JP2001522802A - Use of quinazoline derivatives as tyrosine kinase inhibitors to treat colorectal polyps - Google Patents

Abstract

(57) SUMMARY The present invention provides a method of treating or inhibiting a colon polyp in a mammal in need thereof. Such methods comprise administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Embedded image Wherein X is an optionally substituted phenyl; R and R ₁ are each independently hydrogen, halogen, alkyl, alkoxy, hydroxy or trifluoromethyl; R ₂ is hydrogen, alkyl, alkoxy, hydroxy or Trifluoromethyl; Y is a group selected from the group consisting of formulas (II), (III), (IV), (V), (VI), (VII) and (VIII); R ₃ is independently hydrogen , Alkyl, carboxy, carboalkoxy, phenyl or carboalkyl; n = 2 to 4; provided that each R ₃ of Y may be the same or different]

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to the use of several quinazoline compounds in the treatment and inhibition of colon polyps.

BACKGROUND ART [0002] Colon polyps occur in families (familial adenomatous polyps (FAP)),
Some occur sporadically. Although about 25,000 patients in the United States suffer from FAP, sporadic adenomatous polyps (SAPs) are estimated to occur in about 2 million annually in the United States alone. All of these patients are at risk for developing adenocarcinoma of the colon. In the case of FAP, the risk is virtually 100%, and these patients usually undergo colectomy at an early age. Patients with sporadic polyps are treated with polypectomy, but because of the inherent risk of polyps recurring,
Periodic examination by colonoscopy is necessary. In fact, patients and their siblings are at increased risk of developing colorectal cancer.

[0003] The genetic basis of FAP is related to the presence of mutations in the APC gene. Similar APC mutations have been found in patients with sporadic polyps. Biochemically,
APC mutations occur in connection with increased expression of cyclooxygenase enzymes, especially COX-2. These enzymes are responsible for motility, the normal state of blood vessels (vascular
It is essential for the production of prostenoids (prostaglandins (PG)) that mediate a number of functions in the gut, including tone, angiogenesis and mucosal protection. PG also
It is said to prevent apoptosis, which has been proposed as an explanation for polyp formation.

[0004] Treatments for FAP and SAP focus on inhibiting the COX enzyme.
There is a great deal of evidence for the efficacy of COX inhibitors in reducing polyp formation. These COX inhibitors are primarily NSAIDs such as clinolyl, sulindac, piroxicam and etodolac, all of which appear to have the same effect. A major problem with NSAID therapy is the occurrence of severe side effects such as peptic ulcer, cholestatic hepatitis, and renal papillary necrosis. Long-term treatment of polyps with NSAIDs is therefore considered impractical.

[0005] Recently, activation and overexpression of COX-2 in adenomatous polyps has been proposed to be due to activation of epidermal growth factor receptor (EGFR). EGFR stimulation with one of its ligands, ampyregulin (AR), triggers nuclear targeting of COX-2, polarized PG release, and subsequent mitogenesis in polarized colonic epithelial cells.

SUMMARY OF THE INVENTION The present invention provides a method of treating or inhibiting a colon polyp in a mammal in need thereof. Such a method comprises providing the mammal with Formula 1:

[0007]

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[Wherein, X is halogen, alkyl having 1 to 6 carbons, 1 to 6 carbons as required]
Of alkoxy, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy having 2 to 7 carbons, carboalkyl having 2 to 7 carbons, amino,
And phenyl optionally substituted with one or more substituents selected from the group consisting of alkanoylamino having 1 to 6 carbon atoms; R and R ₁ are each independently hydrogen, halogen, R ₂ is hydrogen, alkyl having 1 to 6 carbons, alkoxy, hydroxy, or trifluoromethyl having 1 to 6 carbons; alkyl having 1 to 6 carbons, alkoxy, hydroxy, or trifluoromethyl having 1 to 6 carbons; Y is

[0009]

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A group selected from the group consisting of: R ₃ is independently hydrogen, alkyl having 1 to 6 carbons, carboxy, carboalkoxy having 1 to 6 carbons, phenyl, or 2 to 7 carbons. Carboalkyl; n = 2 to 4; provided that each R ₃ of Y may be the same or different], or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts include acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, malonic acid, gluconic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, And similarly derived from organic and inorganic acids, such as known acceptable acids.

