EP1039910A1 - 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

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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
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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.)
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EP98956600A
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German (de)
French (fr)
Inventor
Philip Frost
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Wyeth Holdings LLC
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American Cyanamid Co
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    • 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.

Abstract

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 having formula (I), wherein X is phenyl which is optionally substituted; R and R1 are each independently, hydrogen, halogen, alkyl, alkoxy, hydroxy or trifluoromethyl; R2 is hydrogen, alkyl, alkoxy, hydroxy or trifluoromethyl; Y is a radical selected from the group consisting of formulae (II), (III), (IV), (V), (VI), (VII) and (VIII). R3 is independently hydrogen, alkyl, carboxy, carboalkoxy, phenyl, or carboalkyl; n = 2-4; or a pharmaceutically acceptable salt thereof, with the proviso that each R3 of Y may be the same or different.

Description

USE OF QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS FOR TREATING COLONIC POLYPS
This invention relates to the use of certain quinazoline compounds in the 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 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 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 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. 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 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 nuclear targeting of COX-2, release of PG's and subsequent mitogenesis, in polarized colonic epithelial cells. COX-2 inhibitors have been shown to prevent this series of events.
DESCRIPTION OF THE INVENTION
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:
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 Rj are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl; R2 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
R3 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 R3 of Y may be 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 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- pentyl or n-hexyl. Carboxy is defined as a -CO2H radical. Carboalkoxy of 2-7 carbon atoms is defined as a -CO2R" 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- 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 R, R1, and R2 are hydrogen; and those in which R, R1, and R2 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 -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 CO2EL 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 i , R2 and X are as defmed above
with:
i) an acid chloride of Formula 7, wherein Y is as defined above
ii) a mixed anhydride of Formula 8, wherein Y is as defmed above
or iii) a cyclic anhydride of Formula 11 wherein each R5 is independently hydrogen, phenyl, or alkyl of 1-6 carbon atoms
b) reacting a compound of Formula 17 wherein R, Ri, R2 and Y are as defined above and Hal is any suitable halogen
with an aniline of Formula 18 wherein X is as defined above
X-NH2 18
or e) reacting a compound of Formula 24 wherein R, Ri, R2 and Y are as defmed above
with an aniline of Formula 25
H2N-X 25
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, R2, R3, X, and n are as defined above and R4 is alkyl of 1-6 carbon atoms (preferably isobutyl). Y' is a radical selected from the group consisting of:
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 sequence of reaction outlined in flowsheet A, 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 . Reduction of the nitro group of 5 using a 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 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 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., 51 (1986); Niclas, Hans-Joachim; Bohle, Matthias; Rick, Jens-Detlev; Zeuner,Frank; Zoelch, Lothar, Z.Chem., 25(4), 137-138 (1985). FLOWSHEET A
The preparation of the compounds of this invention encompassed by Formula 12 is described below in Flowsheet B wherein R, R\, R2, X, and n are described above. Each R5 is independently hydrogen, phenyl, or alkyl of 1-6 carbon atoms. 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. FLOWSHEET B
THF, pyridine, or (CaHstøN
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 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 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,/. 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. 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 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. FLOWSHEET C
13 14
17
19
The preparation of the compounds of this invention encompassed by Formula 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 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 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
20 21
24
26
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. The following briefly describes the procedure used and the results obtained in this standard pharmacological test procedure.
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.
These data demonstrate that the compounds of this invention effectively inhibit 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 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, 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.
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, 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.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. 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 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 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. The preparation of representative examples of the compounds of this invention is described below.
Example 1 N'-(2-Cyano-4-nitrophenyl)-N.N-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 mefhylene 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 N-( -Bromophenyl)-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°C for 1.5 hours. On cooling, filtration of the resulting solid gives a quantitative yield of N-(3-bromophenyl)-6-nitro-4-quinazolinamine: mp = 267-
270°C; mass spectrum (m/e): 345.
