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US 6,887,870 B1Granted
Heterocyclic sodium/proton exchange inhibitors and method
AssigneeBristol-Myers Squibb Company
InventorsSaleem Ahmad, Shung C. Wu, Steven V. O'Neil, Khehyong Ngu, Karnail S. Atwal, David S. Weinstein
Life of this patent
Estimating the term…
Abstract
Heterocyclic are provided which are sodium/proton exchange (NHE) inhibitors which have the structure wherein n is 1 to 5; X is N or C—R5 wherein R5 is H, halo, alkenyl, alkynyl, alkoxy, alkyl, aryl or heteroaryl; Z is a heteroaryl gorup, R1, R2, R3 and R4 are as defined herein, and where X is N. R1 is preferably aryl or heteroaryl, and are useful as antianginal and cardioprotective agents. In addition, a method is provided for preventing or treating angina pectoris, cardiac dysfunction, myocardial necrosis, and arrhythmia employing the above heterocyclic derivatives.
Claims28
A compound having the structure
- wherein
- n is 4;
- X is N;
- Z is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl group which is selected from the group consisting of imidazole attached at its 4- or 5-position to the ring, aminoimidazole, alkylimidazole, alkylthioimidazole, alkylthio(amino)imidazole, amino-(alkyl)imidazole, (alkanoylamino)imidazole, aminothiazole, aminooxazole, aminooxadiazole, dialkylimidazole, alkyl(alkanoylamino)imidazole, alkyl(amino)imidazole, arylaminocarbonylamino(alkyl)imidazole, alkoxycarbonylamino(alkyl)imidazole, alkylcarbonylamino(alkyl)imidazole, aminotriazole or diaminopyrimidine;
- R1 is heteroaryl;
- and R1 may be unsubstituted or substituted with from one to five substituents;
- and wherein the R1 heteroaryl group is selected from
- R2, R3 and R4 are the same or different and are independently H, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, (alkyl or aryl)3Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroarylamino, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, halogen, haloalkyl, polyhaloalkyl, polyhaloalkoxy, aminothio, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy, acyl, carboxy, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonyl, arylcarbonyloxy, arylcarbonylamino, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroarylcarbonylamino, cyano, nitro, alkenylcarbonylamino, alkynylcarbonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, alkynylaminocarbonylamino, arylaminocarbonylamino, heteroarylaminocarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aminocarbonylamino, alkylaminocarbonyloxy, alkoxycarbonylamino, 1,1-(alkoxyl or aryloxy)2alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring), S(O)2R6R7, —NR6(C═NR7)alkyl, —NR6(C═NR7)alkenyl, —NR6(C═NR7)alkynyl, —NR6(C═NR7)heteroaryl, —NR8(C═NCN)-amino,
- pyridine-N-oxide,
- (where Q is O or H2 and n′ is 0, 1, 2 or 3) or
- tetrazolyl, pyrazolyl, pyridyl, thiazolyl, pyrimidinyl, imidazole, oxazole, or triazole, —PO(R13)(R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy);
- and may be optionally independently substituted with from one to five substituents, which may be the same or different;
- R6, R7, R8, R8a and R9 are the same or different and are independently hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, or cycloheteroalkyl;
- or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and all stereoisomers thereof.
11 more elements
A compound having the structure
A compound having the structure
A compound having the structure
A compound having the following structure
A compound having the structure
- wherein
- n is 4;
- X is N;
- Z is a 5- or 6-membered nitrogen-containing monocycle heteroaryl group which is selected from the group consisting of imidazole attached at its 4- or 5-position to the ring, aminoimidazole, alkylimidazole, alkylthioimidazole, alkylthio(amino)imidazole, amino(alkyl)imidazole, (alkanoylamino)imidazole, aminothiazole, aminooxazole, aminooxadiazole, dialkylimidazole, alkyl(alkanoylamino)imidazole, alkyl(amino)imidazole, arylaminocarbonylamino(alkyl)imidazole, alkoxycarbonylamino(alkyl)imidazole, alkylcarbonylamino(alkyl)imidazole, aminotriazole or diaminopyrimidine;
- R1 is tetrazolyl, pyrazolyl, thiazolyl,
- oxazole, triazole or
- and R1 may be unsubstituted or substituted with from one to five substituents;
- R2, R3 and R4 are the same or different and are independently H, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, (alkyl or aryl)3Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroarylamino, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, halogen, haloalkyl, polyhaloalkyl, polyhaloalkoxy, aminothio, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, hydroxy, acyl, carboxy, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonyl, arylcarbonyloxy, arylcarbonylamino, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroarylcarbonylamino, cyano, nitro, alkenylcarbonylamino, alkynylcarbonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, alkynylaminocarbonylamino, arylaminocarbonylamino, heteroarylaminocarbonylamino, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aminocarbonylamino, alkylaminocarbonyloxy, alkoxycarbonylamino, 1,1-(alkoxyl or aryloxy)2alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring), S(O)2R6R7, —NR6(C═NR7)alkyl, —NR6(C═NR7)alkenyl, —NR6(C═NR7)alkynyl, —NR6(C═NR7)heteroaryl, —NR8(C═NCN)-amino,
- pyridine-N-oxide,
- (where Q is O or H2 and n′ is 0, 1, 2 or 3) or
- tetrazolyl, pyrazolyl, pyridyl, thiazolyl, pyrimidinyl, imidazole, oxazole, or triazole, —PO(R13)(R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy);
- and may be optionally independently substituted with from one to five substituents, which may be the same or different;
- R6, R7, R8, R8a and R9 are the same or different and are independently hydrogen, alkyl, haloalkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, or cycloheteroalkyl;
- or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and all stereoisomers thereof.
11 more elements
Dependencies are inferred from the claim text.