[go: up one dir, main page]

AU1308799A - Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps - Google Patents

Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps Download PDF

Info

Publication number
AU1308799A
AU1308799A AU13087/99A AU1308799A AU1308799A AU 1308799 A AU1308799 A AU 1308799A AU 13087/99 A AU13087/99 A AU 13087/99A AU 1308799 A AU1308799 A AU 1308799A AU 1308799 A AU1308799 A AU 1308799A
Authority
AU
Australia
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.)
Abandoned
Application number
AU13087/99A
Inventor
Philip Frost
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of AU1308799A publication Critical patent/AU1308799A/en
Abandoned legal-status Critical Current

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

WO 99/24037 PCT/US98/23549 -1 USE OF QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS FOR TREATING COLONIC POLYPS This invention relates to the use of certain quinazoline compounds in the 5 treatment and inhibition of colonic polyps. Colonic Polyps occur in both a familial pattern (Familial Adenomatous Polyps (FAP) and sporadically. FAP afflicts approximately 25,000 patients in the US; while it is estimated that sporadic adenomatous polyps (SAP) occur in approximately 2 million 10 people per year in the US alone. All these patients are at risk for developing adenocarcinoma of the colon. In the case of FAP, that risk is virtually 100% and these patients usually undergo a colectomy at an early age. Patients with sporadic polyps are treated with polypectomy and require periodic colonoscopic examination because of their inherent risk of developing recurrent polyps. In fact, parents and siblings of these 15 patients are also at increased risk for developing colorectal cancer. 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 20 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. The therapy of FAP and SAP has focused on inhibiting COX enzymes. 25 Considerable evidence exists for the efficacy of COX inhibitors in reducing polyp formation. These COX inhibitors are predominantly NSAID's such as clinoril, sulindac, piroxicam and etodoloc, all of which appear to be equivalent in their action. A major problem with NSAID therapy has been the development of serious side effects including peptic ulceration, and cholestatic hepatitis and renal papillary necrosis. Long 30 term therapy with NSAIDs for the treatment of polyps is therefore considered to be impractical. It has recently been proposed that the activation and overexpression of COX-2 in adenomatous polyps is due to activation of the epidermal growth factor receptor (EGFR). EGFR stimulation by one of it's ligands - amphiregulin (AR), induces the 35 nuclear targeting of COX-2, release of PG's and subsequent mitogenesis, in polarized WO 99/24037 PCT/US98/23549 -2 colonic epithelial cells. COX-2 inhibitors have been shown to prevent this series of events. DESCRIPTION OF THE INVENTION 5 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 H R
HN
"x YyN 0 R2 N R, 1 10 wherein: 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 15 6 carbon atoms; R and RI 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; 20 Y is a radical selected from the group consisting of RR3 R R 3 R3 R3 3 ~R 3 R3 3' 3 3 3 R 3
R
3
R
3
R
3 R3 R 3 R 3
R
3 R3 3R ' R 3 and
(CR
WO 99/24037 PCT/US98/23549 -3
R
3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; n = 2-4; or a pharmaceutically acceptable salt thereof, with the proviso that each R 3 of Y may be 5 the same or different. 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 10 known acceptable acids. The 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 15 pentyl or n-hexyl. Carboxy is defined as a -CO 2 H 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. When used herein the term halogen refers to chlorine, bromine, iodine or fluorine. When X is substituted, it is preferred that it is mono- , di- , or tri 20 substituted, with monosubstituted being most preferred. When a compound of this invention contains an assymetric center, this invention covers the individual R and S entantiomers as well as the racemate with respect to such compound. Of the compounds of this invention, preferred members include those in which 25 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. A further group of compounds within the invention are those wherein Y is 30 -CH=CH-CO2H, -CH=CH-CO2Et, -CH=C(Me)2, -CH=CH-Et, -CH=CH-CH3, -CH=CH-CH=CH-CH3, -CH=CH2, -CH=CH-Ph, -CH=CH-CH3 or 2-cyclo pentene. R3 is preferably hydrogen, methyl, ethyl, phenyl, CO2H or CO2Et.
WO 99/24037 PCT/US98/23549 -4 A process for the preparation of a compound of Formula 1 as defined above which comprises: a) reducing a 6-amino-4-anilinoquinazoline of Formula 6 wherein R, R 1, R2 and 5 X are as defined above R
HN
"
X
H
2 N N R2 Ri 6 6 with: 10 i) an acid chloride of Formula 7, wherein Y is as defined above 0 YO 7 CI 15 ii) a mixed anhydride of Formula 8, wherein Y is as defined above O OCOR4 8 or iii) a cyclic anhydride of Formula 11 wherein each R 5 is independently 20 hydrogen, phenyl, or alkyl of 1-6 carbon atoms O R0 11 0 b) reacting a compound of Formula 17 wherein R, R1, R2 and Y are as defined 25 above and Hal is any suitable halogen WO 99/24037 PCT/US98/23549 -5 R Hal H YyrN N V N' R2 R1 17 with an aniline of Formula 18 wherein X is as defined above
X-NH
2 5 18 or c) reacting a compound of Formula 24 wherein R, R 1, R2 and Y are as defined above R Y N CN O -- "1 R2 N N(CH 3
)
2
R
1 10 R, 24 with an aniline of Formula 25
H
2 N-X 25 15 wherein X is as defined above. The preparation of the compounds of this invention encompassed by Formula 9 is described below in Flowsheet A where R, RI, R 2 , R 3 , X, and n are as defined above 20 and R 4 is alkyl of 1-6 carbon atoms (preferably isobutyl). Y' is a radical selected from the group consisting of: WO 99/24037 PCT/US98/23549 -6
R
3 ' RR R3 'a 3
,R
3 3,/ a3 ' 3 R3- R'' R 3 R'z' 3
R'
