MXPA00004304A - 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 polypsInfo
- Publication number
- MXPA00004304A MXPA00004304A MXPA/A/2000/004304A MXPA00004304A MXPA00004304A MX PA00004304 A MXPA00004304 A MX PA00004304A MX PA00004304 A MXPA00004304 A MX PA00004304A MX PA00004304 A MXPA00004304 A MX PA00004304A
- Authority
- MX
- Mexico
- Prior art keywords
- amino
- bromophenyl
- carbon atoms
- quinazolinyl
- alkyl
- Prior art date
Links
- 206010051589 Large intestine polyp Diseases 0.000 title claims abstract description 8
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- -1 carboalkoxy Chemical group 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 11
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 5
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 51
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 24
- 206010061529 Polyp Diseases 0.000 claims description 14
- 241000565118 Cordylophora caspia Species 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
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- UUOXJUPRPMFYMJ-UHFFFAOYSA-N N-[4-(3-bromoanilino)quinazolin-6-yl]-3-methylbut-2-enamide Chemical compound C12=CC(NC(=O)C=C(C)C)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 UUOXJUPRPMFYMJ-UHFFFAOYSA-N 0.000 claims description 4
- FDWGPDCUBAYMRY-UHFFFAOYSA-N N-[4-(3-bromoanilino)quinazolin-6-yl]hexa-2,4-dienamide Chemical compound C12=CC(NC(=O)C=CC=CC)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 FDWGPDCUBAYMRY-UHFFFAOYSA-N 0.000 claims description 4
- HTUBKQUPEREOGA-UHFFFAOYSA-N N-[4-(3-BROMO-PHENYLAMINO)-QUINAZOLIN-6-YL]-ACRYLAMIDE Chemical compound BrC1=CC=CC(NC=2C3=CC(NC(=O)C=C)=CC=C3N=CN=2)=C1 HTUBKQUPEREOGA-UHFFFAOYSA-N 0.000 claims description 3
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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 TYROSIN INHIBITORS KINASE FOR THE TREATMENT OF COLONIC POLYPS
This invention describes the use of certain quinazoline compounds in the treatment and inhibition of colonic polyps. Colonic polyps occur both in a familial pattern (familial adenomatous polyps (FAP)) and sporadically. FAPs afflict approximately 25,000 patients in the United States; while it is estimated that sporadic adenomatous polyps (SAP) occur in approximately 2 million people per year in the United States alone. All these patients are at risk of developing adenocarcinoma of the colon. In the case of FAP, the risk is virtually 100% and those patients usually undergo colectomy at an early age. Patients with sporadic polyps are treated with polypectomy and require periodic colonoscopic extermination since there is an inherent risk of developing recurrent polyps. In fact, the parents and siblings of these patients are also prone to increase the risk of developing colorectal cancer. REF .: 119583 The genetic basis for FAP has been associated with the presence of mutations in the APC gene. Similar mutations in APC 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. (of prostaglandin (PG's)) that mediate a number of functions in the intestines including mortality, vascular tone, angiogenesis and mucosal protection. PG's are also involved to discourage apoptosis and this is proposed as an explanation of polyp formation. FAP and SAP therapy has focused on inhibiting COX enzymes. There is considerable evidence for the efficiency of COX inhibitors in reducing polyp formation. These COX inhibitors are predominantly
NSAIDs such as clinoril, salindac, piroxicam and etcdoloc. all of which appear to be equivalent by their action. A major problem with NSAID therapy has been the development of serious side effects including peptic ulceration and cholestatic hepatitis and papillary renal necrosis. Prolonged therapy with NSAIDs for the treatment of polyps is therefore considered impractical. It has recently been proposed that the activation and overexpression of COX-2 in adenomatous polyps is due to the activation of the epidermal growth factor receptor (EGFR). The stimulation of EGFR by one of the ligands -amfiregulin (AR), induces the nuclear target of COX-2, the release of PG's and the subsequent mitogenesis, in polarized colonic epithelial cells. COX-2 inhibitors have been shown to prevent this series of events.
