CN117203209A - Crystalline forms of GnRH receptor antagonists and methods of making the same - Google Patents
Crystalline forms of GnRH receptor antagonists and methods of making the same Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A crystalline form of a GnRH receptor antagonist and a method of making the same. Specifically, E, F, G, K and O crystal forms of the compound of formula (I) and methods for preparing the same are provided.
Description
The present application claims priority from China patent application 2021103630351 with the application date of 2021/4/2. The present application incorporates the entirety of the above-mentioned chinese patent application.
The present disclosure relates to a crystalline form of a GnRH receptor antagonist and a method of preparing the same, which pertains to the medical technology field.
Gonadotropin releasing hormone (GnRH), also known as Luteinizing Hormone Releasing Hormone (LHRH), is a central regulator in the endocrine reproductive system. Gonadotropins such as Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) are secreted and released to regulate normal development of the ovary and corpus luteum, playing an important role in the hypothalamic-pituitary-gonadal axis. GnRH receptors exert their regulatory effects by coupling to G proteins that activate the calcium phosphatidylinositol second messenger system, while LH regulates the production of sex steroids and FSH regulates the development of male spermatogenesis and female follicles.
LH and FSH are released into the circulation and bind to receptors on specific cells of the ovary or testis, stimulating the production of steroids. In the presence of sex steroids, the conditions such as endometriosis, uterine fibroids and prostate cancer are aggravated and need to be treated with GnRH receptor agonists and antagonists.
Peptide compounds have a number of problems to be solved including oral absorbability, dosage form, dose volume, drug stability, sustained action and metabolic stability. The main reason why the small molecule GnRH receptor antagonist is superior to the existing peptide-based therapies is that the small molecule GnRH receptor antagonist can be directly and orally administered, which is convenient and quick.
The indirect tumor inhibition mechanism mediated by GnRH receptor agonists is the indirect inhibition of tumor cell growth by reducing secretion of sex hormones through long-term action on the hypothalamic-pituitary-gonadal axis, resulting in a decrease in pituitary gonadotropins (FSH, LH). GnRH receptor antagonists directly inhibit the release of pituitary gonadotrophin, thereby inhibiting the growth of tumor cells.
WO2015062391a provides a novel structure of a high-efficiency low-toxicity GnRH receptor antagonist, which has excellent effects and actions, and can effectively treat endocrine-reproductive system diseases, and the structure is as follows:
WO2018086608A discloses form I of the compound of formula (I) and WO2018082687a discloses form A, B, C, D of the compound of formula (I).
Disclosure of Invention
The present disclosure provides a crystalline form of a compound of formula (I) and a method for preparing the same.
The present disclosure provides crystalline form E of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.353, 5.808, 9.483, and 18.368. In certain embodiments, form E of the compound of formula (I) has characteristic peaks at 5.353, 5.808, 9.483, 16.608, 17.743, 18.368, 21.914, 23.181 and 23.665. In certain embodiments, form E of the compound of formula (I) has characteristic peaks at 5.353, 5.808, 9.483, 10.381, 12.495, 14.116, 14.512, 15.089, 16.051, 16.608, 17.743, 18.368, 19.157, 20.984, 21.914, 22.341, 23.181, 23.665, 24.437, 25.047, 26.099, 26.683, 27.567, 28.738, 29.761, 30.630, 31.307, 33.803 and 35.861. In certain embodiments, the X-ray powder diffraction pattern of form E of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in figure 1. The present disclosure further provides a process for preparing form E of a compound of formula (I), comprising:
the method comprises the following steps: (a) Mixing a compound shown in a formula (I) with a proper amount of solvent, wherein the solvent is selected from one or more of acetone, isopropyl acetate, methyl tertiary butyl ether, dimethyl sulfoxide, methyl isobutyl ketone, methylene dichloride, water/acetone, methanol/water, chloroform/N, N-dimethylformamide and isopropyl ether; (b) pulping and crystallizing;
or a second method: (a) Mixing a compound shown in a formula (I) with a proper amount of solvent, heating and stirring, wherein the solvent is one or more selected from acetone or water/acetone; (b) cooling and crystallizing;
or the method III: (a) Dissolving a compound shown in a formula (I) in a proper amount of solvent, and filtering, wherein the solvent is one or more selected from acetone, N-methylpyrrolidone, N-dimethylformamide and methanol/dichloromethane; (b) Adding an anti-solvent into the filtrate, and crystallizing, wherein the anti-solvent is one or more selected from methanol, ethanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether, 2-butanone, methyl isobutyl ketone, n-hexane and water.
The present disclosure provides forms F of compounds of formula (I) having X-ray powder diffraction patterns with characteristic peaks at 2Θ angles 9.094, 9.795, 17.895, 18.342, and 22.693. In certain embodiments, form F of the compound of formula (I) has characteristic peaks at 9.094, 9.795, 17.181, 17.895, 18.342, 18.762, 22.693, 24.421, 25.195 and 27.580. In certain embodiments, form F of the compound of formula (I) has characteristic peaks at 4.887, 6.238, 6.448, 9.094, 9.795, 12.987, 14.752, 17.181, 17.895, 18.342, 18.762, 19.222, 20.725, 22.693, 24.075, 24.421, 25.195, 26.822, 27.580, 28.785, 30.034, 31.823 and 33.475. In certain embodiments, the X-ray powder diffraction pattern of form F of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in figure 2.
