EP1039910A1 - Verwendung von chinazoline derivaten als tyrosine kinase hemmer zur behandlung von dickdarmpolypen - Google Patents
Verwendung von chinazoline derivaten als tyrosine kinase hemmer zur behandlung von dickdarmpolypenInfo
- Publication number
- EP1039910A1 EP1039910A1 EP98956600A EP98956600A EP1039910A1 EP 1039910 A1 EP1039910 A1 EP 1039910A1 EP 98956600 A EP98956600 A EP 98956600A EP 98956600 A EP98956600 A EP 98956600A EP 1039910 A1 EP1039910 A1 EP 1039910A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- carbon atoms
- bromophenyl
- quinazolinyl
- alkyl
- 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.)
- Withdrawn
Links
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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to the use of certain quinazoline compounds in the treatment and inhibition of colonic polyps.
- FAP familial Adenomatous Polyps
- SAP sporadic adenomatous polyps
- APC The genetic basis for FAP has been linked to the presence of mutations in the APC gene. Similar APC mutations have been found in patients with sporadic polyps. Biochemically, the APC mutation occurs in conjunction with the increased expression of cyclooxygenase enzymes, particularly COX-2. These enzymes are essential for the production of prostenoids, (prostaglandin's; (PG's)) that mediate a number of functions in the bowel including motility, vascular tone, angiogenesis and mucosal protection. PG's are also purported to discourage apoptosis and this is proposed as an explanation for polyp formation.
- prostenoids prostaglandin's
- COX-2 cyclooxygenase enzymes
- COX inhibitors are predominantly NSAID's such as clinoril, sulindac, piroxicam and etodoloc, all of which appear to be equivalent in their action.
- NSAID therapy has been the development of serious side effects including peptic ulceration, and cholestatic hepatitis and renal papillary necrosis. Long term therapy with NSAIDs for the treatment of polyps is therefore considered to be impractical.
- COX-2 inhibitors have been shown to prevent this series of events.
- This invention provides a method of treating or inhibiting colonic polyps in a mammal in need thereof which comprises administering to said mammal a compound of formula 1:
- X is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1- 6 carbon atoms;
- R and Rj are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl;
- R 2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl;
- Y is a radical selected from the group consisting of
- the pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
- alkyl portion of the alkyl, alkoxy, carboalkoxy, carboalkyl, and alkanoylamino substituents include both straight chain as well as branched carbon chains, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n- pentyl or n-hexyl.
- Carboxy is defined as a -CO2H radical.
- Carboalkoxy of 2-7 carbon atoms is defined as a -CO 2 R" radical, where R" is an alkyl radical of 1-6 carbon atoms.
- Carboalkyl is defined as a -COR" radical, where R" is an alkyl radical of 1-6 carbon atoms.
- R is an alkyl radical of 1-6 carbon atoms.
- halogen refers to chlorine, bromine, iodine or fluorine.
- X is substituted, it is preferred that it is mono- , di- , or tri- substituted, with monosubstituted being most preferred.
- this invention covers the individual R and S entantiomers as well as the racemate with respect to such compound.
- preferred members include those in which R, R 1 , and R 2 are hydrogen; and those in which R, R 1 , and R 2 are hydrogen and X is phenyl either unsubstituted or monosubstituted with halogen or alkyl of 1-6 carbon atoms.
- R, R 1 , and R 2 are hydrogen; and those in which R, R 1 , and R 2 are hydrogen and X is phenyl either unsubstituted or monosubstituted with halogen or alkyl of 1-6 carbon atoms.
- One group of compounds within the invention are those wherein X is monosubstituted in the 3-position, preferably by a halogen, more preferably by bromine.
- R3 is preferably hydrogen, methyl, ethyl, phenyl, CO2H or CO2EL
- each R5 is independently hydrogen, phenyl, or alkyl of 1-6 carbon atoms
- R, Ri, R2, R3, X, and n are as defined above and R 4 is alkyl of 1-6 carbon atoms (preferably isobutyl).
- Y' is a radical selected from the group consisting of:
- each R'3 is independently alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms.
- a 5-nitro-anthranilonitrile of Formula 2 is heated at about 100°C with or without solvent containing an excess of dimethylformamide dimethyl acetal to furnish an amidine of Formula 3. Heating a solution of amidine 3 and the aniline 4 in acetic acid for 1 to 5 hours gives the 6-nitro- 4-anilinoquinazolines of Formula 5 .
- Representative compounds of this invention were evaluated in several standard pharmacological test procedures that showed that the compounds of this invention possess significant activity as inhibitors of protein tyrosine kinases, and are antiproliferative agents. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents.