DESCRIPTION OF THE INVENTION The invention provides a method of treatment or inhibition of colonic polyps in a mammal in need thereof which comprises the administration to said mammal of a compound of formula 1:
Where: X is a phenyl optionally substituted with one or more substituents selected from the group consisting of a halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, cycloalkyl 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; R is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl; And it is a radical selected from the group consisting of
RJ 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, tartaric, citric, 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 open chains and branched carbon chains, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t -butyl, n-pentyl or n-hexyl. The carboxy is defined as a -C02H radical. Carboalkoxy of 2-7 carbon atoms is defined as a -C02R radical ", where R" is an alkyl radical of 1-6 carbon atoms. The carboalkyl is defined as a radical -CORA where the radical R "is an alkyl radical of 1-6 carbon atoms When used herein the term halogen refers to a chlorine, bromine, iodine or fluoro When X is substituted, it is preferred that it be mono-, di- or tri-substituted, monosubstituted being the most preferred When a compound of this invention contains an asymmetric center, this invention covers the individual R and S enantiomers 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, R2 are hydrogen and X is an unsubstituted or mono-substituted phenyl with a halogen or an alkyl of 1-6 carbon atoms A group of compounds within the invention are those in which X is monosubstituted in the 3-position, preferably by a halogen, more preferably by bromine, in addition a group of the compound of the invention. on those where Y is
-CH = CH-C02H, -CH = CH-C02Et, -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-cyclopentane. R3 is preferably hydrogen, methyl, ethyl, phenyl, C02H or C02Et. A process for the preparation of a compound of formula 1 as defined above comprising: a) the reduction of a 6-amino-4-anilinoquinazoline of Formula 6 wherein R, Ri, R2 and X are as defined above
with i) an acid chloride of Formula 7, wherein Y is as defined above Cl
ii) a mixed anhydride of Formula 8, wherein Y is as defined above
or iii) a cyclic anhydride of Formula 11 wherein R5 is independently hydrogen, phenyl or alkyl of 1-6 carbon atoms
b) reacting a compound of formula 17 wherein R, Ri, R2 and are as defined above and Hal is any suitable halogen.
17 With an aniline of Formula 18 where X is as defined above
X-NH?
18
or c) reacting a compound of Formula 24 wherein R, R_, R2 and Y are as defined above
With an aniline of formula 25
H2N-X 25
Where X is as defined above The preparation of the compounds of the present invention included by Formula 9 is described below in flow chart A wherein R. Ri, R2, R3 and n are as defined above and R. is alkyl of 1-6 carbon atoms (preferably isobutyl). Y 'is a radical selected from the group consisting of:
Where 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 reaction sequence summarized in the flow diagram A a 5-nitro-anthranilonitrile of Formula 2 is heated to about 100 ° C with or without a solvent containing an excess of dimethyl acetal dimethylformamide to produce an amidine of Formula 3. Heating a solution of amidine 3 and aniline 4 in acetic acid for 1 to 5 hours to give the 6-nitro-4-anilinoquinazoline of Formula 5. The reduction of the nitro group of 5 using a reducing agent such as iron in a mixing of acetic acid and alcohol at an elevated temperature provides the 6-amino-4-anilinoquinazoline of Formula 6. The acylation of 6 with 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 provides the compounds of this invention represented by Formula 9. In those cases where 7 or 8 have asymmetric carbon atom, they can be used as the racemate or as the individual R or S enantiomers such case the compounds of this invention will be in optically active R and S or racemic forms; respectively. The 5-nitro-anthranilonitriles of formula 2 needed to prepare the compounds of this invention are those already known in the field or can be prepared by methods known in the art as detailed in the following references: Baudet, Recl. Trav. Chim. Pays-Bas, 43, 710 (1924); Hart ans, Recl. Trav. Chim. Pays-Bas, 65, 468, 469 (1946); Taylor et al., J.A er .Chem. Soc., 82, 6958, 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); Nielas, Hans-Joachim; Bohle, Matthias; Rick, Jeans-Detlev; Zeuner, Frank Zoelch, Lothar, Z.Chem., 25 (4), 137-138 (1985). FLOW DIAGRAM A
The preparation of the compounds of this invention included in Formula 12 is described below in flow chart B where R, R_, R2, X and n are as described above. Each R5 is independently hydrogen, phenyl or alkyl of 1-6 carbon atoms. According to the reaction summarized in flow chart B, the 6-amino-4-anilinoquinazolines of Formula 10 (prepared as Flow Chart A) are acylated with a cyclic anhydride of Formula 11 in an inert solvent such as tetrahydrofuran in presence of a basic catalyst such as pyridine or triethylamine. FLOW DIAGRAM B