Example 3
N-(3-BromophenyI")-4.6-quinazolindiamine
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 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 (m/e): 315. Example 4
4-rr4-lf3-Bromopheny amino1-6-quinazolinynamino1-4-oxo-(Z -2-butenoic acid
A 15 ml portion of pyridine was added to 1.6 g of N-(3-bromophenyl)-4,6- 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 efhanol 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 (m/e): M+H 413, 415.
Example 5
4-rr4-[(3-Bromophenyl aminol-6-quinazolinvnaminol-4-oxo-(E)-2-butenoic acid, ethyl ester
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 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 = 259-263°C, mass spectrum (m/e): M+H 441, 443.
Example 6
N-r4-rG-Bromophenyl)aminol-6-quinazolinyl1-3-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 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°C, mass spectrum (m/e): 396, 398. Example 7
N-[4-|"(3-Bromophenv aminol-6-quinazolinyI1-(E)-2-butenamide
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 0.57 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°C, mass spectrum (m/e): M+H 383, 385.
Example 8
N-r4-rf3-Bromophenyl)aminol-6-quinazolinyll-2-methyl-2-propenamide
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 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 °C, mass spectrum (m/e): M+H 383, 385.
Example 9 N-r4-r("3-Bromophenyl)aminol-6-quinazolinyl1-2-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 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. Example 10
4-[f4-r(3-Bromophenv amino1-6-quinazolinyllamino1-4-oxo-(Ε)-2-butenoic acid
A 2.5 ml portion of 10 N aqueous sodium hydroxide was added to 2.3 g of 4-[[4-[(3- 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]amino]-4-oxo-(E)-2-butenoic acid: mass spectrum (m e): M+H 413.
Example 11
N-14-l(3-Bromophenyl)amino]-6-quinazolinyl]-2.4-hexadienamide
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 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°C.
Example 12
N-r4-|Y3-BromophenyDamino1-6-quinazolinyl1-2-cyclopenteneamide
A solution of 0.43 g of 2-cycloperitenoic acid in 5ml of tetrahydrofuran was cooled in an ice bath. A 0.49 ml portion of isobutyl chloroformate followed by a 0.41 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 chromatography on silica gel to give 0.30 g of N-[4-[(3-bromophenyl)amino]-6- quinazolinyl]-2-cyclopenteneamide: mass spectrum (m/e): 409 (M+H, El).
Example 13 N-[4- (3-Bromophenyl)aminol-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°C. After stirring at room temperature for 3.5 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.
Example 14
N-r4-l(3-Bromopheny amino1-6-quinazolinyll-(3-phenyl-2-propynamide)
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 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 0°C 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): 443.2, 445.2 (M+H, electrospray).
Example 15
6-amino-4-chloroquinazoline
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 (CsHi7)3NCH3+ 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 was passed through a small column of silica gel. The solvent was removed at 30°C at reduced pressure giving 6-amino-4-chloroquinazoline which is used in the next step without additional purification. Example 16 f4-chloro-6-quinazolinyll-2-butvnamide
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 brine and saturated sodium bicarbonate and extracted with ether. The ether solution was dried over magnesium sulfate and filtered. The solvent was removed giving [4-chloro- 6-quinazolinyl]-2-butynamide as colored oil that was used in the next step without additional purification.
Example 17
N-["4-[(3-Bromophenyl')amino1-6-quinazolinyn-2-butvnamide
A solution consisting of 1.76 g of [4-chloro-6-quinazolinyl]-2-butynamide and 1.23 g of 3-bromo aniline was refluxed under an inert atmosphere in 23 ml of 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 base.
Example 18
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. 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 (m/e): 188.9 (M+H, electrospray). Example 19
N-f3-Cyano- -riCdimethylarmno)methylenelamino1 phenyn-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°C under 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°C and
30 min. at room temperature. The mixture was diluted with 70 ml of ethyl acetate and 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).
Example 20
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. 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 (m/e): 381, 383.

