CN116925083A - Polymorphic forms of 5H-pyrrolo [2,3-b ] pyrazine derivatives, methods of preparation and uses thereof - Google Patents

Polymorphic forms of 5H-pyrrolo [2,3-b ] pyrazine derivatives, methods of preparation and uses thereof Download PDF

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CN116925083A
CN116925083A CN202310434196.4A CN202310434196A CN116925083A CN 116925083 A CN116925083 A CN 116925083A CN 202310434196 A CN202310434196 A CN 202310434196A CN 116925083 A CN116925083 A CN 116925083A
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salt
malate
tartrate
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陈辉
徐三甲
李菁
杜争鸣
王志伟
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Baiji Shenzhou Suzhou Biotechnology Co ltd
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Abstract

Polymorphic forms of a 5H-pyrrolo [2,3-b ] pyrazine derivative, methods of preparation and use thereof. The present application relates to salts of HPK1 inhibitors (hereinafter referred to as "compound a"), preferably L-malate, and crystalline forms thereof. The application also relates to a preparation process and application of the salt and the crystal form of the compound A.

Description

Polymorphic forms of 5H-pyrrolo [2,3-b ] pyrazine derivatives, methods of preparation and uses thereof
Technical Field
The present application relates to polymorphs of a hematopoietic progenitor kinase 1 (HPK 1) inhibitor (hereinafter "compound a"), preferably the polymorph of L-malate. The application also relates to a preparation process and application of the salt and the crystal form of the compound A.
Background
The compound 4- [2- (2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N, 2-trimethylbenzamide (compound a) is represented by the formula:
WO 2021000925 discloses a series of compounds including compound a. Compound a is described as an HPK1 inhibitor useful in the treatment of a variety of diseases, including cancer.
In order to be made into pharmaceutical products, it is strictly necessary that the active ingredient must have high purity and stability. In particular, in order to maintain high stability over a longer shelf life, the active ingredient must have low hygroscopicity so that the influence of moisture on quality can be avoided. Thus, there is a need to convert the free base of compound a to other forms (e.g., salts) in pursuit of improved properties.
For solid formulations for oral administration comprising the desired active ingredient, the active ingredient needs to have the desired bioavailability so that the active ingredient can be absorbed as much as possible into the blood circulation of the body. However, the relationship between bioavailability and a particular salt is unknown in the art, and new salts of compound a with sufficient bioavailability are highly desirable.
HPK1 is a member of the MAP4K family, which includes MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, MAP4K6/MINK [ Hu, M.C. et al, genes Dev [ Gene and development ],1996.10: pages 2251-64 ]. HPK1 regulates the diverse functions of various immune cells and has been demonstrated for its kinase activity at T Cell Receptors (TCR) [ Liou J. Et al, immunity [ immunol 2000.12 (4): pages 399-408 ], B Cell Receptors (BCR) [ Liou J. Et al, immunity [ immunol 2000.12 (4): pages 399-408 ], transforming growth factor receptors (TGF-. Beta.R) [ Wang, W. Et al, J Biol Chem journal of biochemistry ],1997.272 (36): pages 22771-5; zhou, G.et al, J Biol Chem [ journal of biochemistry ],1999.274 (19): pages 13133-8 ], gs-coupled PGE2 receptor (EP 2 and EP 4) [ Ikegami, R.et al, J Immunol [ journal of immunology ],2001.166 (7): pages 4689-96) are induced upon activation. Overexpression of HPK1 inhibits TCR-induced activation of AP-1 dependent gene transcription in a kinase dependent manner, indicating that HPK1 is necessary for inhibition of the Erk MAPK pathway [ Liou J. Et al, immunity [ immunization ],2000.12 (4): pages 399-408 ], and that this blocking is believed to be an inhibitory mechanism for down-regulating TCR-induced IL-2 gene transcription [ S.Sawasdi kosol et al, immunol Res [ immunology study ],2012.54: pages 262-265 ].