12
The representative compounds of this invention are evaluated with various standard pharmacological test procedures which show that the compounds of this invention possess significant activity as inhibitors of tyrosine protein kinase, and as antiproliferative agents. Based on the activity shown in standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents. The test procedures used and the results obtained are shown below. The preparation of the compounds of this invention included in Formula 19 described below in Flow Chart C where Y, R 4, and X are as described above. According to the reactions summarized in Flow Chart C, 4-chloro-6-nitroquinazoline, 13, (Morley, JS and Simpson, J. Chem., Soc, 360 (1948)) is reduced to 6-amino -4-chloro-quinazoline, 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 a base transfer catalyst. The acylation of 14 with either an acid chloride of Formula 15 or an anhydrous mixture 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 the N-methyl morpholine provides the compounds of Formula 17. In those cases of 15 or 16 having an asymmetric carbon atom, they can be used as the individual R or S racemate or enantiomers in such case the compounds of this invention will be in optically active forms R and S or racemic, respectively. Heating a compound of Formula 17 with an aniline of Formula 18, in an inert solvent such as isopropanol, provides the compounds of this invention represented by Formula 19.
FLOW DIAGRAM C
13 14
Morpholine N-methyl 17
19
The preparation of the compounds of this invention included in Formula 26 is described below in Flow Chart D where Y ', R4, and x are as described above. According to the reactions summarized in Flow Chart D, the nitro group of 20 (prepared as in Flow Chart A) is reduced to the corresponding amino compound 21 using a palladium catalyst and a hydrogen source which may be the same hydrogen or cyclohexane. The 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 provides 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 individual R or S enantiomers wherein the compounds of this invention will be in the optically active R and S or racemic forms, respectively. Heating a compound of Formula 24 with an aniline of Formula 25, in an inert solvent such as acetic acid provides the compounds of this invention represented by Formula 26.
FLOW DIAGRAM D 02N? ? CN cyclohexene H2N? CN
21
THF 24
acetic acid
The ability of the compounds of this invention to treat or inhibit colon polyps is demonstrated in a standard in vivo pharmacological test procedure as described below. The compound of Example 9 is evaluated in this procedure, where it mimics familial adenomatous polyps (FAP) in humans, as a representative compound of this invention. The Min mouse used in this test procedure, commonly the largest model available for FAP, is a breed that has lost both copies of the APC gene. These animals develop multiple intestinal polyps (adenomas) that progress finally to form adenocarcinomas. The polyps that develop in Min mice express EGFR and have the C0X-2 activated. NSAIDs such as sulindac and etalodoc can reduce (but not eradicate) the formulation of the intestinal polyp in those animals that indicate that C0X-2 and the final production of PG 's is probably responsible for these effects. The following summary describes the procedure used and the results obtained in this standard pharmacological test procedure. The compound of Example 9 is mixed with a standard murine food and the animals are given an excess at will of the food. Based on an estimated food intake, the compound of Example 9 is added at an equal concentration with animals that ingest 20 mg / Kg / day. At day 30, 4 treated animals + control animals (only food) are sacrificed and estimated for polyp number. All control animals have more than 30 polyps in their intestines, while the treated animals have none. Identical results were observed at 60 days when 15 animals / group were estimated. Control animals have more than 30 (more) polyps while the treated animals have none. These data demonstrate that the compounds of this invention effectively inhibit polyp formation in animals that have mutations in their APC genes. Based on the results obtained in this standard pharmacological test procedure, the compounds of this invention are useful in the treatment or inhibition of the formation of colonic polyps. The compounds of this invention can be formulated pure or can be combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like can be administered orally in forms such as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, about 0.05% to 5% carrier agents, containing syrups. , for example, from about 10 to 50% sugar, containing elixirs, for example, from about 20 to 50% ethanol, and the like or parenterally in the form of a sterile injectable solution or a suspension containing near 0.05 to 5% carrier agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, close to