3 R3 R33R SR3 R1 3 , Rand3 R1 3 R3 3 R3 R'3 (C(R' 23n wherein 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. According to the 5 sequence of reaction outlined in flowsheet A, a 5-nitro-anthranilonitrile of Formula 2 is heated at about 100 0 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. Reduction of the nitro group of 5 using a 10 reducing agent such as iron in an acetic acid-alcohol mixture at elevated temperature gives the 6-amino-4-anilinoquinazolines of Formula 6. Acylation of 6 with either an acid chloride of Formula 7 or a mixed anhydride of Formula 8 (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 triethylamine gives the compounds 15 of this invention represented by Formula 9. In those cases where 7 or 8 have an asymmetric carbon atom, they can be used as the racemate or as the individual R or S entantiomers in which case the compounds of this invention will be in the racemic or R and S optically active forms, respectively. The 5-nitro-anthranilonitriles of Formula 2 needed to prepare the compounds of this invention are either already known to the art or 20 can be prepared by procedures known in the art as detailed in the following references: Baudet, Recl.Trav.Chim.Pays-Bas, 43, 710 (1924); Hartmans, Recl.Trav.Chim.Pays Bas, 65, 468, 469 (1946) ; Taylor et al., J.Amer.Chem.Soc., 82, 6058,6063 (1960); Taylor et al., J.Amer.Chem.Soc., 82, 3152,3154 (1960); Deshpande; Seshadri, Indian J.Chem., 11 , 538 (1973); Katritzky, Alan R.; Laurenzo, Kathleen S., J.Org.Chem., 25 51 (1986); Niclas, Hans-Joachim; Bohle, Matthias; Rick, Jens-Detlev; Zeuner,Frank; Zoelch, Lothar, Z.Chem., 25(4), 137-138 (1985).
WO 99/24037 PCT/US98/23549 -7 FLOWSHEET A R R X-NH 2 0 2 N C N (CH 3 )2NCH(OCH3)2 0 2 N N 4 " N
CH
3
CO
2 H, R2
NH
2 DMF R2 N N(CH 3
)
2 CH3CO2, R1 R1 2 3 R HNX R HN- X O 2N N Fe H2N N
CH
3 CO2H, C2H50H R2 R2 N) R2 N
R
1 R1 5 6 00 or C
OCOR
4 H R HNX 7 8 Yr NN THF, pyridine, or (C2H5)3N OR2N R1 9 The preparation of the compounds of this invention encompassed by Formula 12 is described below in Flowsheet B wherein R, RI, R 2 , X, and n are described above. Each R 5 is independently hydrogen, phenyl, or alkyl of 1-6 carbon atoms. 5 According to the reaction outlined in Flowsheet B, the 6-amino-4-anilinoquinazolines of Formula 10 (prepared as in Flowsheet A) are acylated with a cyclic anhydride of Formula 11 in an inert solvent such as tetrahydrofuran in the presence of a basic catalyst such as pyridine or triethylamine.
WO 99/24037 PCT/US98/23549 -8 FLOWSHEET B 0 RS O (Z) Rs: R HN-X R5 R5 R5 H R HN ' X
H
2 N 10 NO2 -. z NN Hg 'N 11OH 02C/ R2 N THF, pyridine, or (C 2
H
5
)
3 N R2 R1 R1 10 12 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 5 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. The preparation of the compounds of this invention encompassed by Formula 10 19 is described below in Flowsheet C wherein Y', R4, and X are described above. According to the reactions outlined in Flowsheet C, 4-choro-6-nitroquinazoline, 13, (Morley, JS. and Simpson,J. 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 15 of phase transfer catalyst. Acylation of 14 with either an acid chloride of Formula 15 or a mixed anhydride of Formula 16 (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 17. In those cases where 15 or 16 have an asymmetric carbon atom, they can 20 be used as the racemate or as the individual R or S entantiomers in which case the compounds of this invention will be in the racemic or R and S optically active forms, respectively. Heating a compound of Formula 17 with an aniline of Formula 18, in a inert solvent such as isopropanol, gives the compounds of this invention represented by Formula 19. 25 WO 99/24037 PCT/US98/23549 -9 FLOWSHEET C CII 0 2 N N Na 2 S20 4 , (C 8
H
17
)
3
NCH
3 C H 2 N N THF, H20 N 14 13 Y O or OO CI
"OCOR
4 H
X-NH
2 15 16 Y'.<N N 18 .a I ) (CH 3
)
2 CHOH THF, pyridine, or N (CH3)2CHOH N-methyl morpholine 17 H NX y, H Y N N 0N 19 The preparation of the compounds of this invention encompassed by Formula 5 26 is described below in Flowsheet D wherein Y', R4, and X are described above. According to the reactions outlined in Flowsheet D, 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. Acylation of 21 with either an acid chloride of Formula 22 or a mixed anhydride of 10 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. In those cases where 22 or 23 have an asymmetric carbon atom, they can be used as the racemate or as the individual R or S entantiomers in which case the compounds of this invention WO 99/24037 PCT/US98/23549 -10 will be in the racemic or R and S optically active forms, respectively. Heating a compound of Formula 24 with an aniline of Formula 25, in a inert solvent such as acetic acid gives the compounds of this invention represented by Formula 26. FLOWSHEET D O0 2 N CN cyclohexene
H
2 N CN
C
3 0H, Pd/C N N(CH 3
)
2 CHOH, Pd/C N N(CH 3
)
2 20 21 00 Y' or Y- OY H Cl
OCOR
4 ,or O 22 23 .N N(CH 3
)
2 THF, pyridine, or (C 2
H
5
)
3 N 24
HN
-
.X
H
2 N-X H Y N N acetic acid N 5 26 The ability of the compounds of this invention to treat or inhibit colonic polyps 10 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 15 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 WO 99/24037 PCT/US98/23549 -11 ultimate production of PG's is likely responsible for these effects. The following briefly describes the procedure used and the results obtained in this standard pharmacological test procedure. 5 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 10 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. These data demonstrate that the compounds of this invention effectively inhibit 15 polyp formation in animals having mutations in their APC genes. Based on the results obtained in this standard pharmacological test procedure, the compounds of this invention are useful in treating or inhibiting the formation of colonic polyps. The compounds of this invention may formulated neat or may be combined with 20 one or more pharmaceutically acceptable carriers for administration. 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, 25 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. 30 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 35 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 WO 99/24037 PCT/US98/23549 - 12 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 5 proportionally reduced as indicated by the exigencies of the therapeutic situation. These 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, 10 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. 15 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. In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. 20 These 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 25 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. In all cases, the form must be sterile and 30 must be fluid to the extent that easy syringability 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 35 vegetable oils.
