CN105198879B - A kind of cyclopropanecarbonyl amine derivative C crystal form and preparation method thereof - Google Patents
A kind of cyclopropanecarbonyl amine derivative C crystal form and preparation method thereof Download PDFInfo
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- CN105198879B CN105198879B CN201510599141.4A CN201510599141A CN105198879B CN 105198879 B CN105198879 B CN 105198879B CN 201510599141 A CN201510599141 A CN 201510599141A CN 105198879 B CN105198879 B CN 105198879B
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- amine derivative
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- cyclopropanecarbonyl amine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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 provides a kind of cyclopropanecarbonyl amine derivative C crystal form of formula (I),Its XRPD collection of illustrative plates has diffraction maximum at 2 θ=7.14,8.9,12.521,13.082,16.521,18.401,19.877,20.541,21.517,21.825,24.04,24.764,25.3,26.359,27.5,28.719, wherein 2 θ values error ranges are ± 0.2.The cyclopropanecarbonyl amine derivative C crystal form that the present invention is provided can be in the inflammation for the treatment of or prevention JAK participations, autoimmune disease, proliferative disease, graft-rejection and congenital cartilage deformity or with being applied in the medicine of disease caused by IL6 hypersecretions, and with preferable bioavilability, the qualitative, quantitative information provided simultaneously, has great importance to the curative effect for further studying such solid drugs.
Description
Technical field
The present invention relates to a kind of polymorphic of the cyclopropanecarbonyl amine derivative as JAK inhibitor, in particular it relates to one
Plant cyclopropanecarbonyl amine derivative C crystal form and preparation method thereof.
Background technology
JAK is Janus kinases (Janus Kinase), is a kind of non-receptor type tyrosine protein kinase, is also that a class is non-
The EGFR-TK of transmembrane.Because JAK can phosphorylation cytokine receptor combined with it, and can phosphorylation it is many
The individual signaling molecule containing specific SH2 domains.JAK protein families include 4 members altogether：JAK1, JAK2, JAK3 and TYK2,
They have 7 JAK homeodomains (JAK homology domain, JH) in structure, wherein JH1 domains be kinases area,
JH2 domains are that "false" kinases area, JH6 and JH7 are receptorbinding regions.
TYK2 is the potential target spot of Immunoinflammatory Disorders, rejects research confirmation (Levy by people's science of heredity and mouse
D. with Loomis C., 1655-1658 pages of New England Journal of Medicine 357 (2007)).
JAK1 is the novel targets in Immunoinflammatory Disorders field.By JAK1 and other JAK heterodimericization, with the transducer cell factor
The pro-inflammatory signals conduction of driving.Therefore, it is contemplated that suppression JAK1 and/or other JAK is for a series of inflammatory conditions with other by JAK
The disease of the signal transduction driving of mediation has treatment benefit.
Cyclopropanecarbonyl amine derivative, chemical name N- [5- [4- [(1,1- dioxo -4- thio-morpholinyls) methyl] phenyl]
[1,2,4] triazol [1,5-A] pyridine -2- bases] cyclopropane carboxamide, as shown in formula (I),
A kind of JAK classes inhibitor compound, available for treat or prevent JAK participate in inflammation, autoimmune disease,
Proliferative disease, graft-rejection and congenital cartilage deformity or with disease caused by IL6 hypersecretions.In middle promulgated by the State Council
In bright patent CN 102105471 (WO 2010/010190), the synthetic method of the compound is disclosed；In Chinese invention patent
In CN 102482273 (WO 2010/149769), the purposes of cyclopropanecarbonyl amine derivative is disclosed.Repeat above-mentioned patent
Preparation method, obtains compound powder, is detected as amorphous state.Although as it is known by the man skilled in the art, amorphous big
Most occasions all have higher solubility and dissolution rate than crystal formation, but its is unstable, and hygroscopicity is strong, easily switch to stable
Crystal formation.Therefore, it is amorphous the problem of there is processing stability and bin stability, and in process of production, amorphous particle
Bulk density it is smaller, surface free energy is high, also easily causes cohesion, poor fluidity, elastic deformation a series of formulation problems such as by force,
Have a strong impact on the clinical drug use value of amorphous cyclopropanecarbonyl amine derivative.
It is well known that same medicine, crystal formation is different, its bioavilability may also can have difference, and it is stable in addition
Property, mobility, compressibility may also can be different, application of these physicochemical properties to medicine produces certain influence, so that shadow
Ring the curative effect of medicine.Accordingly, it would be desirable to the crystal formation of the cyclopropanecarbonyl amine derivative with superior physiochemical properties, it can have
Sharply used in medicine processing and pharmaceutical composition.The novel crystal forms for the cyclopropanecarbonyl amine derivative that the present invention is developed do not appear in the newspapers
Road.
