CN101735156B - Poly-crystal L of erlotinib hydrochloride, preparation method and application thereof - Google Patents
Poly-crystal L of erlotinib hydrochloride, preparation method and application thereof Download PDFInfo
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- CN101735156B CN101735156B CN200810203067XA CN200810203067A CN101735156B CN 101735156 B CN101735156 B CN 101735156B CN 200810203067X A CN200810203067X A CN 200810203067XA CN 200810203067 A CN200810203067 A CN 200810203067A CN 101735156 B CN101735156 B CN 101735156B
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- amine hydrochlorate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000013078 crystal Substances 0.000 title abstract description 11
- 229960005073 erlotinib hydrochloride Drugs 0.000 title abstract 2
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 title abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 241000124008 Mammalia Species 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 4
- -1 3-ethynyl phenyl Chemical group 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 9
- 230000014509 gene expression Effects 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 3
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000013019 agitation Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000021463 dry cake Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002512 suppressor factor Substances 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel poly-crystal L of N-(3-acetenyl phenyl amino)-6,7-2(2-methoxy ethyoxyl)-4-quinazoline amine hydrochloride (erlotinib hydrochloride), which is characterized in that the poly-crystal L has an X-ray powder diffraction pattern of a characteristic peak represented by 5.6+-0.2, 10.8+-0.2, 12.2+-0.2, 12.9+-0.2, 16.1+-0.2, 16.7+-0.2, 18.3+-0.2, 20.8+-0.2, 21.2+-0.2, 21.4+-0.2, 22.3+-0.2, 23.2+-0.2 and 24.8+-0.2. The invention further discloses a preparation method for the poly-crystal L and the application for preparing medicine for curing excessive increment diseases of mammal.
Description
Technical field
The present invention relates to novel N-(the 3-ethynyl phenyl is amino)-6, the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate (sieve in distress is for Buddhist nun's hydrochloride), its preparation method with and the medicine of excessive appreciation disease in preparation treatment Mammals in application.
Background technology
The compound N of formula (1)-(the 3-ethynyl phenyl is amino)-6,7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate (general sieve in distress by name is for Buddhist nun's hydrochloride) is applicable to the excessive appreciation disease in the treatment Mammals, for example cancer.
N-(the 3-ethynyl phenyl is amino)-6 was disclosed in the embodiment 20 of WO96/30347 already; Preparation and this application of compound of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate; And the fusing point that specifically discloses this hydrochloride is 228-230 ℃, but this patent is not mentioned the crystal formation of this compound.This compound be Tyrosylprotein kinase for example EGF-R ELISA suppressor factor and can be used to treatment or prevention and Tyrosylprotein kinase EGF-R ELISA diseases associated for example; Like cancer, particularly nonsmall-cell lung cancer, colorectal carcinoma, intractable nonsmall-cell lung cancer, carcinoma of the pancreas, ovarian cancer, mammary cancer, neurospongioma, brain tumor or neck cancer.
In WO01/34574, disclose N-(the 3-ethynyl phenyl is amino)-6, two kinds of different polymorphics of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate are called polymorphic A and polymorph b, and the document is hereby incorporated by.Wherein specifically openly polymorphic A demonstrate and have 2 θ ° and be the X-ray powder diffraction collection of illustrative plates of the characteristic peak of 5.58,9.84,11.25,18.86,22.70,23.50,24.18,24.59,25.40 and 29.24 expressions, as shown in Figure 3; Polymorph b demonstrates to have 2 θ ° and is the X-ray powder diffraction collection of illustrative plates of characteristic peak of 6.26,12.48,13.39,16.96,20.20,21.10,22.98,24.46,25.14 and 26.91 expressions, as shown in Figure 4.
In the described two kinds of polymorphic kinds of WO01/34574, polymorph b is more stable than polymorphic A on thermodynamics, and polymorphic A has solubleness and the dissolution rate better than polymorph b.
In WO2004/072049, disclose N-(the 3-ethynyl phenyl is amino)-6, the third polymorphic of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is called polymorphic E, and the document is hereby incorporated by.Wherein specifically openly polymorphic E demonstrate and have 2 θ ° and be the X-ray powder diffraction collection of illustrative plates of the characteristic peak of 5.7,9.7,10.1,11.3,17.0,17.4,18.9,19.6,21.3,22.8,23.6,24.2,24.7,25.4,26.2,26.7 and 29.3 expressions, as shown in Figure 5.And the fusing point of open polymorphic E is 211-214 ℃.Polymorphic E stablizes more than polymorphic A on thermodynamics and has than better solubleness of polymorph b and dissolution rate.
