CN115160221A - Delitinib crystal form compound and application - Google Patents
Delitinib crystal form compound and application Download PDFInfo
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- CN115160221A CN115160221A CN202210886406.9A CN202210886406A CN115160221A CN 115160221 A CN115160221 A CN 115160221A CN 202210886406 A CN202210886406 A CN 202210886406A CN 115160221 A CN115160221 A CN 115160221A
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- 230000021542 voluntary musculoskeletal movement Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a dellitinib crystal form compound and application. The present application discloses deltinib crystalline form X and crystalline form Y, and discloses methods for the preparation thereof and use for treating amyotrophic lateral sclerosis. And further verifies that other crystal forms and salt forms of the dritinib also have the effect of treating amyotrophic lateral sclerosis through a model animal experiment, and the treatment effect of the crystal form X and the crystal form Y is optimal from the therapeutic effect, and is obviously superior to the prior therapeutic medicament riluzole.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a new crystal form of deltinib, and a preparation method and application thereof.
Background
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrrig's disease and progressive frostbite, is a degenerative disease of the motor nervous system that manifests itself as extensive death of motor neurons in the brainstem, spinal cord and motor cortex regions.
The motor neurons are divided into upper motor neurons and lower motor neurons, wherein the upper motor neurons send signals to a spinal cord from a brain, and then transmit the signals to muscles through the lower motor neurons to control autonomous movement. ALS patients fail to transmit signals to muscles due to massive death of motor neurons, and fail to produce voluntary movement, resulting in gradual muscle atrophy, paralysis and paralysis.
The clinical symptoms of ALS are manifested by difficulty in walking, difficulty in daily activities, spasm, myasthenia, unclear mouth and teeth, clumsiness, dysphagia and cognitive impairment, the disease is a progressive disease, and patients gradually have difficulty in chewing, breathing and the like along with the development and the worsening of the disease, and finally die within 3-5 years due to the failure of spontaneous breathing.
Asia accounts for 50% of the world population and is the largest territory for ALS patients. Epidemiological studies have indicated that the incidence of ALS is as high as 7.4/10 ten thousand. It is expected that by 2040 years, 40 million patients will be diagnosed worldwide.
ALS can be divided into two types, depending on whether the cause is clear. Of these, 10% of patients belong to familial hereditary forms of ALS (ALS), and up to 36 mutant genes have been found to be associated with the pathogenesis of ALS, including tarda binding protein 43 (TARDP-43), copper/zinc superoxide dismutase-1 (Cu, zn-SOD-1), and C9orf72 genes, among others. The remaining up to 90-95% of ALS cases are sporadic cases (sALS).
The pathogenesis of sporadic ALS is complicated, ALS neuropathy is known to be caused by complex interaction of excessive excitation of glutamate activity, free radical generation and cytoplasmic protein aggregation, mitochondrial dysfunction, axon transport process damage caused by accumulation of a large amount of aggregates in neurofibrillary cells, proinflammatory cytokine secretion caused by microglial activation, further cytotoxicity caused by the activation of a calcium-dependent enzyme pathway and motor neuron lesion, but clear etiology and diagnosis standard are still lacked, and the treatment research of ALS is seriously hindered.
To date, there is still a lack of effective treatment modalities for ALS, and symptomatic and physical therapy is the mainstay of clinical therapy.
Riluzole (riluzole) and Edaravone (Edaravone) are currently the only approved drugs by the Food and Drug Administration (FDA) for the treatment of ALS.
Among them, riluzole belongs to the class of benzothiazole compounds, which interfere with NMDA (N-methyl-D-aspartate) receptor mediated responses, blocking voltage-gated sodium channels, and thereby reducing the presynaptic release of glutamate. Riluzole may prolong the patient's life to some extent, postponing the use of tracheotomy and mechanical ventilation. In addition, riluzole has relatively few adverse reactions and most of it can be recovered after withdrawal.
Another medicine is edaravone, which is originally used as a cerebral protective agent, can inhibit local cerebral blood flow around infarction of patients in cerebral infarction acute stage, prevent the development of cerebral edema and cerebral infarction, relieve neurosis, and inhibit delayed neuronal death. The mechanism research suggests that edaravone can scavenge free radicals and inhibit lipid peroxidation, thereby inhibiting oxidative damage of brain cells, vascular endothelial cells and nerve cells, so that edaravone injection is mainly used for improving nervous symptoms, daily life activity and dysfunction caused by acute cerebral infarction. The long-term application of the medicine in treating acute ischemic stroke has good safety. Lays a certain foundation for the examination and approval of new indications. As a nerve protective agent, can scavenge free radicals and protect neurons from oxidative stress and apoptosis damage, and clinical tests prove that the nerve protective agent can delay the reduction of the motor ability of Als patients.
