CN104558041B - Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form - Google Patents
Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form Download PDFInfo
- Publication number
- CN104558041B CN104558041B CN201510051482.8A CN201510051482A CN104558041B CN 104558041 B CN104558041 B CN 104558041B CN 201510051482 A CN201510051482 A CN 201510051482A CN 104558041 B CN104558041 B CN 104558041B
- Authority
- CN
- China
- Prior art keywords
- crystal formation
- agent
- chloro
- phenyl
- quinazoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of compound preparation and particularly relates to a novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)propyl-1-alkynyl)quinazoline-4-p-toluidine sulfonate as well as a preparation method and application of the novel crystal form. The novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)propyl-1-alkynyl)quinazoline-4-p-toluidine sulfonate having a better treating effect for excessive proliferative diseases is further obtained through crystallizing a hydrosolvent, so that not only is the pharmaceutical activity of the phosphorus-containing substituted quinazoline derivative improved, but also the bioavailability of the phosphorus-containing substituted quinazoline derivative is increased, and the blank for researching a drug with the crystal form of the phosphorus-containing substituted quinazoline derivative is made up.
Description
Technical field
The present invention relates to crystal-form compound technical field, be specifically related to phosphorous substituted quinazoline derivant novel crystal forms and
Its preparation method and application.
Background technology
N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynes
Base) quinazoline-4-amine tosilate, it is phosphorous substituted quinazoline derivant, its structural formula is as follows, is by knob gold
The medicine of the treatment excess proliferative disease of pharmaceutical companies research and development, this compound is I receptor kinases inhibitor, can be used for
Relevant disease abnormal to protein kinase activity, such as cancer and inflammation in treatment mammal.
Chinese patent CN102711472A discloses a kind of phosphorous quinazoline derivant and using method thereof, including
N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-
4-amine tosilate, this patent describes various phosphorous quinazoline derivant preparation method in detail and it is excessively increasing
Function in growing property disease and effect.
Crystal formation is the solid matter state that medicine exists, and medicine basic substance state is ground by drug crystal forms research exactly
Study carefully, only chemicals crystal form state had the understanding compared adequately and comprehensively, it is possible to find more be appropriate to treat disease
Sick drug crystal forms solid matter.Drug crystal forms can affect the physicochemical property of medicine, directly affects clinical drug and plays treatment
The basis of disease effect.Therefore, the important component part of drug substance basic research is carried out when drug crystal forms being studied.But
At present, not yet have N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-
1-alkynyl) relevant report of quinazoline-4-amine tosilate drug crystal forms so that there is sky in the basic research of this medicine
In vain.Further, N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynes
Base) quinazoline-4-amine tosilate there is also certain deficiency in terms of drug metabolism, and bioavailability is the highest.
Summary of the invention
In view of this, it is an object of the invention to provide a kind of N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-
The novel crystal forms of (3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine tosilate and preparation side thereof
Method and application so that it is pharmaceutically active can be improved and improve drug bioavailability.
In order to realize foregoing invention purpose, the present invention provides following technical scheme:
N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynes
Base) crystal formation of quinazoline-4-amine tosilate, its x-ray diffractogram of powder is basic as it is shown in figure 1, use CuKαRadiation,
The powder X-ray diffraction represented with 2 θ angles is 5.58 ± 1.00,5.92 ± 1.00,7.64 ± 1.00,8.24 ± 1.00,8.48
±1.00、8.96±1.00、9.84±1.00、11.54±1.00、12.00±1.00、12.95±1.00、13.98±1.00、
14.22±1.00、15.04±1.00、15.50±1.00、16.18±1.00、16.60±1.00、17.16±1.00、18.10
±1.00、19.40±1.00、19.72±1.00、20.36±1.00、21.10±1.00、21.50±1.00、22.24±
1.00、22.84±1.00、23.38±1.00、23.94±1.00、24.42±1.00、24.96±1.00、25.62±1.00、
25.98±1.00、26.56±1.00、27.36±1.00、27.74±1.00、28.82±1.00、29.47±1.00、32.22
±1.00、33.06±1.00、33.66±1.00、35.00±1.00、36.54±1.00、37.40±1.00、37.98±
1.00、38.90±1.00、39.64±1.00、41.08±1.00、41.80±1.00、42.44±1.00、44.10±1.00、
45.62 ± 1.00,47.32 ± 1.00,48.49 ± 1.00,51.78 ± 1.00 have diffraction maximum.