The alkyl portion of the alkyl, alkoxy, carboalkoxy, carboalkyl and alkanoylamino substituents includes both straight and branched carbon chains, eg, methyl, ethyl, n-propyl, i-propyl, n-butyl , I-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like. Carboxy is defined as -CO ₂ H group. Carboalkoxy having 2 to 7 carbon atoms is -CO ₂ R
'' (Where R '' is an alkyl group having 1 to 6 carbon atoms). Carboalkyl is defined as a -COR "group (where R" is an alkyl group having 1 to 6 carbon atoms). As used herein, the term halogen means chlorine, bromine, iodine or fluorine. When X is substituted, it is preferably mono-, di- or trisubstituted, with mono-substitution being most preferred. Where the compounds of the present invention contain asymmetric centers, the present invention includes the individual R and S enantiomers and racemates of such compounds.

Preferred among the compounds of the present invention are those wherein R, R ₁ and R ₂ are hydrogen, and those wherein R, R ₁ and R ₂ are hydrogen and X is unsubstituted phenyl;
Alternatively, phenyl mono-substituted by halogen or alkyl having 1 to 6 carbon atoms may be mentioned. Certain compounds within the scope of the present invention are those wherein X is monosubstituted at the 3-position, preferably by halogen, more preferably by bromine. Additional compounds within the scope of the present invention, Y is _{-CH = CH-CO 2 H,} -
_{CH = CH-CO 2 Et,} -CH = C (Me) 2, -CH = CH-Et, -CH = CH-C
_{H 3, -CH = CH-CH} = CH-CH 3, -CH = CH 2, -CH = CH-Ph, -C≡
It is C-CH ₃ or 2-cyclopentene. R ₃ is preferably hydrogen,
Methyl, ethyl, phenyl, CO ₂ H or CO ₂ Et.

The process for the preparation of the compound of formula 1 as defined above comprises: a) Formula 6:

[0015]

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[Wherein R, R ₁ , R ₂ and X are as defined above], 6-amino-4-anilinoquinazoline represented by the following formula:

[0017]

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Wherein Y is as defined above; ii) Formula 8:

[0019]

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Wherein Y is as defined above, or iii) Formula 11:

[0021]

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Wherein each R ₅ is independently hydrogen, phenyl or a C 1-6 alkyl anhydride; b) Formula 17:

[0023]

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Wherein R, R ₁ , R ₂ and Y are as defined above, and Hal is a suitable halogen.

[0025]

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Wherein X is as defined above; or c) reacting with aniline represented by the formula:

[0027]

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[Wherein R, R ₁ , R ₂ and Y are as defined above], with a compound represented by the formula 25:

[0029]

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Wherein X is as defined above; and reacting with aniline represented by the formula:

The preparation of the compounds of the present invention encompassed by Formula 9 is shown in Flow Sheet A below.
Here, R, R ₁ , R ₂ , R ₃ , X and n are as defined above, R ₄ is alkyl having 1 to 6 carbon atoms (preferably isobutyl), and Y ′ is

[0032]