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 dose 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 this invention are administered in a daily dose of about 0.5 to about 1000 mg / Kg of the body weight of the animal, optionally giving in two doses divided by four times per day, or in forms of sustained release. For most large mammals the total daily dose is about 1 to 100 mg, preferably about 2 to 500 mg. The dosage forms suitable for internal use comprise about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dose regimen can be adjusted to provide the appropriate therapeutic response. For example, various 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 can be administered orally as well as intravenously, intramuscularly or subcutaneously. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycols, nonionic surfactants, and edible oils such as corn, peanut, and sesame oils. appropriate for the nature of the active ingredient and the particular form of administration desired. Adjuvants commonly employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preservatives, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. Preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets, hard fill capsules or liquid fillings. Oral administration of the compound is preferred.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. The active compounds can also be administered parenterally or intraperitoneally. The solutions or suspensions of these active compounds as > A free base or a pharmacologically acceptable salt 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, this preparation contains a preservative to prevent the growth of microorganisms. Pharmaceutical forms acceptable for injectable use include injectable aqueous solutions or dispersants and sterile powders for the provisional preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent of syringeability. It must be stable under 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 a dispersion medium containing, for example, water, ethanol, polyol (for example glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The preparation of the representative examples of the compounds of this invention are described below.
Example 1
N '- (2-cyano-nitrophenyl) -N, N-dimethylformamidine
A portion of 40.8 g of 5-nitro-anthranilonitrile and 40 ml of dimethyl acetal N, N-dimethyl formamide are heated in a steam bath for two hours. The solvents are removed under reduced pressure and the residue is taken up in methylene chloride. After passing the solution through the Magnesol the solvent is removed. After washing with ether, 50.8 g of N '- (2-cyano-4-nitrophenyl) -N, N-dimethyl-formamidine are obtained.
Example 2 N- (3-bromophenyl) -6-nitro-4-quinazolinamine A solution of 23.74 ml of 3-bromo aniline and 40.5 g of N '- (2-cyano-4-nitrophenyl) -N, N-dimethylformamidine in 100 ml of glacial acetic acid are stirred and heated in an oil bath at 148 ° C for 1.5 hours. Upon cooling, filtration of the resulting solid provides a quantitative yield of N- (3-bromophenyl) -6-nitro-4-quinazolinamine; mp = 267-270 ° C; mass spectrum (m / e): 345.
Example 3 N- (3-bromophenyl) -4,6-quinazole diamine 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 are heated in an oil bath at 120 ° C for 2 hours. After filtration of the solid, solid sodium carbonate is added to the filtrate to provide a solid. This is filtered, and the solid is extracted with methanol. The extracts are treated with charcoal and evaporated to a solid. The solid is then washed with ether to obtain 27.5 g of N- (3-bromophenyl) -4,6-quinazolindiamine; mass spectrum (m / e): 315.
Example 4 4- [[4- [(3-Bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (Z) -2-butenoic acid A 15 ml portion of pyridine is added to 1.6 g of N - (3-bromophenyl) -4,6-quinazolindiamine and 0.6 g of maleic anhydride. After stirring overnight, the solvents are removed on the rotary evaporator. The solid is taken with about 400 ml of hot ethanol and the insoluble material is filtered to give 0.33 g of 4 - [[4 - [(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (Z) -2-butenoic; 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 A solution of N- (3-bromophenyl) - 4,6-Quinazolindiamine in 15 ml of pyridine are cooled in an ice bath and a solution of 1.22 g of ethyl fumaryl chloride in 10 ml of methylene chloride are added dropwise. After stirring for 1.5 hours, the reaction is left at room temperature. The solvents are removed under reduced pressure and the residue is treated with water. The red solid is filtered and extracted in hot acetone. After filtration of the insoluble material, the filtrate is concentrated to give 0.45 g of 4- [[4- [(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) ethyl ester. -2-butenoic; mp = 259-263 ° C, mass spectrum (m / e): M + H 441, 443.
