ES2525670T3 - Tratamiento de tumores metastatizados - Google Patents
Tratamiento de tumores metastatizados Download PDFInfo
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- ES2525670T3 ES2525670T3 ES10186757.0T ES10186757T ES2525670T3 ES 2525670 T3 ES2525670 T3 ES 2525670T3 ES 10186757 T ES10186757 T ES 10186757T ES 2525670 T3 ES2525670 T3 ES 2525670T3
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- 206010061289 metastatic neoplasm Diseases 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract 2
- 208000037819 metastatic cancer Diseases 0.000 abstract 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 8
- 206010027476 Metastases Diseases 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 3
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 2
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 2
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 2
- 206010027457 Metastases to liver Diseases 0.000 description 2
- 206010027458 Metastases to lung Diseases 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108010055196 EphA2 Receptor Proteins 0.000 description 1
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 101150009958 FLT4 gene Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 101150048336 Flt1 gene Proteins 0.000 description 1
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101100066427 Homo sapiens FCGR1A gene Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 1
- 101150088608 Kdr gene Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 108700027649 Mitogen-Activated Protein Kinase 3 Proteins 0.000 description 1
- 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 1
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 101150045355 akt1 gene Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- PIQCTGMSNWUMAF-UHFFFAOYSA-N chembl522892 Chemical compound C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 PIQCTGMSNWUMAF-UHFFFAOYSA-N 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compuesto de estructura I, tautómero del compuesto, sal farmacéuticamente aceptable del compuesto, sal farmacéuticamente aceptable del tautómero, o una mezcla de los mismos,**Fórmula** en la que, A es un grupo de la siguiente estructura: en la que, R1 se selecciona de grupos alquilo de cadena lineal o ramificada que tienen desde 1 hasta 6 átomos de carbono, para su uso en un método de tratamiento de un cáncer metastatizado en un sujeto, en el que dicho sujeto padece cáncer de próstata y en el que se inhibe el crecimiento del tumor en el sujeto tras la administración del compuesto de estructura I, el tautómero del compuesto, la sal farmacéuticamente aceptable del compuesto, la sal farmacéuticamente aceptable del tautómero, o la mezcla de los mismos al sujeto.
Description
E10186757
09-12-2014
de tratamiento usando la prueba de Student-Newman Keul (SigmaStat, San Rafael, CA). Para los estudios de supervivencia, se usó la prueba de rangos logarítmicos para determinar la significación entre las curvas de supervivencia de los diversos grupos tratamiento frente a vehículo (Prism, San Diego, CA). Los ratones sacrificados con estados de salud normales a la terminación del estudio se consideraron supervivientes a largo plazo y se
5 censuraron en este análisis. Las diferencias se consideraron estadísticamente significativas a p < 0,05.
RESULTADOS
El compuesto 1 demuestra potente inhibición de la actividad cinasa de FLT3
Se sometió a prueba la especificidad del compuesto 1 frente a diversos paneles de RTK usando ensayos de unión competitiva de ATP con enzimas purificadas tal como se describió anteriormente. Se encontró que el compuesto 1
10 es altamente potente frente a FLT3 (1 nM) con actividad nanomolar frente a c-KIT (2 nM), VEGFR1/2/3 (10 nM); FGFR1/3 (8 nM); PDGFRβ (27 nM) y CSF-1R (36 nM) (véase la siguiente tabla). Para confirmar la selectividad frente a RTK de clase III, IV y V, se sometió a prueba el compuesto 1 frente a otras cinasas en las rutas de PI3K/Akt y MAPK(K) y se encontró que tiene actividad insignificante (CI50 > 10 µM) (véase la siguiente tabla).