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Wherein each R ′ ₃ is independently alkyl having 1 to 6 carbons, carboxy, 1 carbon
To 6 carboalkoxy, phenyl or C2 to C7 carboalkyl]. Following a series of reactions outlined in Flow Sheet A, 5-nitro-anthranilonitrile of Formula 2 is optionally added to a solvent containing excess dimethylformamide dimethyl acetal for about 100
Heating at 0 ° C. gives the amidine of formula 3. A solution of amidine 3 and aniline 4 in acetic acid is heated for 1-5 hours to give 6-nitro-4-anilinoquinazoline of formula 5 Reduction of the nitro group of 5 with a reducing agent such as iron in an acetic acid-alcohol mixture at elevated temperature gives 6-amino-4-anilinoquinazoline of formula 6 The acid chloride of formula 7 or formula 8 in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine or triethylamine
Acylation of 6 with any of the mixed anhydrides of formula (which are prepared from the corresponding carboxylic acid) gives compounds of the present invention of formula 9 If 7 or 8 has asymmetric carbon atoms, they can be used as racemates or as individual R or S enantiomers. In this case, the compound of the present invention is a racemate or an R or S optically active compound, respectively. The 5-nitro-anthranilonitrile of formula 2 required to prepare the compounds of the present invention is already known in the art or is known in the art as detailed in the following documents: Can be manufactured by the methods: Baudet, Reclair Trav. Chimixes des Pais-Bas (Recl. Trav. Chim. Pays-Bas), 43,710 (1924); Hartmanns (H)
artmans), Requeail Death Travox Kimiques Death Pais-Bass (
Recl. Trav. Chim. Pays-Bas), 65,468,469 (1946); Taylor et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.),
82,6058,6063 (1960); Taylor et al., Journal of the American Chemical Society (J. Amer. Chem. Soc.), 82, 3152, 3154 (1960); Deshpande), Seshadri, Indian Journal of Chemistry, 11,538 (1973); Katritzky, Alan R., Lorenzo, Kathleen S.
Kathleen S.), Journal of Organic Chemistry (J. Org. Chem.),
51 (1986); Nicolas, Hans-Joachim, Bohle, Matthias, Rick, Jens-Detlev, Zeuner, Frank, Zoelch, Lothar, Z. Chem., 25 (4), 135-138 (1985).

[0034]

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The preparation of the compounds of the invention encompassed by Formula 12 is shown in Flow Sheet B below. Here, R, R ₁ , R ₂ , X and n are as defined above, and each R ₅ is independently hydrogen, phenyl or alkyl having 1 to 6 carbons. According to the reaction outlined in Flow Sheet B, 6-amino-anilinoquinazoline of Formula 10 (prepared as in Flow Sheet A) is prepared in an inert solvent such as tetrahydrofuran in the presence of a base catalyst such as pyridine or triethylamine. , With a cyclic anhydride of formula 11

[0036]

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Representative compounds of the present invention were evaluated in several standard pharmacological tests. These assays showed that the compounds of the invention have significant activity as inhibitors of protein tyrosine kinases and are growth inhibitory drugs. Therefore, based on the activities shown in standard pharmacological tests, the compounds of the present invention are useful as anti-neoplastic agents. The test method used and the results obtained are shown below.

The preparation of the compounds of the invention encompassed by Formula 19 is shown in Flow Sheet C below.
Here, Y ′, R ₄ and X are as defined above. According to the reaction outlined in Flow Sheet C, 4-chloro-6-nitroquinazoline 13 (Morley, JS)
ley, JS) and Simpson, Journal of the Chemical Society (J. Chem. Soc.), 360 (1948)) in small amounts of phase transfer in a two-phase system consisting of tetrahydrofuran and water. Reduction to 6-amino-4-chloroquinazoline 14 using a reducing agent such as sodium dithionite in the presence of a catalyst. 14 in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine or N-methylmorpholine in the presence of an acid chloride of formula 15 or a mixed anhydride of formula 16 (Prepared from carboxylic acid) to give compounds of formula 17 If 15 or 16 has asymmetric carbon atoms, they can be used as racemates or as individual R or S enantiomers. in this case,
The compounds of the present invention are racemic or R or S optically active compounds, respectively. Heating a compound of formula 17 with an aniline of formula 18 in an inert solvent such as isopropanol gives a compound of the present invention of formula 19.

[0039]

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The preparation of compounds of the present invention encompassed by Formula 26 is shown in Flow Sheet D below. Here, Y ′, R ₄ and X are as defined above. According to the reaction outlined in Flow Sheet D, 20 (prepared as in Flow Sheet A) nitro groups are reduced to the corresponding amino compound 21 using a palladium catalyst and a hydrogen source. The hydrogen source can be hydrogen itself or cyclohexene. 21 in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine or N-methylmorpholine in the presence of an acid chloride of formula 22 or a mixed anhydride of formula 23 (Prepared from a carboxylic acid) to give compounds of formula 24. If 22 or 23 have asymmetric carbon atoms, they can be used as racemates or as individual R or S enantiomers. In this case, the compound of the present invention is a racemate or an R or S optically active compound, respectively. Heating a compound of formula 24 with an aniline of formula 25 in an inert solvent such as acetic acid gives a compound of the present invention of formula 26.