In vitro HPK1-/-T cells have lower TCR activation thresholds, proliferate robustly, produce increased amounts of Th1 cytokines, and HPK 1-/-mice experience increasingly severe autoimmune symptoms [ S.Sawasdimokosol et al, immunol Res [ Immunol ],2012.54: pages 262-265 ]. In humans, HPK1 is down-regulated in peripheral blood mononuclear cells of psoriatic arthritis patients or T cells of Systemic Lupus Erythematosus (SLE) patients [ Batliwalla F.M. et al, mol Med [ molecular medicine ],2005.11 (1-12): pages 21-9 ], indicating that reduced HPK1 activity may contribute to autoimmunity in the patient. In addition, HPK1 can also regulate anti-tumor immunity via T cell dependent mechanisms. In the Lewis lung carcinoma tumor model producing PGE2, tumors of HPK1 knockout mice developed more slowly than wild-type mice [ U.S. patent application No. 2007/0087988]. HPK 1-deficient T cells are more effective in controlling tumor growth and metastasis than wild-type T cells [ Alzabin, S.et al Cancer Immunol Immunother [ cancer immunology and immunotherapy ],2010.59 (3): pages 419-29 ]. Similarly, BMDC from HPK1 knockout mice are more effective in enhancing T cell responses to eradicate Lewis lung carcinoma as compared to wild type BMDC [ Alzabin, S.et al, J Immunol ],2009.182 (10): pages 6187-94 ]. In summary, HPK1 may be a good target for enhancing anti-tumor immunity.
Thus, there remains a need to find new solid forms of compound a or a salt thereof to meet the requirements of the above pharmaceutical formulations.
Disclosure of Invention
The present application discloses an application that addresses the aforementioned challenges and needs by providing a stable salt of compound a, particularly the L-malate salt of compound a, which exhibits a desired crystallinity suitable for use in pharmaceutical formulations.
Prior to the date of filing of the present application, the inventors of the present application have unexpectedly found that L-malic acid can form with compound a crystalline form having the desired crystallinity, high stability, low hygroscopicity.
Aspect 1. One produces compound a: a process for the pharmaceutically acceptable salt of 4- [2- (2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N, 2-trimethylbenzamide, wherein the process comprises step (a) and step (b):
step (a): suspending the free form of compound a in a solvent followed by the addition of an acid;
step (b): the mixture was stirred and the solids were separated to give an acceptable salt of compound a.
Aspect 2. The method of aspect 1, wherein the pharmaceutically acceptable salt is optionally one or more inorganic salts or one or more organic salts; preferably, the pharmaceutically acceptable salt is in the solid state; more preferably, the pharmaceutically acceptable salt is an inorganic salt selected from the group consisting of: hydrochloride, sulfate, phosphate, hydrobromide and/or nitrate; or an organic salt selected from the group consisting of: fumarate, tartrate (L-tartrate, D-tartrate or DL-tartrate), laurate, stearate, gentisate, nicotinate, aspartate (L-aspartate), succinate, adipate, malate (L-malate), maleate, glycolate, gluconate (D-gluconate), lactate (L-lactate), acetate, benzenesulfonate, methanesulfonate, benzoate, naphthalenesulfonate, and/or oxalate;
preferably, the salt is selected from the group consisting of hydrochloride, sulfate, phosphate, hydrobromide, fumarate, tartrate (L-tartrate, D-tartrate or DL-tartrate), aspartate (L-aspartate), succinate, malate (L-malate), maleate, methanesulfonate or methanesulfonate;
more preferably, the salt is selected from the group consisting of L-malate.
Aspect 3. The method of aspect 1, wherein the salt is L-malate;
preferably, the salt is a compound having formula (II):
wherein m is a number from about 0.5 to about 2.0;
more preferably, wherein m is a number from about 0.5 to about 1.5;
even more preferably m is a number selected from the group consisting of: 0.5±0.1, 0.7±0.1, 1.0±0.1, and 1.5±0.1;
even more preferably, m is a number selected from the group consisting of: 0.5.+ -. 0.05, 0.6.+ -. 0.05, 0.7.+ -. 0.05, 0.8.+ -. 0.05, 0.9.+ -. 0.05, 1.0.+ -. 0.05, 1.1.+ -. 0.05, 1.2.+ -. 0.05 and 1.5.+ -. 0.05;
even more preferably, m is 0.95-1.05, 1.05-1.15, 1.15-1.25 or 1.45-1.55;
even more preferably, m is about 0.45, 0.50, 0.55, 0.95, 0.98, 0.99, 1.0, 1.01, 1.02, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.3, 1.4, 1.45 or 1.5.
Aspect 4. The method of aspect 1, wherein the solvent of step (a) is selected from the group consisting of an organic solvent or water, or a combination of an organic solvent and water; preferably the solvent of step (a) is selected from ethanol, acetone, tetrahydrofuran, acetonitrile, water or a combination thereof.