The present disclosure further provides a process for preparing form F of a compound of formula (I), comprising: mixing a compound shown in a formula (I) with a proper amount of water, pulping and crystallizing; or heating the compound shown in the formula (I) and then desolventizing.
The present disclosure provides crystalline form G of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 7.405, 10.337, 13.835, 14.050, 17.563, and 18.517. In certain embodiments, form G of the compound of formula (I) has characteristic peaks at 7.405, 10.337, 13.835, 14.050, 17.563, 18.517, 19.560, 20.914, 21.841, 22.757 and 27.103. In certain embodiments, form G of the compound of formula (I) has characteristic peaks at 4.946, 7.405, 9.968, 10.337, 11.132, 13.835, 14.050, 14.944, 15.157, 17.563, 18.517, 19.379, 19.560, 20.914, 21.841, 22.397, 22.757, 23.894, 24.356, 25.633, 27.103, 28.046, 28.468, 29.683, 30.267, 31.441, 33.881, and 39.523. In certain embodiments, the X-ray powder diffraction pattern of form G of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 3.
The present disclosure further provides a process for preparing form G of a compound of formula (I), comprising:
the method comprises the following steps: (a) Mixing a compound shown in a formula (I) with a proper amount of solvent, wherein the solvent is selected from one or more of methanol, ethanol, isopropanol, N-propanol, ethyl acetate, 2-butanone, nitromethane, water/methanol, water/ethanol, water/isopropanol, ethyl acetate/ethanol, methanol/chloroform, chloroform/N, N-dimethylformamide, cyclohexane, methyl isobutyl ketone, isoamyl alcohol, ethyl acetate/N-heptane, tetrahydrofuran/ethanol, dichloroethane, isopropyl ether and p-xylene; (b) pulping and crystallizing;
or a second method: (a) Mixing a compound shown in a formula (I) with a proper amount of solvent, and heating to dissolve, wherein the solvent is one or more selected from 2-butanone, water/methanol, methanol/acetone, acetone/water, ethanol/acetone and ethanol/acetonitrile; (b) cooling and crystallizing;
or the method III: (a) Dissolving a compound shown in a formula (I) in a proper amount of solvent, and filtering, wherein the solvent is one or more selected from N-methyl pyrrolidone, N-dimethylformamide and methanol/dichloromethane; (b) Adding an anti-solvent into the filtrate, and crystallizing, wherein the anti-solvent is one or more selected from methanol, ethanol, isopropanol, 2-butanone and methyl tertiary butyl ether.
The present disclosure provides crystalline form H of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 4.826, 5.241, 8.575, 9.536, 10.798, 12.945, 13.484, 14.605, 16.313, 16.944, 17.681, 19.258, 19.961, 21.345, 21.762, 22.591, 23.754, 25.048, 25.799, 26.353, 26.851, 27.335, 27.949, and 28.917. In certain embodiments, the X-ray powder diffraction pattern of form H of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 4.
The present disclosure further provides a process for preparing form H of a compound of formula (I), comprising:
the method comprises the following steps: (a) Mixing a compound shown in a formula (I) with a proper amount of solvent, wherein the solvent is one or more selected from o-xylene, ethyl acetate, acetonitrile, isoamyl alcohol, p-xylene and toluene; (b) pulping and crystallizing;
or a second method: (a) Mixing a compound shown in a formula (I) with a proper amount of solvent, and heating to dissolve, wherein the solvent is selected from n-propanol, dimethyl sulfoxide/methanol and dimethyl sulfoxide/ethanol; (b) cooling and crystallizing;
or the method III: (a) Dissolving a compound shown in a formula (I) in a proper amount of solvent, and filtering, wherein the solvent is selected from dimethyl sulfoxide and N, N-dimethylformamide; one or more of N, N-dimethylacetamide; (b) Adding an anti-solvent into the filtrate, and crystallizing, wherein the anti-solvent is one or more selected from methanol, ethanol, isopropanol, n-propanol, methyl isobutyl ketone and n-hexane.
The present disclosure provides crystalline form J of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.762, 7.334, 7.921, 10.856, 11.599, 11.920, 15.916, 17.244, 18.924, 21.329, 23.218, and 27.858. In certain embodiments, the X-ray powder diffraction pattern of form J of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 5.
The present disclosure further provides a process for preparing form J of a compound of formula (I), comprising: mixing the compound shown in the formula (I) with a proper amount of water, pulping and crystallizing.
