Carboxamide compounds and their use as calpain inhibitors V
View Patent ↗The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R 1 , R 2 , R 3 R 4 , R 5 , m and n have the meanings mentioned in the claims and the description, the tautomers thereof, the hydrates thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein R 1 is optionally substituted phenyl-C 1 -C 2 -alkyl or hetaryl-C 1 -C 2 -alkyl, R 2 is optionally substituted aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl or hetaryl-C 1 -C 4 -alkyl, R 3 is C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 2 -C 4 -alkenyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, or phenyl-C 1 -C 3 -alkyl, R 4 and R 5 independently of one another are halogen, CF 3 , CHF 2 , CH 2 F, C 1 -C 2 -alkyl or C 1 -C 2 -alkoxy, and m and n independently of one another are 0 or 1.
1. A carboxamide compound of the formula I
in which
R 1 is benzyl, which may be unsubstituted or carry 1 or 2 identical or different radicals selected from the group consisting of halogen, C 1 -C 2 -alkyl, and C 1 -C 2 -alkoxy;
R 2 is selected from the group consisting of aryl, aryl-C 1 -C 6 -alkyl, and aryl-C 2 -C 6 -alkenyl, where aryl in the last 3 radicals mentioned may be unsubstituted or carry 1, 2, 3, or 4 identical or different radicals R 2c ;
where
R 2c is selected independently of one another from the group consisting of halogen, C 1 -C 2 -alkyl, where the alkyl may be partly or completely halogenated, C 1 -C 2 -alkoxy, and —(CH 2 ) p —NR c6 R c7 with p=0, 1, or 2, where
R c6 is selected from the group consisting of H and C 1 -C 4 -alkyl, and
R c7 is selected from the group consisting of H and C 1 -C 4 -alkyl;
R 3 is selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 3 -haloalkyl, C 3 -C 5 -alkenyl, C 3 -C 5 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, aryl, and aryl-C 1 -C 3 -alkyl;
R 4 and R 5 are selected independently of one another from the group consisting of halogen, NH 2 , CN, CF 3 , CHF 2 , CH 2 F, O—CF 3 , O—CHF 2 , O—CH 2 F, COOH, OCH 2 COOH, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, C 1 -C 2 -alkylthio, and CH 2 NRR′, where
R and R′ are selected independently of one another from the group consisting of hydrogen and C 1 -C 4 -alkyl;
m is 0, 1, or 2; and
n is 0, 1, or 2;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
2. The carboxamide compound of claim 1 , in which m is 0 or 1 and, when m=1, R 5 is selected from the group consisting of F, Cl, CN, CF 3 , C 1 -C 2 -alkyl, and C 1 -C 2 -alkoxy.
3. The carboxamide compound of claim 1 , in which n is 0 or 1 and, when n=1, R 4 is selected from the group consisting of F, Cl, CN, CF 3 , C 1 -C 2 -alkyl, and C 1 -C 2 -alkoxy.
4. The carboxamide compound of claim 1 , in which R 3 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, propenyl, but-2-enyl, but-3-enyl, propinyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclopropyl-methyl.
5. The carboxamide compound of claim 1 , in which R 3 is selected from the group consisting of C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 3 -C 5 -alkenyl, C 3 -C 5 -alkynyl, C 3 -C 6 -cycloalkyl, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, aryl, and aryl-C 1 -C 3 -alkyl.
6. The carboxamide compound of claim 5 , in which R 3 is selected from the group consisting of methyl, ethyl, propenyl, but-2-enyl, but-3-enyl, propinyl, cyclopropanyl, cyclopropanyl-methyl, phenyl, and benzyl.
7. The carboxamide compound of claim 1 , in which R 2 is phenyl, which may be unsubstituted or carry 1 or 2 identical or different radicals R 2c .
8. The carboxamide compound of claim 1 , in which R 2 is phenyl, which may be unsubstituted or carry 1 or 2 identical or different radicals selected from the group consisting of halogen, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, and —(CH 2 ) p —NR c6 R c7 with p=0, 1 or 2, where
R c6 is selected from the group consisting of H and C 1 -C 4 -alkyl, and
R c7 is selected from the group consisting of H and C 1 -C 4 -alkyl.
9. The carboxamide compound of claim 1 , which has the S configuration at the carbon atom carrying the group R 1 .
10. A carboxamide compound which is selected from the group consisting of:
2-[3-(4-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]pyridine-3-carboxamide;
(2R)-2-[3-(4-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]pyridine-3-carboxamide;
(2S)-2-[3-(4-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]pyridine-3-carboxamide;
N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
2-(4-Fluoro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide;
(2R)-2-(4-Fluoro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide;
(2S) 2-(4-Fluoro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide;
N-[4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide;
(2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide;
(2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide;
N-(1-(4-Fluorophenyl)-4-(methoxyamino)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(1-(4-Fluorophenyl)-4-(methoxyamino)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(1-(4-Fluorophenyl)-4-(methoxyamino)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-(1-(3-Fluorophenyl)-4-(methoxyamino)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(1-(3-Fluorophenyl)-4-(methoxyamino)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(1-(3-Fluorophenyl)-4-(methoxyamino)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-(4-(Ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(4-(Ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(4-(Ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-(4-(Allyloxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(4-(Allyloxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(4-(Allyloxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-(4-(Methoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(4-(Methoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(4-(Methoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide;
(2R)-2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide;
(2S)-2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide;
N-[4-(Isopropoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-[4-(Isopropoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-[4-(Isopropoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-[3,4-Dioxo-1-phenyl-4-(propoxyamino)-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-[3,4-Dioxo-1-phenyl-4-(propoxyamino)-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-[3,4-Dioxo-1-phenyl-4-(propoxyamino)-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
2-(3-{4-[(Diethylamino)methyl]phenyl}-1H-pyrazol-1-yl)-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide;
(2R)-2-(3-{4-[(Diethylamino)methyl]phenyl}-1H-pyrazol-1-yl)-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide;
(2S)-2-(3-{4-[(Diethylamino)methyl]phenyl}-1H-pyrazol-1-yl)-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide;
N-(4-{[(2-Methyl-2-propanyl)oxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-(4-{[(2-Methyl-2-propanyl)oxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-(4-{[(2-Methyl-2-propanyl)oxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-{4-[(Cyclopentyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-{4-[(Cyclopentyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-{4-[(Cyclopentyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-[4-(Ethoxyamino)-1-(4-fluorophenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-[4-(Ethoxyamino)-1-(4-fluorophenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-[4-(Ethoxyamino)-1-(4-fluorophenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-[4-(Ethoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-[4-(Ethoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-[4-(Ethoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-{4-[(Cyclobutyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-{4-[(Cyclobutyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-{4-[(Cyclobutyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-{4-[(2,2-Dimethylpropoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-{4-[(2,2-Dimethylpropoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-{4-[(2,2-Dimethylpropoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-{4-[(Cyclopropylmethoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-{4-[(Cyclopropylmethoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-{4-[(Cyclopropylmethoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
N-[4-(Ethoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2R)—N-[4-(Ethoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
(2S)—N-[4-(Ethoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide;
2-[3-(2-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide;
(2R)-2-[3-(2-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide;
(2S)-2-[3-(2-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide;
N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide;
(2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide; and
(2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising at least one carboxamide compound of claim 1 and a carrier.