Aspect 5. The method of aspect 1, wherein the temperature of step (b) is 25 ℃ to 100 ℃; preferably, the temperature of step (b) is from 25 ℃ to 75 ℃;
more preferably, the temperature of step (b) is from 35 ℃ to 65 ℃, or from 35 ℃ to 65 ℃ followed by from 20 ℃ to 30 ℃;
even more preferably, the temperature of step (b) is from 40 ℃ to 60 ℃, or from 40 ℃ to 60 ℃ followed by 20 ℃ to 30 ℃;
even more preferably, the temperature of step (b) is 50 ℃ ± 5 ℃, or 50 ℃ ± 5 ℃ followed by 25 ℃ ± 5 ℃.
Aspect 6. The method of aspect 1, wherein the time of step (b) is 15min to 24h;
preferably, the time of step (a) is 30min-12h;
more preferably, the time of step (b) is 30min-4h at 50 ℃ ± 5 ℃ and then 30min-16h at 25 ℃ ± 5 ℃;
even more preferably, the time of step (b) is 2.+ -. 0.2h at 50.+ -. 5 ℃ and then 12.+ -. 1h at 25.+ -. 5 ℃.
Aspect 7. The method of aspect 1, wherein the salt is in crystalline form.
Aspect 8 the method of aspect 1, wherein the salt is form a L-malate salt characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine or more diffraction peaks having 2Θ angle values independently selected from the group consisting of: 5.06.+ -. 0.2,.+ -. 0.2, 6.97.+ -. 0.2, 7.28.+ -. 0.2, 10.09.+ -. 0.2, 10.49.+ -. 0.2, 13.36.+ -. 0.2, 14.67.+ -. 0.2, 15.13.+ -. 0.2, 16.08.+ -. 0.2, 17.02.+ -. 0.2, 18.10.+ -. 0.2, 18.44.+ -. 0.2, 18.74.+ -. 0.2, 19.54.+ -. 0.2, 20.05.+ -. 0.2, 20.41.+ -. 0.2, 21.07.+ -. 0.2, 22.35.+ -. 0.2, 22.82.+ -. 0.2, 23.45.+ -. 0.2, 23.83.+ -. 0.2, 25.36.+ -. 0.2, 25.72.+ -. 0.2, 28.14.+ -. 0.2, 29.55.+ -. 0.2, 30.57.+ -. 0.2, 31.22.+ -. 0.2, 32.36.+ -. 0.2 and 33.38..0.0.
Aspect 9. The method of aspect 1, wherein the salt is substantially characterized by the powder X-ray diffraction pattern of fig. 8A.
Drawings
FIG. 1A XRPD pattern for Compound A in free form A
FIG. 1B TGA/DSC curve of form A free form of Compound A
FIG. 1C 1H NMR spectrum of the free form of form A of Compound A
FIG. 1D DVS plot of Compound A in free form A
FIG. 2A XRPD overlay of Compound A in free form F
FIG. 2B TGA/DSC curve of form F free form of Compound A
FIG. 3A XRPD pattern for Compound A in free form I
FIG. 3B TGA/DSC curve of form I free form of Compound A
FIG. 4A XRPD overlay of Compound A in its N-type free form
FIG. 5 VT-XRPD overlap for A N and Z free forms
FIG. 6A XRPD overlay of Compound A in free E form
FIG. 7A overlapping VT-XRPD in free form of form E and form W of Compound A
FIG. 8 XRPD pattern for form A L-malate of Compound A
FIG. 8B DSC thermogram of Compound A L-malate salt
FIG. 8C TGA thermogram of form A L-malate of Compound A
FIG. 8D 1H-NMR spectrum of L-malate salt form A of Compound A
FIG. 9A XRPD pattern for Compound A, form B fumarate
FIG. 9B 1H-NMR spectrum of the B-type fumarate salt of Compound A
FIG. 10A XRPD pattern for Compound A D fumarate salt
FIG. 10B DSC thermogram of D-fumarate salt of Compound A
FIG. 10C TGA thermogram of D-fumarate salt of Compound A
FIG. 10D 1H-NMR spectrum of D-fumaric acid salt of Compound A
FIG. 11 XRPD pattern for form A maleate salt of Compound A
FIG. 11B 1H-NMR spectrum of maleate salt form A of Compound A
FIG. 12 XRPD pattern for Compound A, B-succinate
FIG. 12B 1H-NMR spectrum of succinate salt of Compound A
FIG. 13 XRPD pattern for Compound A form A hydrochloride
FIG. 13B 1H-NMR spectrum of Compound A form A hydrochloride
FIG. 14A XRPD pattern for Compound A C hydrochloride
FIG. 14B DSC thermogram of the C-type hydrochloride of Compound A
FIG. 14 TGA thermogram of the C-hydrochloride salt of Compound A
FIG. 14D 1H-NMR spectrum of C-hydrochloride of Compound A
FIG. 15 XRPD pattern for form A sulfate of Compound A
FIG. 15B 1H-NMR spectrum of sulfate form A of Compound A
Detailed Description
Although the free base may theoretically form pharmaceutically acceptable salts with many acids, it has been found that compound a disclosed herein as a specific free base cannot form salts with some acids (e.g., L-aspartic acid) or form crystalline salts with the desired crystallinity.