Claims

We claim:
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
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\ are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl;
R2 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
R3 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 R3 of Y may be the same or different.
2. A method as claimed in Claim 1 wherein R, Ri, and R2 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. Use of a compound of the formula
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 Ri are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl;
R2 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
R3 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 R3 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.
6. Use as claimed in Claim 5 wherein R, Ri, and R2 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.
EP98956600A 1997-11-06 1998-11-04 Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps Withdrawn EP1039910A1 (en)

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Families Citing this family (142)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012227A1 (en) * 1999-08-12 2001-02-22 American Cyanamid Company 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
KR101126560B1 (en) 2003-05-30 2012-04-05 도꾜 다이가꾸 Process for predicting drug response
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
GEP20084551B (en) 2004-05-06 2008-11-25 Warner Lambert Co 4-phenylamino-quinazolin-6-yl-amides
ATE501148T1 (en) 2004-12-14 2011-03-15 Astrazeneca Ab PYRAZOLOPYRIMIDINE COMPOUNDS AS ANTI-TUMOR 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
EP1928861B1 (en) 2005-09-20 2010-11-17 AstraZeneca AB 4- (ih-indazol-5-yl-amino)-quinazoline compounds as erbb receptor tyrosine kinase inhibitors for the treatment of cancer
CA2662236A1 (en) 2006-09-12 2008-03-20 Genentech, Inc. Methods and compositions for the diagnosis and treatment of cancer
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
MX2009007610A (en) 2007-02-06 2009-07-24 Boehringer Ingelheim Int Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof.
US20110104166A1 (en) 2008-01-18 2011-05-05 Stankovic Konstantina M 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
DK2245026T3 (en) 2008-02-07 2012-10-15 Boehringer Ingelheim Int Spirocyclic heterocycles, drug containing these compounds, their use and process for their preparation
EP2303276B1 (en) 2008-05-13 2013-11-13 AstraZeneca AB Fumarate salt of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline
US8426430B2 (en) * 2008-06-30 2013-04-23 Hutchison Medipharma Enterprises Limited Quinazoline derivatives
JP5539351B2 (en) 2008-08-08 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Cyclohexyloxy-substituted heterocycles, medicaments containing these compounds, and methods for producing them
US8597652B2 (en) 2009-03-20 2013-12-03 Genentech, Inc. Multispecific anti-HER antibodies
JP2013510871A (en) 2009-11-12 2013-03-28 ジェネンテック， インコーポレイテッド How to increase the density of dendritic spines
JP2013517220A (en) 2010-01-12 2013-05-16 エフ．ホフマン−ラ ロシュ アーゲー Tricyclic heterocyclic compounds, compositions thereof, and methods of use
SG183333A1 (en) 2010-02-18 2012-09-27 Genentech Inc Neuregulin antagonists and use thereof in treating cancer
JP2013522267A (en) 2010-03-17 2013-06-13 エフ．ホフマン−ラ ロシュ アーゲー Imidazopyridine compounds, compositions, and methods of use
BR112012026470A2 (en) 2010-04-16 2016-08-09 Genentech Inc method to predict tumor cell growth sensitivity and to treat a tumor in a patient
CA2808236A1 (en) 2010-08-31 2012-03-08 Genentech, Inc. Biomarkers and methods of treatment
WO2012035039A1 (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
KR20140047160A (en) 2011-08-12 2014-04-21 에프. 호프만-라 로슈 아게 Indazole compounds, compositions and methods of use
MX2014001766A (en) 2011-08-17 2014-05-01 Genentech Inc Neuregulin antibodies and uses thereof.