The content of the invention
Problem to be solved by this invention is the unstability of existing cyclopropanecarbonyl amine derivative, hygroscopicity and easily turned
The problems such as stable crystal formation, is unfavorable for medicine processing and is used in pharmaceutical composition, the new crystalline substance of cyclopropanecarbonyl amine derivative
Type, the problem of providing more qualitative, quantitative information for the effectiveness study of solid drugs.
In order to solve the above-mentioned technical problem, the invention provides a kind of new crystal formation of cyclopropanecarbonyl amine derivative (with
Call in the following text " cyclopropanecarbonyl amine derivative C crystal form "), as shown in formula (I).
Its XRPD collection of illustrative plates 2 θ=7.14,8.9,12.521,13.082,16.521,18.401,19.877,20.541,
21.517th, there is diffraction maximum at 21.825,24.04,24.764,25.3,26.359,27.5,28.719, wherein 2 θ value error ranges
For ± 0.2.
According to the cyclopropanecarbonyl amine derivative C crystal form of the present invention, with substantially the same with Figure of description Fig. 1
XRPD collection of illustrative plates.
Present invention also offers a kind of method for preparing cyclopropanecarbonyl amine derivative C crystal form, comprise the following steps：In ring
With 1 in cyclopropane carboxamide derivative:150~1:250g/mL ratio adds organic solvent, suspends at room temperature, then filter,
Vacuum drying is so as to obtain the cyclopropanecarbonyl amine derivative C crystal form of off-white powder.
In certain embodiments, the organic solvent is alcohols or any one solvent or two or more molten in esters
Agent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the alcohol organic solvent is n-butanol；The based organic solvent is acetic acid
Ethyl ester.
Those of ordinary skill in the art can be carried out according to its knowledge and experience to the consumption of the inventive method agents useful for same
Adjustment, including scale up or reduce raw material dosage and adjustment solvent load, the scheme of these adjustment is also contained in the present invention
Method in.
In above-mentioned steps, the ratio of cyclopropanecarbonyl amine derivative and solvent is preferably 1:200g/mL.
The compound of cyclopropanecarbonyl amine derivative C crystal form with the present invention is for treatment and autoimmune disease
EGFR-TK (JAK) inhibitor.JAK is one kind of TYR kinases, JAK belong to participation inflammation, autoimmune disease,
Proliferative disease, graft-rejection and congenital cartilage deformity, or with disease caused by IL6 hypersecretions.The present invention's
Compound suppresses JAK1 and JAK2.
Therefore, the use in being used to suppress JAK medicine is being prepared the invention provides cyclopropanecarbonyl amine derivative C crystal form
On the way；And it is anti-for the inflammation for treating or preventing JAK participations, autoimmune disease, proliferative disease, graft rejection preparing
Should and congenital cartilage deformity or with the purposes in the medicine of disease caused by IL6 hypersecretions.
Present invention also offers pharmaceutical composition, its include according to the cyclopropanecarbonyl amine derivative C crystal form of the present invention with
And one or more pharmaceutically acceptable carriers, excipient or diluent.
In some embodiments of the invention, aforementioned pharmaceutical compositions further include other therapeutic agent, and described controls
Treat agent and be selected from chemotherapy or antiproliferative, antiinflammatory, immunological regulation or immunodepressant, neurotrophic factor, for treating itself
The activating agent of immunity disease, the activating agent for treating proliferative disease, the activating agent for treating graft-rejection, use
In the activating agent of congenital cartilage deformity or for treating the activating agent with disease caused by IL6 hypersecretions.
According to the cyclopropanecarbonyl amine derivative C crystal form of the present invention, medicine is conducive to process and make in pharmaceutical composition
With inflammation, autoimmune disease, proliferative disease, graft-rejection and the elder generation that can be participated in treatment or prevention JAK
Nature cartilage is lopsided or with being applied in the medicine of disease caused by IL6 hypersecretions, and with preferable bioavilability,
The qualitative, quantitative information provided simultaneously, has great importance to the curative effect for further studying such solid drugs.
Brief description of the drawings
The XRPD collection of illustrative plates for the cyclopropanecarbonyl amine derivative C crystal form that Fig. 1 provides for the present invention.