The study showed that over the 48 week study period, a comparison between edaravone and placebo showed that the change in ALS FRS-R score was significantly lower in the edaravone-treated group than in the placebo group. Significant differences between edaravone and placebo have been observed at week 24, these results indicate that the benefits of edaravone over placebo are maintained over the course of this 48 week treatment.
The two existing medicines for treating ALS are not essentially in touch with the intrinsic mechanism of the onset of ALS, only regulate excitation conduction between motor neurons to a certain extent, slow down the decline of the motor function of ALS patients and cannot stop or delay the worsening process of ALS. The search for other better effective therapeutic agents is therefore an important task in the study of ALS.
Dellitinib was originally developed by edg cheng de cheng of south beijing, awarded for EOS Pharmaceuticals in 2008, the latter to schuya in 2012 (except in the us, japan and foreign countries). In 2013, the agreement of Schweiya and Shanghai medicine of Chinese academy of sciences to develop the compound in China.
Delititinib is a small molecule inhibitor of multiple tyrosine kinases, is a dual inhibitor of VEGFR and FGFR, and can effectively and selectively inhibit VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2 and IC 50 They were 7nM,25nM,10nM,17.5nM,82.5nM, respectively. Potential oral treatment for solid tumors including colon cancer.
In 2021, the drug was classified as a stage II development drug for chinese small cell lung cancer, and the development company was shanghai and drug research and development limited.
Deltinib, chemical name: 6- (((7- ((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yl) oxy) -N-methyl-1-naphthamide, molecular weight 443.5, CAS number 1058137-84-0, logP =3.24, solubility in water of about 0.00128mg/mL at room temperature, poor water solubility, chemical structure as follows:
chinese patent CN101558055B discloses spiro-substituted compounds as angiogenesis inhibitors, and example 3 shows a synthesis method of the above compound (dellitinib), as follows:
6- (7- ((1-Aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide the product of example 1 (100 mg) was mixed with Pd/C (10%, 40 mg) in EtOH (30 ml) and hydrogenated at 50psi for 12 h. The reaction was filtered through celite and the solvent was evaporated to give the titled product. Mass: (M + 1), 444.
The product of example 1 (100 mg) was mixed with acetic acid (1 ml) and 33% HBr/acetic acid (0.6 ml). The reaction was stirred at room temperature for 1 hour with EtOAc/H 2 Diluting with O, and adding Na 2 CO 3 Alkalization is carried out. The organic layer was dried, evaporated and purified on a silica gel column to give the titled product. Mass: (M + 1), 444.
The obtained product is mixed crystal, and two endothermic peaks are shown on a DSC spectrum at 194 ℃ and 196.07 ℃.
Chinese patent CN104193676A further discloses a synthesis method of the compound. Example 7 therein gives a specific synthesis as follows:
a mixture of the compound from example 6 (0.24g, 0.42mmol) in 2ml40% HBr in acetic acid was stirred at 30 ℃ for 3 hours, then 10mL water was added and the reaction mixture was extracted with AcOEt (2X 10 mL). The organic phase was removed. To the aqueous solution was added dropwise a 50% NaOH solution to attain pH10. The mixture was extracted with DCM (dichloromethane) (3 × 20 mL), the combined organic phases were dried and evaporated to give a crude product containing 6- (7- ((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide (I) with a purity of >94% by LC-MS analysis. The crude product was further purified by silica gel column chromatography eluting with DCM/MeOH (10) to give 6- (7- ((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide (I) which was more than 98% pure by LC-MS analysis (140 mg, yield: 76%).
Chinese patent CN104936946A further discloses a crystal form of the above compound (tentatively named crystal form I), wherein example 7, provides a crystal form of the compound and a preparation method, as follows:
the crude product from example 1 (105 g) was mixed with isopropanol (2.5L) and activated carbon (5 g), the mixture was heated to reflux for 0.5 h to dissolve all the crude product, followed by filtration while hot, then the filtrate was refluxed again for 10 min and cooled to room temperature overnight with slow stirring. The precipitate was filtered and washed with diethyl ether (500 ml x 2) and further dried under high vacuum at 80 ℃ to give the pure product (85 g) with a melting point of 192 ℃ to 196 ℃.
This patent also discloses X-ray diffraction data for the resulting crystalline form, as follows:
DSC has a maximum endothermic peak at about 193 deg.C to 202 deg.C.