For the crystalline forms described above, only the main peaks (i.e., the most characteristic, significant, unique, and/or reproducible peaks) are summarized; additional peaks can be obtained from the diffraction spectrum by conventional methods. The main peaks described above can be reproduced within the error range (either + or-2 at the last given decimal place or + or-0.2 at the prescribed value).
The process for preparing the free base of compound a is disclosed in WO 2021000925 A1. For the above crystalline forms, the crystallization step may be performed by solvent evaporation, cooling, and/or by adding an antisolvent (a solvent which is less capable of dissolving compound a or a salt thereof, including but not limited to those described herein) in a suitable solvent system comprising at least one solvent, to achieve supersaturation in the solvent system.
Crystallization may be performed with or without seed crystals, as described in the present application.
In an embodiment of this aspect, provided herein is L-malate salt of compound a, preferably in the crystalline form described above, more preferably in form a.
The individual crystalline forms provided by the present application are formed under specific conditions, depending on the specific thermodynamic and equilibrium properties of the crystallization process. Thus, the person skilled in the art knows that the crystals formed are the result of the kinetic and thermodynamic properties of the crystallization process. Under certain conditions (e.g., in a particular solvent), a particular crystalline form may have better properties than another crystalline form (or indeed have better properties than any other crystalline form).
In another aspect, provided herein are pharmaceutical compositions, each containing an effective amount of L-malate salt of compound a, preferably in any one of the crystalline forms described above. The active compound may comprise from 1% to 99% (by weight), preferably from 1% to 70% (by weight), or more preferably from 1% to 50% (by weight), or most preferably from 5% to 40% (by weight) of the composition.
In another aspect, provided herein is the use of the above-described salt or crystalline form of compound a in the manufacture of a medicament for the treatment of cancer associated with HPK1 inhibition.
The term "about" as used herein, unless otherwise indicated, means that the number (e.g., temperature, pH, volume, etc.) can vary within ± 10%, preferably within ± 5%.
Solvates are defined herein as compounds formed by solvation, such as a combination of solvent molecules and molecules or ions of a solute. Known solvent molecules include water, alcohols and other polar organic solvents. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol. The preferred solvent is typically water. The solvate compounds formed by solvation with water are sometimes referred to as hydrates.
The following synthetic methods, specific examples, and efficacy tests further describe certain aspects of the application. They should not be used to limit or define the scope of the application in any way.
In some embodiments, the crystalline form has a crystalline purity of at least about 80%, preferably at least about 90%, preferably at least about 95%, preferably about 97%, more preferably about 99% or greater, and most preferably about 100%.
As used herein, the term "crystalline purity" means the percentage of a particular crystalline form of a compound in a sample that may contain an amorphous form of the compound, one or more other crystalline forms of the compound (in addition to the particular crystalline form of the compound), or a mixture thereof. The purity of the crystals was determined by X-ray powder diffraction (XRPD), infrared raman spectroscopy, and other solid state methods.
Examples
The following examples are intended to be exemplary and, although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), some experimental errors and deviations should be accounted for within the knowledge of those skilled in the art. Unless otherwise indicated, temperatures are expressed in degrees celsius. Reagents were purchased from commercial suppliers such as Sigma Aldrich, alfa Aesar or TCI and used without further purification unless otherwise indicated.
1 The H NMR spectrum was recorded on a Bruker instrument that was operated at a specified frequency with a preset pulse sequence.
Powder X-ray diffraction (XRPD) analysis was performed using one of the following methods:
1) A PANalytical X' Pert3 diffractometer equipped with a copper radiation source was used. The samples were interspersed in the middle of the zero background Si scaffold and rotated during the acquisition process. The divergent slit is set to 1/8 continuous illumination. The X-ray tube voltage and amperage were set to 45kV and 40mA, respectively. In a θ - θ goniometer from 3.0 to 40.0 degrees, at Cu wavelength (kα1:Kα2：/>kα2/kα1 intensity ratio: 0.50 Data were collected, 2-theta using a step size of 0.0263 degrees.