[0041]

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The ability of the compounds of the present invention to treat or inhibit colon polyps has been demonstrated in standard pharmacological tests in vivo as described below. The compound of Example 9 was evaluated as a representative compound of the present invention in this manner, mimicking human familial adenomatous polyps (FAP). The Min mouse used in this test is the best FAP model available at the moment, a pedigree that lacks both copies of the APC gene. These animals develop multiple intestinal polyps (adenomas) and eventually progress to form adenocarcinoma. Polyps that develop in Min mice express EGFR and activate COX-2. NSAIDs such as sulindac and etodolac can reduce (but not cure) intestinal polyps that require COX-2 in these animals, but the final production of PGs is likely to have these effects. Is the cause. The method used for this standard pharmacological test and the results obtained are briefly described below.

The compound of Example 9 was mixed with standard rat chow and the animals were allowed free access to food. Based on the estimated food consumption, the compound of Example 9 was
g / kg / day was added at a concentration corresponding to the animal receiving the feed. On day 30, 4 treated animals and 4 control (fed only) animals were killed and evaluated for polyp numbers. All control animals had more than 30 polyps in their intestines, while no treated animals had any. The same result was observed on day 60 when 15 animals / group were evaluated. The control animals had more than 30 (larger) polyps, while the treated animals had none.

These data indicate that the compounds of the present invention effectively inhibit polyp formation in animals having a mutation in the APC gene. Based on the results obtained in this standard pharmacological test method, the compounds of the invention are useful for treating or inhibiting colon polyp formation.

The compound of the present invention may be formulated as it is, or may be combined with one or more pharmaceutically acceptable carriers for administration (eg, solvents, diluents, etc.), tablets, capsules and the like. , A dispersible powder, a granule, or a suspension containing, for example, about 0.05 to 5% of a suspending agent, for example, a syrup containing about 10 to 50% of sugar, for example, about 20%. Oral administration in the form of an elixir containing 50 to 50% ethanol, or a sterile injectable solution containing about 0.05 to 5% of a suspending agent in an isotonic injection solution or isotonic medium Parenteral administration may be carried out in the form of a suspension or the like. Such pharmaceutical preparations may contain, for example, from about 0.05% to about 90%, more usually from about 5% to 60% by weight of the active ingredient in combination with the carrier.

The effective amount of the active ingredients employed can vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated. In general, however, the compounds of the present invention will be administered in a daily dose of about 0.5 to about 1000 mg / kg of animal body weight, optionally in divided doses or sustained release form 2 to 4 times per day. Satisfactory results can be obtained. For most large animals, the total daily dose will be about 1-1000 mg, preferably about 2 mg.
５００500 mg. Dosage forms suitable for internal use contain from about 0.5 to 1000 mg of the active compound intimately mixed with a pharmaceutically acceptable solid or liquid carrier. This dosage regimen may be adjusted to give the optimal therapeutic response. For example, several divided doses may be administered daily and the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

These active compounds may be administered not only orally but also by the intravenous, intramuscular or subcutaneous route. Depending on the nature of the active ingredient and the particular dosage form desired, solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose,
Examples of the liquid carrier include sterilized water, polyethylene glycol, nonionic surfactants, and edible oils such as corn oil, peanut oil, and sesame oil. Convenient adjuvants conventionally used in the manufacture of pharmaceutical compositions include flavoring agents, coloring agents, preservatives, antioxidants such as vitamin E, ascorbic acid, BHT, BHA and the like.

Preferred pharmaceutical compositions from the standpoint of ease of manufacture and administration are solid compositions, especially tablets, hard-filled capsules or liquid-filled capsules. Oral administration of the compounds is preferred.

[0049] In some cases, it may be desirable to administer the compound directly to the respiratory tract in the form of an aerosol.

These active compounds may be administered parenterally or intraperitoneally. When these active compounds are the free bases or pharmaceutically acceptable salts, their solutions or suspensions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powdery preparations 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 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 (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), a suitable mixture thereof, vegetable oil, and the like.