The present disclosure provides crystalline form K of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.165, 9.376, 11.453, 14.824, and 20.395. In certain embodiments, form G of the compound of formula (I) has characteristic peaks at 5.165, 5.638, 8.825, 9.376, 9.602, 11.453, 13.114, 14.824, 19.883, 20.395, 23.094, 24.357 and 28.153. In certain embodiments, the X-ray powder diffraction pattern of form G of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 6.
The present disclosure further provides a process for preparing form K of a compound of formula (I), comprising: mixing the compound shown in the formula (I) with a proper amount of nitromethane, pulping and crystallizing or heating and cooling and crystallizing.
The present disclosure provides crystalline forms L of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.076, 10.267, 10.861, 11.724, 13.257, 16.953, 18.881, 20.362, 21.280, 21.913, 22.992, 24.494, 25.977, 26.665, 27.806, 28.963, 29.618, 30.134, 30.957, 33.779, 35.296, and 38.838. In certain embodiments, the X-ray powder diffraction pattern of the L-form of the compound of formula (I) in terms of diffraction angle 2θ is shown in fig. 7.
The present disclosure further provides a process for preparing form L of a compound of formula (I), comprising: mixing the compound shown in the formula (I) with proper amount of paraxylene, pulping and crystallizing.
The present disclosure provides crystalline forms M of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 6.476, 7.511, 8.855, 10.534, 11.242, 13.901, 14.313, 15.271, 16.779, 17.918, 18.987, 22.576, 23.407, 25.820, 27.477, and 28.415. In certain embodiments, the X-ray powder diffraction pattern of the M-form of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in figure 8.
The present disclosure further provides a process for preparing form M of a compound of formula (I), comprising: mixing the compound shown in the formula (I) with a proper amount of 1, 4-dioxane, pulping and crystallizing or heating and cooling and crystallizing.
The present disclosure provides N-crystalline forms of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 4.799, 5.180, 8.460, 9.437, 10.443, 13.263, 17.245, 18.089, 19.484, 20.618, 23.729, and 25.473. In certain embodiments, the N-crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, as shown in figure 9.
The present disclosure further provides a process for preparing the N-crystalline form of a compound of formula (I), comprising: mixing the compound shown in the formula (I) with a proper amount of normal hexane, and pulping and crystallizing.
The present disclosure provides crystalline form O of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 6.184, 8.459, and 17.072. In certain embodiments, the compound of formula (I) has characteristic peaks at 6.184, 8.459, 9.820, 10.493, 11.215, 12.453, 13.404, 15.573, 17.072, 19.335, 19.982, 21.266, 23.239, 24.209, 25.925, 27.155, 27.965, 29.684 and 30.843 in form O. In certain embodiments, the X-ray powder diffraction pattern of form O of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in figure 10.
The present disclosure further provides a process for preparing form O of a compound of formula (I), comprising: mixing the compound shown in the formula (I) with a proper amount of water, pulping and crystallizing.
The present disclosure provides crystalline form P of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.236, 10.556, 15.920, 17.824, 19.367, 21.324, 23.674, 24.392, 26.713, 27.353, and 34.561. In certain embodiments, the X-ray powder diffraction pattern of the P-crystalline form of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 11.
The present disclosure further provides a process for preparing the P-crystalline form of a compound of formula (I), comprising: (a) Dissolving a compound shown in a formula (I) in a proper amount of dimethyl sulfoxide, and filtering; and (b) adding water into the filtrate, and crystallizing.
The present disclosure provides crystalline forms Q of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 7.298, 7.454, 13.013, 14.246, 17.118, 19.265, 20.933, 22.672, 23.374, and 27.643. In certain embodiments, the X-ray powder diffraction pattern of the Q crystal form of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in figure 12.
The present disclosure further provides a process for preparing the Q crystal form of a compound of formula (I), comprising: heating the M crystal form of the compound shown in the formula (I) to 140 ℃ and desolvating.
The present disclosure provides crystalline forms R of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.524, 8.617, 10.562, 11.194, 11.864, 12.852, 16.739, 17.636, 21.298, 21.877, 24.342, 25.961, 26.303, 28.057, and 29.632. In certain embodiments, the X-ray powder diffraction pattern of the R form of the compound of formula (I) as represented by the angle of diffraction, 2θ, is shown in figure 13.
The present disclosure further provides a process for preparing the R crystalline form of a compound of formula (I), comprising: heating the L crystal form of the compound shown in the formula (I) to 165 ℃ and desolvating.
The present disclosure provides crystalline S forms of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 7.133, 8.187, 9.934, 11.176, 11.788, 12.345, 13.263, 14.353, 14.920, 15.136, 16.762, 17.603, 18.003, 19.271, 21.022, 21.451, 22.687, 24.059, 24.740, 26.591, 27.774, 28.307, 30.059, and 31.015. In certain embodiments, the X-ray powder diffraction pattern of the S-crystal form of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 14.
The present disclosure further provides a process for preparing the S-form of a compound of formula (I), comprising: (a) Adding a compound shown in a formula (I) into a proper amount of N, N-Dimethylformamide (DMF), and heating for dissolution; and (b) adding absolute ethyl alcohol, and crystallizing.
