CN109369531A - A new crystal form of antitumor compound, its preparation method and composition containing the same - Google Patents
A new crystal form of antitumor compound, its preparation method and composition containing the same Download PDFInfo
- Publication number
- CN109369531A CN109369531A CN201811364094.5A CN201811364094A CN109369531A CN 109369531 A CN109369531 A CN 109369531A CN 201811364094 A CN201811364094 A CN 201811364094A CN 109369531 A CN109369531 A CN 109369531A
- Authority
- CN
- China
- Prior art keywords
- crystal forms
- novel crystal
- compounds
- preparation
- chemical compounds
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses antitumoral compounds of a kind of novel crystal forms and preparation method thereof and containing its composition.The compounds of this invention I; that is 1- (2- (bis- (2- chloroethyl) amino) ethylsulfonyl)-7- (trifluoromethyl)-2; 3; 4; the preparation method of the novel crystal forms of 5- tetrahydro-1H- benzo [b] azatropylidene-5- alcohol; chemical compounds I is dissolved in 5 to 6 times of n-butanol/pyridine mixed liquor; n-butanol/pyridine volume ratio is 9:1, is heated to flowing back, after dissolution; it is subsequently cooled to 35 ± 3 DEG C; heat preservation stands 5-6 hours, and crystallization, filtering is precipitated; room temperature in vacuo degree 0.04-0.05Mpa is 1-2 hours dry, obtains I novel crystal forms of above compound.The invention further relates to the pharmaceutical compositions containing above-mentioned crystal form and the chemical compounds I novel crystal forms to be applied in manufacture treatment anti-tumor drug.
Description
Technical field
The present invention relates to containing the pharmaceutical compositions of anti-tumor drug novel crystal forms a kind of, the preparation method of novel crystal forms and this is new
Crystal form is used to manufacture the application in the drug for the treatment of tumour.
Background technique
Cancer has become the big chronic disease for seriously endangering human health at present.Suffer from cancered people every year in the world according to statistics
Have 9,000,000, the patient for dying of cancer is 6,000,000, almost just there is a cancer death each second.Fall ill in China's cancer year people
Number is 1,200,000 or so, and the number for dying of cancer is up to 900,000 or more, and patient to be treated is more than 1,500,000, and has and rise year by year
Trend.Therefore cancer has become the second largest killer for being only second to cardiovascular disease.
Clinical treatment tumour is general to use operation, radiotherapy, the big therapy of chemotherapy three.Though embolic chemotherapy is more quick, control
More rate is very low, meanwhile, clinical research finds that anticancer drug used at present has very big deficiency, finds novel anticancer drug
Have become the hot spot of new drug research.
A kind of benzene such as flowering structure is disclosed in Chinese invention patent 201210445465.9 (authorization on April 9th, 2014)
And azatropylidene analog derivative:
In formula: the R1 are as follows: any one of the alkyl of C1-C4 that hydrogen, halogen, halogen replace；The R2 are as follows: oxygen or hydroxyl
Base；The R3 is any one of hydrogen, the alkyl of C1-C4, C1-C4 alkoxy, halogen, hydroxyl.
When R1 is trifluoromethyl, R2 is hydroxyl, when R3 is chlorine, entitled 1- (2- (bis- (2- chloroethyl) amino) ethyl of chemistry
Sulfonyl) -7- (trifluoromethyl) -2,3,4,5- tetrahydro -1H- benzo [b] azatropylidene -5- alcohol, i.e. chemical compounds I, chemical structural formula:
179.1 DEG C -180.5 DEG C of chemical compounds I fusing point；With good anti-tumor activity, especially human lung adenocarcinoma cell, human milk
Adenocarcinoma cell, gastric carcinoma cells have apparent inhibiting effect.
Summary of the invention
One object of the present invention discloses a kind of antitumoral compounds I of novel crystal forms.
Another object of the present invention discloses a kind of I preparation method of antitumoral compounds of novel crystal forms.
A further object of the present invention discloses I pharmaceutical composition of antitumoral compounds comprising a kind of novel crystal forms.
The invention also discloses a kind of application of I novel crystal forms of antitumoral compounds in manufacture treatment anti-tumor drug.
The content of present invention is specifically described now in conjunction with the purpose of the present invention.
The present invention provides a kind of antitumoral compounds I of novel crystal forms,
The crystal form X-ray powder diffraction characteristic absorption peak (2 θ) and D value see the table below, and error is ± 0.2, see Fig. 1.
Peak intensity is greater than 10 characteristic peak in map:
| 2θ | D value | I/I0 | |
| 1 | 4.8846(8) | 18.077(3) | 96.34 |
| 2 | 9.8203(19) | 8.9995(18) | 100.00 |
| 3 | 14.789(5) | 5.985(2) | 12.72 |
| 4 | 19.4409(15) | 4.5622(3) | 70.31 |
| 5 | 19.719(2) | 4.4986(5) | 28.27 |
| 6 | 23.373(2) | 3.8028(4) | 25.64 |
| 7 | 25.844(3) | 3.4446(4) | 13.70 |
| 8 | 26.400(3) | 3.3733(4) | 10.54 |
| 9 | 27.886(3) | 3.1969(3) | 10.28 |
All characteristic peaks:
The measurement of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allow to have one
Fixed reasonable error range, error range are ± 0.2 °.