Wherein, described N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases)
Acrylate-1-alkynyl) quinazoline-4-amine tosilate is at Chinese patent CN102711472A openly.
The each detailed powder X-ray diffraction parameter of novel crystal forms of the present invention is shown in Table 1, shows as diffraction maximum position: 2-
Theta value (°) or d value ()；Diffraction maximum relative intensity: peak height value (Height%) or peak area value (Area%).
The powder X-ray diffraction peak value of table 1 novel crystal forms of the present invention
It should be understood that 2 θ values of X-ray powder diffraction figure can vary slightly between machine or between sample, its numerical value can
About 1 unit, or about 0.8 unit of difference, or about 0.5 unit of difference, or difference about 0.2 can be differed
Individual unit, or about 0.1 unit of difference, therefore cited numerical value can not be construed to absolute value.It shall again be understood that peak
Relative intensity can change, about 1 unit of the equally possible difference of its numerical value according to the orientation of sample in test, or difference
About 0.8 unit, or about 0.5 unit of difference, or about 0.2 unit of difference, or about 0.1 list of difference
Position, XRPD trace (trace) intensity being therefore included in the present invention is illustrative, is not meant for definitely comparing.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(and 4-methyl isophthalic acid, 4
Azepine phosphine-1-base) acrylate-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuKαRadiation, represents with 2 θ angles
Powder X-ray diffraction 5.58 ± 0.80,5.92 ± 0.80,7.64 ± 0.80,8.24 ± 0.80,8.48 ± 0.80,8.96
±0.80、9.84±0.80、11.54±0.80、12.00±0.80、12.95±0.80、13.98±0.80、14.22±
0.80、15.04±0.80、15.50±0.80、16.18±0.80、16.60±0.80、17.16±0.80、18.10±0.80、
19.40±0.80、19.72±0.80、20.36±0.80、21.10±0.80、21.50±0.80、22.24±0.80、22.84
±0.80、23.38±0.80、23.94±0.80、24.42±0.80、24.96±0.80、25.62±0.80、25.98±
0.80、26.56±0.80、27.36±0.80、27.74±0.80、28.82±0.80、29.47±0.80、32.22±0.80、
33.06±0.80、33.66±0.80、35.00±0.80、36.54±0.80、37.40±0.80、37.98±0.80、38.90
±0.80、39.64±0.80、41.08±0.80、41.80±0.80、42.44±0.80、44.10±0.80、45.62±
0.80,47.32 ± 0.80,48.49 ± 0.80,51.78 ± 0.80 have diffraction maximum.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(and 4-methyl isophthalic acid, 4
Azepine phosphine-1-base) acrylate-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuKαRadiation, represents with 2 θ angles
Powder X-ray diffraction 5.58 ± 0.50,5.92 ± 0.50,7.64 ± 0.50,8.24 ± 0.50,8.48 ± 0.50,8.96
±0.50、9.84±0.50、11.54±0.50、12.00±0.50、12.95±0.50、13.98±0.50、14.22±
0.50、15.04±0.50、15.50±0.50、16.18±0.50、16.60±0.50、17.16±0.50、18.10±0.50、
19.40±0.50、19.72±0.50、20.36±0.50、21.10±0.50、21.50±0.50、22.24±0.50、22.84
±0.50、23.38±0.50、23.94±0.50、24.42±0.50、24.96±0.50、25.62±0.50、25.98±
0.50、26.56±0.50、27.36±0.50、27.74±0.50、28.82±0.50、29.47±0.50、32.22±0.50、