EXAMPLES The preparation of representative examples of the compounds of the present invention is described below.

Example 1 N ′-(2-cyano-4-nitrophenyl) -N, N-dimethylformamidine 5-nitro-anthranilonitrile 40.8 g and N, N-dimethylformamide dimethyl acetal 40 mL Heated on steam bath for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride. The solution was filtered through Magnesol and the solvent was removed. After washing with ether, 50.8 g of N '-(2-cyano-4-nitrophenyl) -N, N-dimethylformamidine were obtained.

Example 2 N- (3-Bromophenyl) -6-nitro-4-quinazolinamine 23.74 mL of 3-bromoaniline and N '-(2-
A solution of 40.5 g of (cyano-4-nitrophenyl) -N, N-dimethylformamidine was stirred and heated in a 148 ° C. oil bath for 1.5 hours. After cooling, the solid obtained is filtered off to give a quantitative yield of N- (3-bromophenyl) -6-nitro-4-quinazolinamine. 267-270 ° C; mass spectrum (m / e): 345.

Example 3 N- (3-bromophenyl) -4,6 -quinazolinediamine 34.5 g of N- (3-bromophenyl) -6-nitro-4-quinazolineamine in 150 mL of ethanol and 150 mL of glacial acetic acid A mixture of 16.8 g of iron powder was heated in a 120 ° C. oil bath for 2 hours. After filtering the solid, solid sodium carbonate was added to the filtrate to obtain a solid. It was filtered and the solid was extracted with methanol. The extract was treated with activated charcoal and evaporated to give a solid. After the solid was washed with ether, 27.5 g of N- (3-bromophenyl) -4,6-quinazolinediamine was obtained. Mass spectrum (m / e): 315.

Example 4 15-mL of 4-[[4-[(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (Z) -2-butenoic acid pyridine was added to N- (3-bromo (Phenyl) -4,6-quinazolinediamine 1.6
g and 0.6 g of maleic anhydride. After stirring overnight, the solvent was removed on a rotary evaporator. The solid is dissolved in about 400 mL of hot ethanol, the insoluble matter is filtered, and 4-[[4-[(3-bromophenyl) amino] -6-quinazolinyl] amino
0.34 g of] -4-oxo- (Z) -2-butenoic acid were obtained. Mass spectrum (m / e): M +
H 413, 415.

Example 5 4-[[4-[(3-Bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) -2-butenoic acid ethyl ester N- ( A solution of (3-bromophenyl) -4,6-quinazolinediamine 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 solvent was removed under reduced pressure and the residue was treated with water. The red solid was filtered and extracted into hot acetone. After filtering the insoluble matter, the filtrate was concentrated and ethyl 4-[[4-[(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) -2-butenoate was added. 0.45 g was obtained. 259-263 ° C; mass spectrum (m / e): M + H 441,443.

[0058] Example 6 N- [4 - [(3- bromophenyl) amino] -6-quinazolinyl] -3-amino-2-butene N'amido N- (3- bromophenyl) in pyridine 15 mL -4, A solution of 1.58 g of 6-quinazolindiamine 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 solvent was removed under reduced pressure. The residue was treated with water and the resulting solid was recrystallized from methyl cellosolve to give N- [4-[(3-bromophenyl) amino] -6-quinazolinyl
0.93 g of] -3-methyl-2-butenamide was obtained. Melting point 300-301 [deg.] C; mass spectrum (m / e): 396,398.

[0059] Example 7 N- [4 - [(3- bromophenyl) amino] -6-quinazolinyl] - (E) N-during-2 Buten'ami de pyridine 15 mL (3- bromophenyl) -4,6 A solution of 1.6 g of -quinazoline diamine was cooled in an ice bath and a solution of 0.57 mL of trans-crotonyl chloride in 6 mL of ether was added dropwise. After stirring and cooling for 2 hours, the solvent was removed under reduced pressure. The residue was treated with water and the solid obtained was recrystallized from n-butanol to give N- [4-[(3-bromophenyl) amino] -6-quinazolinyl]-(E) -2-butenamide 0 .69 g were obtained. 153-160 ° C; mass spectrum (m / e):
M + H 383,385.

