WO2017066103A1 - Nouveaux composés bénéfiques dans le traitement de maladies et de troubles du système nerveux central - Google Patents

Nouveaux composés bénéfiques dans le traitement de maladies et de troubles du système nerveux central Download PDF

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WO2017066103A1
WO2017066103A1 PCT/US2016/056152 US2016056152W WO2017066103A1 WO 2017066103 A1 WO2017066103 A1 WO 2017066103A1 US 2016056152 W US2016056152 W US 2016056152W WO 2017066103 A1 WO2017066103 A1 WO 2017066103A1
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compound
compounds
solution
disease
formula
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Amir Pesyan
Manuel F. Balandrin
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Aurimmed Pharma, Inc.
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Publication of WO2017066103A1 publication Critical patent/WO2017066103A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to novel compounds showing activity in the central nervous systems (CNS). More specifically, the present invention relates to novel compounds with anticonvulsant activity that exhibit increased/improved toxicological safety (i.e., decreased toxicity), increased/improved metabolic stability, longer half-life, and/or a superior side effect profile, while producing similar or increased biological activity (i.e., efficacy), when compared to currently available CNS therapeutic agents.
  • CNS central nervous systems
  • a number of pathological conditions e.g., epilepsy, stroke, bipolar affective disorder, migraine headaches, anxiety, depression, insomnia, schizophrenia, chronic or neuropathic pain, spasticity, spinal cord injury, and chronic neurodegenerative disorders
  • diseases e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease
  • CNS central nervous system
  • These conditions and diseases typically respond to pharmacologic intervention with compounds or substances that modulate CNS activity.
  • Compounds with this activity include the compounds of the present invention, which are herein disclosed to treat abnormalities of the CNS, such as epilepsy.
  • a short half-life in a CNS therapeutic may require its frequent administration in order to sustain therapeutic concentrations of the drug without eliciting adverse effects, and where frequent dosing schedules are required, the cost of therapy may increase.
  • patient compliance tends to decrease.
  • N-alkylation N,N-diethylisovaleramide, which has been marketed previously as a sedative ("Valyl”).
  • this compound has been shown instead to exhibit CNS-stimulating, anxiogenic, and convulsant properties.
  • N-methylated amide derivatives can show either CNS-stimulating or -depressing properties, whereas N-ethyl and larger derivatives generally possess CNS-stimulating properties.
  • ⁇ , ⁇ -di substituted amide compounds such as cropropamide, crotethamide, ethamivan, nikethamide, N,N-diethylisovaleramide, and the insect repellent, DEET (N,N-diethyl-w-toluamide), have all been shown to exhibit CNS- (proconvulsant-) and respiratory-stimulating properties in mammals (including humans).
  • Cropropamide, crotethamide, ethamivan, and niketamide have been used as CNS and respiratory stimulants in humans, e.g., to counteract the potentially life- threatening CNS- and respiratory-depressing effects of barbiturate poisoning (overdose).
  • a series of novel amides with broad pharmaceutical activity Compounds described herein are effective as anticonvulsants, chemical countermeasures, and analgesics. Such compounds also show neuroprotective/neuroreparative effects and activity against spinal muscular atrophy. Such pharmaceutically active compounds show utility in the treatment of central nervous system ("CNS") diseases and disorders, such as anxiety, depression, insomnia, migraine headaches, schizophrenia, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's, ALS, and Huntington's disease) spasticity, and bipolar disorder. Furthermore, such compounds may additionally find utility as analgesics (e.g., for the treatment of chronic or neuropathic pain) and as neuroprotective agents useful in the treatment of stroke(s), and/or traumatic brain and/or spinal cord injuries.
  • CNS central nervous system
  • analgesics e.g., for the treatment of chronic or neuropathic pain
  • neuroprotective agents useful in the treatment of stroke(s), and/or traumatic brain and/or spinal cord injuries
  • amides disclosed herein have a phenyl group attached to the amide moiety via a short and variously branched/substituted aliphatic linker.
  • Other compounds of the invention are amide derivatives of optically active amino acids (e.g., D or L), such as alanine, valine, leucine, isoleucine, or phenylalanine, or the optically inactive amino acids, glycine or taurine.
  • Ri can be one of H, CH 3 , C 2 H 5 , (CH 2 ) 2 S0 3 H, or CHZCOOH.
  • Z can be one of H, CH 3 , CH(CH 3 ) 2 , CH 2 C 6 H 5 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3 .
  • R 2 can be one of H, CH 3 , CH 2 H 5 , (CH 2 ) 2 OCH 3 OCH 3 , or C1-C5 alkyl.