33.06±0.50、33.66±0.50、35.00±0.50、36.54±0.50、37.40±0.50、37.98±0.50、38.90
±0.50、39.64±0.50、41.08±0.50、41.80±0.50、42.44±0.50、44.10±0.50、45.62±
0.50,47.32 ± 0.50,48.49 ± 0.50,51.78 ± 0.50 have diffraction maximum.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(and 4-methyl isophthalic acid, 4
Azepine phosphine-1-base) acrylate-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuKαRadiation, represents with 2 θ angles
Powder X-ray diffraction 5.58 ± 0.20,5.92 ± 0.20,7.64 ± 0.20,8.24 ± 0.20,8.48 ± 0.20,8.96
±0.20、9.84±0.20、11.54±0.20、12.00±0.20、12.95±0.20、13.98±0.20、14.22±
0.20、15.04±0.20、15.50±0.20、16.18±0.20、16.60±0.20、17.16±0.20、18.10±0.20、
19.40±0.20、19.72±0.20、20.36±0.20、21.10±0.20、21.50±0.20、22.24±0.20、22.84
±0.20、23.38±0.20、23.94±0.20、24.42±0.20、24.96±0.20、25.62±0.20、25.98±
0.20、26.56±0.20、27.36±0.20、27.74±0.20、28.82±0.20、29.47±0.20、32.22±0.20、
33.06±0.20、33.66±0.20、35.00±0.20、36.54±0.20、37.40±0.20、37.98±0.20、38.90
±0.20、39.64±0.20、41.08±0.20、41.80±0.20、42.44±0.20、44.10±0.20、45.62±
0.20,47.32 ± 0.20,48.49 ± 0.20,51.78 ± 0.20 have diffraction maximum.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(and 4-methyl isophthalic acid, 4
Azepine phosphine-1-base) acrylate-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuKαRadiation, represents with 2 θ angles
Powder X-ray diffraction 5.58 ± 0.10,5.92 ± 0.10,7.64 ± 0.10,8.24 ± 0.10,8.48 ± 0.10,8.96
±0.10、9.84±0.10、11.54±0.10、12.00±0.10、12.95±0.10、13.98±0.10、14.22±
0.10、15.04±0.10、15.50±0.10、16.18±0.10、16.60±0.10、17.16±0.10、18.10±0.10、
19.40±0.10、19.72±0.10、20.36±0.10、21.10±0.10、21.50±0.10、22.24±0.10、22.84
±0.10、23.38±0.10、23.94±0.10、24.42±0.10、24.96±0.10、25.62±0.10、25.98±
0.10、26.56±0.10、27.36±0.10、27.74±0.10、28.82±0.10、29.47±0.10、32.22±0.10、
33.06±0.10、33.66±0.10、35.00±0.10、36.54±0.10、37.40±0.10、37.98±0.10、38.90
±0.10、39.64±0.10、41.08±0.10、41.80±0.10、42.44±0.10、44.10±0.10、45.62±
0.10,47.32 ± 0.10,48.49 ± 0.10,51.78 ± 0.10 have diffraction maximum.
Additionally, described novel crystal forms is analyzed, wherein by the present invention also by infrared spectrum and differential canning calorimetry
Use infrared spectrum when being analyzed 3281,3201,3125,3055,2992,2967,2920,2868,2681,2537,
2371、2107、1967、1915、1811、1688、1616、1600、1582、1553、1527、1498、1445、1418、1401、
1370、1303、1288、1275、1264、1233、1219、1198、1170、1148、1138、1117、1077、1065、1030、
1004、954、926、896、860、848、835、813、791、778、746、711、680cm-1There is infrared spectrum characteristic peak in place,
The tolerance of its middle infrared spectrum characteristic peak is ± 2cm-1, infrared spectrogram is the most as shown in Figure 2；
When using differential canning calorimetry to be analyzed, show as when the DSC figure that heating rate is 10 DEG C per minute
In spectrum, 2 endothermic peaks of existence are respectively at 163 DEG C ± 3 DEG C and 181 ± 3 DEG C, and its spectrogram is the most as shown in Figure 3.
