CN106432244A - Crystallization form of hedgehog signal pathway inhibitor, and preparation method thereof - Google Patents
Crystallization form of hedgehog signal pathway inhibitor, and preparation method thereof Download PDFInfo
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- CN106432244A CN106432244A CN201610596258.1A CN201610596258A CN106432244A CN 106432244 A CN106432244 A CN 106432244A CN 201610596258 A CN201610596258 A CN 201610596258A CN 106432244 A CN106432244 A CN 106432244A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention relates to a crystallization form of a hedgehog signal pathway inhibitor, and a preparation method thereof, and concretely relates to an I type crystal of N-(2-ethyl-5-(6-(2-(trifluoromethyl)-pyridine-3-yl)imidazo[1,2-b]pyridazine-2-yl)phenyl)-1-methylcyclopropane carboxamide (compound (I)), and a preparation method thereof. The I type crystal of the compound (I) obtained in the invention has the advantages of good crystal form stability and chemical stability, and a crystallization solvent used in the invention has low toxicity and low residual, so the I type crystal of the compound (I) can be well used in clinic treatment.
Description
Technical field
The present invention relates to N- (2- ethyl -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2-
Base) phenyl) -1- methylcyclopropanecarboxamide novel crystal forms and preparation method thereof.
Background technology
Malignant tumor has become as common and serious threat one of people's life and the principal disease of quality of life.With right
The deepening continuously of tumorigenicity and molecular biology research, the key signal path of multiple intracellular tumors correlations is found.
1980, Hedgehog (Hh) gene was found first in fruit bat.It is found that when the mutation of fruit bat is studied hedgehog believes
Number path, Hedgehog signal path also known as Rrinaceus earopaeuss signal path, Hedgehog gene is a kind of merogenesis polarity gene, because of mutation
Drosophila embryos be in hirsutism bulk, exactly like frightened Rrinaceus earopaeuss and gain the name；There are three kinds of hedgehog homologous geness in the mankind, including
Sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).They are in fetal development
In play an important role, control many tissue and organ formation.
Hedgehog signal path is that important cellular physiological processes adjust path, is strictly adjusted under normal circumstances
Control is simultaneously played a significant role in the forming process of cell propagation, cell differentiation and embryo.People gradually had found to be permitted in recent years
Many diseases are all relevant with this signal path, when Hedgehog signal path abnormal activation, can cause the generation of kinds of tumors
And development, including small cell lung cancer, esophageal carcinoma, gastric cancer, cancer of pancreas, colon cancer, carcinoma of prostate etc., account for human tumor
25%.Research has discovered that regulatory factor and the mortifier of some Hedgehog signal paths at present, and such as Hh interacts
Albumen l (Hip1), retarded growth specific gene 1 (GAS-1), vesicular transporter RAB23, bone morphogenetic protein (BMP) with
And phytosterin compound etc., they can suppress propagation that cell causes to Hedgehog signal path response, break up and lure
Guided cell apoptosis, these results of study provide important clue for the treatment of tumor.Cyelopamine is a kind of plant sex steroid
Alkaloid, as the antagonist of Hedgehog signal path, and a kind of promising cancer treatment drugs.Vismodegib
Listing go through for treating basal cell carcinoma, it was demonstrated that the success of hedgehog signal path targeted drug strategy.Therefore, open
The hedgehog signal pathway inhibitor of small molecule is sent out, for the treatment of cancer in clinical position, with very big development prospect.
WO2012088411 discloses a kind of new hedgehog signal pathway inhibitor, and which has following formula (I) institute
Show structure：
Compound shown in formula (I) as a brand-new small molecule hedgehog signal pathway inhibitor, in vitro to target
In the inhibitory action of point and mice body drug effect all than the strong twice of Vismodegib more than；And animal drugs show for result, relative
In Vismodegib, shown in formula (I), compound body accumulation situation is greatly improved.
But WO2012088411 does not further investigate the crystal form of the compound.As well known to those skilled in the art, medicinal
The crystalline structure of active component often have influence on the chemical stability of the medicine, the difference of crystallization condition and condition of storage has can
The change of the crystalline structure of compound can be caused, sometimes can also be along with the crystal formation for producing other forms.Therefore, to drug crystal forms
Research, the particularly research of drug substance stable crystal formation, the subsequent development of medicine tool is of great significance.