- the test procedures used and results obtained are shown below.
- 4-choro-6-nitroquinazoline, 13, (Morley, JS. and Simpson,/. Chem.. Soc, 360 (1948)) is reduced to 6-amino-4- chloroquinazoline, 14, using a reducing agent such as sodium hydrosulfite in a two phase system consisting of tetrahydrofuran and water in the presence of a small amount of phase transfer catalyst.
- a reducing agent such as sodium hydrosulfite in a two phase system consisting of tetrahydrofuran and water in the presence of a small amount of phase transfer catalyst.
- the nitro group of 20 (prepared as in Flowsheet A) is reduced to the corresponding amino compound 21 using a palladium catalyst and a source of hydrogen which can be hydrogen itself or cyclohexene.
- a source of hydrogen which can be hydrogen itself or cyclohexene.
- Acylation of 21 with either an acid chloride of Formula 22 or a mixed anhydride of Formula 23 (which is prepared from the corresponding carboxylic acid) in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine or N-methyl morpholine gives the compounds of Formula 24.
- the ability of the compounds of this invention to treat or inhibit colonic polyps was demonstrated in an in vivo standard pharmacological test procedure as described below.
- the compound of Example 9 was evaluated in this procedure, which emulates familial adenomatous polyps (FAP) in humans, as a representative compound of this invention.
- the Min mouse used in this test procedure currently the best available model for FAP, is a strain which has lost both copies of the APC gene. These animals develop multiple intestinal polyps (Adenomas) that ultimately progress to form adenocarcinomas.
- the polyps that develop in Min mice express EGFR and have activated COX-2.
- NSAID's such as sulindac and etodoloc can reduce (but not eradicate) intestinal polyp formulation in these animals indicating that COX-2 and the ultimate production of PG's is likely responsible for these effects.
- Example 9 The compound of Example 9 was blended with a standard murine chow and animals were given ad libitum access to the food. Based on estimated food consumption, the compound of Example 9 was added at a concentration commensurate with animals ingesting 20 mg/kg/day. At day 30, 4 treated + 4 control (chow alone) animals were sacrificed and assessed for polyp number. All control animals had greater than 30 polyps in their bowel, while the treated animals had none. Identical results were observed at 60 days - when 15 animals/group were assessed. The control animals had greater than 30 (larger) polyps while the treated animals had none.
- the compounds of this invention may formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration.
- pharmaceutically acceptable carriers for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium.
- Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
- the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg.
- Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
- Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
- Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
- the preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred.
- active compounds may also be administered parenterally or intraperitoneally.
- Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringabiUty exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
- N'-(4-Amino-2-cyanophenyl)-N.N-dimethylformamidine A solution of 6.0 g (27.5 mmol) of N'-(2-cyano-4-nitrophenyl)-N,N- dimethylformamidine, 33.9 g (41.8 ml, 412.4 mmol) of cyclohexene, and 0.6 g of 10% Pd/C in 360 ml of methanol was refluxed for 4 hrs. The hot mixture was filtered through Celite.