EXAMPLE 6 N- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] -3-methyl-2-butenamide A solution of 1.58 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 15 ml of pyridine is cooled in an ice bath and a solution of 0.67 ml of 3,3-dimethylacryloyl chloride in 7 ml of ether is added dropwise.
After stirring and cooling for 2 hours, the solvents are removed under reduced pressure. The residue is treated with water and the resulting solid is recrystallized from the methyl cellulose 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-Bromophenyl) amino] -6-quinazolinyl] - (E) -2-butenamide A solution of 1.6 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 15 ml of pyridine is cooled in an ice bath and a 0.57 ml solution of trans-crotonoyl chloride in 6 ml of ether is added drop depleted. After stirring and cooling for 2 hours, the solvents are removed under reduced pressure. The residue is treated with water and the resulting solid is recrystallized with 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- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] -2-methyl-2-propenamide A solution of 1.6 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 15 ml of pyridine is cooled in an ice bath and a solution of 0.59 ml of methacryloyl chloride in 6 ml of ether is added drop depleted. After stirring and cooling for 2 hours, the projections are removed under reduced pressure. The residue is treated with water and the resulting solid is recrystallized with n-butanol (fuel stock). The addition of ether to the cold solution affords 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- [4- (3-Bromophenyl) amino] -6-quinazolinyl] -2-butinamide A solution of 0.50 g of 2-butynoic acid in 10 ml of tetrahydrofuran is cooled in an ice bath. A 0.79 ml portion of isobutyl chloroformate followed by a 0.66 ml portion of morpholine N-methyl are added. After about one minute a solution of 1.6 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 10 ml of pyridine is added. The reaction is left at room temperature and stirred overnight. The solvents are removed under reduced pressure and the solid is recrystallized from n-butanol to give 1.07 g of N- [4- (3-bromophenyl) amino] -6-quinazolinyl] -2-butinamide; mass spectrum (m / e): 381, 383.
Example 10 4- [[4- [(3-Bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) -2-butenoic acid A 2.5 ml portion of an aqueous sodium hydroxide solution ION 2.3 g of the 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 one hour, 2.1 ml of concentrated hydrochloric acid is added, and the reaction is stirred an additional 2 hours. The resulting solid is recrystallized from n-butanol to give 0.97 g of 4 - [[4 - [(3-bromophenyl) amino] -6-quinazolinyl] amino] -oxo- (E) -2-butenoic acid; mass spectrum (m / e): M + H 413.
EXAMPLE 11 N- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] -2,4-hexadienamide A solution of 0.67 g of 2,4-hexadienoic acid in 10 ml of tetrahydrofuran is cooled in an ice bath . A 0.79 ml portion of .isobutyl chloroformate followed by a 0.66 ml portion of N-methyl morpholine are added. After about one minute a solution of 1.6 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 10 ml of pyridine is added. The reaction is left at room temperature and stirred overnight. The solvents are removed under pressure
reduced and the solid recrystallized to give 1.0 g of N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2,4-hexadienamide: mp = 258-260 ° C.
Example 12
N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-cyclopentanoamide
A solution of 0.43 g of 2-cyclopentanoic acid in 5 ml of tetrahydrofuran is cooled in an ice bath. A 0.49 ml portion of isobutyl chloroformate followed by a 0.41 ml portion of morpholine N-methyl are added. After about one minute a solution of 1.0 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 10 ml of pyridine is added. The reaction is left at room temperature and stirred overnight. Another 0.5 equivalents of mixed anhydride are added. The mixture is stirred for 5 hours. The solvents are removed under reduced pressure and the solid is purified by chromatography on silica gel to give 0.30 g of N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-cyclopentanamide; mass spectrum (m / e): M + H 409 (M + H, El).