Crystal compound I has following structure feature:
Chemical compounds I novel crystal forms be white crystalline powder, 165.6 DEG C -166.2 DEG C of fusing point；Purity (HPLC method) 99.8%.
Another object of the present invention, discloses the preparation method of novel crystal forms, and process includes: by chemical compounds I just
It is dissolved by heating in butanol and pyridine mixed solution, obtains the chemical compounds I of novel crystal forms by keeping the temperature to stand.
Particularly chemical compounds I is dissolved in the n-butanol/pyridine (volume ratio) of 9:1 of 5 to 6 times (mass/volume ratio),
It is heated to flowing back, after dissolution, is subsequently cooled to 35 ± 3 DEG C, heat preservation stands 5-6 hours, and crystallization, filtering, room temperature in vacuo degree is precipitated
0.04-0.05Mpa is 1-2 hours dry, obtains I novel crystal forms of above compound.This operation is that obtain above-mentioned novel crystal forms institute required
's.
Chemical compounds I used synthesizes, chemical structure matter according to the method that Chinese invention patent 201210445465.9 provides
Compose (Ms) confirmation, it was demonstrated that chemical structure is correct.
A further object of the present invention provides the pharmaceutical composition comprising chemical compounds I novel crystal forms.Medicine group of the invention
It is as follows to close object preparation: using standard and conventional technique, makes acceptable solid carrier knot on the compounds of this invention and galenic pharmacy
It closes, solid dosage forms, including tablet, discrete particles, capsule, sustained release tablets, sustained release pellet etc. is made.Solid carrier can be at least
A kind of substance can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent, adhesive, disintegrating agent and package
Agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, propylene glycol, polyoxyethylene sorbitan monoleate, dextrin, shallow lake
Powder, gelatin, cellulose substances such as methylcellulose, microcrystalline cellulose, low melt point paraffin, polyethylene glycol, mannitol, cocoa
Rouge etc..
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can be according to patient
The state of an illness, diagnosis the case where be specifically applied, the amount or concentration of compound used are in a wider range
It adjusts, the amount range of reactive compound is 1%~40% (weight) of composition.
The present invention also provides application of the chemical compounds I novel crystal forms in manufacture tumor.
External antitumor action:
Experimental method；Experimental material: laboratory sample, main agents, laboratory apparatus, cell strain；Experimental procedure: cell training
Feeding, mtt assay measurement etc. is consistent with the method that Chinese invention patent 201210445465.9 provides.
Experimental result is as follows:
To the IC of the tumour cell of in vitro culture50(μg/ml)
Stability test:
As a result: from 0-3 months under strong light, appearance, X- powder diffraction do not change the chemical compounds I of novel crystal forms, say
Bright stable crystal form, it is raw without trichite is turned, still keep original crystal form；In addition do not change in relation to substance, content, illustrate novel crystal forms
Have good stability, and is suitble to the manufacture and long term storage of pharmaceutical preparation.
Detailed description of the invention
Fig. 1 is the x-ray diffraction pattern of chemical compounds I novel crystal forms.
Specific embodiment
The present invention will be further explained with reference to the examples below, and professional and technical personnel in the field is made to better understand this
Invention.The examples are merely illustrative, and it is in no way meant to limit the scope of the invention in any way.
Chemical compounds I used in the present invention, i.e. 1- (2- (bis- (2- chloroethyl) amino) ethylsulfonyl) -7- (fluoroform
Base) -2,3,4,5- tetrahydro -1H- benzo [b] azatropylidene -5- alcohol, the side provided according to Chinese invention patent 201210445465.9
Method synthesis, purity 99.4% (HPLC normalization method).
Embodiment 1
Equipped with stirring, thermometer, condenser 1000ml reaction flask in, addition 100 g of compound, I (purity
99.4%), n-butanol/pyridine (9:1, volume ratio) of 550ml, is heated to flowing back, and after dissolution, is cooled to 35 ± 3 DEG C, keeps the temperature quiet
It sets 5.5 hours, crystallization is precipitated, filtering, room temperature in vacuo degree 0.04-0.05Mpa is 1.5 hours dry, white crystalline powder is obtained,
165.6 DEG C -166.2 DEG C of fusing point；Purity (HPLC method) 99.8%, i.e. I novel crystal forms of above compound.
The x-ray diffraction pattern of the crystalline powder is shown in attached drawing.Instrument model and determination condition: Rigaku D/max
2500 type diffractometers；CuKa 40Kv 100mA；2 θ scanning ranges: 0-50 °.
Embodiment 2
Tablet is prepared with following compositions:
Preparation process: the chemical compounds I of novel crystal forms, starch, Sodium carboxymethyl starch, magnesium stearate are pre-dried, and cross 100
Mesh is spare.First the supplementary product starch of recipe quantity, Sodium carboxymethyl starch, magnesium stearate, talcum powder are mixed well.By novel crystal forms
Chemical compounds I be added in the above-mentioned auxiliary material of mixing with being incremented by dilution method, each added-time mixes well 2-3 time, guarantee medicine and auxiliary material
It mixes well, crosses 20 meshes, dry 2h, dry particl cross 16 mesh sieves in 55 DEG C of ventilated drying ovens, are uniformly mixed, in tablet press machine
Upper tabletting.