Tabla. Actividad de 4-amino-5-fluoro-3-[6-(4-metilpiperazin-1-il)-1H-bencimidazol-2-il]quinolin-2(1H)-ona frente a 15 diversas RTK
- RTK
- CI50 (µM)
- FLT3
- 0,001
- c-KIT
- 0,002
- CSF-1R
- 0,036
- FGFR1
- 0,008
- FGFR3
- 0,009
- VEGFR1/Flt1
- 0,01
- VEGFR2/Flk1
- 0,013
- VEGFR3/Flt4
- 0,008
- PDGFRβ
- 0,027
- PDGFRα
- 0,21
- EGFR1
- 2
- c-MET
- >3
- EphA2
- 4
- TIE2
- 4
- IGFR1, HER2, PI-3K. Akt1/3, Raf, ERK-1/2, MEK, p38-α,β,γ
- >10
Los ensayos de RTK in vitro usados para preparar la tabla anterior se realizaron con diversas diluciones del compuesto 1 en presencia de enzimas purificadas y ATP tal como se describió anteriormente. Se incubaron los sustratos peptídicos fosforilados (1 µM) con anticuerpos anti-fosfoespecíficos marcados con europio y se detecto el
29
E10186757
09-12-2014
Tabla X. Resumen de la inhibición del crecimiento tumoral primario de 4T1 mediante el compuesto 1
- Dosis del compuesto 1
- Volumen tumoral medio (mm3) día 18 DE Tratado/Control día 18 % de inhibición máx. (día de estudio) Valor de p frente al vehículo
- vehículo (n=9)
- 2248 780
- 10 mg/kg (n=8)
- 1798 513 0,80 32 (d 11) 0,187
- 30 mg/kg (n=10)
- 1246 318 0,55 45 (d 18) 0,002
- 60 mg/kg (n=10)
- 1248 295 0,56 50 (d 11) 0,002
- 100 mg/kg (n=10)
- 624 184 0,28 74 (d 14) <0,001
- 150 mg/kg (n=9)
- 402 95 0,18 82 (d 18) <0,001
Tabla Y. Eficacia del compuesto 1 sobre la metástasis de pulmón e hígado espontáneo 4T1 tras 17 días de dosificación
- a) Metástasis de hígado
- b) Metástasis de pulmón
- Dosis del compuesto 1
- Incidencia N.º de Metástasis Media ± DE % de inhibición frente al vehículo Valores de p frente al vehículo Incidencia N.º de Metástasis Media ± DE % de inhibición frente al vehículo Valores de p frente al vehículo
- Vehículo (agua) (n=9)
- 8/9 18 ± 15 n/a n/d 9/9 27 ± 14 n/d n/d
- 10 mg/kg (n=8)
- 7/8 22 ± 32 0 0,810 8/8 36 ± 32 0 0,926
- 30 mg/kg (n=10)
- 6/10 3 ± 4 83 0,014 10/10 26 ± 26 0 0,926
- 60 mg/kg (n=10)
- 5/10 1 ± 1 94 0,002 10/10 24 ± 11 11 0,606
- 100 mg/kg (n=10)
- 1/10 4 ± 13 77 0,010 10/10 24 ± 30 13 0,756
- 150 mg/kg (n=9)
- 0/9 0 ± 0 100 0,002 5/10 2 ± 3 91 <0,001
5
En resumen, se confirmó la eficacia de la dosificación oral diaria del compuesto en el modelo de tumor de mama 4T1 murino en este experimento. Se observó la inhibición del crecimiento tumoral primario significativa tras 4 días de tratamiento. Las dosis del compuesto 1 de 30, 60, 100 y 150 mg/kg inhibió el crecimiento tumoral primario en un 45%, 50%, 74% y 82%, respectivamente. El tratamiento con el compuesto 1 dio como resultado la inhibición 10 significativa de las metástasis espontáneas de pulmón e hígado. Se inhibió completamente el número de metástasis de hígado mediante el nivel de dosis de 150 mg/kg y se redujo significativamente a las dosis de 30, 60 y 100 mg/kg. Se redujeron las metástasis de pulmón con significación estadística (91% de inhibición) al nivel de dosis de 150
35
Claims (1)
-
imagen1 imagen2
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US64756805P | 2005-01-27 | 2005-01-27 | |
US647568P | 2005-01-27 | ||
US66924505P | 2005-04-06 | 2005-04-06 | |
US669245P | 2005-04-06 | ||
US72205305P | 2005-09-29 | 2005-09-29 | |
US722053P | 2005-09-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2525670T3 true ES2525670T3 (es) | 2014-12-29 |
Family
ID=36741085
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES06733986T Active ES2374570T3 (es) | 2005-01-27 | 2006-01-27 | Tratamiento de tumores metastalizados. |
ES10186757.0T Active ES2525670T3 (es) | 2005-01-27 | 2006-01-27 | Tratamiento de tumores metastatizados |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES06733986T Active ES2374570T3 (es) | 2005-01-27 | 2006-01-27 | Tratamiento de tumores metastalizados. |
Country Status (23)
Country | Link |
---|---|
US (2) | US20060183750A1 (es) |
EP (2) | EP2301546B1 (es) |
JP (2) | JP5371246B2 (es) |
KR (1) | KR101387985B1 (es) |
CN (1) | CN103893181A (es) |
AT (1) | ATE526025T1 (es) |
AU (1) | AU2006208012B2 (es) |
BR (1) | BRPI0607285A2 (es) |
CA (1) | CA2596084A1 (es) |
CY (1) | CY1112570T1 (es) |
DK (1) | DK1845990T3 (es) |
ES (2) | ES2374570T3 (es) |
HK (1) | HK1155664A1 (es) |
IL (1) | IL184866A0 (es) |
MA (1) | MA29266B1 (es) |
MX (1) | MX2007009099A (es) |
NO (1) | NO20074360L (es) |
PL (2) | PL2301546T3 (es) |
PT (2) | PT2301546E (es) |
SG (1) | SG173317A1 (es) |
SI (1) | SI2301546T1 (es) |
TN (1) | TNSN07294A1 (es) |