However, the above patent does not disclose any advantageous technical effects of the crystalline form.
As the current domestic development enterprises of the compound, shanghai and drug research and development Limited company also research the crystal form of the compound and apply for Chinese patent CN 110483393A.
Dellitinib dihydrate, crystalline form II of dellitinib, and dellitinib dihydrochloride dihydrate are disclosed in the patent. Preparation methods and X-ray diffraction data are also disclosed.
Wherein the Delititinib dihydrate X-ray diffraction data are as follows:
4.0 °, 8.9 °, 11.2 °,14.3 °,15.9 °, 16.4 °, 18.0 °, 18.3 °, 19.7 °, 21.1 °,21.8 °,22.6 °, 23.2 °, 24.5 °, 25.5 °, 26.9 °, 27.1 °, 28.0 °, 28.3 °, 28.9 °, 29.2 °, 30.1 °, 30.4 °, 31.4 °, 32.2 °, 34.3 °, 37.5 °, 39.1 °, an error of about ± 0.2 ° per 2 θ value, wherein the characteristic peaks are: 4.0 °, 8.9 °, 11.2 °, 16.4 °.
Form II X-ray diffraction data for deltinib are as follows:
3.2 °, 8.1 °, 8.5 °, 10.6 °, 12.1 °, 12.7 °, 13.0 °,14.3 °, 15.1 °, 16.1 °, 17.4 °, 18.0 °, 19.0 °, 19.8 °, 20.7 °, 21.4 °, 22.4 °, 23.1 °, 23.5 °,23.9 °, 24.3 °,24.8 °, 25.1 °,26.1 °, 26.8 °, 27.4 °, 28.0 °,29.8 °, 30.2 °, 30.8 °, 31.5 °, 32.1 °, 32.6 °,33.1 °, 33.9 °, 35.1 °, 35.8 °, 36.4 °, 38.5 °, and each 2 θ value has an error of about ± 0.2 °, wherein the characteristic peaks are 10.6 °, 12.7 °,14.3 °.
X-ray diffraction data for the dihydrochloride dihydrate of Delititinib are as follows:
3.2 °, 5.2 °, 6.8 °, 7.8 °, 8.5 °, 10.9 °, 12.2 °, 12.8 °, 15.6 °, 16.0 °, 17.4 °, 18.0 °, 18.3 °, 18.7 °, 19.6 °, 19.9 °, 20.4 °, 20.8 °, 21.0 °,21.7 °, 22.1 °, 22.9 °, 23.5 °,23.9 °, 24.2 °,24.8 °, 25.1 °,25.6 °, 26.0 °, 26.9 °, 27.6 °, 28.5 °, 29.1 °, 29.4 °, 30.1 °, 31.6 °, 32.3 °, 33.2 °, 33.8 °, 35.1 °, 36.4 °, 37.4 °, 37.9 °, 39.3 °, an error of about ± 0.2 ° per 2 θ value, wherein the characteristic peaks are: 5.2 degrees, 6.8 degrees, 7.8 degrees and 10.9 degrees.
Chinese patent CN 110483393A discloses that the above dihydrate, crystal form II and dihydrochloride dihydrate have good stability, and are more suitable for the treatment of tumors.
It is well known that if a compound is developed as a drug, it is important to provide a form of the compound (often referred to as a drug product) that can be safely prepared and purified on a large scale, which is stable on storage and does not degrade. This feature is commonly found in pharmaceutical products that are crystalline and have a high melting point, which tends to be easily purified by recrystallization and stable on storage.
In addition, the drug product must be suitable for formulation into the selected dosage form according to the intended route of administration. For the preparation of solid preparations for oral administration, the properties of the raw materials such as flowability, stability, crystal form stability and the like are particularly important. Compatibility of the drug substance with conventional excipients (e.g., lactose, starch, cellulose, magnesium stearate) is yet another mandatory requirement in oral formulations. In addition, for poorly soluble drugs, further processing will generally be required to achieve the goals of increasing dissolution rate and improving bioavailability. In short, whether a compound is suitable for commercialization as a drug depends on whether a form of the compound having properties of a unique combination determined according to the intended administration route can be found.
Disclosure of Invention
The invention provides crystalline form X of deltinib:
the most intense characteristic peak is confirmed by X-ray diffraction method (XRPD) at the position with the 2 theta angle of 25.1 degrees on the XRPD pattern, and the relative intensity is 100 percent.
Further, form X of dritinib according to the present invention has a characteristic peak at a position with a 2 θ angle of about 9.6 ° on the XRPD pattern with a relative intensity of 76.2%.