Example 13 N- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] -2-propenamide A solution of 2.0 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 10 ml of pyridine is cooled in an ice bath and a solution of 0.61 ml of acryloyl chloride in 30 ml of ether are added dropwise at 0 ° C. After stirring at room temperature for 3.5 hours, the solvents are removed under reduced pressure. The residue is 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- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] - (3-phenyl-2-propinamide) A solution of 0.93 g of 3-phenyl-2-propionic acid in 10 ml of tetrahydrofuran was chill in an ice bath.
A 0.82 ml portion of isobutyl chloroformate followed by a 0.69 ml portion of morpholine N-methyl is added.
After about one minute a solution of 1.0 g of N- (3-bromophenyl) -4,6-quinazolindiamine in 7 ml of pyridine are added. The reaction is left at 0 ° C for one hour. The solvents are removed under reduced pressure and the solid is purified by chromatography on silica gel to give 0.01 g of N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] - (3-phenyl-2-propinamide) Spectrum mass (m / e): 443.2, 445.2 (M + H, electrorocio).
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 phase transfer catalyst (C8H? 7) 3NCH3 + CI "in 97 ml of tetrahydrofuran and 32 ml of water are stirred rapidly for 2 hours.The mixture is diluted with ether and the organic layer is separated.The organic solution is washed with brine and then dried with magnesium sulfate.The solution is passed through from a small column of silica gel The solvent is removed at 30 ° C under reduced pressure to give the 6-amino-4-chloroquinazoline which is used in the next step without further purification.
Example 16 [4-chloro-6-quinazolinyl] -2-butinamide a solution of 1.64 g of 2-butynoic acid in 46 ml of tetrahydrofuran is cooled in an ice bath. A 2.34 ml portion of isobutyl chloroformate followed by a 4.13 ml portion of morpholine N-methyl is added.
After about 10 minutes, this is poured into a solution of 6-amino-4-chloroquinazoline in 46 ml of tetrahydrofuran. This mixture is stirred at room temperature for 2 hours. The mixture is poured into a mixture of brine and saturated sodium bicarbonate and extracted with ether. The ether solution is dried with magnesium sulfate and filtered. The solvent is removed by giving [4-chloro-6-quinazolinyl] -2-butinamide with a colorful oil which is used in the next step without further purification.
Example 17 N- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] -2-butinamide A solution consisting of 1.76 g of [4-chloro-6-quinazolinyl] -2-butinamide and 1.23 g of aniline of 3-bromo is heated to reflux under an inert atmosphere in 23 ml of isopropanol for 40 minutes. The mixture is cooled to room temperature and 200 ml of ether are added giving 0.4 g of N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-butinamide as a hydrochloride salt. Neutralizing with a sodium bicarbonate solution, extracting with ethyl acetate, removing from the solvent, and recrystallizing from 1-butanol gives N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-butinamide as the free base.
Example 18 N '- (4-amino-2-cyanophenyl) -N, -dimethylformamidine To a solution of 6.0 g (27.5 mmol) of N'-cyano-4-nitrophenyl) -N, N-dimethylformamidine, 33.9 g (41.8 ml) , 412.4 mmol) of cyclohexane, and 0.6 g of 10% Pd / C in 360 ml of methanol is heated at reflux for 4 hours. The hot mixture is filtered with Celite. The solvent is removed and the residue is recrystallized from chloroform-carbon tetrachloride providing 4.9 g (95%) of the title compound as a pale gray crystalline solid. Mass spectrum (m / e): 188.9 (M + H, electrorocious).
Example 19 N- [3-Cyano-4- [[(dimethylamino) methylene] amino] phenyl] -2-butinamide To a solution of 2.01 g (23.9 mmol) of 2-butynoic acid and 2.9 ml (22.3 mmol) of chloroformate of isobutyl in 30 ml of tetrahydrofuran is stirred at 0 ° C under a nitrogen atmosphere, 2.42 g (2.63 ml, 22.3 mmol) of N-methyl morpholine are added for more than 3 minutes. After stirring for 15 minutes, a solution of N '- (4-amino-2-cyanophenyl) -N, N-dimethylformamidine and 1.6 g (1.75 ml, 15.9 mmol) of morpholine N-methyl in 25 ml of tetrahydrofuran are added for more than 4 minutes. The mixture is stirred for 30 minutes at 0 ° C and left for 30 minutes at room temperature.