Five days high-temperature stability XRPD collection of illustrative plates of cyclopropanecarbonyl amine derivative C crystal form that Fig. 2 provides for the present invention.
The five days high wet stability XRPD collection of illustrative plates of cyclopropanecarbonyl amine derivative C crystal form that Fig. 3 provides for the present invention.
Five days light durability XRPD collection of illustrative plates of cyclopropanecarbonyl amine derivative C crystal form that Fig. 4 provides for the present invention.
Ten days high-temperature stability XRPD collection of illustrative plates of cyclopropanecarbonyl amine derivative C crystal form that Fig. 5 provides for the present invention.
The ten days high wet stability XRPD collection of illustrative plates of cyclopropanecarbonyl amine derivative C crystal form that Fig. 6 provides for the present invention.
Ten days light durability XRPD collection of illustrative plates of cyclopropanecarbonyl amine derivative C crystal form that Fig. 7 provides for the present invention.
Fig. 8 is the unbodied XRPD collection of illustrative plates of existing cyclopropanecarbonyl amine derivative.
Embodiment
In from detailed description below, aforementioned aspect of the present invention and other aspects of the present invention will be apparent.
The preparation of the cyclopropanecarbonyl amine derivative C crystal form of embodiment 1 to 2
500mg cyclopropanecarbonyl amine derivative raw materials are weighed in container, the solvent (analysis in 100mL tables 1 is separately added into
It is pure), 35 DEG C are suspended 48 hours, and off-white powder is obtained after filtering, vacuum drying.Weigh and calculate its yield.
The preparation of the cyclopropanecarbonyl amine derivative C crystal form of table 1
| Embodiment | Solvent | Yield |
| 1 | N-butanol | 86% |
| 2 | Ethyl acetate | 79% |
Embodiment 3. characterizes cyclopropanecarbonyl amine derivative C crystal form by XRPD figures
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, is penetrated using the multifunctional assembled X of Rigaku UltimaIV models
Line diffractometer is carried out, and specific collection information is as follows：Cu anodes (40kV, 40mA), °/minute of sweep speed 20, scanning range (2 θ
Scope) 3~45 °, scanning step 0.02, slit width 0.01.Using slide directly at test board compacting is to sample progress
Reason.Thereafter XRPD collection of illustrative plates uses similar measuring method.
Determine according to the methods described of embodiment 1 prepare cyclopropanecarbonyl amine derivative C crystal form XRPD collection of illustrative plates, 2 θ=
7.14、8.9、12.521、13.082、16.521、18.401、19.877、20.541、21.517、21.825、24.04、
24.764th, there is diffraction maximum at 25.3,26.359,27.5,28.719, as shown in Figure 1.Wherein 2 θ values error ranges are ± 0.2.Through
Detection, 2 θ values error ranges can also be ± 0.15.The cyclopropanecarbonyl amine derivative C prepared according to the methods described of embodiment 2
Crystal formation, its XRPD collection of illustrative plates and collection of illustrative plates shown in accompanying drawing 1 are essentially identical.
Spread out it will be understood by those skilled in the art that these diffraction maximums are not represented shown by cyclopropanecarbonyl amine derivative C crystal form
Penetrate the detailed situation at peak.2 θ values of X-ray powder diffraction figure be can with machine and with the change in sample preparation and
Change and slight change between batch, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with taking
Become to effect, therefore the intensity shown in the XRD traces contained by the present invention is exemplary, is not used to definitely compare.
The high-temperature stability of the cyclopropanecarbonyl amine derivative C crystal form of embodiment 4. is investigated
Cyclopropanecarbonyl amine derivative C crystal form sample is placed in 60 DEG C of baking ovens, sample is taken out after 5 days and 10 days and carried out
XRPD is tested (as shown in Figure 2 and Figure 5), to investigate stability of crystal form of the sample to temperature.As a result show, crystal formation under hot conditions
C sample stability is general.
The high humidity study on the stability of the cyclopropanecarbonyl amine derivative C crystal form of embodiment 5.
Cyclopropanecarbonyl amine derivative C crystal form sample is placed under 92.5% damp condition, sample is taken after 5 days and 10 days
Go out to carry out XRPD tests (as shown in Figure 3 and Figure 6), to investigate stability of crystal form of the sample to temperature.Test result is shown in table 2
Go out.As a result show, crystal formation C sample stability is general under super-humid conditions.