Content of the invention
It is an object of the invention to provide the novel crystal forms of compound and preparation method shown in a kind of formula (I).
Compound shown in formula (I) has obtained series of crystallization product under different crystallization conditions, and gained crystallized product is entered
Gone X- diffraction and DSC detection, find formula (I) shown in compound under the specific crystallization condition of the present invention, one kind can be obtained
Stable crystal form, is named as the crystallization of I type.
One aspect of the present invention provides the I type of compound shown in formula (I) and crystallizes, it is characterised in that radiated using Cu-Ka,
The X-ray powder diffraction collection for representing with 2 θ angles and interplanar distance is obtained, the crystallization has X-ray as shown in Figure 1
Powder diffraction spectrum, wherein about 4.73 (18.66), 6.25 (14.14), 9.69 (9.12), 12.46 (7.10), 14.55
(6.09), 14.86 (5.96), 15.59 (5.68), 15.90 (5.57), 17.31 (5.12), 18.73 (4.73), 19.32
(4.59), 20.11 (4.41), 20.84 (4.26), 23.19 (3.83), 24.24 (3.67), 24.63 (3.61), 25.04
(3.55), 25.48 (3.49), 26.96 (3.30), 28.49 (3.13), 31.45 (2.84) nearby have characteristic peak, and DSC figure
Spectrum shows there is melting endothermic peak near 192 DEG C.
Another aspect of the present invention provides a kind of method of the I type crystallization for preparing compound shown in formula (I), specifically, bag
Include following steps：
(1) will be in appropriate solvent, cold to any crystal formation or compound solid heating for dissolving shown in unformed formula (I)
But, crystallize；
(2) filtering for crystallizing wash, dry.
In a preferred embodiment of the present invention, in step (1), solvent selected from isopropanol, isopropanol/water, ethyl acetate,
Acetonitrile.
Further, most preferred single solvent is ethyl acetate.
In one embodiment of the invention, preferred mixed solvent is the mixed solvent of isopropanol/water, the two ratio
It is not particularly limited, in a preferred embodiment of the present invention, the two volume ratio is 9：1.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, it is possible to by formula
(I) cooling crystallization after organic solvent heating for dissolving of compound shown in, after the completion of crystallization, through filtration drying, you can needed for obtaining
The crystallization that wants.Specifically, the crystalline solid of institute's leaching is usual under reduced pressure, at 30～100 DEG C or so, preferably 40～60
It is vacuum dried under conditions of DEG C, can be just reached the effect for removing recrystallization solvent.
Determined by differential scanning calorimeter (DSC), X- diffracting spectrum, to compound crystal body shown in the formula (I) that obtains
Crystal formation research is carried out, while being detected to the dissolvent residual of gained crystallization.
Do not contain or the only residual containing lower content according to compound crystal shown in formula (I) prepared by the method for the present invention
Solvent, meets the limitation requirement of the relevant medical product residual solvent of state-promulgated pharmacopoeia regulation, thus the crystallization of the present invention can be relatively
Use as medicating active ingredients well.
Through research show, the present invention prepare formula (I) shown in compound I type crystallization illumination, high temperature, high humidity condition
Stability inferior is good, and in grinding, pressure and under the conditions of being heated etc., stable crystal form, disclosure satisfy that the medicinal of production and transport storage
Require, stable processing technique repeats controlled, can adapt in industrialized production.
The I type crystallization of the present invention may be conveniently used and prepare pharmaceutical composition, and the Pharmaceutical composition includes formula (I) institute
Show compound crystal and at least one pharmaceutically acceptable carrier, excipient or diluent.
Description of the drawings
Fig. 1 is the X-ray powder diffraction collection of the crystallization of compound I type shown in formula (I).
Fig. 2 is the DSC spectrogram of the crystallization of compound I type shown in formula (I).
Fig. 3 is the X-ray powder diffraction collection of the crystallization of compound type III shown in formula (I).
Fig. 4 is the DSC spectrogram of the crystallization of compound type III shown in formula (I).