Claims (4)
1. a kind of novel crystal forms of antitumoral compounds I,
It is characterized by: the crystal form of chemical compounds I uses CuKa ray to measure as characteristic X-ray powder, at following 2 θ angles of diffraction
With characteristic peak, the error of the 2 θ angles of diffraction is 0.2, and map has the 2 θ angles of diffraction and D value of following table；
Novel crystal forms are white crystalline powder, 165.6 DEG C -166.2 DEG C of fusing point.
2. a kind of preparation method of the antitumoral compounds of novel crystal forms described in claim 1, which is characterized in that according to following step
It is rapid to carry out: chemical compounds I to be dissolved in 5 to 6 times of n-butanol/pyridine mixed liquor, n-butanol/pyridine volume ratio is 9:1, heating
To reflux, after dissolution, 35 ± 3 DEG C are subsequently cooled to, heat preservation stands 5-6 hours, and crystallization, filtering, room temperature in vacuo degree is precipitated
0.04-0.05Mpa is 1-2 hours dry, obtains I novel crystal forms of above compound.
3. a kind of composition of the chemical compounds I containing novel crystal forms described in claim 1, which is characterized in that be the chemical combination of novel crystal forms
The composition of object I and one or more pharmaceutically acceptable carriers, excipient or diluent composition.
4. the composition of the antitumoral compounds of novel crystal forms according to claim 3, which is characterized in that it is oral preparation,
For treating breast cancer, lung cancer, gastric cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811364094.5A CN109369531A (en) | 2018-11-16 | 2018-11-16 | A new crystal form of antitumor compound, its preparation method and composition containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811364094.5A CN109369531A (en) | 2018-11-16 | 2018-11-16 | A new crystal form of antitumor compound, its preparation method and composition containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109369531A true CN109369531A (en) | 2019-02-22 |
Family
ID=65389002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811364094.5A Pending CN109369531A (en) | 2018-11-16 | 2018-11-16 | A new crystal form of antitumor compound, its preparation method and composition containing the same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109369531A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911118A (en) * | 2012-11-09 | 2013-02-06 | 天津商业大学 | Benzo-azepine type derivative and preparation method and purpose thereof |
-
2018
- 2018-11-16 CN CN201811364094.5A patent/CN109369531A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911118A (en) * | 2012-11-09 | 2013-02-06 | 天津商业大学 | Benzo-azepine type derivative and preparation method and purpose thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018220045B2 (en) | C-met modulator pharmaceutical compositions | |
| CN101243066B (en) | Delta and epsilon crystal forms of imatinib mesylate | |
| CN102086195B (en) | Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof | |
| RU2603138C1 (en) | Crystalline form of hidamide, method of its production and use | |
| EP1559715B1 (en) | N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n'-(5-methyl-3-isoxazolyl)urea salt in crystalline form | |
| CN107955019A (en) | A kind of salt form, crystal form and preparation method of EGFR inhibitor | |
| CN101691372A (en) | Citric acid alidenafil crystal form C and preparation method and application thereof | |
| TWI603968B (en) | A crystal of flumatinib mesylate, the preparation method and medical use thereof | |
| CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
| CN109369531A (en) | A new crystal form of antitumor compound, its preparation method and composition containing the same | |
| CN103058922A (en) | Crystal form of aromatic urea for antitumor drug and preparation method of crystal form | |
| CN105859691A (en) | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof | |
| CN109320456A (en) | Antitumor compound of new crystal form, its preparation method and composition containing the same | |
| WO2016101868A1 (en) | Β-crystalline form of naputinib tosylate, preparation method therefor and pharmaceutical composition containing same | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN112675171B (en) | VEGFR (vascular endothelial growth factor receptor) activity inhibiting compound pharmaceutical preparation and preparation method thereof | |
| CN105037345B (en) | Antitumoral compounds, preparation method and use | |
| EP4272741A1 (en) | Pharmaceutical composition of multi-target protein kinase inhibitors, and use thereof | |
| WO2024153053A1 (en) | Cdk inhibitor and crystal form of pharmaceutically acceptable salt thereof, and use thereof | |
| CN102796140A (en) | Phosphate-containing isoxazoline derivatives and their preparation method and use | |
| KR20230152118A (en) | Drug composition and its preparation method and use | |
| CN109438388A (en) | Novel crystal forms have blood sugar reducing function compound and preparation method and the composition containing it | |
| CN104829629B (en) | Thiophane simultaneously [2,3 c] pyridine derivate, Preparation Method And The Use containing sulfoamido | |
| CN102417514B (en) | Pyridine derivatives, preparation method thereof, and purpose thereof | |
| WO2023186031A1 (en) | Pharmaceutical composition of multi-target protein kinase inhibitor, use thereof, and method for preparing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |