Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to the use of certain quinazoline compounds in the treatment and inhibition of colonic polyps.
• FAP familial Adenomatous Polyps
• SAP sporadic adenomatous polyps
• APC The genetic basis for FAP has been linked to the presence of mutations in the APC gene. Similar APC mutations have been found in patients with sporadic polyps. Biochemically, the APC mutation occurs in conjunction with the increased expression of cyclooxygenase enzymes, particularly COX-2. These enzymes are essential for the production of prostenoids, (prostaglandin's; (PG's)) that mediate a number of functions in the bowel including motility, vascular tone, angiogenesis and mucosal protection. PG's are also purported to discourage apoptosis and this is proposed as an explanation for polyp formation.
• prostenoids prostaglandin's
• COX-2 cyclooxygenase enzymes
• COX inhibitors are predominantly NSAID's such as clinoril, sulindac, piroxicam and etodoloc, all of which appear to be equivalent in their action.
• NSAID therapy has been the development of serious side effects including peptic ulceration, and cholestatic hepatitis and renal papillary necrosis. Long term therapy with NSAIDs for the treatment of polyps is therefore considered to be impractical.
• COX-2 inhibitors have been shown to prevent this series of events.
• This invention provides a method of treating or inhibiting colonic polyps in a mammal in need thereof which comprises administering to said mammal a compound of formula 1:
• X is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1- 6 carbon atoms;
• R and Rj are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl;
• R 2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl;
• Y is a radical selected from the group consisting of
• the pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
• alkyl portion of the alkyl, alkoxy, carboalkoxy, carboalkyl, and alkanoylamino substituents include both straight chain as well as branched carbon chains, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n- pentyl or n-hexyl.
• Carboxy is defined as a -CO2H radical.
• Carboalkoxy of 2-7 carbon atoms is defined as a -CO 2 R" radical, where R" is an alkyl radical of 1-6 carbon atoms.
• Carboalkyl is defined as a -COR" radical, where R" is an alkyl radical of 1-6 carbon atoms.
• R is an alkyl radical of 1-6 carbon atoms.
• halogen refers to chlorine, bromine, iodine or fluorine.
• X is substituted, it is preferred that it is mono- , di- , or tri- substituted, with monosubstituted being most preferred.
• this invention covers the individual R and S entantiomers as well as the racemate with respect to such compound.
• preferred members include those in which R, R 1 , and R 2 are hydrogen; and those in which R, R 1 , and R 2 are hydrogen and X is phenyl either unsubstituted or monosubstituted with halogen or alkyl of 1-6 carbon atoms.
• R, R 1 , and R 2 are hydrogen; and those in which R, R 1 , and R 2 are hydrogen and X is phenyl either unsubstituted or monosubstituted with halogen or alkyl of 1-6 carbon atoms.
• One group of compounds within the invention are those wherein X is monosubstituted in the 3-position, preferably by a halogen, more preferably by bromine.
• R3 is preferably hydrogen, methyl, ethyl, phenyl, CO2H or CO2EL
• each R5 is independently hydrogen, phenyl, or alkyl of 1-6 carbon atoms
• R, Ri, R2, R3, X, and n are as defined above and R 4 is alkyl of 1-6 carbon atoms (preferably isobutyl).
• Y' is a radical selected from the group consisting of:
• each R'3 is independently alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms.
• a 5-nitro-anthranilonitrile of Formula 2 is heated at about 100°C with or without solvent containing an excess of dimethylformamide dimethyl acetal to furnish an amidine of Formula 3. Heating a solution of amidine 3 and the aniline 4 in acetic acid for 1 to 5 hours gives the 6-nitro- 4-anilinoquinazolines of Formula 5 .
• Representative compounds of this invention were evaluated in several standard pharmacological test procedures that showed that the compounds of this invention possess significant activity as inhibitors of protein tyrosine kinases, and are antiproliferative agents. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents.
• the test procedures used and results obtained are shown below.
• 4-choro-6-nitroquinazoline, 13, (Morley, JS. and Simpson,/. Chem.. Soc, 360 (1948)) is reduced to 6-amino-4- chloroquinazoline, 14, using a reducing agent such as sodium hydrosulfite in a two phase system consisting of tetrahydrofuran and water in the presence of a small amount of phase transfer catalyst.
• a reducing agent such as sodium hydrosulfite in a two phase system consisting of tetrahydrofuran and water in the presence of a small amount of phase transfer catalyst.
• the nitro group of 20 (prepared as in Flowsheet A) is reduced to the corresponding amino compound 21 using a palladium catalyst and a source of hydrogen which can be hydrogen itself or cyclohexene.
• a source of hydrogen which can be hydrogen itself or cyclohexene.
• Acylation of 21 with either an acid chloride of Formula 22 or a mixed anhydride of Formula 23 (which is prepared from the corresponding carboxylic acid) in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine or N-methyl morpholine gives the compounds of Formula 24.
• the ability of the compounds of this invention to treat or inhibit colonic polyps was demonstrated in an in vivo standard pharmacological test procedure as described below.
• the compound of Example 9 was evaluated in this procedure, which emulates familial adenomatous polyps (FAP) in humans, as a representative compound of this invention.
• the Min mouse used in this test procedure currently the best available model for FAP, is a strain which has lost both copies of the APC gene. These animals develop multiple intestinal polyps (Adenomas) that ultimately progress to form adenocarcinomas.
• the polyps that develop in Min mice express EGFR and have activated COX-2.
• NSAID's such as sulindac and etodoloc can reduce (but not eradicate) intestinal polyp formulation in these animals indicating that COX-2 and the ultimate production of PG's is likely responsible for these effects.
• Example 9 The compound of Example 9 was blended with a standard murine chow and animals were given ad libitum access to the food. Based on estimated food consumption, the compound of Example 9 was added at a concentration commensurate with animals ingesting 20 mg/kg/day. At day 30, 4 treated + 4 control (chow alone) animals were sacrificed and assessed for polyp number. All control animals had greater than 30 polyps in their bowel, while the treated animals had none. Identical results were observed at 60 days - when 15 animals/group were assessed. The control animals had greater than 30 (larger) polyps while the treated animals had none.
• the compounds of this invention may formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration.
• pharmaceutically acceptable carriers for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium.
• Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
• the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg.
• Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
• Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
• Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
• the preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred.
• active compounds may also be administered parenterally or intraperitoneally.
• Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringabiUty exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• N'-(4-Amino-2-cyanophenyl)-N.N-dimethylformamidine A solution of 6.0 g (27.5 mmol) of N'-(2-cyano-4-nitrophenyl)-N,N- dimethylformamidine, 33.9 g (41.8 ml, 412.4 mmol) of cyclohexene, and 0.6 g of 10% Pd/C in 360 ml of methanol was refluxed for 4 hrs. The hot mixture was filtered through Celite.
• N-f4-r(3-Bromopheny amino1-6-quinazolinyll-2-butvnamide A solution of 3.0 g (11.8 mmol) of N-[3-cyano-4-[[(dimethylamino)- methylenejamino] phenyl]-2-butynamide and 2.23 g (12.98 mmol) of 3-bromo aniline in 18 ml of acetic acid was refluxed gently with stirring under nitrogen for 1 hr 15 min.. The mixture was cooled in an ice bath and a solid mass formed.

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• 1998
  • 1998-11-04 NZ NZ503991A patent/NZ503991A/en unknown
  • 1998-11-04 AU AU13087/99A patent/AU1308799A/en not_active Abandoned
  • 1998-11-04 PL PL98340800A patent/PL340800A1/xx unknown
  • 1998-11-04 IL IL13562298A patent/IL135622A0/xx unknown
  • 1998-11-04 CN CN98810806A patent/CN1278176A/zh active Pending
  • 1998-11-04 CA CA002306155A patent/CA2306155A1/en not_active Abandoned
  • 1998-11-04 EP EP98956600A patent/EP1039910A1/en not_active Withdrawn
  • 1998-11-04 WO PCT/US1998/023549 patent/WO1999024037A1/en not_active Application Discontinuation
  • 1998-11-04 JP JP2000520129A patent/JP2001522802A/ja active Pending
  • 1998-11-04 BR BR9814116-3A patent/BR9814116A/pt not_active IP Right Cessation
  • 1998-11-04 HU HU0004286A patent/HUP0004286A3/hu unknown
  • 1998-11-04 KR KR1020007004883A patent/KR20010031813A/ko not_active Application Discontinuation
  • 1998-11-05 AR ARP980105592A patent/AR016415A1/es unknown
  • 1998-11-05 ZA ZA9810134A patent/ZA9810134B/xx unknown
• 2000
  • 2000-04-27 NO NO20002166A patent/NO20002166L/no not_active Application Discontinuation

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