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate the skill of the present invention
Art scheme, and non-limiting the spirit and scope of the invention.
Experiment test instrunment used
1st, DSC spectrum
INSTRUMENT MODEL：Mettler Toledo DSC 1Staree System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：40-250℃
2nd, x-ray diffraction pattern
INSTRUMENT MODEL：Bruker D8Focus X-ray powder diffraction instrument
Ray：Monochromatic Cu-K alpha ray
Scan mode：θ/2 θ, sweep limitss：2-40°
Voltage：40KV electric current：40mA
Embodiment 1
Take compound shown in (1.0g, 2.15mmol) formula (I) (disclosing method preparation by WO2012088411) to be added to
In 25ml single port bottle, 5ml ethyl acetate is added, be heated to reflux molten clear, stirring cooling crystallization is to room temperature, and concentrating under reduced pressure falls about 2ml
Ethyl acetate, sucking filtration, dry solid 783mg, yield be.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 1.Should
Crystallize about 4.73 (18.66), 6.25 (14.14), 9.69 (9.12), 12.46 (7.10), 14.55 (6.09), 14.86
(5.96), 15.59 (5.68), 15.90 (5.57), 17.31 (5.12), 18.73 (4.73), 19.32 (4.59), 20.11
(4.41), 20.84 (4.26), 23.19 (3.83), 24.24 (3.67), 24.63 (3.61), 25.04 (3.55), 25.48
(3.49), 26.96 (3.30), there is characteristic peak at 28.49 (3.13) and 31.45 (2.84) places.DSC spectrogram is shown in Fig. 2, has sharp melting
192 DEG C of endothermic peak, this crystal formation is defined as I crystal.
Embodiment 2
Take compound shown in (1.0g, 2.15mmol) formula (I) (disclosing method preparation by WO2012088411) to be added to
In 25ml single port bottle, 8ml isopropanol is added, be heated to reflux molten clear, stirring cooling crystallization to room temperature, sucking filtration, dry solid
749mg, yield is 74.9%.The X-ray diffraction of the crystallized sample and DSC spectrogram are compared through research, determine product for I crystal.
Embodiment 3
Taking compound shown in (1.0g, 2.15mmol) formula (I) (method preparation being disclosed by WO2012088411) adds 8ml
90% isopropanol, heats molten clear, continues backflow 10 minutes, cooling, and stirring turns crystalline substance, a sucking filtration, dry solid 775mg, and yield is
77.5%.The X-ray diffraction of the crystallized sample and DSC spectrogram are compared through research, determine product for I crystal.
Embodiment 4
Taking compound shown in (1.0g, 2.15mmol) formula (I) (method preparation being disclosed by WO2012088411) adds 10ml
Acetonitrile, heats molten clear, continues backflow 10 minutes, cooling, and stirring turns crystalline substance, a sucking filtration, dry solid 703mg, yield be.
The X-ray diffraction of the crystallized sample and DSC spectrogram are compared through research, determine product for I crystal.
Embodiment 5
Repeat all operationss of WO2012088411 embodiment 633, by 2- ethyl -5- (6- (2- (trifluoromethyl) pyridine -
3- yl) imidazo [1,2-b] pyridazine -2- base) aniline (500mg, 1.30mol), acetonitrile (5ml) and pyridine (0.315ml) addition
In flask.Stir the mixed liquor and 1- methylcyclopropyl groups carboxylic acid chlorine (169mg, 1.43mmol) is added, and this is stirred at room temperature and mix
Close liquid 4 hours.When reaction is completed, the mixed liquor, and by silica gel chromatography purification (the two of 0-80% ethyl acetate are concentrated with silica gel
Chloromethanes solution), obtain the crystallization (400mg, 66%) of compound I.The crystallized sample through X-ray diffraction and DSC spectrogram warp
Research is compared, it was demonstrated that not I crystal, is defined as III crystal formation herein, but III crystal formation is probably a kind of mixing crystal formation, DSC
Collection of illustrative plates shows which two melting endothermic peaks occurs in close positions, and this crystal formation is unstable, it may occur however that the conversion of crystal formation, leads
The risk for causing the absorption of medicine to change, therefore cannot Clinical practice.