2) A PANalytical Empyrean diffractometer equipped with a copper radiation source was used. The samples were interspersed in the middle of the zero background Si scaffold and rotated during the acquisition process. The diverging slit is arranged for automatic continuous illumination. The X-ray tube voltage and amperage were set to 45kV and 40mA, respectively. At from 3.0 to 40.0 degreesIn the θ - θ goniometer, at Cu wavelength (kα1:Kα2：/>kα2/kα1 intensity ratio: 0.50 Data were collected, 2- θ used a step size of 0.0167 degrees.
3) A Bruker D8 Advance diffractometer equipped with a copper radiation source was used. The samples were interspersed in the middle of the zero background Si scaffold and rotated during the acquisition process. The divergent slit was set to 10.0mm continuous illumination. The X-ray tube voltage and amperage were set to 40kV and 40mA, respectively. In a θ - θ goniometer from 2.0 to 40.0 degrees, at Cu wavelength (kα:) Data were collected and 2-theta used a step size of 0.02 degrees.
Thermogravimetric (TGA) analysis was performed using one of the following methods:
1) A TA TGA 5500 thermogravimetric analyzer was used. The samples were weighed into an open aluminum pan and protected with a nitrogen flow. The sample was heated from ambient temperature to 350 ℃ with a heating rate of 10 ℃/min.
2) A TA TGA 5500 thermogravimetric analyzer was used. The samples were weighed into an open aluminum pan and protected with a nitrogen flow. The sample was heated from ambient temperature to 300 ℃ with a heating rate of 10 ℃/min.
Differential Scanning Calorimetry (DSC) analysis was performed using a TADSC 2500 differential scanning calorimeter. The samples were weighed into a crimped aluminum pan (crimped aluminum pan) and protected with a nitrogen flow. The sample was heated from ambient temperature to the target temperature with a heating rate of 10 ℃/min.
Dynamic Vapor Sorption (DVS) analysis was performed using SMS DVS Intrinsic using one of the following methods:
1) The sample was weighed into a microbalance. The relative humidity was set to 0% (N) 2 The flow was 200 sccm). When the weight of the sample changes within 10min<0.001wt% or by 180 minutes maximum equilibration time, assuming equilibration is achieved. Then willThe relative humidity was gradually increased to 90% in 10% RH increments, then to 95% and then to 90% and then decreased to the final 0% RH in 10% RH reductions. Between the two equilibration steps, dm/dt was 0.002%/min. In each equilibration step, the weight of the sample varied over a period of 10min<0.001wt% or by 180 minutes maximum equilibration time, assuming equilibration is achieved.
2) The sample was weighed into a microbalance. The relative humidity is set to be approximately ten digits (N 2 The flow was 200 sccm). When the weight of the sample changes within 10min<0.001wt% or by 180 minutes maximum equilibration time, assuming equilibration is achieved. The relative humidity was then gradually increased to 90% in 10% RH increments, then to 95%, then to 90%, then reduced to 0% in 10% RH decrements, then to 90% in 10% RH increments, then to the final 95% RH. Between the two equilibration steps, dm/dt was 0.002%/min. In each equilibration step, the weight of the sample varied over a period of 10min<0.001wt% or by 180 minutes maximum equilibration time, assuming equilibration is achieved.
3) The sample was weighed into a microbalance. The relative humidity was set to 40% (N) 2 The flow was 200 sccm). When the weight of the sample changes within 60min<0.001wt% or by a maximum equilibration time of 360 minutes, assuming equilibrium is reached. The relative humidity was then reduced to 0% with a 10% rh reduction, then increased to 90% with a 10% rh increase, then to 95%, then to 90%, then reduced to the final 40% rh with a 10% rh reduction. Between the two equilibration steps, dm/dt was 0.002%/min. In each equilibration step, the weight of the sample varied over 60min<0.001wt% or by a maximum equilibration time of 360 minutes, assuming equilibrium is reached.
In the following examples, the following abbreviations may be used:
example 1: preparation of form A free form of Compound A and XRPD data
Compound a (110 g, obtained in the same manner as disclosed in WO 2021000925 A1) was dissolved in refluxing anhydrous EtOH (2000 mL) until all solids were dissolved. The solution was cooled to 10 ℃ and stirred for 5h, at which time a large amount of solids appeared. The solid was collected by filtration and the material was recrystallized from anhydrous EtOH (2200 mL). The solid was collected by filtration and then dried under vacuum to give compound a (62 g, 54%) as form a free form.