- N-f4-r(3-Bromopheny amino1-6-quinazolinyll-2-butvnamide A solution of 3.0 g (11.8 mmol) of N-[3-cyano-4-[[(dimethylamino)- methylenejamino] phenyl]-2-butynamide and 2.23 g (12.98 mmol) of 3-bromo aniline in 18 ml of acetic acid was refluxed gently with stirring under nitrogen for 1 hr 15 min.. The mixture was cooled in an ice bath and a solid mass formed.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US96508497A | 1997-11-06 | 1997-11-06 | |
US965084 | 1997-11-06 | ||
PCT/US1998/023549 WO1999024037A1 (en) | 1997-11-06 | 1998-11-04 | Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1039910A1 true EP1039910A1 (de) | 2000-10-04 |
Family
ID=25509419
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98956600A Withdrawn EP1039910A1 (de) | 1997-11-06 | 1998-11-04 | Verwendung von chinazoline derivaten als tyrosine kinase hemmer zur behandlung von dickdarmpolypen |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP1039910A1 (de) |
JP (1) | JP2001522802A (de) |
KR (1) | KR20010031813A (de) |
CN (1) | CN1278176A (de) |
AR (1) | AR016415A1 (de) |
AU (1) | AU1308799A (de) |
BR (1) | BR9814116A (de) |
CA (1) | CA2306155A1 (de) |
HU (1) | HUP0004286A3 (de) |
IL (1) | IL135622A0 (de) |
NO (1) | NO20002166L (de) |
NZ (1) | NZ503991A (de) |
PL (1) | PL340800A1 (de) |
WO (1) | WO1999024037A1 (de) |
ZA (1) | ZA9810134B (de) |
Families Citing this family (147)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU783116B2 (en) * | 1999-08-12 | 2005-09-29 | Wyeth Holdings Corporation | NSAID and EFGR kinase inhibitor containing composition for the treatment or inhibition of colonic polyps and colorectal cancer |
US6432979B1 (en) | 1999-08-12 | 2002-08-13 | American Cyanamid Company | Method of treating or inhibiting colonic polyps and colorectal cancer |
US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
GB0309850D0 (en) | 2003-04-30 | 2003-06-04 | Astrazeneca Ab | Quinazoline derivatives |
MXPA05012939A (es) | 2003-05-30 | 2006-05-17 | Astrazeneca Uk Ltd | Procedimiento. |
GB0326459D0 (en) | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
AU2005239878B9 (en) | 2004-05-06 | 2010-01-07 | Warner-Lambert Company Llc | 4-phenylamino-quinazolin-6-yl-amides |
ATE501148T1 (de) | 2004-12-14 | 2011-03-15 | Astrazeneca Ab | Pyrazolopyrimidinverbindungen als antitumormittel |
WO2006071079A1 (en) * | 2004-12-29 | 2006-07-06 | Hanmi Pharm. Co., Ltd. | Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof |
DE602006018331D1 (de) | 2005-09-20 | 2010-12-30 | Astrazeneca Ab | 4-(1h-indazol-5-ylamino)chinazolinverbindungen als inhibitoren der erbb-rezeptortyrosinkinase zur behandlung von krebs |
ES2530438T3 (es) | 2006-09-12 | 2015-03-02 | Genentech Inc | Procedimientos y composiciones para el diagnóstico y tratamiento del cáncer de pulmón utilizando el gen de KIT o KDR como marcador genético |
EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
WO2008095847A1 (de) | 2007-02-06 | 2008-08-14 | Boehringer Ingelheim International Gmbh | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US20110104166A1 (en) | 2008-01-18 | 2011-05-05 | Stankovic Konstantina M | Methods and Compositions for Treating Polyps |
TWI472339B (zh) | 2008-01-30 | 2015-02-11 | Genentech Inc | 包含結合至her2結構域ii之抗體及其酸性變異體的組合物 |
EP2245026B1 (de) | 2008-02-07 | 2012-08-01 | Boehringer Ingelheim International GmbH | Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
JP5739802B2 (ja) | 2008-05-13 | 2015-06-24 | アストラゼネカ アクチボラグ | 4−(3−クロロ−2−フルオロアニリノ)−7−メトキシ−6−{[1−(n−メチルカルバモイルメチル)ピペリジン−4−イル]オキシ}キナゾリンのフマル酸塩 |
US8426430B2 (en) * | 2008-06-30 | 2013-04-23 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