JP2014526538A (en) 2011-09-20 2014-10-06 エフ．ホフマン−ラ ロシュ アーゲー Imidazopyridine compounds, compositions and methods of use
SG11201402510TA (en) 2011-11-30 2014-06-27 Genentech Inc Erbb3 mutations in cancer
SG11201406079TA (en) 2012-03-27 2014-10-30 Genentech Inc Diagnosis and treatments relating to her3 inhibitors
CN104994879A (en) 2013-02-22 2015-10-21 霍夫曼-拉罗奇有限公司 Methods of treating cancer and preventing drug resistance
CA2902263A1 (en) 2013-03-06 2014-09-12 Genentech, Inc. Methods of treating and preventing cancer drug resistance
US10035801B2 (en) 2013-03-13 2018-07-31 Genentech, Inc. Pyrazolo compounds and uses thereof
AU2014239903A1 (en) 2013-03-14 2015-09-17 Genentech, Inc. Combinations of a MEK inhibitor compound with an HER3/EGFR inhibitor compound and methods of use
RU2015139054A (en) 2013-03-14 2017-04-19 Дженентек, Инк. METHODS FOR TREATING CANCER AND PREVENTION OF DRUG RESISTANCE OF CANCER
EP2968537A1 (en) 2013-03-15 2016-01-20 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
RU2016112568A (en) 2013-09-05 2017-10-06 Дженентек, Инк. ANTIPROLIFERATIVE COMPOUNDS
WO2015049325A1 (en) 2013-10-03 2015-04-09 F. Hoffmann-La Roche Ag Therapeutic inhibitors of cdk8 and uses thereof
CA2925598A1 (en) 2013-10-18 2015-04-23 Genentech, Inc. Anti-rspo antibodies and methods of use
RU2719487C2 (en) 2013-12-17 2020-04-17 Дженентек, Инк. Methods of treating cancer using antagonists binding to components of the signal path pd-1, and taxanes
EP3527587A1 (en) 2013-12-17 2019-08-21 F. Hoffmann-La Roche AG Combination therapy comprising ox40 binding agonists and pd-l1 binding antagonists
BR112016021383A2 (en) 2014-03-24 2017-10-03 Genentech Inc METHOD TO IDENTIFY A PATIENT WITH CANCER WHO IS LIKE OR LESS LIKELY TO RESPOND TO TREATMENT WITH A CMET ANTAGONIST, METHOD TO IDENTIFY A PATIENT WITH PREVIOUSLY TREATED CANCER, METHOD TO DETERMINE THE EXPRESSION OF THE HGF BIOMARKER, ANTI-C-MET ANTAGONIST AND ITS USE, DIAGNOSTIC KIT AND ITS PREPARATION METHOD
UA121112C2 (en) 2014-03-31 2020-04-10 Дженентек, Інк. Anti-ox40 antibodies and methods of use
JP6588461B2 (en) 2014-03-31 2019-10-09 ジェネンテック， インコーポレイテッド Combination therapy comprising an anti-angiogenic agent and an OX40 binding agonist
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
CN107073125A (en) 2014-09-19 2017-08-18 基因泰克公司 CBP/EP300 and BET inhibitor is used for the purposes for the treatment of cancer
CN107912040B (en) 2014-10-10 2021-04-06 基因泰克公司 Pyrrolidine amide compounds as histone demethylase inhibitors
CA2966523A1 (en) 2014-11-03 2016-05-12 Genentech, Inc. Assays for detecting t cell immune subsets and methods of use thereof
BR112017009159A2 (en) 2014-11-03 2018-03-06 Genentech, Inc. methods and biomarkers to predict efficacy and evaluation of ox40 agonist treatment
US20160152720A1 (en) 2014-11-06 2016-06-02 Genentech, Inc. Combination therapy comprising ox40 binding agonists and tigit inhibitors
MA40940A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
WO2016077375A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Bromodomain inhibitors and uses thereof
MA40943A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
EP3221360A1 (en) 2014-11-17 2017-09-27 F. Hoffmann-La Roche AG Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
JP6771464B2 (en) 2014-11-27 2020-10-21 ジェネンテック， インコーポレイテッド 4,5,6,7-Tetrahydro-1H-pyrazolo [4,3-C] Pyridine-3-amine compound as CBP and / or EP300 inhibitor
MX2017006864A (en) 2014-12-23 2017-08-28 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