Embodiment 6
Placement is divided by open for the I type crystallized product of 1 gained of embodiment, investigate at illumination (4500Lux), heat (40 DEG C,
60 DEG C), the stability of sample under the conditions of high humidity (RH75%, RH90%).Sample time is investigated for 5 days and 10 days, HPLC is detected
Purity is shown in Table 1.
The stability of the I type crystallized sample of compound shown in table 1, formula (I)
Study on the stability result shows, compound I type crystallized sample shown in formula (I) open place under conditions of, illumination,
High temperature and super-humid conditions are little to its stability influence.
Embodiment 7
The crystallization of compound I type shown in formula (I) will be ground, heat and compressing tablet process as obtained in 1 method of embodiment, grind
Study carefully result and show stable crystal form, detailed experimental data is referring to table 2 below.
The special stability study of the I crystal of compound shown in table 2, formula (I)
Embodiment 8
Placement is divided by open for compound I type crystallized product shown in formula (I) as obtained in 1 method of embodiment, investigate sample
In the stability that room temperature (25 DEG C, RH60%) keeps sample for a long time, detailed experimental data is referring to table 3 below.
The I crystal sample room temperature of compound shown in table 3, formula (I) keep sample under the conditions of study on the stability
This product is placed for a long time through 25 DEG C, RH60% condition, period sampling measuring, as a result shows sample stable crystal form, relevant
Material has no significant change, stable crystal form, and it is stable to show that this product is placed 36 months under this condition.
Claims (5)
1. the I type crystallization of compound shown in formula (I), it is characterised in that radiated using Cu-Ka, obtain with 2 θ angles and interplanar distance
The X-ray powder diffraction collection of expression, the crystallization has X-ray powder diffraction collection as shown in Figure 1, wherein about
4.73 (18.66), 6.25 (14.14), 9.69 (9.12), 12.46 (7.10), 14.55 (6.09), 14.86 (5.96), 15.59
(5.68), 15.90 (5.57), 17.31 (5.12), 18.73 (4.73), 19.32 (4.59), 20.11 (4.41), 20.84
(4.26), 23.19 (3.83), 24.24 (3.67), 24.63 (3.61), 25.04 (3.55), 25.48 (3.49), 26.96
(3.30), 28.49 (3.13), 31.45 (2.84) nearby have characteristic peak,
2. the method that one kind prepares the I type crystallization of compound shown in formula as claimed in claim 1 (I), under methods described includes
State step：
1) by any crystal formation or unformed N- (2- ethyl -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b]
Pyridazine -2- base) phenyl) -1- methylcyclopropanecarboxamide solid heating for dissolving in appropriate solvent, cooling, crystallize；Wherein institute
Solvent is stated selected from isopropanol, isopropanol/water, ethyl acetate, acetonitrile；
2) filtering for crystallizing wash, dry.
3. method according to claim 2, it is characterised in that step 1) described in solvent be ethyl acetate.
4. a kind of pharmaceutical composition, which contains I type crystallization of compound shown in formula according to claim 1 (I) and at least
A kind of pharmaceutically acceptable carrier, excipient or diluent.
5. the pharmaceutical composition described in the I type crystallization of compound shown according to claim 1 to formula (I) or claim 4
Purposes in the medicine for preparing the treatment disease relevant with hedgehog signal pathway inhibitor；The disease is preferably pernicious swollen
Tumor, more preferably basal cell carcinoma, gastric cancer, cancer of pancreas, pulmonary carcinoma.
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| CN201510471424 | 2015-08-04 | ||
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103261198A (en) * | 2010-12-22 | 2013-08-21 | 江苏恒瑞医药股份有限公司 | 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103261198A (en) * | 2010-12-22 | 2013-08-21 | 江苏恒瑞医药股份有限公司 | 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives |
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Effective date of registration: 20210625 Address after: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HENGRUI MEDICINE Co.,Ltd. Patentee after: Tianjin Hengrui Pharmaceutical Co.,Ltd. Address before: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee before: JIANGSU HENGRUI MEDICINE Co.,Ltd. |
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