The high wet stability of the cyclopropanecarbonyl amine derivative C crystal form of table 2
| Sample | Color | Gain in weight |
| C crystal form | Off-white color | 0.00% |
| C crystal form after five days | Off-white color | 4.83% |
| C crystal form after ten days | Off-white color | 4.81% |
The light durability of the cyclopropanecarbonyl amine derivative C crystal form of embodiment 6 is investigated
Cyclopropanecarbonyl amine derivative C crystal form sample is placed under 4500lux intensities of illumination, by sample after 5 days and 10 days
Take out and carry out XRPD tests (as shown in figs. 4 and 7), to investigate stability of crystal form of the sample to temperature.As a result show, illumination bar
Crystal formation C sample stability is general under part.
The unbodied preparation of the cyclopropanecarbonyl amine derivative of embodiment 7
Due to the synthetic method and Chinese invention patent CN that are used in Chinese invention patent CN 102482273
The synthetic method used in 102105471 is completely the same, therefore two according to described in Chinese invention patent CN 102482273
The method of kind, prepares cyclopropanecarbonyl amine derivative.After the organic layer containing cyclopropanecarbonyl amine derivative is obtained, by organic layer
Through anhydrous MgSO4Dry and be evaporated in vacuo.Final compound is obtained by flash chromatography or preparation HPLC after purification.
As shown in figure 8, being determined through XRPD, the final product of gained is amorphous samples.
The cyclopropanecarbonyl amine derivative C crystal form of embodiment 8 and unbodied solubility compare
Excessive C crystal form and amorphous powder are separately added into 20mL sample bottles, appropriate water is added, 24 is shaken at room temperature
After hour, sampling detection solubility.Crystal formation C water solubility is 42.22 μ g/mL, and unbodied water solubility is 100.32 μ g/
mL。
Derive it can be seen from the results that the cyclopropanecarbonyl amine derivative C crystal form of the present invention has than cyclopropane carboxamide
The amorphous low solubility of thing.
Although those skilled in the art is it should be understood that for illustrative purposes, this document describes the tool of the present invention
Body embodiment, but various modifications can be carried out to it without departing from the spirit and scope of the present invention.Therefore, it is of the invention specific
Embodiment and embodiment should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Claims (8)
1. a kind of cyclopropanecarbonyl amine derivative C crystal form of formula (I), it is characterised in that
Its XRPD collection of illustrative plates 2 θ=7.14,8.9,12.521,13.082,16.521,18.401,19.877,20.541,
21.517th, there is diffraction maximum at 21.825,24.04,24.764,25.3,26.359,27.5,28.719, wherein 2 θ value error ranges
For ± 0.2.
2. cyclopropanecarbonyl amine derivative C crystal form as claimed in claim 1, it is characterised in that it has and Figure of description
XRPD collection of illustrative plates substantially the same Fig. 1.
3. prepare the method for cyclopropanecarbonyl amine derivative C crystal form as claimed in claim 1 or 2, it is characterised in that including with
Lower step：With 1 in cyclopropanecarbonyl amine derivative:150~1:250g/mL ratio adds organic solvent, hangs at room temperature
It is floating, then filter, be dried in vacuo so as to obtain the cyclopropanecarbonyl amine derivative C crystal form of off-white powder,
Wherein, any one solvent or two or more solvents of the organic solvent for alcohols or in esters are with arbitrary proportion
Mixed solvent, and
The alcohol organic solvent is n-butanol；
The based organic solvent is ethyl acetate.
4. cyclopropanecarbonyl amine derivative C crystal form as claimed in claim 1 or 2 is being prepared for suppressing in JAK medicine
Purposes.
5. cyclopropanecarbonyl amine derivative C crystal form as claimed in claim 1 or 2 is being prepared for treating or preventing JAK participations
Inflammation, autoimmune disease, proliferative disease, graft-rejection and congenital cartilage deformity or secreted with IL6
Purposes in the medicine of disease caused by many.
6. pharmaceutical composition, it includes cyclopropanecarbonyl amine derivative C crystal form as claimed in claim 1 or 2.
7. pharmaceutical composition as claimed in claim 6, it also includes one or more pharmaceutically acceptable carriers, excipient
Or diluent.
8. pharmaceutical composition as claimed in claim 6, it further includes other therapeutic agent, and described therapeutic agent, which is selected from, to be changed
Treat or antiproliferative, antiinflammatory, immunological regulation or immunodepressant, neurotrophic factor, for treating autoimmune disease
Activating agent, the activating agent for treating proliferative disease, the activating agent for treating graft-rejection, for congenital soft
The activating agent of bone malformation or for treating and the activating agent of disease caused by IL6 hypersecretions.
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