EP2313397B1 (de) | 2008-08-08 | 2016-04-20 | Boehringer Ingelheim International GmbH | Cyclohexyloxy-substituierte heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
MY152068A (en) | 2009-03-20 | 2014-08-15 | Genentech Inc | Bispecific anti-her antibodies |
AR078986A1 (es) | 2009-11-12 | 2011-12-14 | Genentech Inc | Un metodo para promover la densidad de espinas dendriticas |
TW201129565A (en) | 2010-01-12 | 2011-09-01 | Hoffmann La Roche | Tricyclic heterocyclic compounds, compositions and methods of use thereof |
CN102892779B (zh) | 2010-02-18 | 2016-12-21 | 基因泰克公司 | 神经调节蛋白拮抗剂及其在治疗癌症中的用途 |
MX2012010265A (es) | 2010-03-17 | 2012-10-01 | Hoffmann La Roche | Compuestos de imidazopiridina, composiciones y metodos de uso. |
MX2012011887A (es) | 2010-04-16 | 2012-11-30 | Genentech Inc | Foxo 3a como biomarcador predictivo para la eficacia del inhibidor de la via de quinasa pi3k/akt. |
DK2612151T3 (en) | 2010-08-31 | 2017-10-02 | Genentech Inc | BIOMARKETS AND METHODS OF TREATMENT |
BR112013006016A2 (pt) | 2010-09-15 | 2016-06-07 | Hoffmann La Roche | compostos de azabenzotiazol, composições e métodos de uso |
BR112013011520A2 (pt) | 2010-11-19 | 2019-09-24 | Hoffmann La Roche | pirazolo piridinas e pirazolo piridinas e seu uso como inibidores de tyk2 |
WO2012085176A1 (en) | 2010-12-23 | 2012-06-28 | F. Hoffmann-La Roche Ag | Tricyclic pyrazinone compounds, compositions and methods of use thereof as janus kinase inhibitors |
WO2013007765A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Fused tricyclic compounds for use as inhibitors of janus kinases |
WO2013007768A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors |
RU2014105624A (ru) | 2011-08-12 | 2015-09-20 | Ф. Хоффманн-Ля Рош Аг | Соединения индазола, способ их применения и фармацевтическая композиция |
CN103890007A (zh) | 2011-08-17 | 2014-06-25 | 霍夫曼-拉罗奇有限公司 | 神经调节蛋白抗体及其用途 |
WO2013041539A1 (en) | 2011-09-20 | 2013-03-28 | F. Hoffmann-La Roche Ag | Imidazopyridine compounds, compositions and methods of use |
SG11201402510TA (en) | 2011-11-30 | 2014-06-27 | Genentech Inc | Erbb3 mutations in cancer |
JP2015514710A (ja) | 2012-03-27 | 2015-05-21 | ジェネンテック, インコーポレイテッド | Her3阻害剤に関する診断及び治療 |
KR20150118159A (ko) | 2013-02-22 | 2015-10-21 | 에프. 호프만-라 로슈 아게 | 암의 치료 방법 및 약물 내성의 예방 방법 |
KR20150123250A (ko) | 2013-03-06 | 2015-11-03 | 제넨테크, 인크. | 암 약물 내성의 치료 및 예방 방법 |
CN105980386B (zh) | 2013-03-13 | 2021-08-13 | 基因泰克公司 | 吡唑并化合物及其用途 |
US20140271634A1 (en) | 2013-03-14 | 2014-09-18 | The Regents Of The University Of California | Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use |
WO2014153030A2 (en) | 2013-03-14 | 2014-09-25 | Genentech, Inc. | Methods of treating cancer and preventing cancer drug resistance |
CN105339001A (zh) | 2013-03-15 | 2016-02-17 | 基因泰克公司 | 治疗癌症和预防癌症耐药性的方法 |
US9505767B2 (en) | 2013-09-05 | 2016-11-29 | Genentech, Inc. | Pyrazolo[1,5-A]pyrimidin-7(4H)-onehistone demethylase inhibitors |
TW201605857A (zh) | 2013-10-03 | 2016-02-16 | 赫孚孟拉羅股份公司 | Cdk8之醫療性抑制劑及其用途 |
CN105744954B (zh) | 2013-10-18 | 2021-03-05 | 豪夫迈·罗氏有限公司 | 抗rspo2和/或抗rspo3抗体及其用途 |
EP3083686B2 (de) | 2013-12-17 | 2023-03-22 | F. Hoffmann-La Roche AG | Verfahren zur krebsbehandlung unter verwendung von pd-1-achsen-bindenden antagonisten und taxanen |
EP3083687A2 (de) | 2013-12-17 | 2016-10-26 | F. Hoffmann-La Roche AG | Kombinationstherapie mit ox40-bindungsagonisten und pd-1-achsenbindungsantagonisten |
WO2015148531A1 (en) | 2014-03-24 | 2015-10-01 | Genentech, Inc. | Cancer treatment with c-met antagonists and correlation of the latter with hgf expression |
PL3126394T3 (pl) | 2014-03-31 | 2020-05-18 | F.Hoffmann-La Roche Ag | Przeciwciała anty-OX40 i sposoby stosowania |