WO 99/24037 PCT/US98/23549 -13 The preparation of representative examples of the compounds of this invention is described below. Example 1 5 N'-(2-Cyano-4-nitrophenyl)-NN-dimethylformamidine A 40.8 g portion of 5-nitro-anthranilonitrile and 40 ml of N, N dimethylformamide dimethyl acetal were heated on a steam bath for 2 hours. The solvents were removed at reduced pressure and the residue was taken up in methylene 10 chloride. After passing this solution through Magnesol the solvent was removed. After washing with ether 50.8 g of N'-(2-cyano-4-nitrophenyl)-N,N-dimethyl formamidine was obtained. Example 2 15 N-(3-Bromophenvyl)-6-nitro-4-quinazolinamine A solution of 23.74 ml of 3-bromo aniline and 40.5 g N'-(2-cyano-4 nitrophenyl)-N,N-dimethylformamidine in 100 ml of glacial acetic acid was stirred and heated in an oil bath at 148 0 C for 1.5 hours. On cooling, filtration of the resulting solid 20 gives a quantitative yield of N-(3-bromophenyl)-6-nitro-4-quinazolinamine: mp = 267 270 0 C; mass spectrum (mle): 345. Example 3 N-(3-Bromophenvl)-4,6-quinazolindiamine 25 A mixture of 34.5 g of N-(3-bromophenyl)-6-nitro-4-quinazolinamine and 16.8 g of iron powder in 150 ml of ethanol and 150 ml of glacial acetic acid was heated in an oil bath at 120'C for 2 hours. After filtration of the solid, solid sodium carbonate was added to the filtrate giving a solid. This was filtered, and the solid was extracted with 30 methanol. The extracts were treated with charcoal and evaporated to a solid. After washing the solid with ether 27.5 g of N-(3-bromophenyl)-4,6-quinazolindiamine was obtained: mass spectrum (mle): 315.
WO 99/24037 PCT/US98/23549 - 14 Example 4 4-ff4-f(3-Bromophenyl)aminol-6-quinazolinyllaminol-4-oxo-(Z)-2-butenoic acid A 15 ml portion of pyridine was added to 1.6 g of N-(3-brominophenyl)-4,6 5 quinazolindiamine and 0.6 g of maleic anhydride. After stirring overnight, the solvents were removed on the rotary evaporator. The solid was taken up in about 400 ml of hot ethanol and the insoluble material filtered to give 0.33 g of 4-[[4-[(3 Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(Z)- 2 -butenoic acid: mass spectrum (mle): M+H 413, 415. 10 Example 5 4-_[4-[(3-Bromophenyl)aminol-6-quinazolinyllaminol- 4 -oxo-(E)- 2 -butenoic acid, ethyl ester 15 A solution of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 1.22 g of ethyl fumaryl chloride in 10 ml of methylene chloride was added dropwise. After stirring for 1.5 hours, the reaction was allowed to come to room temperature. The solvents were removed at reduced pressure 20 and the residue was treated with water. The red solid was filtered and extracted into hot acetone. After filtration of the insoluble material, the filtrate was concentrated to give 0.45 g of 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2 butenoic acid, ethyl ester: mp = 259-263oC, mass spectrum (mne): M+H 441, 443. 25 Example 6 N-[4- (3-Bromophenyl)aminol-6-quinazolinyll-3-methyl- 2 -butenamide A solution of 1.58 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.67 ml of 3,3-dimethylacryloyl 30 chloride in 7 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid was recrystallized from methyl cellusolve to give 0.97 g of N-[4 [(3-bromophenyl)amino]-6-quinazolinyl]-3-methyl-2-butenamide: mp = 300-301 0 C, mass spectrum (m/e): 396, 398. 35 WO 99/24037 PCT/US98/23549 -15 Example 7 N-4-[(3-Bromophenyl)aminol-6-quinazolinyll-(E)-2-butenamide A solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of 5 pyridine was cooled in an ice bath and a solution of 0.57 ml of trans-crotonoyl chloride in 6 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid recrystallized from n-butanol to give 0.69 g of N-[4-[(3 bromophenyl)amino]-6-quinazolinyl]-(E)- 2 -butenamide: mp = 153-160 0 C, mass 10 spectrum (m/e): M+H 383, 385. Example 8 N-[4(3-Bromophenyl)aminol-6-quinazolinyll-2-methyl-2-propenamide 15 A solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.59 ml of methacryoyl chloride in 6 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the 20 resulting solid was taken up in n-butanol (warming). Addition of ether to the cooled solution gives 0.44 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]- 2 -methyl- 2 propenamide: mp = 40-245 0 C, mass spectrum (m/e): M+H 383, 385. Example 9 25 N-[4-[(3-Bromophenyl)amino]-6-quinazolinyll-2-butynamide A solution of 0.50 g of 2-butynoic acid in 10 ml of tetrahydrofuran was cooled in an ice bath. A 0.79 ml portion of isobutyl chloroformate followed by a 0.66 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.6 g 30 of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The reaction was allowed to come to room temperature and stir overnight. The solvents were removed at reduced pressure and the solid was recrystallized from n-butanol to give 1.07 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide: mass spectrum (m/e): 381, 383. 