The present disclosure also provides a pharmaceutical composition comprising a crystalline form of a compound of formula (I) as described above or a crystalline form prepared by the process described above, and optionally from a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure also provides a method of preparing a pharmaceutical composition comprising the step of mixing a crystalline form of the compound of formula (I) or a crystalline form prepared by the method described above with a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure also provides the use of a crystalline form of a compound of formula (I) as described above, or a crystalline form prepared by the process as described above, or a composition prepared by the process as described above, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with a GnRH receptor antagonist, said disease being selected from endocrinal reproductive system diseases.
The "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.2, including the case where numbers exceeding 1 decimal are rounded. For example, the E form of the compound of formula (I) has a characteristic peak at a2θ angle 9.094, and the error range of 9.1,2 θ after rounding is 9.1±0.2.
Crystallization described in this disclosure includes, but is not limited to, stirring, cooling, concentrating, volatilizing, beating, and crystallization.
The starting materials used in the methods of preparing the crystalline forms of the present disclosure may be any form of the compounds of formula (I), including but not limited to: amorphous, any crystalline form, and the like.
The term "differential scanning calorimetric analysis or DSC" in the present disclosure refers to measuring the temperature difference and the heat flow difference between a sample and a reference during the temperature rising or constant temperature process of the sample, so as to characterize all physical changes and chemical changes related to thermal effects, and obtain phase change information of the sample.
The drying temperature in the present disclosure is generally 25 to 100 ℃, preferably 40 to 70 ℃, and the drying temperature can be either normal pressure drying or reduced pressure drying.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
FIG. 1 is an XRPD pattern for form E of compound (I).
FIG. 2 is an XRPD pattern for form F of compound (I).
FIG. 3 is an XRPD pattern for form G of compound (I).
Fig. 4 is an XRPD pattern of compound H crystalline form of formula (I).
FIG. 5 is an XRPD pattern for compound J crystalline form of formula (I).
FIG. 6 is an XRPD pattern for form K of compound (I).
FIG. 7 is an XRPD pattern for form L of compound (I).
FIG. 8 is an XRPD pattern for form M of compound (I).
FIG. 9 is an XRPD pattern for form N of compound of formula (I).
FIG. 10 is an XRPD pattern for form O of compound (I).
FIG. 11 is an XRPD pattern for form P of compound (I).
FIG. 12 is an XRPD pattern for form Q of compound of formula (I).
FIG. 13 is an XRPD pattern for form R of compound (I).
Fig. 14 is an XRPD pattern of crystalline form S of compound (I).
The present disclosure will be explained in more detail below with reference to examples or experimental examples, which are only for illustrating technical solutions in the present disclosure, and do not limit the spirit and scope in the present disclosure.
Experimental methods for which specific conditions are not noted in the examples in this disclosure are generally in accordance with conventional conditions, or in accordance with conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
Reagents used in the present disclosure are commercially available.
Test conditions of the instrument used for the experiments in this disclosure:
1. differential scanning calorimeter (Differential Scanning Calorimeter DSC)
Instrument model: mettler Toledo DSC 3+STARe System
Sweep gas: nitrogen gas; nitrogen purge rate: 50mL/min
Rate of temperature rise: 10.0 ℃/min
Temperature range: 25-250 ℃ (or 25 ℃ -220 ℃)
2. X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)
Instrument model: BRUKER D8 discover X-ray powder diffractometer
Rays: monochromatic Cu-K alpha rays
Scanning mode: θ/2θ, scan range (2θ range): 3-40 DEG
Voltage: 40kV, current: 40mA
3. Thermogravimetric analyzer (Thermogravimetric Analysis, TGA)
Instrument model: mettler Toledo TGA2
Sweep gas: nitrogen gas; nitrogen purge rate: 50mL/min
Rate of temperature rise: 10.0 ℃/min
Temperature range: 25-400 ℃ (or 25 ℃ -350 ℃)
4. DVS is dynamic moisture adsorption
Surface Measurement Systems intrinsic is adopted for detection, the humidity is increased from 0-95% to 10% at 25 ℃, and the judgment standard is that the quality change dM/dT of each gradient is less than 0.002%, TMAX is 360min, and the two circles are circulated.
Example 1: preparation of crystalline form E of Compound of formula (I)
500mg of the compound of formula (I) (prepared as described in example 11 of WO2015062391A 1) are added to 15mL of acetone, stirred at room temperature, filtered off with suction or centrifuged and dried at 40℃to give the product. The product was defined as form E as measured by X-ray powder diffraction, the XRPD pattern shown in figure 1 and the characteristic peak positions shown in table 1.
TABLE 1
Example 2: preparation of crystalline form E of Compound of formula (I)
20mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was dissolved in 1mL of acetone, and the mixture was heated and stirred, filtered while it was hot, cooled and crystallized, centrifuged, and dried at 40℃to obtain the product. The product is E crystal form through X-ray powder diffraction detection.
