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US 6,204,267 B1Granted
Methods of modulating serine/thereonine protein kinase function with quinazoline-based compounds
AssigneeSugen, Inc.
InventorsPeng C. Tang, Gerald McMahon, Heinz Weinberger, Bernhard Kutscher, Harald App
Life of this patent
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Abstract
The present invention is directed in part towards methods of modulating the function of serine/threonine protein kinases with quinazoline-based compounds. The methods incorporate cells that express a serine/threonine protein kinase, such as RAF. In addition, the invention describes methods of preventing and treating serine/threonine protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to quinazoline compounds and pharmaceutical compositions comprising these compounds.
Claims18
A quinazoline compound having a structure set forth in formulas VI or VII:
- wherein
- (a) R1 and R2 are independently selected form the group consisting of hydrogen and —NH2, provided at least one of R1 and R2 is —NH2;
- (b) R6, R7, R8, R9, and R10 are independently selected from the group consisting of
- (i) hydrogen,
- provided that at least one of R6, R7, R8, R9, and R10 is a non-hydrogen moiety if R2 is —NH2;
- (ii) saturated or unsaturated alkyl,
- provided that when R2 is —NH2, then R8 is not methyl, propyl, isopropyl, t-butyl, 1,1-dimethylpropyl, or n-hexyl;
- (iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl
- provided that when R2 is —NH2, then X2 and X3 are not both hydrogen or ethyl;
- (iv) halogen,
- provided that only one R6, R7, R8, R9, and R10 is a halogen, also provided that when R2 is —NH2, then R8 is not chlorine, bromine, or fluorine, and when R2 is —NH2, then R6 and R7 are not chlorine;
- (v) trihalomethyl
- provided that when R2 is —NH2, then R8 is not trifluoromethyl;
- and
- (vi) OX9, where X9 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and a five-membered or six-membered heteroaryl or six-membered aryl ring moiety
- provided that when R2 is —NH2, then R8 is not hydroxy or methoxy,
- also provided that when R2 is —NH2, then R6 or R7 are not each methoxy.
14 more elements
A quinazoline compound having a structure set forth in formula VIII or IX:
- wherein
- (a) R1 and R2 are independently selected from the group consisting of hydrogen and —NH2, provided at least one of R1 and R2 is —NH2;
- (b) R6, R7, R8, R9, and R10 are independently selected from the group consisting of
- (i) hydrogen, provided that at least one of R6, R7, R8, R9, and R10 is a non-hydrogen moiety if R2 is —NH2;
- (ii) saturated or unsaturated alkyl;
- (iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
- and
- (iv) halogen, provided that only one of R6, R7, R8, R9, and R10 are halogen, also provided that when R2 is —NH2, then R8 is not chlorine, bromine, or fluorine, and when R2 is —NH2, then R6 or R7 are not chlorine;
- (v) trihalomethyl;
- and
- (vi) OX9, where X9 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and a five-membered or six-membered heteroaryl or six-membered aryl ring moiety.
8 more elements
A quinazoline compound selected from the group consisting of:
A method of modulating the function of a serine/threonine protein kinase with a quinazoline-based compound, comprising the step of contacting cells expressing said serine/threonine protein kinase with said compound, or a pharmaceutically acceptable salt thereof,
- wherein said function of said serine/threonine protein kinase is related to cancer or fibrotic disorders;
- and
- wherein said compound has the formula set forth in structure II:
- wherein
- (a) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- (b) n is 0, 1, 2, 3, or 4;
- (c) A1 is carbon;
- (d) A2, A3, A4, A5, and A6 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
- provided that if any of A2, A3, A4, A5, or A6 is nitrogen, oxygen, or sulfur, said A2, A3, A4, A5, or A6 is not substituted with R6, R7, R8 , R9, or R10;
- (e) R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of
- (i) hydrogen;
- (ii) saturated or unsaturated alkyl;
- (iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- (iv) halogen or trihalomethyl;
- (v) a ketone of formula —CO—X4, where X4 is selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- (vi) a carboxylic acid of formula —(X5)n5—COOH or ester of formula —(X6)n6—COO—X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n5 and N6 are each independently 0 or 1;
- (vii) an alcohol of formula (X8)n8—OH or an alkoxy moiety of formula —(X8)n8—O—X9, where X8 and X9 are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n8 is 0 or 1, and where said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
- (viii) —NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties, wherein said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
- (ix) —SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- and
- (x) a five-membered or six-membered heteroaryl or six-membered aryl ring moiety optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
- (f) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8, R9, and R10 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of the aryl or heteroaryl ring to which R3, R4, and R5 or R6, R7, R8, R9, and R10 are attached;
- and
- (g) R11 and R12 are independently selected from the group consisting of
- (i) hydrogen;
- and
- (ii) saturated or unsaturated alkyl.
24 more elements
A method of treating an abnormal condition in an organism in need thereof, wherein said abnormal condition is a disease associated with an aberration in a signal transduction pathway characterized by an interaction between a serine/threonine protein kinase and a natural binding partner, said method comprising the step of administering a quinazoline-based compound of formula II to said organism,
- wherein
- (a) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- (b) n is 0, 1, 2, 3, or 4;
- (c) A1 is carbon;
- (d) A2, A3, A4, A5, and A6 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
- provided that if any of A2, A3, A4, A5, or A6 is nitrogen, oxygen, or sulfur, said A2, A3, A4, A5, or A6 is not substituted with R6, R7, R8, R9, or R10;
- (e) R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from the group consisting of
- (i) hydrogen;
- (ii) saturated or unsaturated alkyl;
- (iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- (iv) halogen or trihalomethyl;
- (v) a ketone of formula 'CO—X4, where X4 is selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl moieties;
- (vi) a carboxylic acid of formula —(X5)n5—COOH or ester of formula '(X6)n6—COO—X7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl moieties and where n5 and n6 are each independently 0 or 1;
- (vii) an alcohol of formula (X8)n8—OH or an alkoxy moiety of formula —(X8)n8—O—X9, where X8 and X9 are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n8 is 0 or 1, and where said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
- (viii) —NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties, wherein said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
- (ix) —SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
- (x) a five-membered or six-membered heteroaryl or six-membered aryl ring moiety optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
- (f) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8, R9, and R10 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of the aryl or heteroaryl ring to which R3, R4, R5 or R6, R7, R8, R9, and R10 are attached;
- (g) R11 and R12 are independently selected from the group consisting of
- (i) hydrogen;
- (ii) saturated or unsaturated alkyl.
18 more elements
Dependencies are inferred from the claim text.