Table 1: characterization XRPD information for form a free form of compound a
Form A free form was studied in the process solvent EtOH/H 2 O and MeOH/H 2 Stability of solid form in O. No form a change was observed in MeOH at 50 ℃. No form change was observed under laboratory conditions, indicating good physical stability of the sample. For HPLC area purity (area purity), an approximately 1.2 area% decrease was observed in Vis (10000 Lux) for 5 days. The purity variation was less than 0.4 area% under all remaining conditions (40 ℃/75% RH/open for 2 weeks, 60 ℃/seal for 10 days, RT/92.5% RH/open for 10 days, 25 ℃/60% RH/open for 8 weeks and UV (290. Mu.w/cm 2) for 3 days).
Example 2: preparation of form F free form of Compound A and XRPD data
In a glass vial, compound a, form a free form (19.6 mg) was suspended in acetonitrile (0.50 mL). The slurry was stirred using magnetic stirring for 1 week at 50 ℃. The resulting solid was isolated to give compound a in the form F free form.
Table 2: characterization XRPD information of form F free form of compound a
Example 3: preparation of form I free form of Compound A and XRPD data
In a glass vial, form A free form of compound A (20.2 mg) was suspended in toluene (0.50 mL). The slurry was stirred using magnetic stirring for 1 week at 50 ℃. The resulting solid was isolated to give compound a in the free form of form I.
Table 3: characterization XRPD information for form I free form of compound a
Example 4: preparation of the N-form free form of Compound A and XRPD data
In a vial with a perforated cap, compound A form A free form (20.9 mg) was dissolved in EtOH/water (1.0 mL, 4:1) to slowly evaporate. After 1 week, the solid was isolated to give compound a in the N-type free form.
Table 4: characterization XRPD information of N-type free form of compound a
Example 5: preparation of the Z-free form of Compound A and XRPD data
The Z-free form of compound A was heated to 100deg.C under nitrogen to give compound A in the Z-free form.
Table 5: characteristic XRPD information for the Z free form of compound a
Example 6: preparation of E-form free form of Compound A and XRPD data
In a glass vial, form a free form of compound a (20.2 mg) was suspended in acetone (0.50 mL). The slurry was stirred using magnetic stirring for 1 week at 50 ℃. The resulting solid was isolated to give compound a in the form E free form.
Table 6: characteristic XRPD information for the E free form of compound a
Example 7: preparation of the W-free form of Compound A and XRPD data
The form E free form of compound a was heated to 100 ℃ under nitrogen to give compound a in form W free form.
Table 7: characterization XRPD information of the W-free form of compound a
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Example 8: preparation of form A L-malate salt of Compound A and XRPD data
In a glass vial, form A free form of compound A (50 mg) was suspended in ethanol (0.50 mL) followed by the addition of L-malic acid (15 mg). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as form a L-malate. The stoichiometric ratio of compound a to malic acid was 1:1.
The A-type L-malate has hygroscopicity. It absorbs about 7.9% water from 40% RH to 95% RH at 25 ℃. No form change was observed after DVS testing.
Form a L-malate is a highly crystalline hemihydrate. DSC T at 80.9 DEG C Initiation The endothermic peak is shown, corresponding to dehydration. Thereafter, a melting peak appears at the Tstart at 190.4 ℃. Decomposition occurs during melting. TGA shows a weight loss of about 1.5% up to 121 ℃. No residual solvent was detected. KF analysis showed about 2.7% by weight water (molar ratio 0.67 equivalent). Form a L-malate is chemically and physically stable in an open container at 25 ℃/92% rh, in an open container at 40 ℃/75% rh, and in a closed container at 60 ℃ for 1 week.
Table 8: characteristic XRPD information for form a L-malate salt of compound a
Example 9: preparation of form B fumarate salt of compound a and XRPD data
In a glass vial, form a free form of compound a (50 mg) was suspended in acetone (0.50 mL) followed by the addition of fumaric acid (7 mg). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as form B fumarate salt. The stoichiometric ratio of compound A to fumaric acid was 1:0.5.