Example 3: preparation of crystalline form E of Compound of formula (I)
50mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was dissolved in 1mL of acetone at room temperature, filtered, 0.3mL of methanol was added to the filtrate, and the mixture was crystallized and dried at 40℃to obtain the product. The product is E crystal form through X-ray powder diffraction detection.
Example 4: preparation of crystalline form F of Compound of formula (I)
300mg of the compound of formula (I) (prepared according to the method of example 11 of WO2015062391A 1) was added to 10mL of water, stirred with heating, filtered with suction, and dried at 40℃to give the product. The product was defined as form F as measured by X-ray powder diffraction, the XRPD pattern shown in figure 2 and the characteristic peak positions shown in table 2.
TABLE 2
Example 5: preparation of crystalline form F of Compound of formula (I)
The S crystal form of the compound shown in the formula (I) (prepared by the method of the example 26) is heated to 165 ℃ and the solvent is removed to obtain the target product. The product is in the form of F crystal form through X-ray powder diffraction detection.
Example 6: preparation of Compound G Crystal form of formula (I)
150mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 10mL of methanol, heated and stirred, centrifuged, and dried at 40℃to obtain the product. The product was defined as form G as detected by X-ray powder diffraction, the XRPD pattern shown in figure 3 and the characteristic peak positions shown in table 3.
TABLE 3 Table 3
Example 7: preparation of Compound G Crystal form of formula (I)
10mg of the compound of formula (I) (prepared as described in example 11 of WO2015062391A 1) was added to 1mL of methyl isobutyl ketone, stirred at room temperature, centrifuged and dried at 40℃to obtain the product. The product is in the form of G crystal by X-ray powder diffraction detection.
Example 8: preparation of Compound G Crystal form of formula (I)
15mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was added to 1mL of 2-butanone, and the mixture was heated and stirred, filtered while it was still hot, cooled, crystallized, centrifuged and dried at 40℃to obtain the product. The product is in the form of G crystal by X-ray powder diffraction detection.
Example 9: preparation of Compound G Crystal form of formula (I)
75mg of the compound of formula (I) (prepared according to the method of example 11 of WO2015062391A 1) was added to 3mL of methanol/acetone (V: V=3:1), the solution was heated, filtered while hot, cooled to crystallize, centrifuged, and dried at 40℃to obtain the product. The product is in the form of G crystal by X-ray powder diffraction detection.
Example 10: preparation of Compound G Crystal form of formula (I)
50mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was dissolved in 0.2mL of N-methylpyrrolidone at room temperature, filtered, 0.1mL of methanol was added to the filtrate, and crystallization and drying at 40℃were performed to obtain the product. The product is in the form of G crystal by X-ray powder diffraction detection.
Example 11: preparation of Compound G Crystal form of formula (I)
250mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was dissolved in 1mL of N, N-dimethylformamide at room temperature, filtered, and 0.5mL of ethanol was added to the filtrate, slurried, crystallized, and dried at 40℃to give the product. The product is in the form of G crystal by X-ray powder diffraction detection.
Example 12: preparation of Compound H Crystal form of formula (I)
50mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 4mL of o-xylene, stirred at room temperature, centrifuged and dried at 40℃to obtain the product. The product was defined as form H as measured by X-ray powder diffraction, the XRPD pattern shown in figure 4 and the characteristic peak positions shown in table 4.
TABLE 4 Table 4
Example 13: preparation of Compound H Crystal form of formula (I)
10mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was dissolved in 1mL of n-propanol, stirred with heating, filtered while hot, cooled to crystallize, centrifuged, and dried at 40℃to obtain the product. The product is H crystal form through X-ray powder diffraction detection.
Example 14: preparation of Compound H Crystal form of formula (I)
50mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was dissolved in 0.2mL of dimethyl sulfoxide at room temperature, filtered, 0.1mL of methanol was added to the filtrate, and the mixture was crystallized and dried at 40℃to obtain the product. The product is H crystal form through X-ray powder diffraction detection.
Example 15: preparation of Compound J Crystal form of formula (I)
150mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 10mL of water, stirred at room temperature and centrifuged to obtain the objective product. The product was defined as form J as detected by X-ray powder diffraction, the XRPD pattern is shown in FIG. 5 and the characteristic peak positions are shown in Table 5.
TABLE 5
Example 16: preparation of Compound K Crystal form of formula (I)
150mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 3mL of nitromethane, stirred at room temperature, centrifuged, and dried at 40℃to obtain the product. The product was defined as form K as measured by X-ray powder diffraction, the XRPD pattern shown in figure 6 and the characteristic peak positions shown in table 6.
TABLE 6
Example 17: preparation of Compound K Crystal form of formula (I)
20mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was dissolved in 1mL of nitromethane, and the mixture was heated and stirred, filtered while it was still hot, cooled, crystallized, centrifuged and dried at 40℃to obtain the product. The product is K crystal form through X-ray powder diffraction detection.