Further, the crystalline form X of dellitinib of the present invention has characteristic peaks at positions of about 11.3 °,12.5 °,15 °,15.8 °,16.2 °,18.6 °,19.4 °,22.6 °, 23.3 °,23.8 °,24.9 °,25.6 °, and 26.4 ° in XRPD pattern, and the relative intensity is greater than 20%.
Further, the crystalline form X of dellitinib of the present invention has characteristic peaks at the positions of about 5.7 °,10.8 °,14.3 °,17 °,19.3 °,21.8 °,23.4 °,25 °,25.8 ° and 30.3 ° of 2 θ angle on XRPD pattern, with relative intensity greater than 10%.
Further, form X of dellitinib of the present invention has characteristic peaks at positions of about 14.8 °,22 °,24.8 °,26.1 °,27.5 °,28.8 °,29.9 °,33.1 °, 38.6 °, and 42 ° in the XRPD pattern, with relative intensities greater than 5%.
Further, form X of dritinib according to the invention has an XRPD pattern as shown in figure 1.
XRPD data for form X of deltinib described herein are shown in table 1.
Table 1 XRPD data for form X of dellitinib is as follows:
due to the difference of the measurement conditions, the 2 theta angle and the relative intensity of each peak on the XRPD diffraction pattern can be changed, and the 2 theta angle change within +/-0.2 degrees is considered as a reasonable error.
The crystal form X of the deltinib provided by the invention has a melting point of 204 ℃ and a purity of more than 99.5% by Differential Scanning Calorimetry (DSC) analysis.
The invention also provides a crystal form Y of the dellitinib:
the XRPD pattern has the strongest characteristic peak at the position with the 2 theta angle of 9.2 degrees, and the relative intensity is 100 percent.
Further, crystalline form Y of dritinib according to the present invention has a characteristic peak at a position with a 2 θ angle of about 12.4 ° on the XRPD pattern with a relative intensity of 45.1%.
Further, the crystalline form Y of dritinib has characteristic peaks at the positions of about 10.5 °,23.9 ° and 25.6 ° of 2 θ angle on XRPD pattern, and the relative intensity is more than 20%.
Further, form Y of deltinib according to the present invention has characteristic peaks at the position of XRPD pattern at 2 θ angle of about 11.7 °,14.6 °,17.3 °,21.7 °,24.4 °,26.1 °,27.0 °, 27.3 °,27.9 °, with relative intensity greater than 10%.
Further, the crystalline form Y of dritinib has characteristic peaks at the positions of 2 θ angles of about 13.0 °,15.9 °,18.5 °,21.3 °,25.0 °,28.7 ° and 29.8 ° on the XRPD pattern, and the relative intensity is greater than 5%.
Further, crystalline form Y of dritinib of the present invention has an XRPD pattern as shown in figure 2.
XRPD data for form Y of dellitinib of the invention are shown in table 2.
Table 2 XRPD data for form Y of dellitinib are as follows:
the 2 theta angle and relative intensity of each peak on the XRPD diffractogram may vary due to differences in measurement conditions, and variation in 2 theta angle within ± 0.2 is generally considered a reasonable error.
The crystal form Y of the deltinib provided by the invention has a melting point of 198 ℃ and a purity of more than 99.5% by Differential Scanning Calorimetry (DSC) analysis.
The invention further provides a crystal form X, and the preparation method of the crystal form Y comprises the following steps:
putting the de-rietinib compound in a solvent, heating and refluxing, cooling to a certain temperature, crystallizing, filtering to obtain a crude crystal product, and vacuum drying to remove residual solvent to obtain a final crystal product.
Preferably, the solvent which can be selected when preparing the crystal form X is n-propanol, methyl ethyl ketone, cyclohexane and acetonitrile, and the crystallization temperature is 60-65 ℃.
The solvent is preferably n-propanol.
The preferable solvent for preparing the crystal form Y is tetrahydrofuran and diisopropyl ether, and the crystallization temperature is 40-50 ℃.
The solvent is preferably tetrahydrofuran.
The invention finally provides the use of deltinib for the preparation of a medicament for the treatment of amyotrophic lateral sclerosis, in particular form X, form Y.
The novel crystalline form X, Y of dellitinib according to the present invention may be used in the preparation of a pharmaceutical composition for oral administration for the treatment of amyotrophic lateral sclerosis. In particular solid dosage forms such as tablets, hard gelatin capsules.