Sweep it should be understood that deviation may be had to have similar situation, infrared spectrum and differential with X-ray powder diffraction figure numerical value
Retouch the numerical value cited in Calorimetric Techniques and can not be construed to absolute value.
Present invention also offers a kind of N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 nitrogen
Miscellaneous phosphine-1-base) acrylate-1-alkynyl) quinazoline-4-amine tosilate mixing crystal formation, comprise the of the present invention of arbitrary proportion
Novel crystal forms.
Novel crystal forms of the present invention in the Proliferation Ability of different people tumor cell line being tested with Lapatinib, its IC50
It is intended to the IC less than Lapatinib50, show that the pharmaceutically active of novel crystal forms of the present invention is more excellent.Meanwhile, the present invention is to N-(3-chlorine
Generation-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine pair
Toluene fulfonate and crystal formation of the present invention carry out pharmacokinetic trial, and result shows, crystal formation of the present invention is to reach peak dense
Degree and area under the drug-time curve aspect are substantially better than existing compound, show that crystal formation of the present invention has more preferable biological utilisation
Degree.
Based on this, the invention provides described N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl-
1,4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine tosilate crystal formation or its mixing crystal formation treated in preparation
Application in degree proliferative disease medicine.
As preferably, described excess proliferative disease is cancer or inflammation.It is furthermore preferred that described cancer is breast carcinoma, stomach
Cancer, colon cancer, pulmonary carcinoma, cortical carcinoma or ovarian cancer.
The present invention also provides for one and treats excess proliferative disease medicine, including the consolidating of crystal formation of the present invention of effective dose
Body material and pharmaceutically acceptable excipient.
Effective dose of the present invention refers to reach the pharmacologic agent dosage of therapeutical effect；Described excipient refers in medicine system
Additament in addition to principal agent in agent, it is possible to be referred to as adjuvant.Such as the adhesive in tablet, filler, disintegrating agent, lubricant；In
Wine in pill agent, vinegar, medicine juice etc.；Base portion in semi-solid preparation ointment, cream；Preservative in liquid preparation,
Antioxidant, correctives, aromatic, cosolvent, emulsifying agent, solubilizing agent, osmotic pressure regulator, coloring agent etc. all can be described as figuration
Agent, as preferably, excipient of the present invention is wetting agent, dispersant, pH adjusting agent, antioxidant, filler, diluent, increasing
Solvent, suspending agent, correctives, binding agent, disintegrating agent, osmotic pressure regulator, flocculant, antiplastering aid, suspending agent, emulsifying agent and anti-
One or more in rotten agent, it is highly preferred that specially lactose, starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose
Element, Pulvis Talci, magnesium stearate, Carboxymethyl cellulose sodium, or be lactose, starch, microcrystalline Cellulose, magnesium stearate, methylol
Sodium cellulosate.
As preferably, described excess proliferative disease is cancer or inflammation.It is furthermore preferred that described cancer is breast carcinoma, stomach
Cancer, colon cancer, pulmonary carcinoma, cortical carcinoma or ovarian cancer.
As preferably, excess proliferative disease medicine of the present invention is tablet, capsule, pill, injection, slow releasing preparation medicine
Thing or controlled release preparation medicine, more preferably tablet or capsule.
Present invention also offers the preparation method of described novel crystal forms, with water for solvent at a temperature of 40 DEG C～80 DEG C by N-
(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-
Amine tosilate sample is completely dissolved, and stands under temperature 4 DEG C～20 DEG C, relative humidity 10%～75%, condition of normal pressure
Crystallize, it is thus achieved that described crystal formation.
As preferably, during described dissolving, temperature is 60 DEG C；
As preferably, temperature during described removal methanol solvate is 10 DEG C；
As preferably, relative humidity during described removal methanol solvate is 42.5%.
As preferably, described N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphines-
1-yl) acrylate-1-alkynyl) mass volume ratio of quinazoline-4-amine tosilate sample and water is 1g:30mL-40mL.