[0060] EXAMPLE 8 N- [4 - [(3- bromophenyl) amino] -6-quinazolinyl] -2-methyl-2-N-in the pro Pen'amido pyridine 15 mL (3- bromophenyl) -4,6 A solution of 1.6 g of -quinazoline diamine was cooled in an ice bath and a solution of 0.59 mL of methacryloyl chloride in 6 mL of ether was added dropwise. After stirring and cooling for 2 hours, the solvent was removed under reduced pressure. The residue was treated with water and the resulting solid was added to n-butanol (while warming).
) Dissolved. Ether is added to the cooled solution to give 0.44 g of N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2-methyl-2-propenamide. Melting point 40-245 [deg.] C; mass spectrum (m / e): M + H 383,385.

Example 9 A solution of 0.50 g of 2-butyric acid in 10 mL of N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2-butynamide tetrahydrofuran was cooled in an ice bath. After adding 0.79 mL of isobutyl chloroformate, 0.66 mL of N-methylmorpholine was added. After about 1 minute, a solution of 1.6 g of N- (3-bromophenyl) -4,6-quinazolinediamine in 10 mL of pyridine was added. The reaction was returned to room temperature and stirred overnight. The solvent was removed under 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-[[4-[(3-Bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) -2-butenoic acid 2.5 mL of a 10 N aqueous sodium hydroxide solution was added. 4- in 25 mL of ethanol
[[4-[(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E)-
Ethyl 2-butenoate (Example 5) was added to 2.3 g. After stirring for 1 hour, 2.1 mL of concentrated hydrochloric acid was added and the reaction was stirred for another 2 hours. The obtained solid was recrystallized from n-butanol to give 4-[[4-[(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) -2-butenoic acid 0.97 g was obtained. Mass spectrum (m / e): M + H 413.

[0063] Example 11 N- [4 - [(3- bromophenyl) amino] -6-quinazolinyl] -2,4-hexadiene amide in tetrahydrofuran 10mL ice solvent solution of 2,4-hexadiene acid 0.67g during Cooled in bath. After adding 0.79 mL of isobutyl chloroformate, 0.66 mL of N-methylmorpholine was added. After about 1 minute, N-
A solution of 1.6 g of (3-bromophenyl) -4,6-quinazolinediamine was added. The reaction was brought to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the solid was recrystallized to obtain 1.0 g of N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2,4-hexadienamide. 258-260 ° C.

Was cooled in - [[(3-bromophenyl) amino] -6-quinazolinyl 4] -2-cyclopentene amide in tetrahydrofuran in an ice bath a solution of 2-cyclopentene acid 0.43g during 5mL [0064] Example 12 N- . After adding 0.49 mL of isobutyl chloroformate, 0.41 mL of N-methylmorpholine was added. After about 1 minute, N- (3-
A solution of 1.0 g of (bromophenyl) -4,6-quinazolinediamine was added. The reaction was warmed to room temperature and stirred overnight. An additional 0.5 equivalents of the mixed anhydride was added. The mixture was stirred for 5 hours. The solvent was removed under 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-cyclopentenamide. Obtained. Mass spectrum (m / e): 409 (M + H, EI).

Example 13 N- [3-[(3-bromophenyl) amino] -6-quinazolinyl] -2-propenamido N- (3-bromophenyl) -4,6-quinazolinediamine in 10 mL A solution of 2.0 g was cooled in an ice bath and a solution of 0.61 mL of acryloyl chloride in 30 mL of ether was added dropwise at 0 ° C. After stirring at room temperature for 3.5 hours, the solvent was removed under reduced pressure. The residue was purified by chromatography to obtain 0.2 g of N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2-propenamide. Mass spectrum (m / e): M + H 369.

[0066] Example 14 N- [4 - [(3- bromophenyl) amino] -6-quinazolinyl] - (3-phenyl-2-flop Ropin'amido) 3-phenyl-2-propionic acid in tetrahydrofuran 10 mL 0. 93g
Was cooled in an ice bath. After adding 0.82 mL of isobutyl chloroformate, N-
0.69 mL of methylmorpholine was added. After about 1 minute, a solution of 1.0 g of N- (3-bromophenyl) -4,6-quinazolinediamine in 7 mL of pyridine was added. The reaction was left at 0 ° C. for 1 hour. The solvent was removed under reduced pressure and the solid was purified by chromatography on silica gel to give N- [4-[(3-bromophenyl) amino] -6-quinazolinyl]-(3-phenyl-2-propynamide ) 0.01 g was obtained. Mass spectrum (m / e): 443.2, 445.2 (M + H, electrospray).

