(R)(4-Pentyloxy-benzyl)-(tetrahydro-furan-2-ylmethyl)-amine; monoamine oxidase inhibitors; neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urologic, metabolic and gastrointestinal diseases
Inventors
Salvati, Patricia • Caccia, Carla • Melloni, Piero • Restivo, Alessandra • Sabido David, Cibele • Vallese, Stefania
Assignees
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Publication Number
US-7649005-B2
Publication Date
2010-01-19
Expiration Date
Abstract
This invention is related to compounds of general formula (I) wherein X is oxygen or sulphur or a NR7 group; R1 is C3-C8 alkyl, or C1-C8 alkyl substituted by phenoxy or phenyl, both phenoxy or phenyl being optionally substituted by one or more fluoro, chloro, trifluoromethyl, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy; R2, R3 are independently hydrogen, C1-C6 alkyl, halogen, trifluoromethyl, hydroxy or C1-C6 alkoxy; R4 is hydrogen, C1-C8 alkyl; R5, R6 are independently hydrogen, C1-C3 alkyl, optionally substituted by hydroxy or phenyl; R7 is hydrogen or straight or branched C1-C3 alkyl; Het is a five to seven membered, saturated or unsaturated heteromonocyclic or an eight to ten membered, saturated or unsaturated heterobicyclic group, containing one or more heteroatoms chosen independently from nitrogen, oxygen and sulphur, said mono- or bicyclic groups being optionally substituted by C1-C6alkyl, halogen, hydroxyl or C1-C6 alkoxy; and the pharmaceutically acceptable salts or prodrug thereof, that are active as sodium and/or calcium channel modulators and/or as selective MAO-B inhibitors and therefore useful in preventing, alleviating and curing a wide range of pathologies, including, but not limited to, neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urologic, metabolic and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role.
Core Innovation
The invention provides benzylaminomethylene heterocycles defined by a general formula (I), where the structure is characterized by variable groups X, R1-R7, and a heterocycle Het with defined ring size and heteroatom content. X is oxygen, sulphur or an NR7 group, while R1 is a C3-C8 alkyl or a C1-C8 alkyl optionally substituted by phenoxy or phenyl with further optional substituents, and R2-R6 and R7 define permitted hydrogen, alkyl, halogen, trifluoromethyl, hydroxy, and C1-C6 alkoxy options.
The heterocycle Het is a five to seven membered saturated or unsaturated heteromonocyclic group or an eight to ten membered saturated or unsaturated heterobicyclic group containing one or more heteroatoms independently chosen from nitrogen, oxygen and sulphur. The monocyclic or bicyclic Het group may be optionally substituted by C1-C6 alkyl, halogen, hydroxyl or C1-C6 alkoxy, and the structure scope is further constrained by proviso exclusions that rule out named Het groups under specified conditions, including indole, benzo[b]furan, benzo[b]thiophen, chroman in particular circumstances, and 2-pyridyl under specified circumstances.
The invention further includes pharmaceutically acceptable salts and, in the medicament aspect, compounds exhibiting sodium and/or calcium channel modulating activity and/or selective MAO-B inhibiting activity. The medicament comprises a compound according to formula I or its pharmaceutically acceptable salts, and the disclosure also includes a pharmaceutical composition formulation with a suitable carrier and/or diluent and optional other therapeutic agents.
Claims Coverage
The claim set contains two independent claims. Independent claim 1 is directed to the defined compound of formula I, including specified proviso exclusions, and independent claim 2 is directed to a medicament comprising such a formula I compound for sodium and/or calcium channel modulation and/or selective MAO-B inhibition.
Formula I compound with defined substituent ranges and heterocycle scope
A compound according to formula I wherein X is oxygen, sulphur or a NR7 group; R1 is C3-C8 alkyl or C1-C8 alkyl substituted by phenoxy or phenyl with optional substituents; R2 and R3 are independently hydrogen, C1-C6 alkyl, halogen, trifluoromethyl, hydroxy or C1-C6 alkoxy; R4 is hydrogen or C1-C8 alkyl; R5 and R6 are independently hydrogen or C1-C3 alkyl optionally substituted by hydroxy or phenyl; R7 is hydrogen or straight or branched C1-C3 alkyl; and Het is a five to seven membered heteromonocyclic or an eight to ten membered heterobicyclic group containing one or more heteroatoms chosen independently from nitrogen, oxygen and sulphur, with the monocyclic or bicyclic groups optionally substituted by C1-C6 alkyl, halogen, hydroxyl or C1-C6 alkoxy, or pharmaceutically acceptable salts thereof.
Multiple proviso exclusions for Het under defined substituent conditions
The compound of formula I is further limited by provisos excluding specific Het ring systems under specified conditions, including that Het cannot be indole, benzo[b]furan, benzo[b]thiophen, chroman when R5 and R6 are both hydrogen, or 2-pyridyl, together with additional provisos tied to combinations of X-R1 and specified hydrogen/alkyl selections for other substituent variables such as R2, R3, R4, R5 and R6.
Medicament with sodium and/or calcium channel modulating activity and/or selective MAO-B inhibiting activity
A medicament comprising a compound according to formula I or pharmaceutically acceptable salts thereof selected such that the medicament has sodium and/or calcium channel modulating activity and/or selective MAO-B inhibiting activity.
Medicament structural exclusions including Het restrictions and X-R1 related provisos
The medicament includes a formula I compound with proviso exclusions, including that Het cannot be an indole, chroman when R5 and R6 are both hydrogen, and when X-R1 is an ortho O-(CH2)m-p-CF3-phenyl group and R2, R3, R5 and R6 are hydrogen, Het cannot be pyridyl, and it further covers the pharmaceutically acceptable salts or prodrug thereof.
Overall, the claim coverage is centered on a tightly defined formula I chemical scaffold with Het ring scope and multiple proviso exclusions, and on a medicament using those compounds for sodium and/or calcium channel modulation and/or selective MAO-B inhibition, with additional structural proviso exclusions and coverage of salts or prodrugs.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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