The pharmaceutical composition may comprise at least one excipient selected from the group consisting of: fillers (e.g., lactose, microcrystalline cellulose, pregelatinized starch), binders (e.g., polyvinylpyrrolidone), disintegrants (e.g., croscarmellose sodium), lubricants (e.g., magnesium stearate), surfactants (e.g., sodium lauryl sulfate). In addition, the pharmaceutical composition may optionally comprise at least one further excipient selected from colorants, solvents, antimicrobial agents, coating agents, flavoring agents and olfactory modulating agents. The tablets may be coated with a conventional coating containing, for example, polyvinyl alcohol or polyethylene glycol. The pharmaceutical composition can be prepared into almost any solid dosage form, such as tablets, capsules, powders, pills or granules. The preferred dosage form is a tablet or hard gelatin capsule. Tablets or hard capsules can be prepared by mixing deltinib with at least one pharmaceutically acceptable excipient and compressing the mixture into tablets or into hard capsules, and the tablets can be further coated.
The abbreviation profile of the present application:
ALS: amyotropic Lameral Sclerosis, amyotrophic Lateral Sclerosis
fALS: familial hereditary amyotrophic lateral sclerosis
TARDP-43: tardna binding protein 43
Cu, zn-SOD-1: copper/zinc superoxide dismutase-1
sALS: hair-dispersing ALS
riluzole: riluzole
FDA: food and Drug Administration, U.S. Food and Drug Administration
NMDA: N-methyl-D-aspartate, N-methyl-D-aspartic acid
VEGFR: vascular endothelial growth factor receptor
FGFR: fibroblast growth factor receptor
EtOH: ethanol
Pd/C: palladium/carbon
Psi, pounds force per square inch, pressure unit
Mass: molecular weight
HBr: hydrobromic acid
EtOAc: ethyl acetate
H 2 O: water (W)
Na 2 CO 3 : sodium carbonate
DSC: differential scanning calorimetry
NaOH: sodium hydroxide
DCM: methylene dichloride
LC-MS: liquid phase-mass spectrometer
MeOH: methanol
X-ray: x-ray
XRPD: x ray diffraction method
API: crude drug
DNA: deoxyribonucleic acid
And (3) PCR: polymerase chain reaction for polymerase chain reaction
SPF: specific pathogen Free, pathogen Free
CMC: sodium carboxymethylcellulose
Brief description of the drawings
Figure 1 is an XRPD of deltinib form X.
Figure 2 is an XRPD of deltinib form Y.
Detailed Description
The advantageous effects of the present invention are further illustrated by the following experiments. It is not limited to the following embodiments, and those skilled in the art may make equivalent substitutions or changes without departing from the spirit of the present invention.
Comparative example 1: process and crystal form of API existing patent
Crystalline form I of deltinib was prepared according to CN104936946A, and crystalline form II, dihydrate, dihydrochloride dihydrate of deltinib was prepared according to CN 110483393A, respectively.
EXAMPLE 1 preparation of form X
Mixing 1g of Delitinib sample with 10ml of n-propanol, heating to 85 ℃ under the magnetic stirring condition until the sample is suspended or dissolved, stirring for 8 hours under the heat preservation condition, rapidly cooling to 60 ℃ according to the speed of 10 ℃/h, stirring for 6 hours under the heat preservation condition, and filtering to obtain 0.95g of crystal form X sample with the purity of 99.6%.
The X-ray diffraction pattern of the obtained sample is shown in the attached figure 1.
EXAMPLE 2 preparation of form X
Mixing 1g of Delitinib sample with 10ml of methyl ethyl ketone, heating to 70 ℃ under the magnetic stirring condition until the sample is suspended or dissolved, stirring for 8 hours under the heat preservation condition, rapidly cooling to 60 ℃ according to the speed of 10 ℃/h, stirring for 10 hours under the heat preservation condition, and filtering to obtain 0.85g of crystal form X sample with the purity of 99.8%.
EXAMPLE 3 preparation of form X
Mixing 1g of dellitinib sample with 10ml of cyclohexane, heating to 75 ℃ under the condition of magnetic stirring until the sample is suspended or dissolved, stirring for 8 hours under the condition of heat preservation, rapidly cooling to 65 ℃ according to the speed of 10 ℃/h, stirring for 10 hours under the condition of heat preservation, and filtering to obtain 0.91g of a crystal form X sample with the purity of 99.6%.