AU2015241038A1 (en) | 2014-03-31 | 2016-10-13 | Genentech, Inc. | Combination therapy comprising anti-angiogenesis agents and OX40 binding agonists |
WO2016036873A1 (en) | 2014-09-05 | 2016-03-10 | Genentech, Inc. | Therapeutic compounds and uses thereof |
WO2016044694A1 (en) | 2014-09-19 | 2016-03-24 | Genentech, Inc. | Use of cbp/ep300 and bet inhibitors for treatment of cancer |
CN107912040B (zh) | 2014-10-10 | 2021-04-06 | 基因泰克公司 | 作为组蛋白脱甲基酶抑制剂的吡咯烷酰胺化合物 |
EP3215850B1 (de) | 2014-11-03 | 2019-07-03 | F. Hoffmann-La Roche AG | Tests zum nachweis von te-zell-immununtergruppen und verfahren zur verwendung davon |
SG11201703521UA (en) | 2014-11-03 | 2017-05-30 | Genentech Inc | Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment |
US20160152720A1 (en) | 2014-11-06 | 2016-06-02 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and tigit inhibitors |
JP6639497B2 (ja) | 2014-11-10 | 2020-02-05 | ジェネンテック, インコーポレイテッド | ブロモドメインインヒビターおよびその使用 |
MA40943A (fr) | 2014-11-10 | 2017-09-19 | Constellation Pharmaceuticals Inc | Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de bromodomaines |
MA40940A (fr) | 2014-11-10 | 2017-09-19 | Constellation Pharmaceuticals Inc | Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de bromodomaines |
SG11201703605QA (en) | 2014-11-17 | 2017-06-29 | Genentech Inc | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
JP6771464B2 (ja) | 2014-11-27 | 2020-10-21 | ジェネンテック, インコーポレイテッド | Cbpおよび/またはep300インヒビターとしての、4,5,6,7−テトラヒドロ−1h−ピラゾロ[4,3−c]ピリジン−3−アミン化合物 |
WO2016106340A2 (en) | 2014-12-23 | 2016-06-30 | Genentech, Inc. | Compositions and methods for treating and diagnosing chemotherapy-resistant cancers |
WO2016109546A2 (en) | 2014-12-30 | 2016-07-07 | Genentech, Inc. | Methods and compositions for prognosis and treatment of cancers |
WO2016112284A1 (en) | 2015-01-09 | 2016-07-14 | Genentech, Inc. | (piperidin-3-yl)(naphthalen-2-yl)methanone derivatives and related compounds as inhibitors of the histone demethylase kdm2b for the treatment of cancer |
WO2016112298A1 (en) | 2015-01-09 | 2016-07-14 | Genentech, Inc. | Pyridazinone derivatives and their use in the treatment of cancer |
WO2016112251A1 (en) | 2015-01-09 | 2016-07-14 | Genentech, Inc. | 4,5-dihydroimidazole derivatives and their use as histone demethylase (kdm2b) inhibitors |
WO2016123391A1 (en) | 2015-01-29 | 2016-08-04 | Genentech, Inc. | Therapeutic compounds and uses thereof |
JP6636031B2 (ja) | 2015-01-30 | 2020-01-29 | ジェネンテック, インコーポレイテッド | 治療用化合物およびその使用 |
MA41598A (fr) | 2015-02-25 | 2018-01-02 | Constellation Pharmaceuticals Inc | Composés thérapeutiques de pyridazine et leurs utilisations |
AU2016246695A1 (en) | 2015-04-07 | 2017-10-26 | Genentech, Inc. | Antigen binding complex having agonistic activity and methods of use |
IL295002A (en) | 2015-05-12 | 2022-09-01 | Genentech Inc | Therapeutic and diagnostic methods for cancer containing a pd–l1 binding antagonist |
PL3303632T5 (pl) | 2015-05-29 | 2023-07-03 | F. Hoffmann-La Roche Ag | Terapeutyczne i diagnostyczne sposoby stosowane w nowotworze |
CN107810011A (zh) | 2015-06-08 | 2018-03-16 | 豪夫迈·罗氏有限公司 | 使用抗ox40抗体治疗癌症的方法 |
CN107750164A (zh) | 2015-06-08 | 2018-03-02 | 豪夫迈·罗氏有限公司 | 使用抗ox40抗体和pd‑1轴结合拮抗剂治疗癌症的方法 |
JP6896650B2 (ja) | 2015-06-17 | 2021-06-30 | ジェネンテック, インコーポレイテッド | Pd−1軸結合アンタゴニスト及びタキサンを使用した局所進行性または転移性乳癌の治療方法 |
CN108026110B (zh) | 2015-08-26 | 2022-02-08 | 国家公共部门基金会卡洛斯三世国家癌症研究中心(F.S.P.Cnio) | 作为蛋白激酶抑制剂的稠合三环化合物 |
CN113956358A (zh) | 2015-09-25 | 2022-01-21 | 豪夫迈·罗氏有限公司 | 抗tigit抗体和使用方法 |
AU2016369528B2 (en) | 2015-12-16 | 2021-04-22 | Genentech, Inc. | Process for the preparation of tricyclic PI3K inhibitor compounds and methods for using the same for the treatment of cancer |