From above technical scheme, the present invention is crystallized by aqueous solvent, and then obtains treatment excess proliferative disease effect
Fruit more preferably N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynes
Base) quinazoline-4-amine tosilate novel crystal forms, the medicine not only increasing this phosphorous substituted quinazoline derivant is lived
Property, and improve its bioavailability, compensate for the blank of its crystal formation drug research.
Accompanying drawing explanation
Fig. 1 shows N-of the present invention (3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepines
Phosphine-1-base) acrylate-1-alkynyl) the X-ray powder diffraction figure of quinazoline-4-amine tosilate crystal formation；
Fig. 2 shows N-of the present invention (3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepines
Phosphine-1-base) acrylate-1-alkynyl) infrared spectrogram of quinazoline-4-amine tosilate crystal formation；
Fig. 3 shows N-of the present invention (3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepines
Phosphine-1-base) acrylate-1-alkynyl) Differential Scanning Calorimetry of quinazoline-4-amine tosilate crystal formation.
Detailed description of the invention
The invention discloses novel crystal forms of phosphorous substituted quinazoline derivant and its preparation method and application, this area skill
Art personnel can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and
Changing apparent to those skilled in the art, they are considered as being included in the present invention.The novel crystal forms of the present invention,
Preparation method and application is described by preferred embodiment, related personnel substantially can without departing from present invention,
In spirit and scope, method described herein and application it is modified or suitably changes and combine, realize and apply the present invention
Technology.
N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, the 4 azepine phosphine-1-that the present invention provides
Base) acrylate-1-alkynyl) agents useful for same all can be buied by market in quinazoline-4-amine tosilate crystal formation and preparation method thereof.
Wherein, N-(3-chloro-4-(3-fluoro Bian epoxide) the phenyl)-6-that used (3-(4-methyl isophthalic acid, 4 azepine phosphines-
1-yl) acrylate-1-alkynyl) quinazoline-4-amine tosilate can buy from NewGen Therapeutics, Inc., it is possible to makes by the following method
Standby acquisition:
By 450g (0.823mol) compound N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid,
4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine (shown in formula I, purchased from NewGen Therapeutics, Inc.), p-methyl benzenesulfonic acid
298g (1.731mol), adds in solvent 4500ml (isopropanol: water=10:1), and mechanical agitation is heated to backflow, and reaction 10 is little
Time, natural cooling cooling, solid separates out, and after filtration, filter cake adds the making beating of 2000ml methanol, is dried to constant weight, obtains after filtration
Yellow solid N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynes
Base) quinazoline-4-amine tosilate.
Below in conjunction with embodiment, the present invention is expanded on further.
Embodiment 1: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid,
4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 200mg N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases)
Acrylate-1-alkynyl) quinazoline-4-amine tosilate sample is dissolved completely in 7.0mL water, is placed in 60 DEG C of water-baths, makes sample
Product are completely dissolved, and are positioned over 10 DEG C, relative humidity is 42.5%, in the calorstat of normal pressure, stands 24 hours crystallizes, will collect
To solid be placed in 60 DEG C of constant pressure and dries 24 hours and get final product, yield 81%, the sample obtained is carried out powder X-ray diffraction divides
Analysis, its diffracting spectrum as it is shown in figure 1, infrared spectrum as in figure 2 it is shown, Differential Scanning Calorimetry as shown in Figure 3.
Embodiment 2: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid,
4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mg N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases)
Acrylate-1-alkynyl) quinazoline-4-amine tosilate sample is dissolved completely in 4.0mL methanol, is placed in 40 DEG C of water-baths, makes
Sample is completely dissolved, and is positioned over 20 DEG C, relative humidity is 10%, in the calorstat of normal pressure, stands 24 hours crystallizes, will collect
To solid be placed in 60 DEG C of constant pressure and dries 24 hours and get final product, yield 78%, the sample obtained is carried out powder X-ray diffraction divides
Analysis, its diffracting spectrum is basic as it is shown in figure 1, infrared spectrum is basic as in figure 2 it is shown, Differential Scanning Calorimetry is basic such as Fig. 3 institute
Show, consistent with the qualification result of embodiment 1.