Example 15 6.25 g of 4-chloro-6-nitroquinazoline, 10.8 g of sodium dithionite and phase transfer catalyst in 97 mL of 6-amino-4- chloroquinazoline tetrahydrofuran and 32 mL of water
A mixture consisting of 0.3 g of (C ₈ H ₁₇ ) ₃ NCH ₃ ⁺ Cl ⁻ was rapidly stirred for 2 hours. The mixture was diluted with ether and the organic layer was separated. The organic solution was washed with a saline solution and dried over magnesium sulfate. This solution was passed through a small column of silica gel. The solvent was removed at 30 ° C. under reduced pressure to give 6-amino-4-chloroquinazoline. This is used for the next step without further purification.

Example 16 [4-Chloro-6-quinazolinyl] -2- butynamide A solution of 1.64 g of 2-butynic acid in 46 mL of tetrahydrofuran was cooled in an ice bath. After addition of 2.34 mL of isobutyl chloroformate, 4.13 mL of N-methylmorpholine was added. After about 10 minutes, it was poured into a solution of 6-amino-4-chloroquinazoline in 46 mL of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours. The mixture was poured into a mixture of brine and saturated sodium bicarbonate solution and extracted with ether. The ether solution was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give [4-chloro-6-quinazolinyl] -2
-Butynamide was obtained as a colored oil. This was used in the next step without further purification.

Example 17 1.76 g of N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2-butynamide [4-chloro-6-quinazolinyl] -2-butynamide and 3-bromoaniline A solution consisting of 1.23 g was refluxed in 23 mL of isopropanol under an inert atmosphere for 40 minutes. The mixture was cooled to room temperature, 200 mL of ether was added, and N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2-butynamide was added.
4 g were obtained as the hydrochloride. Neutralize with sodium bicarbonate solution, extract with ethyl acetate, remove the solvent, recrystallize from 1-butanol to give N- [4-[(3-bromophenyl) amino] -6-quinazolinyl]- 2-butynamide is obtained as the free base.

Example 18 N ′-(4-Amino-2-cyanophenyl) -N, N-dimethylformamidine N ′-(2-Cyano-4-nitrophenyl) -N, N- in 360 mL of methanol
6.0 g (27.5 mmol) of dimethylformamidine, 33.9 g of cyclohexene (
41.8 mL, 412.4 mmol), and 0.6 g of 10% Pd / C were refluxed for 4 hours. The hot mixture was filtered through Celite. The solvent was removed and the residue was recrystallized from chloroform-carbon tetrachloride to give 4.9 g (95%) of the title compound.
Was obtained as a light gray crystalline solid. Mass spectrum (m / e): 188.9 (M + H, electrospray).

[0071] EXAMPLE 19 N-[3- cyano-4 - [[(dimethylamino) methylene] amino] phenyl] -2-butyne amide in tetrahydrofuran 30 mL 2.01 g 2-butyne acid in (23.9 Mimoru
) And isobutyl chloroformate (2.9 mL, 22.3 mmol) were added at 0 ° C. under nitrogen while adding 2.42 g (2.63 mL, 22.3 mmol) of N-methylmorpholine over 3 minutes. With stirring. After stirring for 15 minutes, tetrahydrofuran 25m
A solution of 1.6 g (1.75 mL, 15.9 mmol) of N '-(4-amino-2-cyanophenyl) -N, N-dimethylformamidine and N-methylmorpholine in L was added for 4 minutes. The mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 30 minutes. The mixture was diluted with 70 mL of ethyl acetate and poured into a mixture of brine and saturated sodium bicarbonate solution. The organic layer was dried (MgSO ₄ ) 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 yield 3.61 g (89%) of an off-white solid. Mass spectrum (m / e): 255.0 (M + H, electrospray).