PL3400246T3 (pl) | 2016-01-08 | 2021-03-08 | F. Hoffmann-La Roche Ag | Sposoby leczenia nowotworów z dodatnim markerem cea z wykorzystaniem antagonistów wiążących oś pd-1 oraz przeciwciał dwuswoistych anty-cea/anty-cd3 |
JP6821693B2 (ja) | 2016-02-29 | 2021-01-27 | ジェネンテック, インコーポレイテッド | がんのための治療方法及び診断方法 |
WO2017180864A1 (en) | 2016-04-14 | 2017-10-19 | Genentech, Inc. | Anti-rspo3 antibodies and methods of use |
CA3019921A1 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
MX2018012493A (es) | 2016-04-15 | 2019-06-06 | Genentech Inc | Métodos para controlar y tratar el cáncer. |
JP2019518426A (ja) | 2016-04-15 | 2019-07-04 | ジェネンテック, インコーポレイテッド | がんの診断及び治療方法 |
CN109476641B (zh) | 2016-05-24 | 2022-07-05 | 基因泰克公司 | Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途 |
EP3464286B1 (de) | 2016-05-24 | 2021-08-18 | Genentech, Inc. | Pyrazolopyridinderivate zur behandlung von krebs |
EP3469099A1 (de) | 2016-06-08 | 2019-04-17 | F. Hoffmann-La Roche AG | Diagnose- und therapieverfahren für krebs |
WO2018027204A1 (en) | 2016-08-05 | 2018-02-08 | Genentech, Inc. | Multivalent and multiepitopic anitibodies having agonistic activity and methods of use |
WO2018029124A1 (en) | 2016-08-08 | 2018-02-15 | F. Hoffmann-La Roche Ag | Therapeutic and diagnostic methods for cancer |
KR20190072528A (ko) | 2016-10-06 | 2019-06-25 | 제넨테크, 인크. | 암에 대한 치료 및 진단 방법 |
CN110267678A (zh) | 2016-10-29 | 2019-09-20 | 霍夫曼-拉罗奇有限公司 | 抗mic抗体和使用方法 |
WO2018160841A1 (en) | 2017-03-01 | 2018-09-07 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
AU2018250875A1 (en) | 2017-04-13 | 2019-10-03 | F. Hoffmann-La Roche Ag | An interleukin-2 immunoconjugate, a CD40 agonist, and optionally a PD-1 axis binding antagonist for use in methods of treating cancer |
CA3073073A1 (en) | 2017-09-08 | 2019-03-14 | F. Hoffmann-La Roche Ag | Diagnostic and therapeutic methods for cancer |
US11369608B2 (en) | 2017-10-27 | 2022-06-28 | University Of Virginia Patent Foundation | Compounds and methods for regulating, limiting, or inhibiting AVIL expression |
MX2020004567A (es) | 2017-11-06 | 2020-08-13 | Genentech Inc | Metodos diagnosticos y terapeuticos para el cancer. |
CA3100200A1 (en) | 2018-05-21 | 2019-11-28 | Nanostring Technologies, Inc. | Molecular gene signatures and methods of using same |
US20200030443A1 (en) | 2018-06-23 | 2020-01-30 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor |
CN112839644A (zh) | 2018-07-18 | 2021-05-25 | 豪夫迈·罗氏有限公司 | 用pd-1轴结合拮抗剂、抗代谢物和铂剂治疗肺癌的方法 |
EP3847154A1 (de) | 2018-09-03 | 2021-07-14 | F. Hoffmann-La Roche AG | Carboxamid- und sulfonamidderivate zur verwendung als tead-modulatoren |
AU2019342099A1 (en) | 2018-09-19 | 2021-04-08 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
EP4249917A3 (de) | 2018-09-21 | 2023-11-08 | F. Hoffmann-La Roche AG | Diagnosemethoden für dreifach-negativen brustkrebs |
CA3116324A1 (en) | 2018-10-18 | 2020-04-23 | Genentech, Inc. | Diagnostic and therapeutic methods for sarcomatoid kidney cancer |
CN113396230A (zh) | 2019-02-08 | 2021-09-14 | 豪夫迈·罗氏有限公司 | 癌症的诊断和治疗方法 |
AU2020228383A1 (en) | 2019-02-27 | 2021-09-23 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-CD20 or anti-CD38 antibodies |
CA3131268A1 (en) | 2019-02-27 | 2020-09-03 | Epiaxis Therapeutics Pty Ltd | Methods and agents for assessing t-cell function and predicting response to therapy |
WO2020223233A1 (en) | 2019-04-30 | 2020-11-05 | Genentech, Inc. | Prognostic and therapeutic methods for colorectal cancer |
TW202108616A (zh) | 2019-05-03 | 2021-03-01 | 美商建南德克公司 | 用抗pd-l1抗體治療癌症之方法 |
CN112300279A (zh) | 2019-07-26 | 2021-02-02 | 上海复宏汉霖生物技术股份有限公司 | 针对抗cd73抗体和变体的方法和组合物 |
TW202124439A (zh) | 2019-09-04 | 2021-07-01 | 美商建南德克公司 | Cd8結合劑及其用途 |
