OA12301A - Polymorphic forms/hydrates of N-Ä4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-ylÜ-acrylamide dihydrochloride. - Google Patents
Polymorphic forms/hydrates of N-Ä4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-ylÜ-acrylamide dihydrochloride. Download PDFInfo
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- OA12301A OA12301A OA1200200394A OA1200200394A OA12301A OA 12301 A OA12301 A OA 12301A OA 1200200394 A OA1200200394 A OA 1200200394A OA 1200200394 A OA1200200394 A OA 1200200394A OA 12301 A OA12301 A OA 12301A
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- OA
- OAPI
- Prior art keywords
- dihydrochloride
- morpholin
- chloro
- quinazolin
- fluorophenylamino
- Prior art date
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- APKCVDHNSCWOIP-UHFFFAOYSA-N CCC(CCCC(C)(C)CC(C)[U])N=O Chemical compound CCC(CCCC(C)(C)CC(C)[U])N=O APKCVDHNSCWOIP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
072307
Polymorphie forms/hydrates of N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]- acrylamide dihydrochloride
The N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-5 ylpropoxy)-quinazolin-6-yl]-acrylamide dihydrochloride of the formula:
(O
is a représentative of a new class of highly effectiveirréversible tyrosine kinase inhibitors of the EGF 10 receptor which, inter alia, is to be used for,thetreatment of different tumours (WO-97/38983) . Thepréparation of the corresponding free base is described inthe US Patent Application 60/109065 with the applicationdate of 19th November, 1998.
It is known that different polymorphie forms/hydrates ofan active material can hâve a strong influence on thestability, the solubility, the formulation properties andthe préparation of a médicament. 15 012301
Furthermore, different polymorphie forms/hydrates of anactive material can strongly influence the action itselfsince various take-up and distribution speeds in the bodycan hâve the resuit of different concentration of theactive material at the place of action and thus differentbiological actions are to be expected.
In the case of the préparation of the compound (I) fromthe free base, it has, surprisingly, been shown that thecompound (I) is able to form different polymorphieforms/hydrates. These differ clearly in their X-ray powderdiagrams, differential scanning calorimetry curves and thewater values measured according to the Karl Fischer methodand - less clearly - by their IR spectra.
In that the different polymorphie forms/hydrates of thecompound (I) can be clearly characterised by the mentionedphysical détermination processes, the above-mentioned factthat the appearance of unknown polymorphie forms/hydratesof an active material exercises a strong influence on thepréparation of a médicament, can be taken into account inthe case of the formulation of the médicament in questionand official conditions (e.g. the conditions of the FDA),according to which no médicaments can be marketed whichhâve been produced with the use of polymorphie forms/hydrates of an active material not clearlycharacterised by physical or Chemical parameters.
In the scope of relevant investigations, four different polymorphie forms/hydrates of the compound (I) hâve been prepared and characterised, namely, the form A with about 3 mole of water, the form B as polymorphie compound of the Üi2301 form A also with about 3 mole of water, the form H withabout 7 mole of water and the form M with about 1 mole ofwater.
The characterisation of the different forms A to M of thecompound (I) took place from their X-ray powder diagrams,differential scanning calorimetry diagrams and IR spectra,as well as by their water values determined according tothe Karl Fischer method and their elementary analysisvalues. The said diagrams and spectra are illustrated inthe drawings.
In detail are shown:
Figures la to IVa X-ray powder diagrams of the forms A, Band M of the compound (I);
Figures Ib to IVb differential scanning calorimetrydiagrams of the forms A, B, H and M of the compound (I)and
Figures le to IVc the IR spectra of the forms A, B, H andM of the compound (I) . ,
In the case of the préparation of the compound (I) fromthe free base and aqueous hydrochloric acid in a mixtureof 20 parts absolute éthanol and 1 part water, the form Mof the compound (I) results with about 1 mol water.
If the form M of the compound (I) is crystallised out from a mixture of 10 parts absolute éthanol and 1 Part water, the compound (I) is obtained in the form A with about 3 mol of water. In the case of the crystallising out of the form A of the compound (I) from water and subséquent 012301 suitable drying of the crystals obtained, there resuits acompound polymorphie to form A of the compound (I) whichis designated as form B and also contains about 3 mol ofwater.
The préparation of the compound (I) from the free base andhydrochloric acid in water leads, after suitable drying ofthe product, to the form B of the compound (I).