35 WO 99/24037 PCT/US98/23549 - 16 Example 10 4-f4[(3-Bromophenyl)aminol-6-quinazolinyllamino- 4 -oxo-(E)- 2 -butenoic acid A 2.5 ml portion of 10 N aqueous sodium hydroxide was added to 2.3 g of 4-[[4-[(3 5 bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)- 2 -butenoic acid ethyl ester (Example 5) in 25 ml of ethanol. After stirring for an hour, 2.1 ml of concentrated hydrochloric acid was added, and the reaction was stirred an additional 2 hours. The resulting solid was recrystallized from n-butanol to give 0.97 g of 4-[[4-[(3 Bromophenyl)amino]-6-quinazolinyl]Iamino]- 4 -oxo-(E)- 2 -butenoic acid: mass spectrum 10 (m/e): M+H 413. Example 11 N-[4-(3-Bromophenyl)aminol-6-quinazolinyl-2,4-hexadienamide 15 A solution of 0.67g of 2,4-hexadienoic acid in 10 ml of tetrahydrofuran was cooled in an ice bath. A 0.79 ml portion of isobutyl chloroformate followed by a 0.66 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The 20 reaction was allowed to come to room temperature and stir overnight. The solvents were removed at reduced pressure and the solid was recrystallized to give 1.0 g of N [4-[(3-bromophenyl)amino]-6-quinazolinyl]-2,4-hexadienamide: mp = 258-260 0 C. 25 Example 12 N-[4-[(3-Bromophenyl)aminol-6-quinazolinyll-2-cyclopenteneamide A solution of 0.43 g of 2-cyclopenitenoic acid in 5ml of tetrahydrofuran was cooled in an ice bath. A 0.49 ml portion of isobutyl chloroformate followed by a 0.41 30 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The reaction was allowed to come to room temperature and stir overnight. Another 0.5 equivalents of mixed anhydride was added. The mixture was stirred for 5 hours. The solvents were removed at reduced pressure and the solid was purified by 35 WO 99/24037 PCT/US98/23549 - 17 chromatography on silica gel to give 0.30 g of N-[4-[(3-bromophenyl)amino]-6 quinazolinyl]-2-cyclopenteneamide: mass spectrum (mle): 409 (M+H, EI). Example 13 5 N-[4-[(3-Bromophenyl)amino-6-quinazolinyll-2-propenamide A solution of 2.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was cooled in an ice bath and a solution of 0.61 ml of acryoyl chloride in 30 ml of ether was added dropwise at 0 0 C. After stirring at room temperature for 3.5 10 hours, the solvents were removed at reduced pressure. The residue was purified by chromatography to give 0.2 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2 propenamide: mass spectrum (m/e): M+H 369. 15 Example 14 N-[4-f(3-Bromophenyl)amino]l-6-quinazolinvl]l-(3-phenvl-2-propvnamide) A solution of 0.93 g of 3-phenyl-2-propynoic acid in 10ml of tetrahydrofuran was cooled in an ice bath. A 0.82 ml portion of isobutyl chloroformate followed by a 20 0.69 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 7 ml of pyridine was added. The reaction at 0OC for 1 hr.. The solvents were removed at reduced pressure and the solid was purified by chromatography on silica gel to give 0.01 g of N-[4-[(3 bromophenyl)amino]-6-quinazolinyl]-(3-phenyl-2-propynamide): mass spectrum (m/e): 25 443.2, 445.2 (M+H, electrospray). Example 15 6-amino-4-chloroquinazoline 30 A mixture consisting of 3.25 g of 4-chloro-6-nitroquinazoline, 10.8 g of sodium hydrosulfite, and 0.3 g of the phase transfer catalyst (C 8
H
17
)
3
NCH
3 + Cl- in 97 ml of tetrahydrofuran and 32 ml of water was stirred rapidly for 2 hours. The mixture was diluted with ether and the organic layer was separated. The organic solution was washed with brine and then dried over magnesium sulfate. The solution 35 was passed through a small column of silica gel. The solvent was removed at 30 0 C at reduced pressure giving 6-amino-4-chloroquinazoline which is used in the next step without additional purification.
WO 99/24037 PCT/US98/23549 -18 Example 16 [4-chloro-6-quinazolinyll-2-butynamide 5 A solution of 1.64 g of 2-butynoic acid in 46 ml of tetrahydrofuran was cooled in an ice bath. A 2.34 ml portion of isobutyl chloroformate followed by a 4.13 ml portion of N-methyl morpholine were added. After about 10 minutes, this was poured into a solution of 6-amino-4-chloroquinazoline in 46 ml tetrahydrofuran. This mixture was stirred at room temperature for 2 hours. The mixture was poured into a mixture of 10 brine and saturated sodium bicarbonate and extracted with ether. The ether solution was dried over magnesium sulfate and filtered. The solvent was removed giving 14-chloro 6-quinazolinyl]-2-butynamide as colored oil that was used in the next step without additional purification. 15 Example 17 N-[4-[(3-Bromophenyl)aminol-6-quinazolinyll-2-butynamide A solution consisting of 1.76 g of 14-chloro-6-quinazolinyl]-2-butynamide and 1.23 g of 3-bromo aniline was refluxed under an inert atmosphere in 23 ml of 20 isopropanol for 40 minutes. The mixture was cooled to room temperature and 200 ml of ether was added giving 0.4 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]- 2 butynamide as the hydrochloride salt. Neutralizing with sodium bicarbonate solution, extracting with ethyl acetate, removal of the solvent, and recyrstallization from 1 butanol gives N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide as the free 25 base. Example 18 N'-(4-Amino-2-cvanophenyl)-N,N-dimethylformamidine A solution of 6.0 g (27.5 mmol) of N'-(2-cyano-4-nitrophenyl)-N,N 30 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. Solvent was removed and the residue was recrystallized from chloroform-carbon tetrachloride giving 4.9 g (95%) of the title compound as a light gray crystalline solid, mass spectrum (mle): 188.9 (M+H, electrospray).
WO 99/24037 PCT/US98/23549 -19 Example 19 N-[3-Cyano-4-r[[(dimethylamino)methylene] amino] phenyll-2-butvnamide To a solution of 2.01 g (23.9 mmol) of 2-butynoic acid and 2.9 ml (22.3 mmol) isobutyl chloroformate in 30 ml tetrahydrofuran was stirred at 0 0 C under 5 nitrogen as 2.42 g (2.63 ml, 22.3 mmol) of N-methyl morpholine was added over 3 min. After stirring for 15 min., a solution of N'-(4-amino-2-cyanophenyl)-N,N dimethylformamidine and 1.6 g (1.75 ml, 15.9 mmol) of N-methyl morpholine in 25 ml tetrahydrofuran was added over 4 min. The mixture was stirred 30 min. at 0 0 C and 30 min. at room temperature. The mixture was diluted with 70 ml of ethyl acetate and 10 poured into a mixture of brine and saturated sodium bicarbonate. The organic layer was dried (MgSO4) and filtered through a pad of silica gel. The solvent was removed and the residue was stirred with 50 ml of ether. The suspended solid was collected to give 3.61 g (89%) of an off-white solid, mass spectrum (m/e): 255.0 (M+H, electrospray). 15 Example 20 N-[4-[(3-Bromophenyl)aminol-6-quinazolinyl]-2-butvnamide A solution of 3.0 g (11.8 mmol) of N-[3-cyano-4-[[(dimethylamino) methylene]amino] phenyl]-2-butynamide and 2.23 g (12.98 mmol) of 3-bromo aniline 20 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. The solid was collected by filtration and washed with ether-acetonitrile 1:1 to give a yellow solid which was recrystallized from ethanol giving 2.51 g of N-[4-[(3-bromophenyl)amino]-6 quinazolinyl]-2-butynamide: mass spectrum (mle): 381, 383.