Example 18: preparation of crystalline form L of Compound of formula (I)
50mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 4mL of paraxylene, stirred at room temperature, centrifuged, and dried at 40℃to obtain the product. The product was defined as form L as measured by X-ray powder diffraction, the XRPD pattern shown in figure 7 and the characteristic peak positions shown in table 7.
TABLE 7
Example 19: preparation of crystalline form M of Compound of formula (I)
50mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was added to 2mL of 1, 4-dioxane, stirred with heating, centrifuged, and dried at 40℃to give the product. The product was defined as form M as measured by X-ray powder diffraction, the XRPD pattern shown in figure 8 and the characteristic peak positions shown in table 8.
TABLE 8
Example 20: preparation of crystalline form M of Compound of formula (I)
15mg of the compound of formula (I) (prepared by the method of example 11 of WO2015062391A 1) was added to 1mL of 1, 4-dioxane, and the mixture was heated and stirred, filtered while it was still hot, cooled to crystallize, centrifuged, and dried at 40℃to obtain the product. The product is in the form of M crystal form through X-ray powder diffraction detection.
Example 21: preparation of the N Crystal form of the Compound of formula (I)
10mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 1mL of n-hexane, stirred at room temperature, centrifuged, and dried at 40℃to obtain the product. The product was defined as the N-form by X-ray powder diffraction detection, the XRPD pattern shown in figure 9 and the characteristic peak positions shown in table 9.
TABLE 9
Example 22: preparation of Compound O Crystal form of formula (I)
50mg of the compound of formula (I) (prepared as in example 11 of WO2015062391A 1) was added to 4mL of water, stirred at room temperature, centrifuged and dried at 40℃to obtain the product. The product was defined as form O as measured by X-ray powder diffraction, the XRPD pattern shown in figure 10 and the characteristic peak positions shown in table 10.
Table 10
Example 23: preparation of the P Crystal form of the Compound of formula (I)
0.4g of the compound of formula (I) (prepared as described in example 11 of WO2015062391A 1) was dissolved in 3mL of dimethyl sulfoxide at room temperature, filtered, 1.5mL of water was added to the filtrate, crystallized, suction filtered, and dried at 40℃to obtain the product. The product was defined as P-crystalline form as measured by X-ray powder diffraction, the XRPD pattern shown in figure 11 and the characteristic peak positions shown in table 11.
TABLE 11
Example 24: preparation of crystalline form Q of Compound of formula (I)
Heating the M crystal form (prepared according to example 20) of the compound shown in the formula (I) to 140 ℃, and removing the solvent to obtain the target product. The product was defined as form Q as measured by X-ray powder diffraction, the XRPD pattern shown in figure 12 and the characteristic peak positions shown in table 12.
Table 12
Example 25: preparation of crystalline form R of Compound of formula (I)
The L crystal form of the compound shown in the formula (I) (prepared according to the example 18) is heated to 165 ℃ and the solvent is removed to obtain the target product. The product was defined as form R as measured by X-ray powder diffraction, the XRPD pattern shown in figure 13 and the characteristic peak positions shown in table 13.
TABLE 13
Example 26: preparation of crystalline form S of Compound of formula (I)
1.0g of the compound of formula (I) (prepared according to the method of example 11 of WO2015062391A 1) was added to 8mL of DMF, heated for dissolution, 56mL of absolute ethanol was added, stirred for crystallization, suction filtration and drying under reduced pressure at 60℃to obtain the product. The product was defined as crystalline S by X-ray powder diffraction, XRPD patterns shown in figure 14, and the characteristic peak positions shown in table 14.
TABLE 14
Example 27: study of Crystal form stability
And (3) placing the G crystal form and the I crystal form of the compound shown in the formula (I) in an open and flat way, and respectively examining the stability of the sample under the conditions of high temperature (40 ℃ and 60 ℃) and high humidity (RH 75% and RH 92.5%), wherein the sampling examination period is 1 month. The HPLC purity results are shown in Table 14.
TABLE 14
The stability investigation result shows that the stability of the G crystal form is better than that of the I crystal form sample under the conditions of high temperature (40 ℃ and 60 ℃) and the stability of the G crystal form is equivalent under the conditions of high humidity (RH 75% and RH 92.5%).
Example 28: crystal form hygroscopicity study
The F, G, I, K and O crystal forms of the compound shown in the formula (I) are Surface Measurement Systems intrinsic, the humidity range is examined to be 0% -95% from 40% at 25 ℃, the step is 10%, and the judgment standard is that the quality change dM/dT of each gradient is less than 0.002%, TMAX is 360min and 2 cycles. The detailed results are shown in Table 15.
TABLE 15
| Sample of | 0％RH-80.0％RH | Moisture permeability | Crystal form |
| F crystal form | 0.74％ | Slightly moisture-absorbing property | Unchanged |
| G crystal form | 0.34％ | Slightly moisture-absorbing property | Unchanged |
| I crystal form | 4.17％ | Having moisture-permeability | Unchanged |
| K crystal form | 0.84％ | Slightly moisture-absorbing property | Unchanged |
| O crystal form | 2.16％ | Having moisture-permeability | Unchanged |
The wettability investigation result shows that the wettability of the I crystal form is larger, and the weight is increased by 4.17% when the RH is 0% -80%; F. the G crystal form and the K crystal form have slightly hygroscopicity, and when RH is 0% -80%, weight gain is 0.74%, 0.34% and 0.84% respectively; the O crystal form has hygroscopicity, and the weight is increased by 2.16 percent when the RH is 0-80 percent.