Summary of the invention
First purpose of the present invention is to provide a kind of N-(the 3-ethynyl phenyl is amino)-6 of novelty; The polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate; It is characterized in that said polymorphic L demonstrates that to have 2 θ ° be the X-ray powder diffraction collection of illustrative plates of characteristic peak of 5.6 ± 0.2,10.8 ± 0.2,12.2 ± 0.2,12.9 ± 0.2,16.1 ± 0.2,16.7 ± 0.2,18.3 ± 0.2,20.8 ± 0.2,21.2 ± 0.2,21.4 ± 0.2,22.3 ± 0.2,23.2 ± 0.2 and 24.8 ± 0.2 expressions.
Wherein " ± 0.2 " is measuring error scope of permission.
N-of the present invention (the 3-ethynyl phenyl is amino)-6, the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is characterised in that its X-ray powder diffraction collection of illustrative plates has the characteristic peak of above-mentioned 2 θ ° expression, the approaching following numerical value of its relative intensity:
| 2θ° | Relative intensity |
| 5.6 | 100 |
| 10.8 | 24.8 |
| 12.2 | 5.3 |
| 12.9 | 3.6 |
| 16.1 | 7.4 |
| 16.7 | 5.6 |
| 18.3 | 22.4 |
| 20.8 | 10.5 |
| 21.2 | 7.1 |
| 21.7 | 11.0 |
| 22.3 | 6.7 |
| 23.2 | 8.3 |
| 24.8 | 14.1 |
The term here " approaching " is meant the uncertainty of relative intensity measure value.Those skilled in the art understand that the uncertainty of relative intensity depends on measuring condition very much.The relative intensity value can for example change in ± 30% scope or preferably in ± 10% scope, change.
Above-mentioned crystal polymorphic L has X-ray powder diffraction collection of illustrative plates shown in Figure 1.
Above-mentioned crystal polymorphic L can describe characteristic with its fusing point.So, N-of the present invention (the 3-ethynyl phenyl is amino)-6, the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is characterized in that fusing point is 250 ℃-253 ℃.
Second purpose of the present invention provides a kind of method for preparing above-mentioned crystal polymorphic L, and said method is included in and makes N-(the 3-ethynyl phenyl is amino)-6, the step of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate recrystallization in the aqueous hydrochloric acid.
The pH of said aqueous hydrochloric acid is preferably between 1-5.
This method can may further comprise the steps:
A) the reflux HCl aqueous solution and N-(the 3-ethynyl phenyl is amino)-6,7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is to form solution;
B) this solution is cooled to 80 ℃-0 ℃;
C) filter.
When through method for preparing, will obtain above-mentioned crystal polymorphic L.
The 3rd purpose of the present invention provides said N-(the 3-ethynyl phenyl is amino)-6, the application in the medicine of the excessive appreciation disease of the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate in preparation treatment Mammals.
Preferred described excessive appreciation disease is a cancer.
Preferred said cancer is nonsmall-cell lung cancer, colorectal carcinoma, intractable nonsmall-cell lung cancer, carcinoma of the pancreas, ovarian cancer, mammary cancer, neurospongioma, brain tumor or neck cancer.
N-according to the invention (the 3-ethynyl phenyl is amino)-6, the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is because its fusing point is higher, and is therefore more stable than known polymorphic A, B and E on thermodynamics.
Description of drawings
Fig. 1 is the X ray diffracting spectrum of the embodiment of the invention 1 gained polymorphic L;
Fig. 2 is the DSC collection of illustrative plates of the embodiment of the invention 1 gained polymorphic L;
Fig. 3 is the X ray diffracting spectrum of disclosed polymorphic A among the WO01/34574;
Fig. 4 is the X ray diffracting spectrum of disclosed polymorph b among the WO01/34574;
Fig. 5 is the X ray diffracting spectrum of disclosed polymorphic E among the WO2004/072049.
Embodiment
The concrete condition determination of X-ray powder diffraction is in following examples: adopt Bruker D8ADVANCE appearance to measure.Condition determination is following: CuKa 40Kv 40mA is a light source, 0.02 ° of step-length, and sweep velocity: 8 °/min, sweep limit: 3 °～80 °, room temperature.
