Patent NZ-613709-A (NZ)
Title: Chroman-spirocyclic piperidine amides as modulators of ion channels
Inventor: HADIDA-RUAH SARA SABINA
IPC: C07D495/10
Filed: 2012-02-16
Abstract: Disclosed are (aryl)(spiro[chroman-2,4’-piperidine]-1’-yl)methanone derivatives and analogues as represented by the general formula (I), or a pharmaceutically acceptable salt thereof, wherein: W is N or CR1, or one W is a bond and the remaining W are N, NR1, or CR1, wherein up to two W are N or NR1; a dashed circle denotes aromaticity or heteroaromaticity; R1 is H, a fully saturated alkyl, haloalkyl, halo, CN, SO2R7, SR7, SOR7, NR7COR7, NR7CO2R7, CON(R7)2, SO2N(R7)2, CF3, OCF3, OCHF2, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, a fully saturated straight chain or branched (C1-C8)-R8, or a cyclic (C3-C8)-R8, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more substituents selected from halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl, and wherein up to two CH2 units of the straight chain, branched or cyclic group may be replaced with O, S, SO, or CF2; R2 is alkyl, alkoxy, halo, CN, OR7a, N(R7)2, NR7SO2R7, SO2R7, SR7, SOR7, CO2R7, NR7COR7, NR7CO2R7, CON(R7)2, SO2N(R7)2, CF3, OCF3, OCHF2, CH2OCHF2, CH2OCH2CHF2, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, a straight chain or branched (C1-C8)-R8, or a cyclic (C3-C8)-R8, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted with one or more substituents of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl, and wherein up to two CH2 units of the straight chain, branched or cyclic group may be replaced with O, CO, S, SO, SO2 or NR7, with the proviso that R2 is not OH; R3 is alkyl or cycloalkyl, wherein up to two CH2 units may be replaced by O, NR8, S, SO, SO2, or 2 occurrences of R3 taken together form a cycloalkyl group; R7 is H, alkyl, fluoroalkyl, or cycloalkyl; R7a is alkyl, fluoroalkyl, or cycloalkyl; R8 is H, CF3, CO2R7, OH, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, N(R7)2, NR7COR7, CON(R7)2, CN, or SO2R7, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted with one or more substituents of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl; A is aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more substituents of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl; X is O, S, or SO; n is an integer from 1 to 4 inclusive; and o is an integer from 0 to 4 inclusive; wherein, unless specified otherwise, the alkyl, haloalkyl, cycloalkyl, heterocycloalkyl and alkoxy groups include a completely saturated carbon chain or an aliphatic carbon chain containing one or more units of unsaturation. Representative compounds include (4-isopropoxy-3-methoxyphenyl)(4-isopropoxyspiro[chroman-2,4’-piperidine]-1’-yl)methanone, (4-isopropylsulfonyl-2-methylphenyl)(6-fluoro-4-ethoxy-spiro[chroman-2,4’-piperidine]-1’-yl)methanone, (3,4-dimethoxyphenyl)(4-phenyl-spiro[chroman-2,4’-piperidine]-1’-yl)methanone, (4-(2-hydroxypropan-2-yl)-3-methylphenyl)(6-cyano-4-isopropoxy-spiro[chroman-2,4’-piperidine]-1’-yl)methanone, (4-isopropoxy-3-methylphenyl)(spiro[chroman-2,4’-piperidine]-1’-yl)methanone, (4-isopropoxy-3-methoxyphenyl)(4-(methylthiomethyl)spiro[chroman-2,4’-piperidine]-1’-yl)methanone, etc. etc.. Also disclosed is a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier, for the treating or lessening the severity of the pain in a subject afflicted with acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, palpitations, hypertension, migraine, or abormal gastro-intestinal motility.