Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.

This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

This invention is directed to methods of preparing benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.

This invention is directed to methods of preparing benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.

A substituted alkenylbenzene compound of formula (4):

##STR00001##

wherein X.sup.1 is selected from the group consisting of a halogen atom, SF.sub.5, C.sub.1-C.sub.6haloalkyl, hydroxy C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.8halocycloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6haloalkylthio, C.sub.1-C.sub.6haloalkylsulfinyl and C.sub.1-C.sub.6haloalkylsulfonyl; X.sup.3 is selected from the group consisting of a hydrogen atom, halogen atom, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6alkylthio; X.sup.4 is selected from the group consisting of a hydrogen atom, halogen atom, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and C.sub.1-C.sub.4haloalkoxy; R.sup.3 is C(R.sup.3a)(R.sup.3b)R.sup.3c, where R.sup.3a and R.sup.3b independently of each other are a halogen atom, or R.sup.3a and R.sup.3b together form 3- to 6-membered ring together with the carbon atom bonding them by forming a C.sub.2-C.sub.5haloalkylene chain, and R.sup.3c is selected from the group consisting of a hydrogen atom, halogen atom, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, C.sub.1-C.sub.4haloalkoxy and C.sub.1-C.sub.4haloalkylthio, with a proviso that in case where X.sup.1 is a fluorine atom, chlorine atom or trifluoromethyl, and both X.sup.2 and X.sup.3 are a hydrogen atom, in case where both X.sup.1 and X.sup.2 are fluorine atom and X.sup.3 is a hydrogen atom, and in case where both X.sup.1 and X.sup.2 are trifluoromethyl and X.sup.3 is a hydrogen atom, R.sup.3c is a hydrogen atom, chlorine atom, bromine atom, iodine atom, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, C.sub.1-C.sub.4haloalkoxy or C.sub.1-C.sub.4haloalkylthio.

A substituted alkenylbenzene compound of formula (4):

##STR00001##

wherein X.sup.1 is selected from the group consisting of a halogen atom, SF.sub.5, C.sub.1-C.sub.6haloalkyl, hydroxy C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.8halocycloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6haloalkylthio, C.sub.1-C.sub.6haloalkylsulfinyl and C.sub.1-C.sub.6haloalkylsulfonyl; X.sup.3 is selected from the group consisting of a hydrogen atom, halogen atom, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6alkylthio; X.sup.4 is selected from the group consisting of a hydrogen atom, halogen atom, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and C.sub.1-C.sub.4haloalkoxy; R.sup.3 is C(R.sup.3a)(R.sup.3b)R.sup.3c, where R.sup.3a and R.sup.3b independently of each other are a halogen atom, or R.sup.3a and R.sup.3b together form 3- to 6-membered ring together with the carbon atom bonding them by forming a C.sub.2-C.sub.5haloalkylene chain, and R.sup.3c is selected from the group consisting of a hydrogen atom, halogen atom, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, C.sub.1-C.sub.4haloalkoxy and C.sub.1-C.sub.4haloalkylthio, with a proviso that in case where X.sup.1 is a fluorine atom, chlorine atom or trifluoromethyl, and both X.sup.2 and X.sup.3 are a hydrogen atom, in case where both X.sup.1 and X.sup.2 are fluorine atom and X.sup.3 is a hydrogen atom, and in case where both X.sup.1 and X.sup.2 are trifluoromethyl and X.sup.3 is a hydrogen atom, R.sup.3c is a hydrogen atom, chlorine atom, bromine atom, iodine atom, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, C.sub.1-C.sub.4haloalkoxy or C.sub.1-C.sub.4haloalkylthio.