CN107406414B (en) 2015-01-09 2022-04-19 基因泰克公司 (piperidin-3-yl) (naphthalen-2-yl) methanone derivatives as inhibitors of histone demethylase KDM2B for the treatment of cancer
EP3242874B1 (en) 2015-01-09 2018-10-31 Genentech, Inc. Pyridazinone derivatives and their use in 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
CN107531692B (en) 2015-01-29 2020-12-25 基因泰克公司 Therapeutic compounds and uses thereof
CN107438593B (en) 2015-01-30 2020-10-30 基因泰克公司 Therapeutic compounds and uses thereof
MA41598A (en) 2015-02-25 2018-01-02 Constellation Pharmaceuticals Inc PYRIDAZINE THERAPEUTIC COMPOUNDS AND THEIR USES
AU2016246695A1 (en) 2015-04-07 2017-10-26 Genentech, Inc. Antigen binding complex having agonistic activity and methods of use
SI3294770T1 (en) 2015-05-12 2021-01-29 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
AU2016270625B2 (en) 2015-05-29 2022-10-06 Genentech, Inc. Therapeutic and diagnostic methods for cancer
CN107810011A (en) 2015-06-08 2018-03-16 豪夫迈·罗氏有限公司 Use the method for anti-OX40 antibodies for treating cancer
AU2016274584A1 (en) 2015-06-08 2018-01-04 Genentech, Inc. Methods of treating cancer using anti-OX40 antibodies and PD-1 axis binding antagonists
CN107771076A (en) 2015-06-17 2018-03-06 豪夫迈·罗氏有限公司 Use the axle binding antagonists of PD 1 and the method for Taxane treatment Locally Advanced or metastatic breast cancer
US10208056B2 (en) 2015-08-26 2019-02-19 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Condensed tricyclic compounds as protein kinase inhibitors
EP3389662B1 (en) 2015-12-16 2021-12-01 Genentech, Inc. Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer
WO2017118675A1 (en) 2016-01-08 2017-07-13 F. Hoffmann-La Roche Ag Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies
CN109196121B (en) 2016-02-29 2022-01-04 基因泰克公司 Methods for treatment and diagnosis of cancer
EP3443004A1 (en) 2016-04-14 2019-02-20 H. Hoffnabb-La Roche Ag Anti-rspo3 antibodies and methods of use
CA3018406A1 (en) 2016-04-15 2017-10-19 Genentech, Inc. Diagnostic and therapeutic methods for cancer
EP3443120A2 (en) 2016-04-15 2019-02-20 H. Hoffnabb-La Roche Ag Methods for monitoring and treating cancer
KR20190003958A (en) 2016-04-15 2019-01-10 제넨테크, 인크. Treatment and monitoring of cancer
CN115028617A (en) 2016-05-24 2022-09-09 基因泰克公司 Heterocyclic inhibitors of CBP/EP300 and their use in the treatment of cancer
MA45146A (en) 2016-05-24 2021-03-24 Constellation Pharmaceuticals Inc PYRAZOLOPYRIDINE DERIVATIVES FOR THE TREATMENT OF CANCER
WO2017214373A1 (en) 2016-06-08 2017-12-14 Genentech, Inc. Diagnostic and therapeutic methods for cancer
EP3494139B1 (en) 2016-08-05 2022-01-12 F. Hoffmann-La Roche AG Multivalent and multiepitopic anitibodies having agonistic activity and methods of use
CN109476748B (en) 2016-08-08 2023-05-23 豪夫迈·罗氏有限公司 Methods for treatment and diagnosis of cancer
TWI775781B (en) 2016-10-06 2022-09-01 美商建南德克公司 Therapeutic and diagnostic methods for cancer
US11555076B2 (en) 2016-10-29 2023-01-17 Genentech, Inc. Anti-MIC antibodies and methods of use
CN110546277A (en) 2017-03-01 2019-12-06 豪夫迈·罗氏有限公司 Methods for diagnosis and treatment of cancer
KR20190136076A (en) 2017-04-13 2019-12-09 에프. 호프만-라 로슈 아게 Interleukin-2 immunoconjugates, CD40 agonists and optional PD-1 axis binding antagonists for use in cancer treatment methods
MX2020002553A (en) 2017-09-08 2020-07-22 Hoffmann La Roche Diagnostic and therapeutic methods for cancer.