WO (1) | WO2006081445A2 (es) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1313734E (pt) | 2000-09-01 | 2010-02-09 | Novartis Vaccines & Diagnostic | Derivados aza heterocíclicos e sua utilização terapêutica |
JP4613130B2 (ja) | 2002-08-23 | 2011-01-12 | ノバルティス バクシンズ アンド ダイアグノスティックス,インコーポレーテッド | ベンゾイミダゾールキノリノンおよびそれらの使用 |
KR101319122B1 (ko) * | 2005-05-13 | 2013-10-23 | 노파르티스 아게 | 약물 저항성 암을 치료하는 방법 |
US20110178097A1 (en) * | 2005-05-23 | 2011-07-21 | Novartis Ag | Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactic acid salts |
AR070924A1 (es) * | 2008-03-19 | 2010-05-12 | Novartis Ag | Formas cristalinas y dos formas solvatadas de sales del acido lactico de 4- amino -5- fluoro-3-(5-(4-metilpiperazin-1-il ) -1h- bencimidazol-2-il) quinolin -2-(1h) - ona |
US20120064008A1 (en) * | 2009-05-20 | 2012-03-15 | Bruce Zetter | Compositions for the treatment of metastatic cancer and methods of use thereof |
ES2707625T3 (es) * | 2010-04-16 | 2019-04-04 | Novartis Ag | Compuesto orgánico para su utilización en el tratamiento del cáncer de hígado |
KR20140023358A (ko) * | 2011-05-19 | 2014-02-26 | 노파르티스 아게 | 선양 낭성 암종의 치료에 사용하기 위한 4-아미노-5-플루오로-3-[6-(4-메틸피페라진-1-일)-1h-벤즈이미다졸-2-일]-1h-퀴놀린-2-온 |
IN2014DN05869A (es) * | 2012-01-31 | 2015-05-22 | Novartis Ag | |
KR102494647B1 (ko) * | 2016-07-14 | 2023-01-31 | 브리스톨-마이어스 스큅 컴퍼니 | 비시클릭 헤테로아릴 치환된 화합물 |
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US3663606A (en) * | 1966-06-21 | 1972-05-16 | Mitsui Toatsu Chemicals | Organic imino-compounds |
DE2363459A1 (de) | 1973-12-20 | 1975-06-26 | Basf Ag | Neue fluoreszierende chinolinverbindungen |
US4659657A (en) * | 1982-12-24 | 1987-04-21 | Bayer Aktiengesellschaft | Chromogenic and fluorogenic esters for photometric or fluorimetric determination of phosphatases or sulphatases |
US5073492A (en) * | 1987-01-09 | 1991-12-17 | The Johns Hopkins University | Synergistic composition for endothelial cell growth |
JPH0699497B2 (ja) | 1987-04-16 | 1994-12-07 | 富士写真フイルム株式会社 | 光重合性組成物 |
DE3932953A1 (de) * | 1989-10-03 | 1991-04-11 | Boehringer Mannheim Gmbh | Neue 2-bicyclo-benzimidazole, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
GB9108547D0 (en) | 1991-04-22 | 1991-06-05 | Fujisawa Pharmaceutical Co | Quinoline derivatives |
US5710158A (en) * | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
US5480883A (en) * | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
USRE37650E1 (en) * | 1991-05-10 | 2002-04-09 | Aventis Pharmacetical Products, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US5856115A (en) * | 1991-05-24 | 1999-01-05 | Fred Hutchinson Cancer Research Center | Assay for identification therapeutic agents |
EP1306095A3 (en) * | 1992-03-05 | 2003-06-25 | Board Of Regents, The University Of Texas System | Methods and compositions for targeting the vasculature of solid tumors |
JP3142378B2 (ja) | 1992-06-22 | 2001-03-07 | ティーディーケイ株式会社 | 有機el素子 |
US5981569A (en) * | 1992-11-13 | 1999-11-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease |
US5792771A (en) * | 1992-11-13 | 1998-08-11 | Sugen, Inc. | Quinazoline compounds and compositions thereof for the treatment of disease |
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2006
- 2006-01-27 JP JP2007553278A patent/JP5371246B2/ja not_active Expired - Fee Related
- 2006-01-27 BR BRPI0607285-2A patent/BRPI0607285A2/pt not_active IP Right Cessation
- 2006-01-27 DK DK06733986.1T patent/DK1845990T3/da active
- 2006-01-27 KR KR1020077019428A patent/KR101387985B1/ko not_active IP Right Cessation
- 2006-01-27 US US11/342,257 patent/US20060183750A1/en not_active Abandoned
- 2006-01-27 ES ES06733986T patent/ES2374570T3/es active Active
- 2006-01-27 EP EP10186757.0A patent/EP2301546B1/en not_active Revoked
- 2006-01-27 WO PCT/US2006/002979 patent/WO2006081445A2/en active Application Filing
- 2006-01-27 PL PL10186757T patent/PL2301546T3/pl unknown
- 2006-01-27 SI SI200631858T patent/SI2301546T1/sl unknown
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- 2006-01-27 CA CA002596084A patent/CA2596084A1/en not_active Abandoned
- 2006-01-27 MX MX2007009099A patent/MX2007009099A/es not_active Application Discontinuation
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- 2006-01-27 ES ES10186757.0T patent/ES2525670T3/es active Active
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- 2006-01-27 EP EP06733986A patent/EP1845990B1/en not_active Not-in-force
- 2006-01-27 CN CN201410121175.8A patent/CN103893181A/zh active Pending
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