Example 29: crystal form solubility and intrinsic dissolution studies
Solubility determination: 5mg of the compound of formula (I) in G, I and K crystal form are added to 1mL of simulated empty stomach intestinal juice (FaSSIF), the mixture is placed in a constant temperature shaking table at 37 ℃ and magnetically stirred at 500rpm, after 20 hours, the supernatant is centrifuged and filtered, and the filtrate is subjected to sample concentration measurement by an HPLC method.
Intrinsic dissolution rate determination: four samples of the crystal form G, I of the compound represented by the formula (I) were taken, 1mg each, and the intrinsic dissolution rate (dissolution conditions: temperature 37.+ -. 1 ℃ C., rotational speed 250rpm, medium volume 20 mL) in FaSSIF was measured by an optical fiber micro-dissolution instrument.
Test results: the solubility of the G crystal form (10 ug/ml) in the FaSSIF is 2 times that of the I crystal form (5 ug/ml), and the solubility of the K crystal form (20 ug/ml) is 4 times that of the I crystal form (5 ug/ml); the intrinsic dissolution rate of the G crystal form in FaSSIF (1.48-1.69 ug/(min cm) 2 ) The intrinsic dissolution rate of the I crystal form is (0.728-0.813 ug/(min cm) 2 ) Nearly 2 times.
Example 30
10mg of the compound of formula (I) (prepared according to the method of example 11 of WO2015062391A 1) was taken and 1mL of isopropyl acetate was added, and the mixture was stirred at room temperature for 8 hours to obtain form I, and after 2 days, the crystal was converted into form E.
75mg of the compound shown in the formula (I) (prepared according to the method of example 11 of WO2015062391A 1) is taken, 3mL of acetone/water (volume ratio is 5:1) mixed solvent is added, the mixture is heated to 70 ℃ for dissolution, filtered while the mixture is hot, cooled to room temperature, crystallized to obtain the I crystal form, and the E crystal form is obtained after stirring for 1 day.
Claims (14)
- Form E of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic peaks at 2 theta angles 5.353, 5.808, 9.483 and 18.368, preferably at 5.353, 5.808, 9.483, 16.608, 17.743, 18.368, 21.914, 23.181 and 23.665, more preferably at 5.353, 5.808, 9.483, 10.381, 12.495, 14.116, 14.512, 15.089, 16.051, 16.608, 17.743, 18.368, 19.157, 20.984, 21.914, 22.341, 23.181, 23.665, 24.437, 25.047, 26.099, 26.683, 27.567, 28.738, 29.761, 30.630, 31.307, 33.803 and 35.861, most preferably having an X-ray powder diffraction pattern expressed in diffraction angle 2 theta as shown in figure 1,
- form F of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 9.094, 9.795, 17.895, 18.342 and 22.693, preferably at 9.094, 9.795, 17.181, 17.895, 18.342, 18.762, 22.693, 24.421, 25.195 and 27.580, more preferably at 4.887, 6.238, 6.448, 9.094, 9.795, 12.987, 14.752, 17.181, 17.895, 18.342, 18.762, 19.222, 20.725, 22.693, 24.075, 24.421, 25.195, 26.822, 27.580, 28.785, 30.034, 31.823 and 33.475, most preferably in terms of diffraction angle 2Θ, as shown in fig. 2.
- Form G of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 7.405, 10.337, 13.835, 14.050, 17.563 and 18.517, preferably at 7.405, 10.337, 13.835, 14.050, 17.563, 18.517, 19.560, 20.914, 21.841, 22.757 and 27.103, more preferably at 4.946, 7.405, 9.968, 10.337, 11.132, 13.835, 14.050, 14.944, 15.157, 17.563, 18.517, 19.379, 19.560, 20.914, 21.841, 22.397, 22.757, 23.894, 24.356, 25.633, 27.103, 28.046, 28.468, 29.683, 30.267, 31.441, 33.881 and 39.523, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, as shown in fig. 3.
- Form K of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 5.165, 9.376, 11.453, 14.824 and 20.395, preferably at 5.165, 5.638, 8.825, 9.376, 9.602, 11.453, 13.114, 14.824, 19.883, 20.395, 23.094, 24.357 and 28.153, most preferably in terms of diffraction angle 2Θ, as shown in fig. 6.
- A crystalline form O of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 6.184, 8.459 and 17.072, preferably at 6.184, 8.459, 9.820, 10.493, 11.215, 12.453, 13.404, 15.573, 17.072, 19.335, 19.982, 21.266, 23.239, 24.209, 25.925, 27.155, 27.965, 29.684 and 30.843, more preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ angles, as shown in fig. 10.