If the form B of the compound (I) is dissolved in absolutemethanol and the solvent allowed to evaporate at roomtempérature, the form H of the compound (I) resuits withabout 7 mole of water. The form H can also be obtained bycrystallisation of the forms A or B from IN hydrochloricacid and suitable drying of the crystals obtained.
As already mentioned, the different polymorphie forms/hydrates A, B, H and M of the compound (I) obtainedin reproducible ways clearly differ in their X-ray powderdiagrams and differential scanning calorimetry diagrams,as well as in the water values according to Karl Fischer,as well as less clearly in their IR spectra. A furtherdifférence between the various forms consists in adiffering stability towards the heating of the solidsubstance at 80°C or 150°C. In comparison to the forms Aor B, the form M proves to be the more stable form.
It is to be pointed out that in the préparation of thecompound (I) from the free base and hydrochloric acid,Products can also be obtained which, according to X-raypowder diagrams, are mixed forms of A and B and, like theforms A and B themselves, crystallise with a definitewater content of 3 mole of water. 012301
The different forms of the compound (I) according to theinvention are suitable in the same way as the compound (I)itself for use as irréversible tyrosine kinase inhibitorsand thus for the making available of médicaments for thetreatment of cancer, arteriosclerosis, restenosis,endometriosis and psoriasis.
The following Examples are to illustrate the invention inmore detail but in no way to limit.
Example 1
Préparation of N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]-acrylamidedihydrochloride form M. A 6 1 three-necked flask equipped wich a mechanicalstirrer, a reflux condenser and a dropping funnel issupplied with 300 g N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy) -quinazolin-6-yl] -acrylamide and4 1 abs. éthanol. With stirring, the suspension is heatedto 35°C. A mixture of 100 ml conc. hydrochloric acid and100 ml water is then added dropwise thereto within 30 sand the reaction mixture further heated to 74°C. At 40°C,a clear solution résulte, at about 50°C the solutionbecomes turbid and the crystallisation commences. Withstirring, one allows the reaction mixture to cool slowlyto room température and then cools further in an icebathfor 2 h to 2°C. The precipitated crystals are filtered offwith suction and dried in a circulating drying cabinet for40 h at 60°C. Thereafter, the product is carefully sievedthrough a 0.5 mm Kressner sieve. One obtains 314.2 g ofproduct. 012301
Water according to Karl Fischer: 2.84%.Elementary analysis: (C24H25C1FN5O3 x 2HC1 x H2O) c H N Cl F Cl (ion.) cale.: 49.97 5.07 12.14 18.44 3.29 12.29 found: 50.08 5.18 12.08 18.38 3.15 12.20
Example 2
Préparation of N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy) -quinazolin-6-yl]-acrylamidedihydrochloride form A A suspension of 120 g N-[4-(3-chloro-4-fluoro- phenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]acrylamide dihydrochloride form M and 300 ml of a mixtureof 10 parts abs. éthanol and 1 part of water (v/v) isheated, with stirring, to 75°C. The yellowish solution isfiltered through a folded filter and the filtrate slowlycooled with stirring. One further stirs for 3 h at roomtempérature and then for 2 h in an ice-bath. Theprecipitated product is filtered off with suction anddried for 3 h at 40°C and 36 h at 60 °C in a circulatingdrying cabinet. One obtains 10.7 g of product.
Water according to Karl Fischer: 8.82%.
Elementary analysis: (C24H25ClFN5O3 x 2HC1 x 3H2O) C H N Cl F Cl (ion.) cale.: 47.03 5.43 11.43 17.35 3.10 11.57 found: 47.05 5.30 11.47 17.50 2.98 11.53 012301
Example 3
Préparation of N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]-acrylamidedihydrochloride form B A Suspension of 250 g N-[4-(3-chloro-4-fluoro- phenylamino) -7- (3-morpholin-4-ylpropoxy)-quinazlon-6-yl]-acrylamide dihydrochloride form A in 2.6 1 water is -heated, with stirring, to 50°C. The slightly turbidsolution is sucked through a Büchner funnel (porosity a)and the filtrate cooled to room température withoutstirring. After standing overnight in a refrigerator at4°C, the precipitated product is filtered off withsuction, washed out with 100 ml water and dried in avacuum desiccator over calcium chloride at 20 mbar for 3days. The product obtained is sieved over a 1 mm Kresnersieve. One obtains 212.2 g of product.
