CN104558042B - Phosphorous substituted novel crystal forms of quinazoline derivant and its preparation method and application - Google Patents
Phosphorous substituted novel crystal forms of quinazoline derivant and its preparation method and application Download PDFInfo
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- CN104558042B CN104558042B CN201510051797.2A CN201510051797A CN104558042B CN 104558042 B CN104558042 B CN 104558042B CN 201510051797 A CN201510051797 A CN 201510051797A CN 104558042 B CN104558042 B CN 104558042B
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Abstract
The present invention relates to field of compound preparation, novel crystal forms of more particularly to N (3 chloro 4 (3 fluoro Bian epoxide) phenyl) 6 (3 (4 methyl Isosorbide-5-Nitrae azepine phosphine, 1 bases) the third 1 alkynyl) 4 amine tosilate of quinazoline and its preparation method and application.The present invention passes through water and methanol, ethanol, normal propyl alcohol, isopropanol, acetone, acetonitrile, tetrahydrofuran or dioxane mixed solvent crystallization or employing grinding physics rotating crystal method as made by different ratio, and then obtain better N (3 chloro 4 (3 fluoro Bian epoxide) phenyl) 6 (3 (4 methyl 1 for the treatment of excess proliferative disease, 4 azepine phosphine, 1 base) the third 1 alkynyls) 4 amine tosilate novel crystal forms of quinazoline, not only increase the pharmaceutically active of the phosphorous substituted quinazoline derivant, and improve its bioavailability, compensate for the blank of its crystal formation drug research.
Description
Technical field
The present invention relates to crystal-form compound technical field, and in particular to the novel crystal forms of phosphorous substituted quinazoline derivant and
Its preparation method and application.
Background technology
N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 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, the compound is I receptor kinases inhibitor, be can be used for
The disease extremely related to protein kinase activity, such as cancer and inflammation in treatment mammal.
Chinese patent CN102711472A discloses a kind of phosphorous quinazoline derivant and its using method, including
N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -
4- amine tosilate, the patent describes various phosphorous quinazoline derivant preparation methoies in detail and which is excessively increasing
Function and effect in growing property disease.
Crystal formation is the solid matter state that medicine is present, and drug crystal forms research is exactly that medicine basic substance state is ground
Study carefully, only have the understanding for comparing adequately and comprehensively to chemicalses crystal form state, be possible to searching and be more appropriate to treatment disease
The drug crystal forms solid matter of disease.Drug crystal forms can affect the physicochemical property of medicine, directly affect clinical drug and play 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 to N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl-s
1- alkynyls) quinazoline -4- amine tosilate drug crystal forms relevant report so that the basic research of the medicine occurs empty
In vain.Also, N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynes
Base) also presence is certain not enough in terms of drug metabolism for quinazoline -4- amine tosilate, and bioavailability is not high.
The content 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 epoxides) phenyl) -6-
The novel crystal forms of (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate and its preparation side
Method and application so as to 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 epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynes
Base) quinazoline -4- amine tosilate crystal formation, its x-ray diffractogram of powder is basic as shown in figure 1, using CuKαRadiation,
There is diffraction maximum 19.78 ± 1.00 with the powder X-ray diffraction that 2 θ angles are represented.
Wherein, N- (3- chloro -4- (the 3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate disclosed in Chinese patent CN102711472A.
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 values (°) or d values ()；Diffraction maximum relative intensity：Peak height value (Height%) or peak area value (Area%).
The powder X-ray diffraction peak value of 1 novel crystal forms of the present invention of table
It should be understood that 2 θ values of X-ray powder diffraction figure can be varied 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 be changed according to the orientation of sample in test, its numerical value it is equally possible difference about 1 unit, 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, therefore XRPD traces (trace) intensity being included in the present invention is illustrative, is not meant for definitely comparing.
Preferably, the invention provides N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4
Azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formation, using CuKαRadiation, is represented with 2 θ angles
Powder X-ray diffraction have diffraction maximum 19.78 ± 0.80.
Preferably, the invention provides N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4
Azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formation, using CuKαRadiation, is represented with 2 θ angles
Powder X-ray diffraction have diffraction maximum 19.78 ± 0.50.
Preferably, the invention provides N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4
Azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formation, using CuKαRadiation, is represented with 2 θ angles
Powder X-ray diffraction have diffraction maximum 19.78 ± 0.20.