Embodiment 1
With the pH about 30ml is the N-(the 3-ethynyl phenyl is amino)-6 of 3 the HCI aqueous solution and 0.5g, and 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate joins in the reaction kettle, under agitation reflux.Be cooled to 60 ℃, under this temperature, stir 1h, filter, obtain dry cake 0.41g.Desciccate is confirmed as polymorphic L with X-ray powder diffraction and DSC collection of illustrative plates.This polymorphic L demonstrates has the 2 θ ° of X-ray powder diffraction collection of illustrative plates for the characteristic peak of about 5.6,10.8,12.2,12.9,16.1,16.7,18.3,20.8,21.2,21.4,22.3,23.2 and 24.8 expressions, as shown in Figure 1.The fusing point that records this polymorphic L is 250 ℃-253 ℃.
With the pH about 20ml is the N-(the 3-ethynyl phenyl is amino)-6 of 1 the HCl aqueous solution and 0.5g, and 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate joins in the reaction kettle, under agitation reflux.Be cooled to 5 ℃, under this temperature, stir 1h, filter, obtain dry cake 0.38g.Desciccate is confirmed as polymorphic L with X-ray powder diffraction and DSC collection of illustrative plates.The fusing point that records this polymorphic L is 250 ℃-253 ℃.
With the pH about 50ml is the N-(the 3-ethynyl phenyl is amino)-6 of 5 the HCl aqueous solution and 0.5g, and 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate joins in the reaction kettle, under agitation reflux.Be cooled to 30 ℃, under this temperature, stir 1h, filter, obtain dry cake 0.35g.Desciccate is confirmed as polymorphic L with X-ray powder diffraction and DSC collection of illustrative plates.The fusing point that records this polymorphic L is 250 ℃-253 ℃.
Embodiment 4
With the pH about 40ml is the N-(the 3-ethynyl phenyl is amino)-6 of 2 the HCl aqueous solution and 0.5g, and 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate joins in the reaction kettle, under agitation reflux.Be cooled to 0 ℃, under this temperature, stir 1h, filter, obtain dry cake 0.35g.Desciccate is confirmed as polymorphic L with X-ray powder diffraction and DSC collection of illustrative plates.The fusing point that records this polymorphic L is 250 ℃-253 ℃.
Embodiment 5
With the pH about 30ml is the N-(the 3-ethynyl phenyl is amino)-6 of 4 the HCl aqueous solution and 0.5g, and 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate joins in the reaction kettle, under agitation reflux.Be cooled to 80 ℃, under this temperature, stir 1h, filter, obtain dry cake 0.36g.Desciccate is confirmed as polymorphic L with X-ray powder diffraction and DSC collection of illustrative plates.The fusing point that records this polymorphic L is 250 ℃-253 ℃.
Experimental example 1: the fusing point of measuring polymorphic L, E, A and B
N-(the 3-ethynyl phenyl is amino)-6, the fusing point of each crystal polymorphic L, E, A and the B of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is compiled through for example P.J.Haines; " Principlesof Thermal Analysis and Calorimetry ", Royal Society of Chemistry, Cambridge; UK; 2002) described expression scanning calorimetry mensuration, specific as follows: adopt NETZSCH TG209F1 to measure, condition determination is following: use alumina crucible; under nitrogen purging, with the temperature rise rate of 10 ℃/min, scan 280 ℃ from 20 ℃.
The DSC collection of illustrative plates of polymorphic L wherein of the present invention is as shown in Figure 2.
| Fusing point (T is initial)/[℃] | |
| Polymorphic L | 250-253 |
| Polymorphic E | 211-214 |
| Polymorphic A | 205-208 |
| Polymorph b | 227-231 |
Experimental example 2: the stability of research polymorphic L, E, A and B
Respectively polymorphic A, polymorph b, polymorphic E and polymorphic L are put into 60 ℃ thermostat container, placed 10 days, the stability of these crystal formations is studied through HPLC.
1, sample purity is measured
Chromatographic condition: use octadecylsilane chemically bonded silica to be weighting agent; With 50mM/L phosphate-buffered salt (regulating pH to 7.5 with sodium hydroxide) and methyl alcohol volume ratio is that the mixing solutions of 3:7 is as moving phase; Column temperature is 40 ℃; The detection wavelength is 254nm.Through internal mark method determination purity.