Water according to Karl Fischer: 8.6%
Elementary analysis: (C24H25C1FN5O3 x 2HC1 x 3H2O) c H N Cl F Cl (ion.) cale.: 47.03 5.43 11.43 17.35 3.10 11.57 found: 47.28 5.35 11.50 17.47 2.94 11.32
Example 4
Préparation of N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy) -quinazolin-6-yl] -acrylamidedihydrochloride form H 2 g N- [4-(3-Chloro-4-fluorophenylamino)-7-(3-morpholin-4 ylpropoxy) -quinazolin-6-yl] -acrylamide dihydrochloride form B are dissolved in 80 ml abs. methanol at room température. The solution is filtered into a 012301 crystallisation dish and kept open under an extractor upto the complété évaporation of the solvent (7 days).Water according to Karl Fischer: 19.95%
Elementary analysis: (C24H25CIFN5O3 x 2HC1 x 7H20) C H N Cl F Cl (ion.) cale. : 42.08 6.03 10.22 15.53 2.77 10.35 found: 42.16 6.20 10.24 15.76 2.68 10.11
Example 5
N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-guinazolin-6-yl]-acrylamide dihydrochlorideform H
Form H can also be obtained as follows by crystallisationof form B from IN hydrochloric acid: A suspension of 1 g N-[4-(3-chloro-4-fluorophenyl-amino)- 7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]-acrylamidedihydrochloride form B and 20 ml IN hydrochloric acid isheated with stirring to 60 °C. One allows the filteredsolution to cool to room température with stirring andthen keeps it overnight in a refrigerator at -$°C. Theprecipitated product is filtered off with suction, washedout with a little water and, after comminution andtransférai into a crystallisation dish, dried for 2 daysat room température in the open dish in the air.
Example 6
Température stress experiments
For the investigation of the thermal stability, the solid forms A, B and M are heated in open test tubes (1: 110 mm, 012301
d: 5 mm) or in test tubes closed by means of a glass stampin an oïl bath at températures and for a period of time asgiven in the Table. Subseguently, the purity of theremaining products is investigated by means of HPLC 5 methods (column: LunaRP18 (25 x 0.46 cm); mobile phase:acetonitrilezmethanol: 0.02M aq. ammoniumacetate:triethylamine (55:5:40:0.05).
Température Stress Form HPLC Purity Start [rel%] Stress j Conditions HPLC Purity [rel%] A 99.28 7 d, 80°C 97.51 99.02 (s) 16 hr, 100°C, then 8 hr, 150°C 25.28 23.45 (s) B 99.77 7 d, 80°C 89.39 84.40 (s) 16 hr, 100°C, then 8 hr, 150°C 75.32 75.28 (s) M 99.49 8 d, 80°C 99.62 99.61 (S) 16 hr, 100°C, then 8 hr, 150°C 99.43 99.43 (s) (s): test tube with glass stamp 10
Claims (21)
1. Polymorphie forms/hydrates of N-[4-(3-chloro-4-fluorophenylamino) -7- (3-morpholin-4-ylpropoxy) -quinazolin-6-yl]-acrylamide dihydrochloride 5 corresponding to the following formula
(I)
2. Form A of the dihydrochloride according to Claim 1containing about 3 mol of water.
3. Form B of the dihydrochloride according to claim 1 as 10 polymorphie compound to form A according to Claim 2 also with about 3 mole of water. 1
4. Form H of the dihydrochloride according to Claim 1containing about 7 mole of water.
5. Form M of the dihydrochloride according to Claim 1 15 containing about 1 mole of water.
6. Form A of the dihydrochloride according to Claim 1and 2, characterised by diffraction peaks 2 Θ in the 012301 11 X-ray powder diagram at 8.7760°, 23.2083°, 28.8604°,37.2905° .
7. Form A of the dihydrochloride according to claim 6additionally characterised by a differential scanningcalorimetry diagram according to Fig. Ib.
8. Form B of the dihydrochloride according to claim 1and 3 as polymorphie compound of form A according toClaim 2, characterised by diffraction peaks 2 Θ inthe X-ray powder diagram at 11.0986°, 19.0075°, 25.5280°.
9. Form B of the dihydrochloride according to claim 8additionally characterised by a differential scanningcalorimetry diagram according to Fig. Ilb.
10. Form M of the dihydrochloride according to claim 1and 4, characterised by diffraction peaks 2 Θ in theX-ray powder diagram at 7.4267°, 12.0027°, 24.9997°,35.1642°. I
11. Form H of the dihydrochloride according to claim 10,additionally characterised by a differential scanningcalorimetry diagram according to Fig. Illb.