Preferably, the invention provides N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4
Azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formation, using CuKαRadiation, is represented with 2 θ angles
Powder X-ray diffraction have diffraction maximum 19.78 ± 0.10.
Additionally, the present invention is also analyzed to the novel crystal forms by infrared spectrum, wherein being carried out point using infrared spectrum
During analysis 3407,2961,2916,2869,2566,1618,1591,1578,1561,1531,1497,1446,1396,1374,
1338、1302、1255、1214、1157、1120、1077、1060、1031、1008、951、925、894、814、784、749、
710、680cm-1There is infrared spectrum characteristic peak in place, the tolerance of its middle infrared spectrum characteristic peak is ± 2cm-1, infrared spectrum
Figure is substantially as shown in Figure 2；
It should be understood that may have deviation that there is similar situation with X-ray powder diffraction figure numerical value, cited in infrared spectrum
Numerical value can not be construed to absolute value.
Present invention also offers a kind of N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 nitrogen
Miscellaneous phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate mixing crystal formations, comprising the of the present invention of arbitrary proportion
Novel crystal forms.
Novel crystal forms of the present invention with Lapatinib in the test of the Proliferation Ability of different human tumor cell lines, 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 epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine pair
Toluene fulfonate and crystal formation of the present invention carry out pharmacokinetic trial, as a result show, crystal formation of the present invention is dense up to peak
Existing compound is substantially better than in terms of degree and area under the drug-time curve, shows that crystal formation of the present invention has more preferable biological utilisation
Degree.
Based on this, the invention provides the N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl -
1,4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations or its mixing crystal formation treated in preparation
Application in degree proliferative disease medicine.
Preferably, the excess proliferative disease is cancer or inflammation.It is furthermore preferred that the cancer is breast carcinoma, stomach
Cancer, colon cancer, pulmonary carcinoma, cortical carcinoma or ovarian cancer.
The present invention also provides one kind and treats excess proliferative disease medicine, including crystal formation of the present invention or the institute of effective dose
State mixing crystal formation, and pharmaceutically acceptable excipient.
Effective dose of the present invention refers to the pharmacology agent dose that can reach therapeutical effect；The excipient is referred in medicine system
Additament in agent in addition to principal agent, alternatively referred to as adjuvant.Such as the adhesive in tablet, filler, disintegrating agent, lubricant；In
Wine, vinegar, medicine juice in pill agent etc.；Base portion in semi-solid preparation ointment, cream；Preservative in liquid preparation,
Antioxidant, correctivess, aromatic, cosolvent, emulsifying agent, solubilizing agent, osmotic pressure regulator, coloring agent etc. can be described as figuration
Agent, preferably, excipient of the present invention is wetting agent, dispersant, pH adjusting agent, antioxidant, filler, diluent, increasing
Solvent, suspending agent, correctivess, 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.
Preferably, the excess proliferative disease is cancer or inflammation.It is furthermore preferred that the cancer is breast carcinoma, stomach
Cancer, colon cancer, pulmonary carcinoma, cortical carcinoma or ovarian cancer.
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 the novel crystal forms, using water and the mixing of methanol mixed solvent, water and ethanol
Solvent, water and normal propyl alcohol mixed solvent, water and isopropyl alcohol mixed solvent 3, water and acetone mixed solvent, water and acetonitrile mixing are molten
Any one of agent, water and tetrahydrofuran mixed solvent, water and dioxane mixed solvent will at a temperature of 15 DEG C～60 DEG C
N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -
After 4- amine tosilate samples are completely dissolved, mixed solvent is removed with Rotary Evaporators and obtain the crystal formation.
Preferably, the preparation method of the novel crystal forms uses volume ratio water：Methanol is 1:1st, water：Ethanol is 1:2nd, water：
Normal propyl alcohol is 2:3rd, water：Isopropanol is 1:3rd, water：Acetone is 1:1st, water：Acetonitrile is 1:2nd, water：Tetrahydrofuran is 1:3 or water：Two
Six ring of oxygen is 1:4 mixed solvent is at a temperature of 15 DEG C～60 DEG C by N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6-
After (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are completely dissolved, use
Rotary Evaporators remove mixed solvent and obtain the crystal formation.
Preferably, the pressure of the Rotary Evaporators is -0.01Mpa；Preferably, the rotating speed of the Rotary Evaporators
For 90rpm；Preferably, the working time of the Rotary Evaporators is 30min；It is further preferred that the Rotary Evaporators
Pressure be -0.01Mpa, rotating speed be 90rpm, the working time be 30min.
