Fluorinated arylalkylaminocarboxamide derivatives
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Publication Number
US-9447029-B2
Publication Date
2016-09-20
Expiration Date
Abstract
Fluorinated arylalkylaminocarboxamide derivatives of formula (I) are described wherein W, J, n, R1, R2, R3, R4, R5 and R6 have the meanings as defined in the specification and pharmaceutically salts thereof, pharmaceutical compositions containing them as active ingredients and their use as sodium and/or calcium channel modulators useful in preventing, alleviating and curing a wide range of pathologies, including neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urological, and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role.
Core Innovation
The invention relates to fluorinated arylalkylaminocarboxamide derivatives of general formula I, including pharmaceutically acceptable salts. The compounds are defined by substituent and ring-forming options, and are provided as a single optical isomer in isolated form or as mixtures in any proportion.
The disclosure addresses drug-drug interaction risk arising from CYP2D6 inhibition associated with voltage-gated sodium and/or calcium channel modulators, particularly relevant for CYP2D6-poor metabolizer phenotypes. It emphasizes compounds that are substantially free of or have reduced CYP2D6 inhibitory activity, together with pharmaceutically acceptable hydrochloride salt forms.
The invention is additionally directed to use of the compounds as voltage-gated sodium and/or calcium channel modulators for treating a disorder caused by dysfunctions of voltage-gated sodium and/or calcium channels. The therapeutic framework includes patient selection based on CYP2D6 poor metabolizer status or CYP2D6 inhibitor use.
Claims Coverage
The consolidated claim coverage comprises a compound claim to general formula I and a therapeutic method claim for disorders caused by dysfunction of voltage-gated sodium and/or calcium channels. The inventive features below merge the repeated and non-conflicting claim elements explicitly present across the input items.
General formula I fluorinated arylalkylaminocarboxamide derivatives
A compound of general formula I with W defined as A-[(CH2)m-O]- or A-[(CH2)m-O], m being 1 or 2, J being hydrogen, n being 1, and R1, R2, R2', R3, R4, R5, and R6 defined by the stated options, including ring formation where R3 and R4 taken together with the adjacent nitrogen atom form an azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl ring, with optional methyl substitution on the piperidinyl ring.
Optical isomer or mixture and pharmaceutically acceptable salt coverage
The compound of general formula I is included as a single optical isomer in isolated form or as a mixture in any proportion, together with pharmaceutically acceptable salt forms, including hydrochloride where specified.
Method of treating dysfunction of voltage-gated sodium and/or calcium channels
A method of treating a disorder in a patient whose condition is caused by dysfunctions of voltage-gated sodium and/or calcium channels by administering an effective amount of a sodium and/or calcium channel-modulating compound of claim 1.
Disorder category selection
The disorder caused by dysfunctions of voltage-gated sodium and/or calcium channels is selected from neurological, pain, sensory, cardiovascular, endocrine, liver, inflammatory, gastrointestinal, genito-urinary, ophthalmic, and eating disorders.
CYP2D6-related patient condition constraint
The patient is a poor metabolizer with very little or no CYP2D6 function or is taking one or more CYP2D6 inhibitor drugs.
Overall, the claims cover a structured family of formula I compounds with specified substitution and ring-forming constraints, optionally as single optical isomers or mixtures and as pharmaceutically acceptable salts, including hydrochloride. The therapeutic coverage ties these compounds to treating disorders caused by dysfunction of voltage-gated sodium and/or calcium channels, with refinements for disorder categories and CYP2D6-related patient conditions.
Stated Advantages
Compounds are substantially free of or have reduced CYP2D6 inhibitory activity, to mitigate CYP2D6-related drug-drug interaction risk, particularly for CYP2D6-poor metabolizer phenotypes.
Provides voltage-gated sodium and/or calcium channel modulation for treating, preventing, or alleviating a broad range of disorders caused by dysfunctions of voltage-gated sodium and/or calcium channels.
Documented Applications
Treating, preventing, or alleviating disorders in a patient whose condition is caused by dysfunctions of voltage-gated sodium and/or calcium channels, including neurological disorders and pain disorders (neuropathic pain, chronic pain, acute pain), and psychiatric disorders such as schizophrenia-related cognitive impairment.
Application categories enumerated for the channel-dysfunction framework include neurological, pain, sensory, cardiovascular, endocrine, liver, inflammatory, gastrointestinal, genito-urinary, ophthalmic, and eating disorders.
Use in patients who are poor metabolizers with very little or no CYP2D6 function or who are taking one or more CYP2D6 inhibitor drugs.
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