12. Form M of the dihydrochloride according to claim 1and 5, characterised by diffraction peaks 2 Θ in theX-ray powder diagram at 4.8985°, 9.7296°, 27.1578°,35.7101°. 012301 12
13. Form M of the dihydrochloride according to claim 12,additionally characterised by a differential scanningcalorimetry diagram according to Fig. IVb.
14. Process for the préparation of the form A of thedihydrochloride according to Claim 2 from the freebase N-[4-(3-chloro-4-fluorophenylamino)-7- (3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamidemade available in the usual way and aqueoushydrochloric acid, characterised in that the reactionis carried out in a mixture of 20 parts absoluteéthanol and 1 part of water for the formation of theform M and the formed form M is crystallised out froma mixture of 10 parts absolute éthanol and 1 part ofwater.
15. Process for the préparation of the form B of thedihydrochloride according to claim 3 as polymorphouscompound to form A according to claim 2, characterised in that the form A obtained accordingto Claim 14 is crystallised from water and thecrystals obtained are dried in suitable way. I
16. Process for the préparation of the form B of thedihydrochloride according to claim 3 as polymorphiecompound to form A according to claim 2 bypréparation of the dihydrochloride from the free baseN-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]-acrylamide made availablein usual known way and hydrochloric acid in water aswell as suitable drying of the dihydrochlorideobtained. 012301 13
17. Process for the préparation of the form H of thedihydrochloride according to Claim 4 by a) dissolvingin absolute éthanol of the form B obtained accordingto the process according to claim 15 or 16 andleaving the éthanol to evaporate at room températureor b) dissolving and crystallising of the form Aobtained according to claim 14 or of the form B _obtained according to claim 15 or 16 in or from INhydrochloric acid and suitable drying of the crystalsobtained.
18. Process for the préparation of the form M of thedihydrochloride according to claim 5 from the freebase N-[4-(3-chloro-4-fluorophenylamino)-7-{3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamidemade available in usual known manner and aqueoushydrochloric'acid, characterised in that the reactionis carried out in a mixture of 20 parts absoluteéthanol and 1 part of water.
19. Form A of the dihydrochloride according to laim 2obtainable according to the process according toclaim 14.
20. Form B of the dihydrochloride according to claim 3 aspolymorphie compound to form A according to claim 2obtainable according to the process according toclaim 15 or 16.
21. Form H of the dihydrochloride according to claim 4obtainable according to the process according toclaim 17 012301 14 22. 23 . Form M of the dihydrochloride according to claim 5obtainable according to the process according toClaim 18. Use of one of the dihydrochloride forms A, B, Hand/or M according to one of Claims 1 to 13 or 19 to22, possibly together with usual carriers oradjuvants, for the préparation of a médicament withirréversible tyrosine kinase inhibition action.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10031971A DE10031971A1 (de) | 2000-06-30 | 2000-06-30 | Polymorphe Formen/Hydrate von N-[4-(3-Chlor-4-fluor-phenylamino)-7-(3-morpholin-4-yl-propoxy)-chinazolin-6-yl]-acrylamid Dihydrochlorid, Verfahren zu ihrer Herstellung sowie die Verwendung derselben zur Herstellung von Medikamenten mit irreversibler Tyrosinkinasehemmwirkung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA12301A true OA12301A (en) | 2003-11-10 |
Family
ID=7647397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA1200200394A OA12301A (en) | 2000-06-30 | 2001-06-15 | Polymorphic forms/hydrates of N-Ä4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-ylÜ-acrylamide dihydrochloride. |