Preferably, N- (3- chloro -4- (3- fluoro Bian epoxides) the phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphines -
1- yls) propyl- 1- alkynyl) mass volume ratio of quinazoline -4- amine tosilate samples and mixed solvent is 100mg:4mL-
8mL。
Present invention also offers the preparation method of another novel crystal forms, by N- (3- chloro -4- (3- fluoro Bian oxygen
Base) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate samples adopt
The crystal formation is obtained with grinding physics rotating crystal method；Wherein, the ratio of grinding media to material of the grinding physics rotating crystal method is 1:10-30:1, grinding
Rotating speed is 50-800r/min, and milling time is no less than 0.5h.
Preferably, the ratio of grinding media to material of the grinding physics rotating crystal method is 3:1-10:1；Preferably, grinding rotating speed is 200-
400r/min；Preferably, milling time is 1-8h.It is further preferred that the ratio of grinding media to material of the grinding physics rotating crystal method is 3:
1-10:1, grinding rotating speed is 200-400r/min, and milling time is 1-8h.
Preferably, 15min is often rotated in grinding, stop 2min.
From above technical scheme, the present invention by water and methanol, ethanol, normal propyl alcohol, isopropanol, acetone, acetonitrile, four
Hydrogen furan or dioxane mixed solvent crystallization or employing grinding physics rotating crystal method as made by different ratio, and then controlled
Treat excess proliferative disease better N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 nitrogen
Miscellaneous phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate novel crystal forms, not only increase the phosphorous substituted quinoline azoles
The pharmaceutically active of quinoline derivant, and its bioavailability is improve, compensate for the blank of its crystal formation drug research.
Description of the drawings
Fig. 1 shows N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepines
Phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations X-ray powder diffraction figure；
Fig. 2 shows N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepines
Phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations infrared spectrogram.
Specific embodiment
The invention discloses phosphorous substituted novel crystal forms of quinazoline derivant and its preparation method and application, this area skill
Art personnel can use for reference present disclosure, be suitably modified technological parameter realization.Specifically, all similar replacements and
Change 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,
Method described herein and application are modified in spirit and scope or suitably change and combine, realize and apply the present invention
Technology.
N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- that the present invention is provided
Base) propyl- 1- alkynyl) agents useful for same can be buied by market in quinazoline -4- amine tosilate crystal formations and preparation method thereof.
Wherein, used N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (and 4- methyl isophthalic acids, 4 azepine phosphines -
1- yls) propyl- 1- alkynyl) quinazoline -4- amine tosilate can buy from NewGen Therapeutics, Inc., also can make by the following method
It is standby to obtain：
By 450g (0.823mol) compound N-(3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine (shown in formula I, purchased from NewGen Therapeutics, Inc.), p-methyl benzenesulfonic acid
298g (1.731mol), adds solvent 4500ml (isopropanols：Water=10:1) in, mechanical agitation is heated to backflow, and reaction 10 is little
When, natural cooling cooling, solid is separated out, and after filtration, filter cake adds the beating of 2000ml methanol, is dried to constant weight, obtains after filtration
Yellow solid N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynes
Base) quinazoline -4- amine tosilate.
With reference to embodiment, the present invention is expanded on further.
Embodiment 1：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 6.0mL mixed solvents：Methanol volume ratio 1:1),
Solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystal formation described in 83mg, right
The crystal formation of acquisition carries out powder x-ray diffraction analysis, and its diffracting spectrum is as shown in figure 1, infrared spectrum is as shown in Figure 2.
Embodiment 2：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 8.0mL mixed solvents：Ethanol volume ratio 1:2),
Solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystal formation described in 85mg, right
The sample of acquisition carries out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is basic such as Fig. 2 institutes
Show, it is consistent with the qualification result of embodiment 1.
Embodiment 3：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 4.0mL mixed solvents：Isopropanol volume ratio 1:
3), solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystal formation described in 82mg,
Sample to obtaining carries out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is basic such as Fig. 2 institutes
Show, it is consistent with the qualification result of embodiment 1.
Embodiment 4：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 8.0mL mixed solvents：Normal propyl alcohol volume ratio 2:
3), solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystal formation described in 77mg,
Sample to obtaining carries out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is basic such as Fig. 2 institutes
Show, it is consistent with the qualification result of embodiment 1.