EXAMPLE 4 preparation of form X
Mixing 1g of Delitinib sample with 10ml of acetonitrile, heating to 75 ℃ under the condition of magnetic stirring until the sample is suspended or dissolved, stirring for 10 hours under the condition of heat preservation, rapidly cooling to 60 ℃ according to the speed of 10 ℃/h, stirring for 10 hours under the condition of heat preservation, and filtering to obtain 0.93g of crystal form X sample with the purity of 99.7%.
Example 5: preparation of form Y
Mixing 1g of Delitinib sample with 10ml of tetrahydrofuran, heating to 60 ℃ under the magnetic stirring condition until the sample is suspended or dissolved, stirring for 10 hours under the heat preservation condition, rapidly cooling to 40 ℃ according to the speed of 10 ℃/h, stirring for 10 hours under the heat preservation condition, and filtering to obtain 0.94g of crystal form Y sample with the purity of 99.5%.
The X-ray diffraction pattern of the obtained sample is shown in the attached figure 2.
Example 6: preparation of form Y
Mixing 1g of Delititinib sample with 10ml of diisopropyl ether, heating to 60 ℃ under the condition of magnetic stirring until the sample is completely dissolved, rapidly cooling to 50 ℃ at the speed of 10 ℃/h, preserving heat, stirring for 10h, and filtering to obtain 0.85g of crystal form Y sample with the purity of 99.5%.
Example 7
Protective effects of Delitinib crystal form X, Y and other crystal forms, hydrates on SOD1G93A transgenic mice (ALS model mice) (refer to literature for neuroprotective therapy research of Ducheng and amyotrophic lateral sclerosis model mice)
7.1 acquisition of the SOD1-G93A transgenic mice
SOD1G93A gene is SOD1 number 93 glycine mutation alanine, the mutant gene is transferred into mouse body to obtain SOD1-G93A transgenic mouse. The mouse can present phenotypes similar to human ALS diseases after onset, such as acroparalysis, muscular atrophy, motor neuron degeneration and the like, is the most classical ALS mouse model and is widely applied to pathogenesis and treatment research of ALS diseases.
The breeding method of the SOD1-G93A mouse comprises the following steps: mating a male mouse carrying the mutant SOD1 gene with a wild female mouse with the same background to obtain offspring, extracting DNA from the offspring through tail shearing treatment, amplifying through Polymerase Chain Reaction (PCR), performing DNA gel electrophoresis, judging the genotype of the offspring according to an electrophoresis result, and simultaneously expressing the mutant SOD1 gene and an internal reference gene as a transgenic mouse, and only expressing the internal reference gene as the wild mouse. Or directly purchased. The breeding environment of the mice is SPF grade, and the room temperature is constant.
7.2 Experimental groups and administrations
The samples used in the experiments were crystalline form I, crystalline form II, dihydrate, dihydrochloride dihydrate (comparative example 1 sample) prepared according to CN104936946A and CN 110483393A as well as crystalline form X and crystalline form Y (example sample) prepared according to the examples of the present application.
The sample preparation process comprises the following steps: taking the above samples, respectively, micronizing to particle size of no more than 20 μm, and suspending in 1% CMC water solution at 1 mg/ml.
The mice are administrated by gastric lavage, and the gastric lavage dose is 0.3ml/10g/d. 40 SOD1-G93A mice were selected and randomly divided into eight groups (five per group):
(1) Vehicle group (negative control group, n = 5), 1-degree cmc aqueous solution treatment was given at a dose of 0.3ml/10 g/d;
(2) Treatment groups (therapy group, n = 5), each treatment sample was administered at a dose of 0.3ml/10g/d (comparative example 1 and example);
(3) Riluzole treated group (riluzole group, n =5, positive control group), riluzole powder was also micronized so that the particle size was not more than 20 microns, suspended in 1% cmc aqueous solution. Riluzole was given intragastric at a dose of 0.3ml/10g/d.
The transgenic mice are subjected to intragastric administration once a day from the age of 60 days until death is judged.
7.3 rotating rod test (evaluation of sports function)
In the experiment, the attack time of the SOD1-G93A mouse is judged mainly by a Rotarod test (Rotarod test), and the specific judgment method is as follows:
from the age of 63 days (namely the 4 th day of the beginning of the test), the mice are placed on a rotating rod tester (the diameter is 4cm, the rotating speed is 20 r/min), training is carried out for 5min every day, and adaptive training is carried out for 7 days; starting normal test at 70 days old, testing each mouse 3 times a day, and recording the longest time of stay on a rotating rod tester; if the longest retention time of the mice on a certain day is less than 5min, recording the day as the disease onset date of the mice, and taking the time distance between the disease onset date and the birth date as the disease onset time.