TW201923089A (en) 2017-11-06 2019-06-16 美商建南德克公司 Diagnostic and therapeutic methods for cancer
CA3100200A1 (en) 2018-05-21 2019-11-28 Nanostring Technologies, Inc. Molecular gene signatures and methods of using same
WO2019246557A1 (en) 2018-06-23 2019-12-26 Genentech, Inc. Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
KR20210034622A (en) 2018-07-18 2021-03-30 제넨테크, 인크. Lung cancer treatment method using PD-1 axis binding antagonist, anti-metabolite, and platinum agent
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
AU2019342099A1 (en) 2018-09-19 2021-04-08 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
EP4249917A3 (en) 2018-09-21 2023-11-08 F. Hoffmann-La Roche AG Diagnostic methods for triple-negative breast cancer
CN113196061A (en) 2018-10-18 2021-07-30 豪夫迈·罗氏有限公司 Methods of diagnosis and treatment of sarcoma-like renal cancer
WO2020163589A1 (en) 2019-02-08 2020-08-13 Genentech, Inc. 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
WO2020172712A1 (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
CN114269376A (en) 2019-05-03 2022-04-01 豪夫迈·罗氏有限公司 Methods of treating cancer with anti-PD-L1 antibodies
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
CR20220095A (en) 2019-09-04 2022-06-06 Genentech Inc Cd8 binding agents and uses thereof
MX2022003610A (en) 2019-09-27 2022-04-20 Genentech Inc Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies.
US20230024096A1 (en) 2019-10-29 2023-01-26 Hoffmann-La Roche Inc. Bifunctional compounds for the treatment of cancer
KR20220092580A (en) 2019-11-06 2022-07-01 제넨테크, 인크. Diagnosis and treatment methods for the treatment of blood cancer
MX2022005775A (en) 2019-11-13 2022-06-09 Genentech Inc Therapeutic compounds and methods of use.
CR20220330A (en) 2019-12-13 2022-08-04 Genentech Inc Anti-ly6g6d antibodies and methods of use
EP4076667A1 (en) 2019-12-20 2022-10-26 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
EP4096646A1 (en) 2020-01-27 2022-12-07 Genentech, Inc. Methods for treatment of cancer with an anti-tigit antagonist antibody
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
EP4143345A1 (en) 2020-04-28 2023-03-08 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
WO2021257503A1 (en) 2020-06-16 2021-12-23 Genentech, Inc. Methods and compositions for treating triple-negative breast cancer
MX2022015881A (en) 2020-06-18 2023-01-24 Genentech Inc 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
WO2022031749A1 (en) 2020-08-03 2022-02-10 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
JP2023544407A (en) 2020-10-05 2023-10-23 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 antibodies
WO2022133345A1 (en) 2020-12-18 2022-06-23 Erasca, Inc. Tricyclic pyridones and pyrimidones
JP2024506339A (en) 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 Bicyclic tetrahydroazepine derivatives for the treatment of cancer
WO2022251296A1 (en) 2021-05-25 2022-12-01 Erasca, Inc. Sulfur-containing heteroaromatic tricyclic kras inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023018699A1 (en) 2021-08-10 2023-02-16 Erasca, Inc. Selective kras inhibitors
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
US20230202984A1 (en) 2021-11-24 2023-06-29 Genentech, Inc. Therapeutic compounds and methods of use
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
WO2024020432A1 (en) 2022-07-19 2024-01-25 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024033388A1 (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
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033458A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9924037A1 *

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