Embodiment 3: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid,
4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 1g N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-
1-alkynyl) quinazoline-4-amine tosilate sample is dissolved completely in 30.0mL methanol, is placed in 80 DEG C of water-baths, makes sample
Product are completely dissolved, and are positioned over 4 DEG C, relative humidity is 75%, in the calorstat of normal pressure, stands 24 hours crystallizes, collection obtained
Solid be placed in 60 DEG C of constant pressure and dries 24 hours and get final product, yield 82%, to obtain sample carry out powder x-ray diffraction analysis,
Its diffracting spectrum is basic as it is shown in figure 1, infrared spectrum basic as in figure 2 it is shown, Differential Scanning Calorimetry basic as it is shown on figure 3,
Consistent with the qualification result of embodiment 1.
Embodiment 4:N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases)
Acrylate-1-alkynyl) quinazoline-4-amine tosilate crystal formation inhibited proliferation to different people tumor cell line
Taking and be in one bottle of cell in good condition exponential phase of growth, add 0.05% tryptic digestive juice, digestion makes patch
Parietal cell comes off, and counts 2～4 × 104Individual/ml, makes cell suspension；Obtained cell suspension is inoculated on 96 orifice plates, 180 μ l/ holes,
Put constant temperature CO2Incubator is cultivated 24 hours；Add the test medicine of variable concentrations, 20 μ l/ holes, cultivate 72h；Add detection examination
Agent (CCK-8) detects after hatching 1-2h；With enzyme-linked immunosorbent assay instrument light absorption value in every hole at wavelength 450nm, and by following public affairs
Formula calculates cell inhibitory rate.IC50 is calculated after obtaining suppression ratio.Test medicine is N-(3-chloro-4-(3-fluoro Bian epoxide) benzene
Base)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynyl) quinazoline-4-amine tosilate crystal formation, compare medicine
For Lapatinib (Lapatinib) and N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepines
Phosphine-1-base) acrylate-1-alkynyl) quinazoline-4-amine p-methyl benzenesulfonic acid salt compound (being called for short KU004 tosilate), respectively process
To different tumor cell IC50Value the results are shown in Table 2.
The table 2 each test medicine IC to different people tumor cell50Value
As seen from the above table, the handkerchief that draws that novel crystal forms of the present invention is below comparison to the IC50 value of different tumor cells replaces
Buddhist nun, it is seen that the structure of novel crystal forms improves the pharmaceutically active of this compound, and is better than the effect of similar drugs on the market.
Embodiment 5: pharmacokinetic trial
With N-(3-chloro-4-(3-fluoro Bian epoxide) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) acrylate-1-alkynes
Base) quinazoline-4-amine tosilate and crystal formation of the present invention carry out pharmacokinetic trial for detection object, and result is shown in
Table 3.
Table 3 pharmacokinetic trial result
| Cmax(μg/mL) | Tmax | AUC | |
| Former compound | 5.878 | 6 | 65.335 |
| Crystal formation of the present invention | 8.049 | 6 | 88.845 |
As shown in Table 3, the blood drug level of crystal formation of the present invention is able to maintain that long period, and medicine relative to former compound
Time area under curve be substantially better than original compound, bioavailability is higher.
Embodiment 6: the medicine (tablet) for the treatment of excess proliferative disease of the present invention
Use the described novel crystal forms sterling of embodiment 1 preparation, add lactose, starch, low-substituted hydroxypropyl cellulose, crystallite
Cellulose, Pulvis Talci, magnesium stearate, Carboxymethyl cellulose sodium as preparing the adjunct ingredient of tablet, proportioning according to a certain percentage
Making the tablet that every content of dispersion is 100～500mg, tablet formulation ratio is shown in Table 4；
Table 4 tablet prepare formula
Lactose, starch, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose are mixed homogeneously with novel crystal forms sterling crude drug,
Adding 1% Carboxymethyl cellulose sodium solution appropriate, make soft material, granulation of sieving, the drying of wet grain, sieve granulate, adds stearic acid
Magnesium and Pulvis Talci mix homogeneously, tabletting, to obtain final product.
