Substituted quinazoline derivatives for use in gastrointestinal diseases
First Claim
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1. A compound of structure (I) ##STR9## in which R1 to R4 are the same or different and are each hydrogen, C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 alkylthio, C1-4 alkanoyl, amino, C1-6 alkylamino, diC1-4 alkylamino, halogen, trifluoromethyl, hydroxy, hydroxyC1-4 -alkyl, carboxyC1-4 alkoxy, hydroxyC1-4 alkoxy, C1-4 alkoxyC1-4 alkoxy, O(CH2)m Het, C1-4 -alkylNR9 R10 or O(CH2)m NR9 R10 in which m is 2 to 4 and R9 and R10 are the same or different and are each hydrogen, C1-4 alkyl, Het or --(CH2)n Ar, or R9 and R10 together with the nitrogen to which they are attached form a piperidino, morpholino, imadazolyl, pyridyl or pyrrolidine ring;
- provided that at least two of R1 to R4 are hydrogen;
R5 and R6 are the same, or different and are each hydrogen, C1-4 alkyl, --(CH2)n Ar, or R5 and R6 together with the nitrogen atom to which they are attached form a piperidino, morpholino, imidazolyl, pyridyl or pyrrolidine ring;
R7 and R8 are the same or different and are each hydrogen, C1-4 alkyl, (CH2)n Ar1, or R7 and R8 together with the nitrogen atom to which they are attached form a piperidino, morpholino, imidazolyl, pyridyl or pyrrolidine ring;
n is 0 to 4;
Ar is phenyl;
Ar1 is phenyl;
Het is pyridyl or imidazolyl,Wherein Ar, Ar1 and Het may be unsubstituted or substituted by 1 to 3 substituents selected from C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-4 alkanoyl or trifluoromethyl;
and pharmaceutically acceptable salts thereof, provided that;
when R1 to R4 are the same or different and are each hydrogen, C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 alkylthio, C1-4 alkanoyl, amino, C1-4 alkylamino, diC1-4 -alkylamino, halogen or trifluoromethyl, then(a) R5, R6, R7 and R8 are not all hydrogen;
(b) at least one of R5 or R6 is (CH2)n Ar;
or R7 or R8 is (CH2)n Ar1 ;
(c) when R1 and R4 are hydrogen, and either one of R2 or R3 is C1-4 alkoxy, the other is not hydrogen or C1-4 alkoxy.
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Abstract
2,4-diaminoquinazoline compounds are inhibitors of the H+ K+ ATPase enzyme and useful for the treatment of diseases of the stomach based on excessive gastric acid secretion. A compound of the invention is 2-[2-methyl-4-fluorophenyl)amino]-4-(N-methylphenylamino)quinazoline.
74 Citations
40 Claims
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1. A compound of structure (I) ##STR9## in which R1 to R4 are the same or different and are each hydrogen, C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 alkylthio, C1-4 alkanoyl, amino, C1-6 alkylamino, diC1-4 alkylamino, halogen, trifluoromethyl, hydroxy, hydroxyC1-4 -alkyl, carboxyC1-4 alkoxy, hydroxyC1-4 alkoxy, C1-4 alkoxyC1-4 alkoxy, O(CH2)m Het, C1-4 -alkylNR9 R10 or O(CH2)m NR9 R10 in which m is 2 to 4 and R9 and R10 are the same or different and are each hydrogen, C1-4 alkyl, Het or --(CH2)n Ar, or R9 and R10 together with the nitrogen to which they are attached form a piperidino, morpholino, imadazolyl, pyridyl or pyrrolidine ring;
- provided that at least two of R1 to R4 are hydrogen;
R5 and R6 are the same, or different and are each hydrogen, C1-4 alkyl, --(CH2)n Ar, or R5 and R6 together with the nitrogen atom to which they are attached form a piperidino, morpholino, imidazolyl, pyridyl or pyrrolidine ring; R7 and R8 are the same or different and are each hydrogen, C1-4 alkyl, (CH2)n Ar1, or R7 and R8 together with the nitrogen atom to which they are attached form a piperidino, morpholino, imidazolyl, pyridyl or pyrrolidine ring; n is 0 to 4; Ar is phenyl; Ar1 is phenyl; Het is pyridyl or imidazolyl, Wherein Ar, Ar1 and Het may be unsubstituted or substituted by 1 to 3 substituents selected from C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-4 alkanoyl or trifluoromethyl; and pharmaceutically acceptable salts thereof, provided that; when R1 to R4 are the same or different and are each hydrogen, C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 alkylthio, C1-4 alkanoyl, amino, C1-4 alkylamino, diC1-4 -alkylamino, halogen or trifluoromethyl, then (a) R5, R6, R7 and R8 are not all hydrogen; (b) at least one of R5 or R6 is (CH2)n Ar;
or R7 or R8 is (CH2)n Ar1 ;(c) when R1 and R4 are hydrogen, and either one of R2 or R3 is C1-4 alkoxy, the other is not hydrogen or C1-4 alkoxy. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
- provided that at least two of R1 to R4 are hydrogen;
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39. A method of treating gastric acid secretion which comprises administering to a mammal in need thereof an effective amount of a compound of structure (IA) ##STR10## R1 to R4 are the same or different and are each hydrogen, C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 alkylthio, C1-4 alkanoyl, amino, C1-6 alkylamino, diC1-4 alkylamino, halogen, trifluoromethyl, hydroxy, hydroxyC1-4 -alkyl, carboxyC1-4 alkoxy, hydroxyC1-4 alkoxy, C1-4 alkoxyC1-4 alkoxy, O(CH2)m Het, C1-4 -alkylNR9 R10 or O(CH2)m NR9 R10 in which m is 2 to 4 and R9 and R10 are the same or different and are each hydrogen, C1-4 alkyl, Het or --(CH2)n Ar, or R9 and R10 together with the nitrogen to which they are attached form a piperidino, morpholino, imadazolyl, pyridyl or pyrrolidine ring;
- provided that at least two of R1 to R4 are hydrogen;
R5 and R6 are the same, or different and are each hydrogen, C1-4 alkyl, --(CH2)n Ar, or R5 and R6 together with the nitrogen atom to which they are attached form a piperidino, morpholino, imidazolyl, pyridyl or pyrrolidine ring; R7 and R8 are the same or different and are each hydrogen, C1-4 alkyl, (CH2)n Ar1, or R7 and R8 together with the nitrogen atom to which they are attached form a piperidino, morpholino, imidazolyl, pyridyl or pyrrolidine ring; n is 0 to 4; Ar is phenyl; Ar1 is phenyl; Het is pyridyl or imidazolyl, Ar, Ar1 and Het may be unsubstituted or substituted by 1 to 3 substituents selected from C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-4 alkanoyl or trifluoromethyl; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (40)
- provided that at least two of R1 to R4 are hydrogen;
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Current AssigneeSmithKline Beecham Intercredit BV.
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Original AssigneeSmithKline Beecham Intercredit BV.
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InventorsKeeling, David J., Leach, Colin A., Ife, Robert J., Brown, Thomas H.
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Primary Examiner(s)Ivy, C. Warren
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Assistant Examiner(s)TURNIPSEED, JAMES
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Application NumberUS07/520,561Time in Patent Office553 DaysField of Search544/291, 544/293, 544/80, 544/119, 514/260, 514/231.5, 514/232.5US Class Current514/266.4CPC Class CodesC07D 239/95 with hetero atoms directly ...