Claims (9)

1. A method of treating or inhibiting colonic polyps in a mammal in need thereof which comprises administering to said mammal a compound of the formula X H R HN' x y.H Y N N R2 N R, 1 wherein: 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 R 1 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 SRR3R R 3 R 3 R 3 R 3 R 3 R 3 R3R 3 R3 'R3 R3 R3 R3 R3 R3 R3 R3 - 3 andR R3"- ' R\(CR) n 3 R 3 R 3 R3 3R R3 (C(R3)2)n R 3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; n = 2-4; WO 99/24037 PCT/US98/23549 -21 or a pharmaceutically acceptable salt thereof, with the proviso that each R 3 of Y may be the same or different.
2. A method as claimed in Claim 1 wherein R, R 1 , and R 2 are hydrogen or a pharmaceutically acceptable salt thereof.
3. A method as claimed in Claim 1 or Claim 2 wherein X is phenyl unsubstituted or substituted with halogen or alkyl of 1-6 carbon atoms.
4. A method as claimed in any one of Claims 1 to 3 in which N-[4-[(3 Bromophenyl)amino]-6-quinazolinyl]-2-butynamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-methyl-2-propenamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2,4-hexadienamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-(E)-2-butenamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-3-methyl-2-butenamide, 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(Z)-2-butenoic acid, 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid, 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid, ethyl ester, N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-cyclopentenamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-propenamide, N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(3-phenyl-2-propynamide) or a pharmaceutically acceptable salt of any of these is administered. WO 99/24037 PCT/US98/23549 - 22
5. Use of a compound of the formula X H R HN Y NN \ N R2 R, 1 wherein: 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 R 1 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 RR3R R3 R3 R3 R 3 R 3 3 3 R 3 R 3 R 3 R 3 R3 - ,and R3 R 3 R 3 33R3 'R 3 3 , nd (C(R3)n R 3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; n = 2-4; or a pharmaceutically acceptable salt thereof, with the proviso that each R 3 of Y may be the same or different, in the preparation of a medicament for the treatment or inhibition of colonic polyps in a mammal. WO 99/24037 PCT/US98/23549 - 23
6. Use as claimed in Claim 5 wherein R, R 1 , and R 2 are hydrogen or a pharmaceutically acceptable salt thereof.
7. Use as claimed in Claim 5 or Claim 6 wherein X is phenyl unsubstituted or substituted with halogen or alkyl of 1-6 carbon atoms.
8. Use as claimed in any one of Claims 5 to 7 in which the compound administered is N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-butynamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-methyl-2-propenamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2,4-hexadienamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-(E)-2-butenamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-3-methyl-2-butenamide, 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(Z)-2-butenoic acid, 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid, 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(E)-2-butenoic acid, ethyl ester, N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-cyclopentenamide, N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-propenamide, N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(3-phenyl-2-propynamide)
9. A pharmaceutical composition for treating or inhibiting colonic polyps in a mammal which comprises a compound of formula 1 as defined in claim 5 and optionally a pharmaceutical carrier.
AU13087/99A 1997-11-06 1998-11-04 Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps Abandoned AU1308799A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US96508497A 1997-11-06 1997-11-06
US08965084 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
AU1308799A true AU1308799A (en) 1999-05-31

Family

ID=25509419

Family Applications (1)

Application Number Title Priority Date Filing Date
AU13087/99A Abandoned AU1308799A (en) 1997-11-06 1998-11-04 Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps

Country Status (15)

Country Link
EP (1) EP1039910A1 (en)
JP (1) JP2001522802A (en)
KR (1) KR20010031813A (en)
CN (1) CN1278176A (en)
AR (1) AR016415A1 (en)
AU (1) AU1308799A (en)
BR (1) BR9814116A (en)
CA (1) CA2306155A1 (en)
HU (1) HUP0004286A3 (en)
IL (1) IL135622A0 (en)
NO (1) NO20002166L (en)
NZ (1) NZ503991A (en)
PL (1) PL340800A1 (en)
WO (1) WO1999024037A1 (en)
ZA (1) ZA9810134B (en)