Embodiment 5：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 6.0mL mixed solvents：Acetone volume ratio 1:1),
Solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystal formation described in 78mg, right
The sample of acquisition carries out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is basic such as Fig. 2 institutes
Show, it is consistent with the qualification result of embodiment 1.
Embodiment 6：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 7.0mL mixed solvents：Acetonitrile volume ratio 1:2),
Solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystal formation described in 83mg, right
The sample of acquisition carries out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is basic such as Fig. 2 institutes
Show, it is consistent with the qualification result of embodiment 1.
Embodiment 7：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 6.0mL mixed solvents：Dioxane volume ratio
1:4), solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystalline substance described in 81mg
Type, the sample to obtaining carry out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is substantially as schemed
It is shown in 2, consistent with the qualification result of embodiment 1.
Embodiment 8：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
By 100mgN- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are dissolved in (water in 6.0mL mixed solvents：Tetrahydrofuran volume ratio
1:3), solvent is removed with Rotary Evaporators, pressure is -0.01Mpa, and rotating speed 90rpm, time are that 30min obtains crystalline substance described in 85mg
Type, the sample to obtaining carry out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is substantially as schemed
It is shown in 2, consistent with the qualification result of embodiment 1.
Embodiment 9：Prepare N- of the present invention (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids,
4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations
Weigh 5g N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) quinazoline -4- amine tosilate samples are placed in ball mill agate mortar, agate ball quality 30g, ball material
Than being about 6:1.Drum's speed of rotation is 400r/min, turns 15min and stops 2min, obtains crystal formation described in 3.8g in 120min samplings, right
The sample of acquisition carries out powder x-ray diffraction analysis, and its diffracting spectrum is basic as shown in figure 1, infrared spectrum is basic such as Fig. 2 institutes
Show, it is consistent with the qualification result of embodiment 1.
Embodiment 10：N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases)
Propyl- 1- alkynyl) inhibited proliferation of the quinazoline -4- amine tosilate crystal formations to different human tumor cell lines
Take in one bottle of cell in good condition exponential phase of growth, add 0.05% tryptic digestive juice, digestion to make 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 CO2Cultivate 24 hours in incubator；The test medicine of variable concentrations is added, 72h is cultivated in 20 μ l/ holes；Add detection examination
Detect after agent (CCK-8) incubation 1-2h；With light absorption value of the enzyme-linked immunosorbent assay instrument at the wavelength 450nm per hole, and press following public affairs
Formula calculates cell inhibitory rate.IC is calculated after obtaining suppression ratio50.Test medicine is N- (3- chloro -4- (3- fluoro Bian epoxides) benzene
Base) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate crystal formations, comparison medicine
For Lapatinib (Lapatinib) and N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepines
Phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine p-methyl benzenesulfonic acid salt compounds (abbreviation KU004 tosilate), it is each to process
To different tumor cell IC50Value the results are shown in Table 2.
IC of the 2 each test medicine of table to different human tumor cells50Value
As seen from the above table, novel crystal forms of the present invention to the IC50 values of different tumor cells be below compare drawing handkerchief replace
Buddhist nun, it is seen that the structure of novel crystal forms improves the pharmaceutically active of the compound, and better than the effect of similar drugs on the market.
Embodiment 11：Pharmacokinetic trial
With N- (3- chloro -4- (3- fluoro Bian epoxides) phenyl) -6- (3- (4- methyl isophthalic acids, 4 azepine phosphine -1- bases) propyl- 1- alkynes
Base) quinazoline -4- amine tosilate and crystal formation of the present invention carry out pharmacokinetic trial for detection object, as a result see
Table 3.
3 pharmacokinetic trial result of table
| Cmax(μg/mL) | Tmax | AUC | |
| Former compound | 5.878 | 6 | 65.335 |
| Crystal formation of the present invention | 10.259 | 6 | 97.335 |
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
When area under curve be substantially better than original compound, bioavailability is higher.
Embodiment 12：The medicine (tablet) for the treatment of excess proliferative disease of the present invention
The novel crystal forms sterling prepared using embodiment 1, addition Lactose, starch, low-substituted hydroxypropyl cellulose, crystallite
Cellulose, Pulvis Talci, magnesium stearate, Carboxymethyl cellulose sodium as the adjunct ingredient for preparing tablet, proportioning according to a certain percentage
Tablet of the every content of dispersion in 100～500mg is made, tablet formulation ratio is shown in Table 4；
Table 4 tablet prepares formula
Lactose, starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed homogeneously with novel crystal forms sterling crude drug,
Add 1% Carboxymethyl cellulose sodium solution appropriate, make soft material, granulation of sieving, wet grain drying, sieve granulate, adds stearic acid
Magnesium and Pulvis Talci mix homogeneously, tabletting, obtain final product.
