Derivatives of 3-(Guanidinocarbonyl) heterocycle, methods of preparation and intermediates thereof, their use as medicaments, and pharmaceutical compositions therefrom
View Patent ↗The present invention discloses and claims compounds of formula I and their pharmaceutically acceptable salts, and methods of using said compounds of formula I, either alone or in combination with other medicaments, as antiarrhythmic medicaments with a cardioprotective component for prophylaxis or treatment of infarction, for the treatment of angina pectoris, and as inhibitors of pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias and of heart failure. Pharmaceutical compositions comprising compounds of formula I or compounds of formula I in combination with one or more other medicaments and processes for the preparation of compounds of formula I are also disclosed and claimed.
1. A compound of formula I
wherein
X 1 is N;
X 2 , X 3 and X 4 are; CR 2 ;
R 2 is H, F, Cl, Br, I, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, SO 2 alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, NRaRb, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, hydroxyalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or dialkylaminoalkyl with each alkyl having independently 1, 2, 3, 4, 5 or 6 carbon atoms;
R1 is aryl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, arylalkyl with alkyl having 1, 2, 3 or 4 carbon atoms, heteroarylalkyl with alkyl having 1, 2, 3 or 4 carbon atoms or heteroaryl,
wherein said aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, F, Cl, Br, I, NO 2 , NH 2 , alkylamino with alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, NRaRb, alkylcarbonylamino having 1, 2, 3, 4, 5 or 6 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O) n R 3 , CO 2 H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONH 2 , CONRaRb, alkylsulfonylamino with alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cyano, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms and SO 3 H;
n is 0,1 or 2;
Ra and Rb are, independently of one another, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or
Ra and Rb form together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain another heteroatom chosen from the group consisting of O, S and N; and
R 3 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH 2 ; or
a racemate, an enantiomer or a diastereomer thereof, or mixtures thereof, a tautomers thereof, or a pharmaceutically acceptable salt thereof.
2. The compound of formula I according to claim 1 , wherein
X 1 is N;
X 2 , X 3 and X 4 are CR 2 ;
R 2 is H; and
R1 is aryl or heteroaryl,
wherein said aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, F, Cl, Br, I, NO 2, NH 2 , alkylamino with alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, NRaRb, alkylcarbonylamino having 1, 2, 3, 4, 5 or 6 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O) n R 3 , CO 2 H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3,4, 5 or 6 carbon atoms, CONH 2 , CONRaRb, alkylsulfonylamino with alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cyano, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms and SO 3 H.
3. The compound of formula I according to claim 2 , wherein
R1 is aryl or heteroaryl selected from the group of pyridine, pyrimidine, pyrazine, thiazole, imidazole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, quinoxaline, benzothiazole, benzimidazole, indole, 7-azaindole and pyrrolo[2,3-d]pyrimidine,
wherein said aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, F, Cl, Br, I, NO 2 , NH 2 , alkylamino with alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, NRaRb, alkylcarbonylamino having 1, 2, 3, 4, 5 or 6 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O) n R 3 , CO 2 H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONH 2 , CONRaRb, alkylsulfonylamino with alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cyano, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms and SO 3 H.
4. The compound of formula I according to claim 3 , wherein
X 1 is N
R1 is phenyl or heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine, thiazole, imidazole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, quinoxaline, benzothiazole, benzimidazole, indole, 7-azaindole and pyrrolo[2,3-d]pyrimidine,
wherein said phenyl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, NH 2 , NRaRb, hydroxyl and S(O) n R 3 ;
n is 2;
Ra and Rb are, independently of one another, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; and
R 3 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
and racemates, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof.
5. The compound of formula I according to claim 4 selected from the group consisting of:
N-[1-quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-quinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-quinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-quinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-quinolin-8-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(isoquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(cinnolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinazolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinazolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(2-methylquinazolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(1,5-naphthyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(1,6-naphthyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(1,7-naphthyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(1,8-naphthyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(2-amino-1,8-naphthyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinoxalin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(benzothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(benzimidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(indol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(indol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(1-(methylsulfonyl)indol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(7-azaindol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(7-methylpyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(2-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(2-hydroxyquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine, and
N-[1-(2-hydroxy-quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine.
6. The compound of formula I according to claim 5 selected from the group consisting of:
N-[1-(2-hydroxyquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine,
N-[1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine, and
N-[1-(2-hydroxy-quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine.
7. A pharmaceutical composition for human, veterinary or phytoprotective use comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable carriers or additives.
8. A pharmaceutical composition for human, veterinary or phytoprotective use comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable carriers or additives, and further in combination with one or more other pharmacologically active ingredients or medicaments.
9. A process for preparing the compound according to claim 1 , comprising reacting a compound of formula II
wherein X 1 , X 2 , X 3 , X 4 and R1are as defined in claim 1 and L is a leaving group, with guanidine.