Table 9: characteristic XRPD information of form B fumarate salt of compound a
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Example 10: preparation of D-fumarate salt of Compound A and XRPD data
In a glass vial, compound a form a free form (50 mg) was suspended in tetrahydrofuran (0.50 mL), followed by the addition of fumaric acid (13 mg). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as the D-form fumarate salt. The stoichiometric ratio of compound a to fumaric acid was 1:1.
The D-form fumarate salt of Compound A had a medium crystallinity and the melting initiation temperature was 160.5 ℃.
Table 10: characterization XRPD information of D fumarate salt of compound a
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Example 11: preparation of form a maleate salt of compound a and XRPD data
In a glass vial, compound a form a free form (50 mg) was suspended in acetonitrile (0.50 mL), followed by the addition of maleic acid (13 mg). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as the maleate salt of form a. The stoichiometric ratio of compound a to maleic acid is 1:1.
Table 11: characterization XRPD information of maleate salt form a of compound a
Example 12: preparation of compound a form B succinate and XRPD data
In a glass vial, compound a form a free form (50 mg) was suspended in tetrahydrofuran (0.50 mL), followed by addition of succinic acid (14 mg). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as a B-form succinate salt with high crystallinity. The stoichiometric ratio of compound A to succinic acid was 1:1.
Table 12: characteristic XRPD information for compound a, form B succinate
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Example 13: preparation of form A hydrochloride of Compound A and XRPD data
In a glass vial, compound a form a free form (50 mg) was suspended in tetrahydrofuran (0.50 mL), followed by the addition of hydrochloric acid (115 μl, 1.0M). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as form a hydrochloride. The stoichiometric ratio of compound A to hydrogen chloride was 1:1.
Table 13: characteristic XRPD information for form a hydrochloride of compound a
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Example 14: preparation of form C hydrochloride of compound a and XRPD data
In a glass vial, compound a form a free form (50 mg) was suspended in acetonitrile (0.50 mL), followed by the addition of hydrochloric acid (115 μl, 1.0M). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as form C hydrochloride. The stoichiometric ratio of compound A to hydrogen chloride was 1:1.
Form C hydrochloride has a moderate degree of crystallinity. DSC showed a dehydration onset temperature of 53.4.
Table 14: characteristic XRPD information for form C hydrochloride of compound a
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Example 15: preparation of form a sulfate of compound a and XRPD data
In a glass vial, compound a form a free form (50 mg) was suspended in acetonitrile (0.50 mL), followed by the addition of sulfuric acid (115 μl, 1.0M). The mixture was stirred at 50 ℃ for 2h using magnetic stirring, then at 25 ℃ for 12h. The resulting solid was isolated to give compound a as form a sulfate. The stoichiometric ratio of compound A to sulfuric acid was 1:0.5.
Table 15: characteristic XRPD information for form a sulphates of compound a
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The foregoing examples and description of certain embodiments should be regarded as illustrative rather than limiting the application as defined by the claims. As will be readily appreciated, many variations and combinations of the features set forth above can be used without departing from the application as set forth in the claims. All such variations are intended to be included within the scope of the present application. All references cited are incorporated herein by reference in their entirety.
It will be appreciated that even though any prior art publications are referred to herein, such reference does not constitute an admission that the publications form a part of the common general knowledge in the art in any country.
In the claims which follow and in the preceding embodiments of the application, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the application.
The disclosures of all publications, patents, patent applications, and published patent applications cited herein by reference (identifying citation) are hereby incorporated by reference in their entirety.

Claims (9)

1. A compound a is produced: a process for the pharmaceutically acceptable salt of 4- [2- (2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N, 2-trimethylbenzamide, wherein the process comprises step (a) and step (b):
step (a): suspending the free form of compound a in a solvent followed by the addition of an acid;
step (b): the mixture was stirred and the solids were separated to give an acceptable salt of compound a.
2. The method of claim 1, wherein the pharmaceutically acceptable salt is optionally one or more inorganic salts or one or more organic salts; preferably, the pharmaceutically acceptable salt is in the solid state; more preferably, the pharmaceutically acceptable salt is an inorganic salt selected from the group consisting of: hydrochloride, sulfate, phosphate, hydrobromide and/or nitrate; or an organic salt selected from the group consisting of: fumarate, tartrate (L-tartrate, D-tartrate or DL-tartrate), laurate, stearate, gentisate, nicotinate, aspartate (L-aspartate), succinate, adipate, malate (L-malate), maleate, glycolate, gluconate (D-gluconate), lactate (L-lactate), acetate, benzenesulfonate, methanesulfonate, benzoate, naphthalenesulfonate, and/or oxalate;
preferably, the salt is selected from the group consisting of hydrochloride, sulfate, phosphate, hydrobromide, fumarate, tartrate (L-tartrate, D-tartrate or DL-tartrate), aspartate (L-aspartate), succinate, malate (L-malate), maleate, methanesulfonate or methanesulfonate;
more preferably, the salt is selected from the group consisting of L-malate.