Families Citing this family (154)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432979B1 (en) 1999-08-12 2002-08-13 American Cyanamid Company Method of treating or inhibiting colonic polyps and colorectal cancer
ATE341341T1 (en) * 1999-08-12 2006-10-15 Wyeth Corp PHARMACEUTICAL FORMULATION CONTAINING NSAID AND EGFR KINASE INHIBITORS FOR TREATING OR INHIBITING COLON 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
BRPI0410634A (en) 2003-05-30 2006-06-13 Astrazeneca Uk Ltd process
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
AP2204A (en) 2004-05-06 2011-02-07 Warner Lambert Co 4-phenylamino-quinazolin-6-yl-amides.
US7947676B2 (en) 2004-12-14 2011-05-24 Astrazeneca Ab Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents
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
WO2007034144A1 (en) 2005-09-20 2007-03-29 Astrazeneca Ab 4- (ih-indazol-s-yl-amino)-quinazoline compounds as erbb receptor tyrosine kinase inhibitors for the treatment of cancer
ES2530438T3 (en) 2006-09-12 2015-03-02 Genentech Inc Procedures and compositions for the diagnosis and treatment of lung cancer using the KIT or KDR gene as a genetic marker
EP1921070A1 (en) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation
EP2118075A1 (en) 2007-02-06 2009-11-18 Boehringer Ingelheim International GmbH Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
WO2009092052A2 (en) 2008-01-18 2009-07-23 Massachusetts Eye And Ear Infirmary Methods and compositions for treating polyps
TWI472339B (en) 2008-01-30 2015-02-11 Genentech Inc Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof
CN101939316B (en) 2008-02-07 2013-10-02 贝林格尔.英格海姆国际有限公司 Spirocyclic heterocyclic compound, medicine containing said compound, use thereof and preparation method thereof
BRPI0912170A2 (en) 2008-05-13 2015-10-13 Astrazeneca Ab compound, form, process for preparation thereof, pharmaceutical composition, use of a compound, and method for treating cancer in a warm-blooded animal
US8426430B2 (en) * 2008-06-30 2013-04-23 Hutchison Medipharma Enterprises Limited Quinazoline derivatives
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
ES2572728T3 (en) 2009-03-20 2016-06-02 F. Hoffmann-La Roche Ag Bispecific anti-HER antibodies
KR20120103587A (en) 2009-11-12 2012-09-19 제넨테크, 인크. A method of promoting dendritic spine density
TW201129565A (en) 2010-01-12 2011-09-01 Hoffmann La Roche Tricyclic heterocyclic compounds, compositions and methods of use thereof
CN102892779B (en) 2010-02-18 2016-12-21 基因泰克公司 Neuregulin antagonist and the purposes in treatment cancer thereof
CA2793024A1 (en) 2010-03-17 2011-09-22 F. Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
WO2011130654A1 (en) 2010-04-16 2011-10-20 Genentech, Inc. Fox03a as predictive biomarker for pi3k/akt kinase pathway inhibitor efficacy
RU2013114360A (en) 2010-08-31 2014-10-10 Дженентек, Инк. BIOMARKERS AND TREATMENT METHODS
CA2812087A1 (en) 2010-09-15 2012-03-22 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
JP2013542966A (en) 2010-11-19 2013-11-28 エフ．ホフマン−ラ ロシュ アーゲー Pyrazolopyridines and their use as TYK2 inhibitors and their use
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
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
WO2013007765A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
CA2843499A1 (en) 2011-08-12 2013-02-21 F. Hoffmann-La Roche Ag Indazole compounds, compositions and methods of use
MX2014001766A (en) 2011-08-17 2014-05-01 Genentech Inc Neuregulin antibodies and uses thereof.
KR20140082710A (en) 2011-09-20 2014-07-02 에프. 호프만-라 로슈 아게 Imidazopyridine compounds, compositions and methods of use
CN106987620A (en) 2011-11-30 2017-07-28 霍夫曼-拉罗奇有限公司 Erbb3 mutation in cancer
JP2015514710A (en) 2012-03-27 2015-05-21 ジェネンテック， インコーポレイテッド Diagnosis and treatment of HER3 inhibitors
JP2016509045A (en) 2013-02-22 2016-03-24 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト How to treat cancer and prevent drug resistance
WO2014138364A2 (en) 2013-03-06 2014-09-12 Genentech, Inc. Methods of treating and preventing cancer drug resistance
MX2015011898A (en) 2013-03-13 2016-05-05 Genentech Inc Pyrazolo compounds and uses thereof.
CA2903480A1 (en) 2013-03-14 2014-09-25 Genentech, Inc. 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
MX2015011899A (en) 2013-03-15 2016-05-05 Genentech Inc Methods of treating cancer and preventing cancer drug resistance.
CA2922925A1 (en) 2013-09-05 2015-03-12 Genentech, Inc. Antiproliferative compounds
TW201605857A (en) 2013-10-03 2016-02-16 赫孚孟拉羅股份公司 Therapeutic inhibitors of CDK8 and uses thereof
CA2925598A1 (en) 2013-10-18 2015-04-23 Genentech, Inc. Anti-rspo antibodies and methods of use
KR20240017102A (en) 2013-12-17 2024-02-06 제넨테크, 인크. Methods of treating cancers using pd-1 axis binding antagonists and taxanes
BR112016013963A2 (en) 2013-12-17 2017-10-10 Genentech Inc combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
WO2015148531A1 (en) 2014-03-24 2015-10-01 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with hgf expression
EP3126394B1 (en) 2014-03-31 2019-10-30 F.Hoffmann-La Roche Ag Anti-ox40 antibodies and methods of use
KR20160146747A (en) 2014-03-31 2016-12-21 제넨테크, 인크. Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists
JP6814730B2 (en) 2014-09-05 2021-01-20 ジェネンテック， インコーポレイテッド Therapeutic compounds and their use
JP2017529358A (en) 2014-09-19 2017-10-05 ジェネンテック， インコーポレイテッド Use of CBP / EP300 inhibitors and BET inhibitors for the treatment of cancer
JP6783230B2 (en) 2014-10-10 2020-11-11 ジェネンテック， インコーポレイテッド Pyrrolidone amide compounds as inhibitors of histone demethylase
MX2017005750A (en) 2014-11-03 2017-12-15 Genentech Inc Assays for detecting t cell immune subsets and methods of use thereof.
EP3215637B1 (en) 2014-11-03 2019-07-03 F. Hoffmann-La Roche AG Methods and biomarkers for predicting efficacy and valuation of an ox40 agonist treatment
WO2016073282A1 (en) 2014-11-06 2016-05-12 Genentech, Inc. Combination therapy comprising ox40 binding agonists and tigit inhibitors
MA40943A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
EP3218376B1 (en) 2014-11-10 2019-12-25 Genentech, Inc. Bromodomain inhibitors and uses thereof
MA40940A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
SG11201703605QA (en) 2014-11-17 2017-06-29 Genentech Inc Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
US9763922B2 (en) 2014-11-27 2017-09-19 Genentech, Inc. Therapeutic compounds and uses thereof
SG11201704707PA (en) 2014-12-23 2017-07-28 Genentech Inc Compositions and methods for treating and diagnosing chemotherapy-resistant cancers
CN107208138A (en) 2014-12-30 2017-09-26 豪夫迈·罗氏有限公司 Methods and compositions for cancer prognosis and treatment
EP3242872B1 (en) 2015-01-09 2019-07-03 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
JP6889661B2 (en) 2015-01-09 2021-06-18 ジェネンテック， インコーポレイテッド 4,5-Dihydroimidazole derivative and its use as a histone dimethylase (KDM2B) inhibitor
WO2016112298A1 (en) 2015-01-09 2016-07-14 Genentech, Inc. Pyridazinone derivatives and their use in the treatment of cancer
EP3250571B1 (en) 2015-01-29 2022-11-30 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016123387A1 (en) 2015-01-30 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
MA41598A (en) 2015-02-25 2018-01-02 Constellation Pharmaceuticals Inc PYRIDAZINE THERAPEUTIC COMPOUNDS AND THEIR USES
EP3280736A1 (en) 2015-04-07 2018-02-14 F. Hoffmann-La Roche AG Antigen binding complex having agonistic activity and methods of use
HRP20201900T4 (en) 2015-05-12 2024-06-07 F. Hoffmann - La Roche Ag THERAPEUTIC AND DIAGNOSTIC PROCEDURES IN CANCER
IL294138A (en) 2015-05-29 2022-08-01 Genentech Inc Therapeutic and diagnostic methods for cancer
CA2985483A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies
US20170000885A1 (en) 2015-06-08 2017-01-05 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
IL256080B2 (en) 2015-06-17 2025-06-01 Genentech Inc Methods for treating locally advanced or metastatic breast cancer using PD-1 axis-binding antagonists and taxanes