Embodiment 13：The medicine (capsule) for the treatment of excess proliferative disease of the present invention
The novel crystal forms sterling prepared using embodiment 2, addition Lactose, starch, low-substituted hydroxypropyl cellulose, crystallite
Cellulose, Pulvis Talci, magnesium stearate, Carboxymethyl cellulose sodium as the adjunct ingredient for preparing tablet, proportioning according to a certain percentage
Capsule product of each content of dispersion in 100～500mg is made, tablet formulation ratio is shown in Table 5；
Table 5 capsule prepares formula
Lactose, starch, Microcrystalline Cellulose are mixed homogeneously with novel crystal forms sterling crude drug, 1% hydroxymethyl cellulose is added
Appropriate sodium solution, makes wet grain and dries the granulate that sieves, and adds magnesium stearate mix homogeneously, insertion capsule to be obtained；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 is obtained.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, 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 benzyloxies) phenyl) -6- (3- (4- methyl isophthalic acids, 4- azepine phosphine -1- bases) propyl- 1- alkynyl)
The crystal formation of quinazoline -4- amine tosilate, it is characterised in that its X- powder diffractogram as shown in Figure 1.
2. a kind of N- (3- chloro -4- (3- fluorinated benzyloxies) phenyl) -6- (3- (4- methyl isophthalic acids, 4- azepine phosphine -1- bases) propyl-s 1-
Alkynyl) quinazoline -4- amine tosilate mixing crystal formations, it is characterised in that including arbitrary proportion claim 1 described in it is brilliant
Type.
3. crystal formation described in claim 1 or mixing crystal formation described in claim 2 are in treatment excess proliferative disease medicine is prepared
Application.
4. application according to claim 3, it is characterised in that the excess proliferative disease is cancer or inflammation.
5. one kind treats excess proliferative disease medicine, it is characterised in that including effective dose claim 1 described in crystal formation or power
Profit requires to mix crystal formation described in 2, and pharmaceutically acceptable excipient.
6. it is according to claim 5 to treat excess proliferative disease medicine, it is characterised in that the excess proliferative disease
For cancer or inflammation.
7. it is according to claim 5 treatment excess proliferative disease medicine, it is characterised in that its dosage form be tablet, capsule,
Pill, injection, slow releasing preparation or controlled release preparation.
8. it is according to claim 5 to treat excess proliferative disease medicine, it is characterised in that the excipient is moistening
Agent, dispersant, pH adjusting agent, antioxidant, filler, diluent, solubilizing agent, suspending agent, correctivess, binding agent, disintegrating agent, ooze
Thoroughly in pressure regulator, flocculant, antiplastering aid, lubricant, emulsifying agent and preservative one or more.
9. the preparation method of crystal formation described in a kind of claim 1, it is characterised in that using water and methanol mixed solvent, water and second
Alcohol mixed solvent, water and normal propyl alcohol mixed solvent, water and isopropyl alcohol mixed solvent, water and acetone mixed solvent, water and acetonitrile are mixed
Any one of bonding solvent, water and tetrahydrofuran mixed solvent, water and dioxane mixed solvent is at a temperature of 15 DEG C～60 DEG C
By N- (3- chloro -4- (3- fluorinated benzyloxies) phenyl) -6- (3- (4- methyl isophthalic acids, 4- azepine phosphine -1- bases) propyl- 1- alkynyl) quinoline azoles
After quinoline -4- amine tosilate samples are completely dissolved, mixed solvent is removed with Rotary Evaporators and obtain the crystal formation.
10. the preparation method of crystal formation described in a kind of claim 1, it is characterised in that by N- (3- chloro -4- (3- fluoro benzyloxies
Base) phenyl) -6- (3- (4- methyl isophthalic acids, 4- azepine phosphine -1- bases) propyl- 1- alkynyl) quinazoline -4- amine tosilate samples adopt
The crystal formation is obtained with grinding physics rotating crystal method；Wherein, the ratio of grinding media to material of the grinding physics rotating crystal method is 1:10～30:1, grinding
Rotating speed is 50～800r/min, and milling time is no less than 0.5h.
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