- The crystalline form of any one of claims 1-5, wherein the 2Θ angle error range is ± 0.2.
- A process for preparing the crystalline form E of claim 1, the process comprising:the method comprises the following steps: mixing a compound shown in a formula (I) with a proper amount of solvent, and crystallizing and separating out, wherein the solvent is one or more selected from acetone, isopropyl acetate, methyl tertiary butyl ether, dimethyl sulfoxide, methyl isobutyl ketone, methylene dichloride, water/acetone, methanol/water, chloroform/N, N-dimethylformamide and isopropyl ether;the second method is as follows: mixing a compound shown in a formula (I) with a proper amount of solvent, wherein the solvent is one or more selected from acetone, N-methyl pyrrolidone, N-dimethylformamide and methanol/methylene dichloride; adding an anti-solvent, and crystallizing to separate out, wherein the anti-solvent is one or more selected from methanol, ethanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether, 2-butanone, methyl isobutyl ketone, n-hexane and water.
- A process for preparing form F of claim 2, comprising: mixing a compound shown in a formula (I) with a proper amount of water, and crystallizing; or heating the compound shown in the formula (I) and then desolventizing.
- A process for preparing the form G of claim 3, comprising:the method comprises the following steps: mixing a compound shown in a formula (I) with a proper amount of solvent, and crystallizing and separating out, wherein the solvent is one or more selected from methanol, ethanol, isopropanol, N-propanol, ethyl acetate, 2-butanone, nitromethane, water/methanol, water/ethanol, water/isopropanol, methanol/acetone, acetone/water, ethanol/acetone, ethanol/acetonitrile, ethyl acetate/ethanol, methanol/chloroform, chloroform/N, N-dimethylformamide, cyclohexane, methyl isobutyl ketone, isoamyl alcohol, ethyl acetate/N-heptane, tetrahydrofuran/ethanol, dichloroethane, isopropyl ether and p-xylene;the second method is as follows: mixing a compound shown in a formula (I) with a proper amount of solvent, wherein the solvent is one or more selected from N-methyl pyrrolidone, N-dimethylformamide and methanol/methylene dichloride; adding an anti-solvent, crystallizing and separating out, wherein the anti-solvent is one or more selected from methanol, ethanol, isopropanol, 2-butanone and methyl tertiary butyl ether.
- A process for preparing the form K of claim 4, comprising: mixing the compound shown in the formula (I) with a proper amount of nitromethane, and crystallizing.
- A process for preparing the form O of claim 5, the process comprising: mixing the compound shown in the formula (I) with a proper amount of water, and crystallizing.
- A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 6 or a crystalline form produced by a process according to any one of claims 7 to 11, and optionally from a pharmaceutically acceptable carrier, diluent or excipient.
- A process for the preparation of a pharmaceutical composition comprising the step of mixing a crystalline form according to any one of claims 1 to 6 or a crystalline form prepared by a process according to any one of claims 7 to 11 with a pharmaceutically acceptable carrier, diluent or excipient.
- Use of a crystalline form according to any one of claims 1 to 6, or a crystalline form produced by a process according to any one of claims 7 to 11, or a composition according to claim 12, or a composition produced according to claim 13, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases associated with GnRH receptor antagonists, selected from diseases of the endocrinological system.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110363035 | 2021-04-02 | ||
| CN2021103630351 | 2021-04-02 | ||
| PCT/CN2022/084873 WO2022206968A1 (en) | 2021-04-02 | 2022-04-01 | Crystalline forms of gnrh receptor antagonist and preparation method therefor |
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| CN117203209A true CN117203209A (en) | 2023-12-08 |
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| CN202280025169.5A Pending CN117203209A (en) | 2021-04-02 | 2022-04-01 | Crystalline forms of GnRH receptor antagonists and methods of making the same |
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| CN (1) | CN117203209A (en) |
| TW (1) | TW202302592A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RS59457B1 (en) * | 2013-10-30 | 2019-11-29 | Shanghai hengrui pharmaceutical co ltd | Pyrazolopyrimidone or pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof |
| TWI751220B (en) * | 2016-11-07 | 2022-01-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | Polymorphism of gnrh receptor antagonist and a preparation method thereof |
| EP3539545B1 (en) * | 2016-11-14 | 2021-08-11 | Jiangsu Hengrui Medicine Co., Ltd. | Crystalline form of gnrh receptor antagonist and preparation method therefor |
| EP3660017A4 (en) * | 2017-07-28 | 2020-12-30 | Jiangsu Hengrui Medicine Co., Ltd. | Method for preparing pyrimidone heteroaryl derivative and intermediate of pyrimidone heteroaryl derivative |
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- 2022-04-01 WO PCT/CN2022/084873 patent/WO2022206968A1/en active Application Filing
- 2022-04-01 CN CN202280025169.5A patent/CN117203209A/en active Pending
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| WO2022206968A1 (en) | 2022-10-06 |
| TW202302592A (en) | 2023-01-16 |
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