Respectively polymorphic A, polymorph b, polymorphic E and polymorphic L are configured to the solution of 2mg/mL with moving phase, respectively get 8 μ L and inject liquid chromatograph, the record color atlas.
2, samples contg is measured
The method of measuring method reference sample purity testing is measured with external standard method.
The above-mentioned stability of polymorphic L that experiment showed, is superior to polymorphic A, polymorph b, polymorphic E.
Claims (7)
- (1.N-the 3-ethynyl phenyl is amino)-6; The polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate; It is characterized in that said polymorphic L demonstrates that to have 2 θ ° be the X-ray powder diffraction collection of illustrative plates of characteristic peak of 5.6 ± 0.2,10.8 ± 0.2,12.2 ± 0.2,12.9 ± 0.2,16.1 ± 0.2,16.7 ± 0.2,18.3 ± 0.2,20.8 ± 0.2,21.2 ± 0.2,21.4 ± 0.2,22.3 ± 0.2,23.2 ± 0.2 and 24.8 ± 0.2 expressions.
- 2. N-according to claim 1 (the 3-ethynyl phenyl is amino)-6, the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is characterized in that, said 2 θ ° relative intensity is about following numerical value:
2θ° Relative intensity 5.6 100 10.8 24.8 12.2 5.3 12.9 3.6 16.1 7.4 16.7 5.6 18.3 22.4 20.8 10.5 21.2 7.1 21.7 11.0 22.3 6.7 23.2 8.3 24.8 14.1 - 3. N-according to claim 1 and 2 (the 3-ethynyl phenyl is amino)-6, the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is characterized in that, the fusing point of this polymorphic L is 250 ℃-253 ℃.
- 4. prepare each described N-among the claim 1-3 (the 3-ethynyl phenyl is amino)-6, the method for the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate is characterized in that this method comprises the steps:A) reflux aqueous hydrochloric acid and N-(the 3-ethynyl phenyl is amino)-6,7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate, to form solution, the pH value of said aqueous hydrochloric acid is 1 to 5;B) this solution is cooled to 80 ℃-0 ℃;C) filter.
- 5. each described N-among the claim 1-3 (the 3-ethynyl phenyl is amino)-6, the application in the medicine of the excess proliferative disease of the polymorphic L of 7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate in preparation treatment Mammals.
- 6. application according to claim 5 is characterized in that, described excess proliferative disease is a cancer.
- 7. application according to claim 6 is characterized in that, said cancer is nonsmall-cell lung cancer, colorectal carcinoma, intractable nonsmall-cell lung cancer, carcinoma of the pancreas, ovarian cancer, mammary cancer, neurospongioma, brain tumor or neck cancer.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810203067XA CN101735156B (en) | 2008-11-20 | 2008-11-20 | Poly-crystal L of erlotinib hydrochloride, preparation method and application thereof |
| PCT/CN2009/075015 WO2010057430A1 (en) | 2008-11-20 | 2009-11-18 | Polymorph form l of erlotinib, methods of preparation and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810203067XA CN101735156B (en) | 2008-11-20 | 2008-11-20 | Poly-crystal L of erlotinib hydrochloride, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101735156A CN101735156A (en) | 2010-06-16 |
| CN101735156B true CN101735156B (en) | 2012-07-04 |
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Country Status (2)
| Country | Link |
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| WO (1) | WO2010057430A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914068A (en) * | 2010-08-14 | 2010-12-15 | 浙江华海药业股份有限公司 | Novel crystal form of erlotinib alkali and preparation method thereof |
| CN103772298A (en) * | 2012-10-25 | 2014-05-07 | 鲁南制药集团股份有限公司 | Erlotinib hydrochloride polymorphic substance and preparation method thereof |
| WO2014118737A1 (en) | 2013-01-31 | 2014-08-07 | Ranbaxy Laboratories Limited | Erlotinib salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060154941A1 (en) * | 2005-01-12 | 2006-07-13 | Mai De Ltd. | Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion |
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| US7960545B2 (en) * | 2005-11-23 | 2011-06-14 | Natco Pharma Limited | Process for the prepartion of erlotinib |
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060154941A1 (en) * | 2005-01-12 | 2006-07-13 | Mai De Ltd. | Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion |
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| Publication number | Publication date |
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| WO2010057430A1 (en) | 2010-05-27 |
| CN101735156A (en) | 2010-06-16 |
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