ES2862727T3 (en) 2015-08-26 2021-10-07 Fundacion Del Sector Publico Estatal Centro Nac De Investigaciones Oncologicas Carlos Iii F S P Cnio Fused tricyclic compounds as protein kinase inhibitors
NZ739750A (en) 2015-09-25 2019-11-29 Genentech Inc Anti-tigit antibodies and methods of use
WO2017106647A1 (en) 2015-12-16 2017-06-22 Genentech, Inc. Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer
EP3400246B1 (en) 2016-01-08 2020-10-21 H. Hoffnabb-La Roche Ag Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies
KR20180119632A (en) 2016-02-29 2018-11-02 제넨테크, 인크. Treatment and Diagnosis Methods for Cancer
EP3865511A1 (en) 2016-04-14 2021-08-18 F. Hoffmann-La Roche AG Anti-rspo3 antibodies and methods of use
EP3443120A2 (en) 2016-04-15 2019-02-20 H. Hoffnabb-La Roche Ag Methods for monitoring and treating cancer
WO2017180581A1 (en) 2016-04-15 2017-10-19 Genentech, Inc. Diagnostic and therapeutic methods for cancer
CN109154613A (en) 2016-04-15 2019-01-04 豪夫迈·罗氏有限公司 For monitoring and the method for the treatment of cancer
JP7014736B2 (en) 2016-05-24 2022-02-01 ジェネンテック， インコーポレイテッド Pyrazolopyridine derivatives for the treatment of cancer
JP7160688B2 (en) 2016-05-24 2022-10-25 ジェネンテック， インコーポレイテッド Heterocyclic inhibitors of CBP/EP300 and their use in treating cancer
JP2019527037A (en) 2016-06-08 2019-09-26 ジェネンテック， インコーポレイテッド Diagnosis and treatment methods for cancer
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
JP7579056B2 (en) 2016-10-06 2024-11-07 ジェネンテック， インコーポレイテッド Therapeutic and diagnostic methods for cancer
CN110267678A (en) 2016-10-29 2019-09-20 霍夫曼-拉罗奇有限公司 Anti-MIC antibodies and methods of use
EP3589754B1 (en) 2017-03-01 2023-06-28 F. Hoffmann-La Roche AG 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
CA3069469A1 (en) 2017-07-21 2019-01-24 Genentech, Inc. Therapeutic and diagnostic methods for cancer
KR102811888B1 (en) 2017-09-08 2025-05-27 에프. 호프만-라 로슈 아게 Diagnosis and treatment of cancer
EP3710001B1 (en) 2017-10-27 2025-06-18 University Of Virginia Patent Foundation Compounds and methods for regulating, limiting, or inhibiting avil expression
ES2984919T3 (en) 2017-11-06 2024-10-31 Hoffmann La Roche Diagnostic and therapeutic procedures for cancer
JP7236164B2 (en) 2018-01-15 2023-03-09 エピアクシス セラピューティクス プロプライエタリー リミテッド Agents and methods for predicting response to therapy
CN112771177A (en) 2018-05-21 2021-05-07 纳米线科技公司 Molecular gene tags and methods of use thereof
SG11202012446UA (en) 2018-06-23 2021-01-28 Genentech Inc Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
EP3823611A1 (en) 2018-07-18 2021-05-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent
CN112805267B (en) 2018-09-03 2024-03-08 豪夫迈·罗氏有限公司 Formamide and sulfonamide derivatives used as TEAD modulators
CA3111401A1 (en) 2018-09-19 2020-03-26 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
AU2019342133B8 (en) 2018-09-21 2025-08-07 Genentech, Inc. Diagnostic methods for triple-negative breast cancer
AU2019362972A1 (en) 2018-10-17 2021-05-20 The University Of Queensland Epigenetic biomarker and uses therefor
AU2019361983A1 (en) 2018-10-18 2021-05-20 Genentech, Inc. Diagnostic and therapeutic methods for sarcomatoid kidney cancer
EP3921443A1 (en) 2019-02-08 2021-12-15 F. Hoffmann-La Roche AG Diagnostic and therapeutic methods for cancer
CA3130695A1 (en) 2019-02-27 2020-09-03 Genentech, Inc. Dosing for treatment with anti-tigit and anti-cd20 or anti-cd38 antibodies
US20220146495A1 (en) 2019-02-27 2022-05-12 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
MX2021013222A (en) 2019-05-03 2022-01-06 Genentech Inc Methods of treating cancer with an anti-pd-l1 antibody.
CN112300279A (en) 2019-07-26 2021-02-02 上海复宏汉霖生物技术股份有限公司 Methods and compositions directed to anti-CD 73 antibodies and variants
EP4025608A1 (en) 2019-09-04 2022-07-13 F. Hoffmann-La Roche AG Cd8 binding agents and uses thereof
CR20220127A (en) 2019-09-27 2022-05-27 Genentech Inc DOSE ADMINISTRATION FOR TREATMENT WITH ANTI-TIGIT AND ANTI-PD-L1 ANTAGONIST ANTIBODIES
EP4051674A1 (en) 2019-10-29 2022-09-07 F. Hoffmann-La Roche AG Bifunctional compounds for the treatment of cancer
IL292458A (en) 2019-11-06 2022-06-01 Genentech Inc Diagnostic and therapeutic methods for treatment of hematologic cancers
EP4058435A1 (en) 2019-11-13 2022-09-21 Genentech, Inc. Therapeutic compounds and methods of use
EP4072584B1 (en) 2019-12-13 2026-01-28 Genentech, Inc. Anti-ly6g6d antibodies and methods of use
CA3164995A1 (en) 2019-12-20 2021-06-24 Erasca, Inc. Tricyclic pyridones and pyrimidones
TW202142230A (en) 2020-01-27 2021-11-16 美商建南德克公司 Methods for treatment of cancer with an anti-tigit antagonist antibody
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
JP2023520515A (en) 2020-04-03 2023-05-17 ジェネンテック， インコーポレイテッド Therapeutic and diagnostic methods for cancer
JP2023523450A (en) 2020-04-28 2023-06-05 ジェネンテック， インコーポレイテッド Methods and compositions for non-small cell lung cancer immunotherapy
KR20230025691A (en) 2020-06-16 2023-02-22 제넨테크, 인크. Methods and compositions for treating triple negative breast cancer
AU2021293507A1 (en) 2020-06-18 2023-02-02 F. Hoffmann-La Roche Ag Treatment with anti-TIGIT antibodies and PD-1 axis binding antagonists
US11787775B2 (en) 2020-07-24 2023-10-17 Genentech, Inc. Therapeutic compounds and methods of use
EP4189121A1 (en) 2020-08-03 2023-06-07 Genentech, Inc. Diagnostic and therapeutic methods for lymphoma
EP4196612A1 (en) 2020-08-12 2023-06-21 Genentech, Inc. Diagnostic and therapeutic methods for cancer
EP4217071A1 (en) 2020-09-23 2023-08-02 Erasca, Inc. Tricyclic pyridones and pyrimidones
CA3193952A1 (en) 2020-10-05 2022-04-14 Bernard Martin Fine Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2022133345A1 (en) 2020-12-18 2022-06-23 Erasca, Inc. Tricyclic pyridones and pyrimidones
CA3210553A1 (en) 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives for the treatment of cancer
JP2024520457A (en) 2021-05-25 2024-05-24 エラスカ・インコーポレイテッド Sulfur-containing heteroaromatic tricyclic KRAS inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
TW202321261A (en) 2021-08-10 2023-06-01 美商伊瑞斯卡公司 Selective kras inhibitors
US12110276B2 (en) 2021-11-24 2024-10-08 Genentech, Inc. Pyrazolo compounds and methods of use thereof
US12275745B2 (en) 2021-11-24 2025-04-15 Genentech, Inc. Therapeutic compounds and methods of use
IL315770A (en) 2022-04-01 2024-11-01 Genentech Inc Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
AU2022458320A1 (en) 2022-05-11 2024-11-28 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
IL317449A (en) 2022-06-07 2025-02-01 Genentech Inc Method for determining the efficacy of a lung cancer treatment comprising an anti-pd-l1 antagonist and an anti-tigit antagonist antibody
JP2025523020A (en) 2022-07-13 2025-07-17 ジェネンテック， インコーポレイテッド Administration for Treatment with Anti-FcRH5/Anti-CD3 Bispecific Antibody
IL318252A (en) 2022-07-19 2025-03-01 Genentech Inc Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
CN119677733A (en) 2022-08-11 2025-03-21 豪夫迈·罗氏有限公司 Bicyclic tetrahydrothiazepine derivatives
JP2025526727A (en) 2022-08-11 2025-08-15 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Bicyclic tetrahydrothiazepine derivatives
JP2025526683A (en) 2022-08-11 2025-08-15 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Bicyclic tetrahydrothiazepine derivatives
CN119677732A (en) 2022-08-11 2025-03-21 豪夫迈·罗氏有限公司 Bicyclic tetrahydroazepine 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
TW202448949A (en) 2023-05-05 2024-12-16 美商建南德克公司 Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024254455A1 (en) 2023-06-08 2024-12-12 Genentech, Inc. Macrophage signatures for diagnostic and therapeutic methods for lymphoma
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025049277A1 (en) 2023-08-25 2025-03-06 Genentech, Inc. Methods and compositions for treating non-small cell lung cancer comprising an anti-tigit antagonist antibody and a pd-1 axis binding antagonist