Example 20 N- [3-[(3-bromophenyl) amino] -6-quinazolinyl] -2-butynamidoacetic acid 18 mL of N- [3-cyano-4-[[(dimethylamino) methylene] A solution of 3.0 g (11.8 mmol) of amino] phenyl] -2-butynamide and 2.23 g (12.98 mmol) of 3-bromoaniline was gently refluxed for 1 hour and 15 minutes while stirring under nitrogen. The mixture was cooled in an ice bath and a solid formed.
The solid was collected by filtration and washed with ether-acetonitrile (1: 1) to give a yellow solid. This was recrystallized from ethanol to obtain 2.51 g of N- [4-[(3-bromophenyl) amino] -6-quinazolinyl] -2-butynamide. Mass spectrum (m / e): 381,383.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW [Continued Summary] R ₃ is independently hydrogen, alkyl, carboxy, carboalkoxy, phenyl Or carboalkyl; n = 2-4, provided that each R ₃ of Y may be the same or different]

Claims (9)

[Claims] 1. A method for treating or inhibiting a colonic polyp in a mammal in need thereof, wherein said mammal has the formula: [Wherein, X is halogen, alkyl having 1 to 6 carbons, 1 to 6 carbons, if desired]
Of alkoxy, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy having 2 to 7 carbons, carboalkyl having 2 to 7 carbons, amino,
And phenyl optionally substituted with one or more substituents selected from the group consisting of alkanoylamino having 1 to 6 carbon atoms; R and R ₁ are each independently hydrogen, halogen, R ₂ is hydrogen, alkyl having 1 to 6 carbons, alkoxy, hydroxy, or trifluoromethyl having 1 to 6 carbons; alkyl having 1 to 6 carbons, alkoxy, hydroxy, or trifluoromethyl having 1 to 6 carbons; Y is R ₃ is independently hydrogen, alkyl having 1 to 6 carbons, carboxy, carboalkoxy having 1 to 6 carbons, phenyl, or carboalkyl having 2 to 7 carbons; wherein each R ₃ of Y may be the same or different.] or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, wherein R, R ₁ and R ₂ are hydrogen or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1, wherein X is unsubstituted phenyl or phenyl substituted with halogen or alkyl having 1 to 6 carbon atoms. 4. 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 one of these The method according to any one of claims 1 to 3, wherein the administered salt is administered. 5. A method for the manufacture of a medicament for treating or inhibiting a colonic polyp in a mammal, comprising the step of formula: [Wherein, X is halogen, alkyl having 1 to 6 carbons, 1 to 6 carbons, if desired]
Of alkoxy, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy having 2 to 7 carbons, carboalkyl having 2 to 7 carbons, amino,
And phenyl optionally substituted with one or more substituents selected from the group consisting of alkanoylamino having 1 to 6 carbon atoms; R and R ₁ are each independently hydrogen, halogen, R ₂ is hydrogen, alkyl having 1 to 6 carbons, alkoxy, hydroxy, or trifluoromethyl having 1 to 6 carbons; alkyl having 1 to 6 carbons, alkoxy, hydroxy, or trifluoromethyl having 1 to 6 carbons; Y is R ₃ is independently hydrogen, alkyl having 1 to 6 carbons, carboxy, carboalkoxy having 1 to 6 carbons, phenyl, or carboalkyl having 2 to 7 carbons; wherein each R ₃ of Y may be the same or different.] or a pharmaceutically acceptable salt thereof. 6. The method according to claim 5, wherein R, R ₁ and R ₂ are hydrogen or a pharmaceutically acceptable salt thereof. 7. The use according to claim 5, wherein X is unsubstituted phenyl or phenyl substituted with halogen or alkyl having 1 to 6 carbon atoms. 8. 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] 8. 6-Quinazolinyl] -2-propenamide or N- [4-[(3-bromophenyl) amino] -6-quinazolinyl]-(3-phenyl-2-propynamide). Use according to any one of the preceding claims. 9. A pharmaceutical composition for treating or inhibiting colonic polyps in mammals, comprising a compound of formula 1 as defined in claim 5, optionally comprising:
A pharmaceutical composition further comprising a pharmaceutical carrier.