The mixture is diluted with 70 ml of ethyl acetate and poured into a mixture of brine and saturated sodium bicarbonate. The organic layer is dried with MgSO. and filtered with a pad of silica gel. The solvent is removed and the residue is stirred with 50 ml of ether. The suspended solid is collected to provide 3.61 g (89%) of a white solid. Mass spectrum (m / e): 255.0 (M + H, electrorocious).
Example 20 N- [4- [(3-Bromophenyl) amino] -6-quinazolinyl] -2-butinamide To a solution of 3.0 g (11.8 mmol) of N- [3-cyano-4- [f (dimethylamino) - methylene] amino] phenyl] -2-butinamide and 2.23 g (12.98 mmol) of 3-bromo aniline in 18 ml of acetic acid are heated to reflux gently with stirring under nitrogen for 1 hour 15 minutes. The mixture is cooled in an ice bath and a solid mass is formed. The solid is collected by filtration and washed with ether: acetonitrile 1: 1 to yield a yellow solid which recrystallizes the ethanol to give 2.51 g of N- [4- [(3-bromophenyl) amino} -6-quinazolinyl] -2-butinamide: mass spectrum (m / e) -: 381,
383.
DECLARATION THAT INCLUDES PROCESS It is stated that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
Claims (9)
- CLAIMS 1. A method of treatment or inhibition of colonic polyps in a mammal in need thereof which comprises the administration to said mammal of a compound of the formula: wherein: X is a phenyl optionally substituted with one or more substituents selected from the group consisting of a halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy , carboalkoxy of 2-7 carbon atoms, cycloalkyl 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;
- And it is a radical selected from the group consisting of
- RJ 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 characterized in that R, Ri, and R2 are hydrogen or pharmaceutically acceptable salts thereof. 3. A method as claimed in claim 1 or claim 2 characterized in that X is a phenyl unsubstituted or substituted by halogen or alkyl of 1-6 carbon atoms. 4. A method as claimed in any of claims 1 to 3 characterized in that N- [4 - [(3-bromophenyl) amino] -6-quinazolinyl] -2-butinamide, 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, 4- [[4- [(3-bromophenyl) amino] -6-quinazolinyl] amino] -4-oxo- (E) - ethyl ester - 2-butenoic acid, N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-cyclopentanamide, N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-propenamide, N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] - (3-fetil-2-propinamide), or a pharmaceutically acceptable salt of any a of these is administered.
- 5. The use of a compound of formula: characterized in that: X is a phenyl optionally substituted with one or more substituents selected from the group consisting of a halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy , carboalkoxy of 2-7 carbon atoms, cycloalkyl 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; R? is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl; And it 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. The use as claimed in claim 5 characterized in that R, Ri, and R2 are hydrogen or pharmaceutically acceptable salts thereof.
- 7. The use as claimed in claim 5 or claim 6 characterized in that X is a phenyl unsubstituted or substituted by halogen or alkyl of 1-6 carbon atoms.
- 8. The use as claimed in any of claims 5 to 7 characterized in that the compound administered is N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] -2-butinamide, 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, 4- [[4- [(3-bromophenyl) ami-no] -6- ethyl ester quinazolinyl] amino] -4-oxo- (E) -2-butenoic, N- [4- [(3-bromophenyl) amino] -6-quinazo1inyl] -2-cyclopentanamide, N- [4- [(3-bromophenyl) ) amino] -6-quinazolinyl] -2-propenamide, N- [4- [(3-bromophenyl) amino] -6-quinazolinyl] - (3-fetil-2-propinamide),
- 9. a pharmaceutical composition for the treatment and inhibition of polyps in a mammal characterized in that it comprises a compound of formula 1 as defined in claim 5 and optional nally a pharmaceutical carrier.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/965,084 | 1997-11-06 |
Publications (1)
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MXPA00004304A true MXPA00004304A (en) | 2001-12-13 |
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