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5760041A (en) * 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors

Also Published As

Publication number Publication date
BR9814116A (en) 2000-10-03
CA2306155A1 (en) 1999-05-20
AR016415A1 (en) 2001-07-04
IL135622A0 (en) 2001-05-20
PL340800A1 (en) 2001-02-26
ZA9810134B (en) 2000-05-05
KR20010031813A (en) 2001-04-16
WO1999024037A1 (en) 1999-05-20
NO20002166D0 (en) 2000-04-27
NZ503991A (en) 2001-11-30
HUP0004286A2 (en) 2001-11-28
EP1039910A1 (en) 2000-10-04
HUP0004286A3 (en) 2002-01-28
JP2001522802A (en) 2001-11-20
NO20002166L (en) 2000-06-28
CN1278176A (en) 2000-12-27

Similar Documents

Publication Publication Date Title
AU1308799A (en) Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps
JP3984319B2 (en) Substituted quinazoline derivatives
CA2288705C (en) Use of quinazoline compounds for the treatment of polycystic kidney disease
JP3950337B2 (en) Malignant tumor treatment
CN108524482B (en) Use of 2-(substituted anilino)benzoic acid FTO inhibitors for treating leukemia
MXPA97000883A (en) Derivatives substituted from quinazol
JP4934432B2 (en) Quinazoline derivatives and therapeutic use of quinazoline derivatives
JPH11504031A (en) Quinazoline derivatives
TW201036951A (en) Quinazolinone derivatives useful as vanilloid antagonists
EP2269994A1 (en) The polymorphs of 4-anilinoquinazoline derivatives, the preparation methods and uses thereof
JP2010070514A (en) Pyrazole derivative and its pharmaceutical application
CN103435561B (en) A kind of Novel D-amino acid oxidase inhibitor and preparation thereof and application
JP4828142B2 (en) Novel fused pyrazolyl compounds
CN103965119B (en) Irreversible EGFR tyrosine kinase inhibitor containing zinc binding moiety
US6323209B1 (en) Method of treating or inhibiting colonic polyps
MXPA00004304A (en) Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps
WO2010083649A1 (en) Bisarylurea derivatives and their use
EP1737832B1 (en) 4-anilinoquinazoline derivatives with adenosine-kinase inhibitory properties
CZ20001660A3 (en) Pharmaceutical composition
EP2044937A1 (en) ANALGESIC 5, 9 - METHANOCYCLOOCTA (b) PYRIDIN - 2 (1H) - ONE DERIVATIVES, THEIR PREPARATION METHOD AND USE
WO2018167187A1 (en) 5-carboxamide-2-thiobarbituric acids and use thereof as medicaments
EP3630730B1 (en) Polysubstituted pyrimidines inhibiting the formation of prostaglandin e2, a method of production thereof and use thereof
WO2008046242A1 (en) The novel quinazoline derivatives,preparation methods and uses thereof
WO2001034569A1 (en) Pancreatitis remedies
CN102688233B (en) Benzotriazole Derivative is as the synthesis of RSK2 inhibitor and application

Legal Events

Date Code Title Description
MK5 Application lapsed section 142(2)(e) - patent request and compl. specification not accepted