Country Status (39)
| Country | Link |
|---|---|
| US (1) | US20040034022A1 (fr) |
| EP (1) | EP1299363A1 (fr) |
| JP (1) | JP2004501902A (fr) |
| KR (1) | KR20030014403A (fr) |
| CN (1) | CN1438994A (fr) |
| AP (1) | AP2002002694A0 (fr) |
| AR (1) | AR031854A1 (fr) |
| AU (1) | AU2001283861A1 (fr) |
| BG (1) | BG107352A (fr) |
| BR (1) | BR0112082A (fr) |
| CA (1) | CA2412535A1 (fr) |
| CZ (1) | CZ20024037A3 (fr) |
| DE (1) | DE10031971A1 (fr) |
| DZ (1) | DZ3342A1 (fr) |
| EA (1) | EA005294B1 (fr) |
| EC (1) | ECSP024413A (fr) |
| EE (1) | EE200200714A (fr) |
| GT (1) | GT200100124A (fr) |
| HN (1) | HN2001000134A (fr) |
| HR (1) | HRP20021019A2 (fr) |
| HU (1) | HUP0300900A3 (fr) |
| IL (1) | IL152419A0 (fr) |
| IS (1) | IS6596A (fr) |
| MA (1) | MA26924A1 (fr) |
| MX (1) | MXPA03000101A (fr) |
| NO (1) | NO20026193L (fr) |
| NZ (1) | NZ522001A (fr) |
| OA (1) | OA12301A (fr) |
| PA (1) | PA8520801A1 (fr) |
| PE (1) | PE20020116A1 (fr) |
| PL (1) | PL365127A1 (fr) |
| SK (1) | SK17642002A3 (fr) |
| SV (1) | SV2002000517A (fr) |
| TN (1) | TNSN01090A1 (fr) |
| UA (1) | UA73588C2 (fr) |
| UY (1) | UY26803A1 (fr) |
| WO (1) | WO2002000630A1 (fr) |
| YU (1) | YU99802A (fr) |
| ZA (1) | ZA200209717B (fr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2005239878B9 (en) * | 2004-05-06 | 2010-01-07 | Warner-Lambert Company Llc | 4-phenylamino-quinazolin-6-yl-amides |
| DE102006000122A1 (de) * | 2006-03-17 | 2007-09-20 | Aug. Winkhaus Gmbh & Co. Kg | Schlüssel für einen Schließzylinder und Schließzylinder für einen solchen Schlüssel |
| JP6674027B2 (ja) * | 2015-12-25 | 2020-04-01 | シュアンチュー ファーマ カンパニー，リミティド | キナゾリン誘導体の結晶及びその調製方法 |
| JP6717947B2 (ja) * | 2015-12-25 | 2020-07-08 | シュアンチュー ファーマ カンパニー，リミティド | キナゾリン誘導体の結晶及びその調製方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL190489B1 (pl) * | 1996-04-12 | 2005-12-30 | Warner Lambert Co | Nieodwracalne inhibitory kinaz tyrozyny, kompozycja farmaceutyczna je zawierająca i ich zastosowanie |
| EE200100271A (et) * | 1998-11-19 | 2002-10-15 | Warner-Lambert Company | N-[4-(3-kloro-4-fluorofenüülamino)-7-(3-morfoliin-4-üülpropoksü)kinasoliin-6-üül]ak rüülamiid kui türosiinkinaaside pöördumatu inhibiitor |
-
2000
- 2000-06-30 DE DE10031971A patent/DE10031971A1/de not_active Withdrawn
-
2001
- 2001-06-15 HU HU0300900A patent/HUP0300900A3/hu unknown
- 2001-06-15 YU YU99802A patent/YU99802A/sh unknown
- 2001-06-15 US US10/312,173 patent/US20040034022A1/en not_active Abandoned
- 2001-06-15 UA UA2003010793A patent/UA73588C2/uk unknown
- 2001-06-15 PL PL01365127A patent/PL365127A1/xx not_active Application Discontinuation
- 2001-06-15 WO PCT/EP2001/006733 patent/WO2002000630A1/fr active IP Right Grant
- 2001-06-15 JP JP2002505378A patent/JP2004501902A/ja not_active Withdrawn
- 2001-06-15 NZ NZ522001A patent/NZ522001A/en unknown
- 2001-06-15 CZ CZ20024037A patent/CZ20024037A3/cs unknown
- 2001-06-15 IL IL15241901A patent/IL152419A0/xx unknown
- 2001-06-15 EP EP01962739A patent/EP1299363A1/fr not_active Withdrawn
- 2001-06-15 MX MXPA03000101A patent/MXPA03000101A/es unknown
- 2001-06-15 TN TNTNSN01090A patent/TNSN01090A1/fr unknown
- 2001-06-15 DZ DZ013342A patent/DZ3342A1/fr active
- 2001-06-15 AP APAP/P/2002/002694A patent/AP2002002694A0/en unknown
- 2001-06-15 OA OA1200200394A patent/OA12301A/fr unknown
- 2001-06-15 CN CN01811998A patent/CN1438994A/zh active Pending
- 2001-06-15 AU AU2001283861A patent/AU2001283861A1/en not_active Abandoned
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- 2001-06-15 KR KR1020027017829A patent/KR20030014403A/ko not_active Application Discontinuation
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- 2001-06-15 EA EA200300094A patent/EA005294B1/ru not_active IP Right Cessation
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