Embodiment 7: the medicine (capsule) for the treatment of excess proliferative disease of the present invention
Use the described novel crystal forms sterling of embodiment 2 preparation, add lactose, starch, low-substituted hydroxypropyl cellulose, crystallite
Cellulose, Pulvis Talci, magnesium stearate, Carboxymethyl cellulose sodium as preparing the adjunct ingredient of tablet, proportioning according to a certain percentage
Making the capsule product that each content of dispersion is 100～500mg, tablet formulation ratio is shown in Table 5；
Table 5 capsule prepare formula
Lactose, starch, microcrystalline Cellulose are mixed homogeneously with novel crystal forms sterling crude drug, adds 1% hydroxymethyl cellulose
Sodium solution is appropriate, makes wet grain and dries the granulate that sieves, adds magnesium stearate mix homogeneously, inserts capsule and prepares；Or do not use system
Grain step, and directly novel crystal forms sterling crude drug is mixed homogeneously with excipients, after sieving, it is directly loadable into capsule and prepares.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1.N-(3-chloro-4-(3-fluorinated benzyloxy) phenyl)-6-(3-(4-methyl isophthalic acid, 4-azepine phosphine-1-base) acrylate-1-alkynyl)
The crystal formation of quinazoline-4-amine tosilate, it is characterised in that use CuKαRadiation, the X-ray powder represented with 2 θ angles
Diffraction 5.58,5.92,7.64,8.24,8.48,8.96,9.84,11.54,12.00,12.95,13.98,14.22,15.04,
15.50、16.18、16.60、17.16、18.10、19.40、19.72、20.36、21.10、21.50、22.24、22.84、
23.38、23.94、24.42、24.96、25.62、25.98、26.56、27.36、27.74、28.82、29.47、32.22、
33.06、33.66、35.00、36.54、37.40、37.98、38.90、39.64、41.08、41.80、42.44、44.10、
45.62,47.32,48.49,51.78 have diffraction maximum.
2. N-(3-chloro-4-(3-fluorinated benzyloxy) phenyl)-6-(3-(a 4-methyl isophthalic acid, 4-azepine phosphine-1-base) acrylate-1-
Alkynyl) quinazoline-4-amine tosilate mixing crystal formation, it is characterised in that include described in the claim 1 of arbitrary proportion brilliant
Type.
3. mix crystal formation in preparation treatment excess proliferative disease medicine described in crystal formation described in claim 1 or claim 2
Application.
Application the most according to claim 3, it is characterised in that described excess proliferative disease is cancer or inflammation.
Application the most according to claim 4, it is characterised in that described cancer is breast carcinoma, gastric cancer, colon cancer, pulmonary carcinoma, skin
Matter cancer or ovarian cancer.
6. a treatment excess proliferative disease medicine, it is characterised in that include consolidating of crystal formation described in the claim 1 of effective dose
Body material and pharmaceutically acceptable excipient.
Treatment excess proliferative disease medicine the most according to claim 6, it is characterised in that described excess proliferative disease
For cancer or inflammation.
Treatment excess proliferative disease medicine the most according to claim 6, it is characterised in that it is tablet, capsule, ball
Agent, injection, slow releasing preparation medicine or controlled release preparation medicine.
Treatment excess proliferative disease medicine the most according to claim 6, it is characterised in that described excipient is moistening
Agent, dispersant, pH adjusting agent, antioxidant, filler, diluent, solubilizing agent, suspending agent, correctives, binding agent, disintegrating agent, ooze
Thoroughly press in regulator, flocculant, antiplastering aid, suspending agent, lubricant, emulsifying agent and preservative one or more.