PE20221110A1 (es) | 2019-09-27 | 2022-07-11 | Genentech Inc | Administracion de dosis para tratamiento con anticuerpos antagonistas anti-tigit y anti-pd-l1 |
JP2023511472A (ja) | 2019-10-29 | 2023-03-20 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | がんの治療のための二官能性化合物 |
WO2021092171A1 (en) | 2019-11-06 | 2021-05-14 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
KR20220101138A (ko) | 2019-11-13 | 2022-07-19 | 제넨테크, 인크. | 치료적 화합물 및 사용 방법 |
KR20220113790A (ko) | 2019-12-13 | 2022-08-16 | 제넨테크, 인크. | 항-ly6g6d 항체 및 사용 방법 |
TW202136276A (zh) | 2019-12-20 | 2021-10-01 | 美商艾瑞斯卡公司 | 三環吡啶酮及嘧啶酮 |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
EP4096646A1 (de) | 2020-01-27 | 2022-12-07 | Genentech, Inc. | Methoden zur behandlung von krebs mit einem antitigit-antagonistischen antikörper |
WO2021177980A1 (en) | 2020-03-06 | 2021-09-10 | Genentech, Inc. | Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist |
WO2021202959A1 (en) | 2020-04-03 | 2021-10-07 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2021222167A1 (en) | 2020-04-28 | 2021-11-04 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
KR20230025691A (ko) | 2020-06-16 | 2023-02-22 | 제넨테크, 인크. | 삼중 음성 유방암을 치료하기 위한 방법과 조성물 |
KR20230024368A (ko) | 2020-06-18 | 2023-02-20 | 제넨테크, 인크. | 항-tigit 항체 및 pd-1 축 결합 길항제를 사용한 치료 |
US11787775B2 (en) | 2020-07-24 | 2023-10-17 | Genentech, Inc. | Therapeutic compounds and methods of use |
EP4189121A1 (de) | 2020-08-03 | 2023-06-07 | Genentech, Inc. | Diagnostische und therapeutische verfahren für lymphom |
WO2022036146A1 (en) | 2020-08-12 | 2022-02-17 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
KR20230094198A (ko) | 2020-09-23 | 2023-06-27 | 에라스카, 아이엔씨. | 3환식 피리돈 및 피리미돈 |
KR20230082632A (ko) | 2020-10-05 | 2023-06-08 | 제넨테크, 인크. | 항-fcrh5/항-cd3 이중특이성 항체를 사용한 치료를 위한 투약 |
WO2022133345A1 (en) | 2020-12-18 | 2022-06-23 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
JP2024506339A (ja) | 2021-02-12 | 2024-02-13 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | がんの治療のための二環式テトラヒドロアゼピン誘導体 |
AU2022280025A1 (en) | 2021-05-25 | 2023-12-07 | Erasca, Inc. | Sulfur-containing heteroaromatic tricyclic kras inhibitors |
WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
TW202321261A (zh) | 2021-08-10 | 2023-06-01 | 美商伊瑞斯卡公司 | 選擇性kras抑制劑 |
TW202340212A (zh) | 2021-11-24 | 2023-10-16 | 美商建南德克公司 | 治療性化合物及其使用方法 |
WO2023097195A1 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic indazole compounds and methods of use in the treatment of cancer |
WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
TW202413433A (zh) | 2022-07-19 | 2024-04-01 | 美商建南德克公司 | 用抗fcrh5/抗cd3雙特異性抗體進行治療之給藥 |
WO2024033458A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydroazepine derivatives |
WO2024033389A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033457A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033388A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024085242A2 (en) | 2022-10-21 | 2024-04-25 | Kawasaki Institute Of Industrial Promotion | Non-fouling or super stealth vesicle |
WO2024091991A1 (en) | 2022-10-25 | 2024-05-02 | Genentech, Inc. | Therapeutic and diagnostic methods for multiple myeloma |
WO2024173842A1 (en) | 2023-02-17 | 2024-08-22 | Erasca, Inc. | Kras inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5760041A (en) * | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
-
1998
- 1998-11-04 JP JP2000520129A patent/JP2001522802A/ja active Pending
- 1998-11-04 WO PCT/US1998/023549 patent/WO1999024037A1/en not_active Application Discontinuation
- 1998-11-04 CN CN98810806A patent/CN1278176A/zh active Pending
- 1998-11-04 HU HU0004286A patent/HUP0004286A3/hu unknown