7.4SOD1-G93A transgenic mouse survival period judgment
In the later stage of the disease, the mice can not move due to muscular atrophy and acroparalysis, and are limited in diet and water intake, the mice are placed on the side according to the international common death judgment method of the SOD1-G93A mice, and if the bodies of the mice can not be turned over within 30s, the mice are judged to die. The survival time is the time interval between the birth date and the death date of the mice, and the difference between the average disease onset date and the average survival time of each group of animals is taken as the disease course.
7.5 test results (n =5, data expressed as mean ± standard deviation)
Grouping | Time of onset (Tian) | Survival time (sky) | Course of disease (Tian) |
Negative control (1% CMC) | 90.8±3.4 | 126.6±3.3 | 35.8 |
Positive control (riluzole) | 101.4±3.7 | 138.4±4.6 | 37.0 |
Delitinib crystal form X | 110.2±3.7 | 164.2±4.1 | 54.0 |
Delitinib crystal form Y | 112.6±3.3 | 161.8±4.2 | 49.2 |
Delitinib form I | 94.8±3.7 | 136.4±4.2 | 41.6 |
Delitinib form II | 93.8±3.6 | 136.4±4.1 | 42.6 |
Delitinib dihydrate | 92.2±3.7 | 133.4±4.1 | 41.2 |
Delitinib dihydrochloride dihydrate | 91.2±3.1 | 131.4±4.2 | 40.2 |
In the study, the onset time of SOD1-G93A mice is judged by a rolling rod fatigue test, and as shown in the data in the table above, the onset time of the Delitinib crystal forms I and II, dihydrate and dihydrochloride dihydrate is slightly later than that of the model animals of the negative control group, but no significant difference exists. The disease onset time of the test animals in the Delititinib crystal form X and the Delititinib crystal form Y groups is obviously later than that of the negative control group and the positive control group (the riluzole treatment group). The Delitinib crystal form X and the Delitinib crystal form Y are disclosed to delay the onset time of model animals.
From the survival point of view, the onset time of the deslitinib crystal forms I, II, dihydrate and dihydrochloride dihydrate treatment group model animals is obviously later than that of the negative control group. While the time of onset was significantly later in the de ritinib form X and form Y groups of test animals than in the other groups (including the riluzole treated group). Delitinib treatment is disclosed to prolong the survival of model animals, especially in form X and form Y.
From the aspect of disease course, the disease course of the model animals of the crystal forms I, II, dihydrate and dihydrochloride dihydrate of the dritinib is obviously longer than that of a negative control group and a positive control group, and the disease course of the crystal forms X and Y treatment groups is obviously longer than that of other test groups. The Delitinib is disclosed to be capable of remarkably prolonging the course of diseases of model animals, and particularly, the crystal form X and the crystal form Y are optimal.
In conclusion, the delavirtinib can delay the onset time of diseases (crystal form X and crystal form Y) and prolong the course and survival time (various crystal forms, salts and hydrates), thereby playing a role in treating amyotrophic lateral sclerosis.
The above summary and examples describe the basic principles and main features of the present invention and the advantages of the present invention, and it should be understood by those skilled in the art that the present invention is not limited by the above examples, and the above examples and descriptions are only for illustrating the best technical solution of the present invention, and the present invention can be applied with various changes and modifications without departing from the spirit of the present invention, that is, delbrutinib, especially crystal form X and crystal form Y, as the main drug component of the drug for treating amyotrophic lateral sclerosis, administered alone or in combination with other drugs or adjuvants, all fall within the scope of the present invention as claimed, and the scope of the present invention as claimed is defined by the appended claims and their equivalents.
Claims (10)
1. Crystalline form X of dritinib, characterized by having the strongest characteristic peak with a relative intensity of 100% at a position with a 2 Θ angle of 25.1 on the XRPD pattern.
2. Form X according to claim 1, having a characteristic peak at a 2 Θ angle of about 9.6 position in the XRPD pattern with a relative intensity of 76.2%.
3. Form X according to claim 2, having characteristic peaks with relative intensities greater than 20% at positions in the XRPD pattern at 2 Θ angles of about 12.5, 24.9, 15.8, 15, 23.8, 18.6, 25.6, 22.6, 19.4, 23.3, 11.3, 16.2, 26.4.
4. Form X according to claim 3, wherein the form X of dellitinib has an XRPD pattern as shown in figure 1.
5. Crystalline form Y of dritinib, characterized by the strongest characteristic peak at the position with 2 θ angle of 9.2 in XRPD pattern with relative intensity of 100%.