3. The method of claim 1, wherein the salt is L-malate;
preferably, the salt is a compound having formula (II):
wherein m is a number from about 0.5 to about 2.0;
more preferably, wherein m is a number from about 0.5 to about 1.5;
even more preferably m is a number selected from the group consisting of: 0.5±0.1, 0.7±0.1, 1.0±0.1, and 1.5±0.1;
even more preferably, m is a number selected from the group consisting of: 0.5.+ -. 0.05, 0.6.+ -. 0.05, 0.7.+ -. 0.05, 0.8.+ -. 0.05, 0.9.+ -. 0.05, 1.0.+ -. 0.05, 1.1.+ -. 0.05, 1.2.+ -. 0.05 and 1.5.+ -. 0.05;
even more preferably, m is 0.95-1.05, 1.05-1.15, 1.15-1.25 or 1.45-1.55;
even more preferably, m is about 0.45, 0.50, 0.55, 0.95, 0.98, 0.99, 1.0, 1.01, 1.02, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.3, 1.4, 1.45 or 1.5.
4. The method of claim 1, wherein the solvent of step (a) is selected from an organic solvent or water, or a combination of an organic solvent and water; preferably the solvent of step (a) is selected from ethanol, acetone, tetrahydrofuran, acetonitrile, water or a combination thereof.
5. The process of claim 1, wherein the temperature of step (b) is 25 ℃ to 100 ℃; preferably, the temperature of step (b) is from 25 ℃ to 75 ℃;
more preferably, the temperature of step (b) is from 35 ℃ to 65 ℃, or from 35 ℃ to 65 ℃ followed by from 20 ℃ to 30 ℃;
even more preferably, the temperature of step (b) is from 40 ℃ to 60 ℃, or from 40 ℃ to 60 ℃ followed by 20 ℃ to 30 ℃;
even more preferably, the temperature of step (b) is 50 ℃ ± 5 ℃, or 50 ℃ ± 5 ℃ followed by 25 ℃ ± 5 ℃.
6. The method of claim 1, wherein the time of step (b) is 15min-24h;
preferably, the time of step (a) is 30min-12h;
more preferably, the time of step (b) is 30min-4h at 50 ℃ ± 5 ℃ and then 30min-16h at 25 ℃ ± 5 ℃;
even more preferably, the time of step (b) is 2.+ -. 0.2h at 50.+ -. 5 ℃ and then 12.+ -. 1h at 25.+ -. 5 ℃.
7. The method of claim 1, wherein the salt is in crystalline form.
8. The method of claim 1, wherein the salt is form a L-malate salt characterized by a powder X-ray diffraction pattern comprising three, four, five, six, seven, eight, nine, or more diffraction peaks having 2Θ angle values independently selected from the group consisting of: 5.06.+ -. 0.2,.+ -. 0.2, 6.97.+ -. 0.2, 7.28.+ -. 0.2, 10.09.+ -. 0.2, 10.49.+ -. 0.2, 13.36.+ -. 0.2, 14.67.+ -. 0.2, 15.13.+ -. 0.2, 16.08.+ -. 0.2, 17.02.+ -. 0.2, 18.10.+ -. 0.2, 18.44.+ -. 0.2, 18.74.+ -. 0.2, 19.54.+ -. 0.2, 20.05.+ -. 0.2, 20.41.+ -. 0.2, 21.07.+ -. 0.2, 22.35.+ -. 0.2, 22.82.+ -. 0.2, 23.45.+ -. 0.2, 23.83.+ -. 0.2, 25.36.+ -. 0.2, 25.72.+ -. 0.2, 28.14.+ -. 0.2, 29.55.+ -. 0.2, 30.57.+ -. 0.2, 31.22.+ -. 0.2, 32.36.+ -. 0.2 and 33.38..0.0.
9. The method of claim 1, wherein the salt is characterized substantially by the powder X-ray diffraction pattern of fig. 8A.
CN202310434196.4A 2022-04-24 2023-04-21 Polymorphic forms of 5H-pyrrolo [2,3-b ] pyrazine derivatives, methods of preparation and uses thereof Pending CN116925083A (en)

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