- 1998-11-04 PL PL98340800A patent/PL340800A1/xx unknown
- 1998-11-04 CA CA002306155A patent/CA2306155A1/en not_active Abandoned
- 1998-11-04 IL IL13562298A patent/IL135622A0/xx unknown
- 1998-11-04 BR BR9814116-3A patent/BR9814116A/pt not_active IP Right Cessation
- 1998-11-04 AU AU13087/99A patent/AU1308799A/en not_active Abandoned
- 1998-11-04 KR KR1020007004883A patent/KR20010031813A/ko not_active Application Discontinuation
- 1998-11-04 NZ NZ503991A patent/NZ503991A/en unknown
- 1998-11-04 EP EP98956600A patent/EP1039910A1/de not_active Withdrawn
- 1998-11-05 ZA ZA9810134A patent/ZA9810134B/xx unknown
- 1998-11-05 AR ARP980105592A patent/AR016415A1/es unknown
-
2000
- 2000-04-27 NO NO20002166A patent/NO20002166L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9924037A1 * |
Also Published As
Publication number | Publication date |
---|---|
KR20010031813A (ko) | 2001-04-16 |
BR9814116A (pt) | 2000-10-03 |
HUP0004286A2 (hu) | 2001-11-28 |
IL135622A0 (en) | 2001-05-20 |
WO1999024037A1 (en) | 1999-05-20 |
NO20002166D0 (no) | 2000-04-27 |
PL340800A1 (en) | 2001-02-26 |
ZA9810134B (en) | 2000-05-05 |
AR016415A1 (es) | 2001-07-04 |
HUP0004286A3 (en) | 2002-01-28 |
CN1278176A (zh) | 2000-12-27 |
AU1308799A (en) | 1999-05-31 |
JP2001522802A (ja) | 2001-11-20 |
CA2306155A1 (en) | 1999-05-20 |
NO20002166L (no) | 2000-06-28 |
NZ503991A (en) | 2001-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1039910A1 (de) | Verwendung von chinazoline derivaten als tyrosine kinase hemmer zur behandlung von dickdarmpolypen | |
EP0980244B1 (de) | Verwendung von chinazolin verbindungen zur behandlung von polyzystischer nierenkrankheit | |
JP3950337B2 (ja) | 悪性腫瘍治療薬 | |
US5760041A (en) | 4-aminoquinazoline EGFR Inhibitors | |
US5929080A (en) | Method of treating polycystic kidney disease | |
WO2016155545A1 (zh) | 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用 | |
JP2003507342A (ja) | 結腸ポリープおよび直腸結腸癌の処置または抑制のためのnsaidおよびegfrキナーゼインヒビターを含有する組成物 | |
JP4828142B2 (ja) | 新規な融合ピラゾリル化合物 | |
CN109574936B (zh) | 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 | |
WO2000047206A1 (en) | Use of pyrrolidine derivatives for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of obesity or appetite regulation | |
JP2010070514A (ja) | ピラゾール誘導体及びその医薬用途 | |
CN108503604B (zh) | (4-烷基-5-酰基-2-噻唑)腙衍生物及其医药用途 | |
CN103435561B (zh) | 一种新型d-氨基酸氧化酶抑制剂及其制备和应用 | |
US6323209B1 (en) | Method of treating or inhibiting colonic polyps | |
CN108047160B (zh) | 2-(2-苄亚肼基)-5-酰基噻唑及其医药用途 | |
US8513267B2 (en) | 4-anilinoquinazoline derivatives with adenosine-kinase inhibitor properties | |
MXPA00004304A (en) | Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps | |
WO2010083649A1 (zh) | 双芳基脲类衍生物及用途 | |
CN111909099B (zh) | 嘧啶腙衍生物及其制备方法与应用 | |
CZ20001660A3 (cs) | Farmaceutický prostředek | |
JPH10212235A (ja) | 抗腫瘍剤 | |
WO2008046242A1 (fr) | Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations | |
CN109836356B (zh) | 一种芳甲醚衍生物及其应用 | |
EP3630730B1 (de) | Polysubstituierte pyrimidine, die bildung von prostaglandin e2 hemmen, ein verfahren zu ihrer herstellung und ihre verwendung | |
EP2044937A1 (de) | Analgetische 5,9-methanocycloocta (b) pyridin-2(1h)-on-derivate, ihr herstellungsverfahren und verwendung |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20000417 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20000417;LT PAYMENT 20000417;LV PAYMENT 20000417;RO PAYMENT 20000417;SI PAYMENT 20000417 |
|
17Q | First examination report despatched |
Effective date: 20010808 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20040311 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1029055 Country of ref document: HK |