6. The crystalline dritinib form Y of claim 5, having a characteristic peak in the XRPD pattern at a position with a 2 Θ angle of about 12.4 and a relative intensity of 45.1%.
7. The crystalline dritinib form Y of claim 6, having characteristic peaks in XRPD pattern at positions 2 Θ angles of about 10.5, 23.9, 25.6 with relative intensity greater than 20%.
8. Form Y of claim 5, wherein the form Y of dellitinib has an XRPD pattern as shown in figure 2.
9. Use of dritinib for the preparation of a medicament for the treatment of amyotrophic lateral sclerosis.
10. The use of claim 9, wherein the dritinib further comprises the hydrochloride or hydrate thereof.
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1228091A (en) * | 1996-08-27 | 1999-09-08 | 美国辉瑞有限公司 | Substituted 6,6-hetero-bicyclic derivatives |
CN101558055A (en) * | 2007-03-14 | 2009-10-14 | 美国爱德程实验室有限公司 | Spiro substituted compounds as angiogenesis inhibitors |
CN102356063A (en) * | 2009-03-16 | 2012-02-15 | Eos伦理肿瘤学公司(简称“Eos公司”) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof |
CN104936946A (en) * | 2013-01-18 | 2015-09-23 | 爱德程制药有限公司 | Process for preparing anti-tumor agent 6-(7-((1-aminocyclopropyl) methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and its crystalline |
CN108341818A (en) * | 2017-01-21 | 2018-07-31 | 南京华威医药科技开发有限公司 | Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof |
CN108383846A (en) * | 2016-01-26 | 2018-08-10 | 上海宣创生物科技有限公司 | Ba Ruike is for Buddhist nun's A crystal forms and preparation method thereof |
WO2019048853A1 (en) * | 2017-09-06 | 2019-03-14 | Benevolentai Bio Limited | Treatment of neurodegenerative diseases |
CN110483393A (en) * | 2018-05-14 | 2019-11-22 | 上海海和药物研究开发有限公司 | The vertical crystal form for Buddhist nun of moral |
CN110799512A (en) * | 2017-06-22 | 2020-02-14 | 苏州科睿思制药有限公司 | Crystal form of Baricitinib and preparation method thereof |
-
2022
- 2022-07-26 CN CN202210886406.9A patent/CN115160221A/en active Pending
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1228091A (en) * | 1996-08-27 | 1999-09-08 | 美国辉瑞有限公司 | Substituted 6,6-hetero-bicyclic derivatives |
HK1019597A1 (en) * | 1996-08-27 | 2000-02-18 | Pfizer | Substituted 6, 6-hetero-bicyclic derivatives |
CN101558055A (en) * | 2007-03-14 | 2009-10-14 | 美国爱德程实验室有限公司 | Spiro substituted compounds as angiogenesis inhibitors |
CN102356063A (en) * | 2009-03-16 | 2012-02-15 | Eos伦理肿瘤学公司(简称“Eos公司”) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof |
CN104193676A (en) * | 2009-03-16 | 2014-12-10 | Eos伦理肿瘤学公司(简称“Eos公司”) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof |
CN104936946A (en) * | 2013-01-18 | 2015-09-23 | 爱德程制药有限公司 | Process for preparing anti-tumor agent 6-(7-((1-aminocyclopropyl) methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and its crystalline |
CN108383846A (en) * | 2016-01-26 | 2018-08-10 | 上海宣创生物科技有限公司 | Ba Ruike is for Buddhist nun's A crystal forms and preparation method thereof |
CN108341818A (en) * | 2017-01-21 | 2018-07-31 | 南京华威医药科技开发有限公司 | Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof |
CN110799512A (en) * | 2017-06-22 | 2020-02-14 | 苏州科睿思制药有限公司 | Crystal form of Baricitinib and preparation method thereof |
WO2019048853A1 (en) * | 2017-09-06 | 2019-03-14 | Benevolentai Bio Limited | Treatment of neurodegenerative diseases |
CN110483393A (en) * | 2018-05-14 | 2019-11-22 | 上海海和药物研究开发有限公司 | The vertical crystal form for Buddhist nun of moral |
Non-Patent Citations (2)
Title |
---|
CHRISTAL D. SOHL ET AL.: "Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles’ Heel of Targeted Therapy", 《ACS CHEMICAL BIOLOGY》, vol. 10, pages 1319 * |
MANMAN WEI ET AL.: "Design, synthesis and biological evaluation of a series of novel 2- benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 154, pages 9 - 28, XP055841883, DOI: 10.1016/j.ejmech.2018.05.005 * |
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