10. the preparation method of crystal formation described in a claim 1, it is characterised in that with water for solvent 40 DEG C～80 DEG C of temperature
Lower by N-(3-chloro-4-(3-fluorinated benzyloxy) phenyl)-6-(3-(4-methyl isophthalic acid, 4-azepine phosphine-1-base) acrylate-1-alkynyl) quinoline
Oxazoline-4-amine tosilate sample is completely dissolved, in temperature 4 DEG C～20 DEG C, relative humidity 10%～75%, condition of normal pressure
Lower standing crystallize, it is thus achieved that described crystal formation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510051482.8A CN104558041B (en) | 2015-01-30 | 2015-01-30 | Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510051482.8A CN104558041B (en) | 2015-01-30 | 2015-01-30 | Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104558041A CN104558041A (en) | 2015-04-29 |
| CN104558041B true CN104558041B (en) | 2017-01-11 |
Family
ID=53075201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510051482.8A Active CN104558041B (en) | 2015-01-30 | 2015-01-30 | Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104558041B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101544609A (en) * | 2008-03-25 | 2009-09-30 | 上海艾力斯医药科技有限公司 | Crystallization form of 4-anilinoquinazoline derivatives |
| AU2010266725A1 (en) * | 2009-07-02 | 2012-02-23 | Newgen Therapeutics, Inc. | Phosphorus containing quinazoline compounds and methods of use |
-
2015
- 2015-01-30 CN CN201510051482.8A patent/CN104558041B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104558041A (en) | 2015-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101253176B (en) | Novel crystalline form of a pyridazino [4, 5-b] indole derivative | |
| RU2711077C2 (en) | Salts of epidermal growth factor receptor kinase | |
| RU2603138C1 (en) | Crystalline form of hidamide, method of its production and use | |
| EP3819298A1 (en) | Compound having trka inhibitory activity and pharmaceutical composition, for preventing or alleviating pain, containing same as active ingredient | |
| EP3279201A1 (en) | Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor | |
| CN104558040B (en) | Phosphorous substituted crystal formation of quinazoline derivant and its preparation method and application | |
| EP3613746B1 (en) | Compound of eoc315 mod.i crystal form and preparation method therefor | |
| CN104610364B (en) | Phosphorous substituted novel crystal forms of quinazoline derivant and its preparation method and application | |
| CN105566305B (en) | The polymorph and its preparation method and application of 4- (substituted anilinic) quinazoline derivant xylenesulfonate | |
| KR20230069983A (en) | Solid forms of CDK4 inhibitors | |
| CN104558041B (en) | Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form | |
| CA3089243A1 (en) | Crystal form targeting cdk4/6 kinase inhibitor | |
| CN104558043B (en) | Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form | |
| CN108440456B (en) | Co-crystal of orlistat and organic acid calcium and pharmaceutical composition containing co-crystal | |
| CN104558042B (en) | Phosphorous substituted novel crystal forms of quinazoline derivant and its preparation method and application | |
| US10722469B2 (en) | Method for preparing pharmaceutical composition comprising quinoline derivative or salt thereof | |
| US20210015817A1 (en) | Solid-state forms of abemaciclib, their use and preparation | |
| JP2022540466A (en) | amorphous umbularisib monotosylate | |
| CN106117199A (en) | The dihydroxy ethyl sulfonate of a kind of cell cycle protein dependent kinase inhibitor, its crystal form and preparation method thereof | |
| RU2198171C2 (en) | Novel crystalline modification of 5-fluoro-1-(tetrahydro-2-furyl)-uracil and complex compounds based on thereof exhibiting antitumor effect | |
| CN113956245A (en) | Crystalline forms of clainib and methods of use thereof | |
| CN116554111A (en) | Erlotinib co-amorphous material and preparation method and application thereof | |
| KR20230145030A (en) | Crystalline form of tegavivint, manufacturing method, and use thereof | |
| WO2023239945A1 (en) | Btological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5- yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan- 7-ol crystalline, phosphoric acid salt and its enantiomers | |
| CN104370810B (en) | Montelukast sodium compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |