v), dissolved at 70 ℃ for 0.5H, filtered, the filtrate was stirred at room temperature for 48H, filtered, and the filter cake was dried at 60 ℃ under vacuum to give 9.13g of product form C in 91.3% yield.
Example 13 preparation of hydrate form a
Dissolving 30g of 1- (2, 4-dichlorobenzyl) N- (2, 6-difluorophenyl) -1H-indole-3-formamide with 60mL of acetone to prepare a clear solution, dropwise adding a good solvent of the prepared clear solution into 200mL of N-heptane, stirring while dropwise adding until solid is separated out, and centrifugally separating and drying to obtain 12g of hydrate crystal form A.
Example 14 preparation of Anhydrous crystalline form B
100g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-carboxamide is suspended in 1L of water at room temperature under stirring for 3 days, centrifuged and dried at 45 ℃ for 8 hours to give 62g of anhydrous crystalline form B.
Example 15 preparation of hydrate form D
Dissolving 150g of 1- (2, 4-dichlorobenzyl) -N- (2, 6-difluorophenyl) -1H-indole-3-formamide in 200mL of water, dropwise adding the solution into 1L of water, stirring at room temperature for 3 days after solids are separated out, centrifuging, and drying the solids at 50 ℃ for 8 hours to obtain 80g of hydrate crystal form D.
Experimental example 1 study on hygroscopicity of crystalline form A/B/C/D/G based on dynamic vapor sorption analysis (DVS)
Dynamic water sorption (DVS) curves were collected on DVSIntrinsic in SMS (surface Measurement systems). At 25 deg.CFor relative humidity LiCl, Mg (NO)3)2And deliquescence point correction of KCl.
At a constant temperature of 25 ℃, in a hygroscopicity study based on dynamic vapor sorption analysis (DVS), hydrate form a decreases in mass with decreasing humidity, and then increases in moisture absorption by 0.12% with increasing humidity to 80% RH, indicating that form a is almost non-hygroscopic.
At a constant temperature of 25 ℃, in a hygroscopicity study based on dynamic vapor sorption analysis (DVS), anhydrous crystalline form B increased moisture absorption by 0.14% with increasing humidity to 80% RH, indicating that crystalline form B is almost non-hygroscopic.
At a constant temperature of 25 ℃, in a hygroscopicity study based on dynamic vapor sorption analysis (DVS), anhydrous crystalline form C increased moisture absorption by 0.01% with increasing humidity to 80% RH, indicating that crystalline form C is almost free of hygroscopicity.
At a constant temperature of 25 ℃, in a moisture absorption study based on dynamic vapor sorption analysis (DVS), hydrate crystal form D increases moisture absorption by 0.54% with increasing humidity to 80% RH, indicating that crystal form D is slightly hygroscopic.
At a constant temperature of 25 ℃, in a hygroscopicity study based on dynamic vapor sorption analysis (DVS), anhydrous crystalline form G increased moisture absorption by 0.3% with increasing humidity to 80% RH, indicating that crystalline form G is almost non-hygroscopic.
TABLE 1 DVS study List of A/B/C/D/G crystal forms
*: definition of hygroscopicity refers to Chinese pharmacopoeia 2010 edition
Experimental example 2 stability study of Anhydrous Crystal form C
High performance liquid chromatography was performed on an Agilent 1260 HPLC.
The solid samples of anhydrous crystalline form C were placed at 80 ℃ for 24 hours, at 25 ℃/60% RH and 40 ℃/75% RH for one week, and their chemical purity and change in solid crystalline form were evaluated by HPLC area purity and XRPD characterization results.
Table 2 summary of crystalline form C stability assessment
Experimental example 3 characterization of Anhydrous Crystal form C by polarizing microscope (PLM)
Polarizing microscope data were collected by an Axio scope.a1 zeiss microscope at room temperature.
The shape of the anhydrous crystal form C particles is needle-shaped crystals (fluffy appearance), and the length of the anhydrous crystal form C particles is about 50-100 mu m (shown in figure 3).
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (14)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201910945108.0A CN110885308A (en) | 2019-09-30 | 2019-09-30 | Formamide crystal |
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| CN201910945108.0A CN110885308A (en) | 2019-09-30 | 2019-09-30 | Formamide crystal |
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| CN110885308A true CN110885308A (en) | 2020-03-17 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108602775A (en) * | 2016-01-14 | 2018-09-28 | 贝思以色列女会吏医学中心公司 | Mast cell conditioning agent and application thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108602775A (en) * | 2016-01-14 | 2018-09-28 | 贝思以色列女会吏医学中心公司 | Mast cell conditioning agent and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 方亮，等: "《药剂学》", 31 March 2016 * |
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