  • R1R2 alkox OCF 3 , CO R1R2, where X is (-CH2-) or (-CH 2 -) 2 , where R 5 is one of H, CI, F, CF 3 , CN, C1-C5 alkyl, C1-C5 alkoxy, OCF 3 , or CONR1R2.
  • R 4 can be 1 - 5 and n of R 5 can be 1 - 4.
  • Ar may be an optionally substituted pyrazine, optionally substituted pyridine, or an optionally substituted quinoxaline, wherein up to 5 substituents are optionally present on Ar and each substituent is independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, CH 2 OH, CO H2, CN, and OCH2COOH.
  • Ri may be one of H, CH 3 , C2H5, (CH 2 ) 2 S0 3 H, or CHZCOOH.
  • Z may be one of H, CH 3 , CH(CH 3 ) 2 , CH 2 C 6 H 5 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3 .
  • R 2 may be independently one of H or CH 3 .
  • R 3 may be one of H, CI, F, CF 3 , CN, C1-C5 alkyl, C1-C5 alkoxy, OCF 3 or CONRiR 2 .
  • n may be 0 - 2.
  • Ri can be one of H, CH 3 , C 2 H 5 , (CH 2 ) 2 S0 3 H, or CHZCOOH.
  • Z can be one of H, CH 3 , CH(CH 3 ) 2 , CH 2 C 6 H 5 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3 .
  • R 2 can be one of H or CH 3 .
  • R 3 can be one of H, CI, F, CF 3 , CN, C1-C5 alkyl, C1-C5 alkoxy, OCF 3 , or CONRiR 2 .
  • n can be 1-5.
  • Formula IV and a number of novel amides that exemplify Formula IV are illustrated in Figure 19.
  • Any one of the compounds described above or a combination of the compounds described above can be included in a pharmaceutical composition.
  • the pharmaceutical composition includes a therapeutically effective amount of at least one of the compounds described above admixed with at least one of a pharmaceutically acceptable carrier or an excipient.
  • the therapeutically effective amount is effective for at least one of the following: (a) treating and/or preventing one or more neurodegenerative disease, (b) treating or preventing spinal muscular atrophy, (c) to provide anticonvulsant activity to a subject, (d) to treat and/or prevent convulsions in a subject, (e) to treat and/or prevent seizures in a subject, (f) to treat and/or prevent spasticity in a subject, (g) to treat and/or prevent affective mood disorders in a subject, (h) to treat and/or prevent bipolar mood disorder in a subject, (i) to treat and/or prevent chronic headaches in a subject, (j) to treat and/or prevent cluster headaches in a subject, (k) to treat and/or prevent migraine headaches in a subject, (1) to treat and/or prevent restlessness syndromes in a subject, (m) to treat and/or prevent neuropathic pain in a subject, or (n) to treat and/or prevent movement disorders in a
  • any one of the compounds described above or a combination of the compounds described above can be included as a therapeutic agent in a in a method for treating and/or preventing a neurodegenerative disease or treating and/or preventing spinal muscular atrophy.
  • the therapeutic agent is blended with at least one of the compounds described above blended with at least one of a pharmaceutically acceptable carrier or an excipient.
  • the therapeutic agent may be sufficient to treat and/or prevent the symptoms of at least one of anxiety, depression, insomnia, migraine headaches, schizophrenia, Parkinson's disease, spasticity, Alzheimer's disease, bipolar disorder, chronic or neuropathic pain, stroke, chronic neurodegenerative diseases, cognitive impairment, attention deficit-hyper activity disorder, Huntington's disease, traumatic brain injury, spinal cord injury, or status epilepticus.
  • the therapeutic agent may be sufficient for a chemical countermeasure.
  • FIGURE 1 shows the chemical structures of the novel compounds of the invention that are pharmacologically active in the central nervous systems (CNS) of (for example) mammals, and which exemplify embodiments of the present invention.
  • FIGURE 2 shows the relative biological activity of the compounds of the invention, specifically showing those compounds which are preferred (second category, ED50 ⁇ 300 mg/kg) and most preferred (first category, ED50 ⁇ 100 mg/kg).
  • FIGURE 3A shows the structures of further compounds of the invention, which are also in the category of most preferred compounds.
  • FIGURE 3B shows the structures of further compounds of the invention, which are also in the category of most preferred compounds.
  • FIGURE 3C shows the structures of additional compounds of the invention, which are also in the category of most preferred compounds.
  • FIGURE 3D shows the structures of additional compounds of the invention, which are also in the category of most preferred compounds.
  • FIGURES 4A-40 illustrate examples of the syntheses of various compounds and key intermediates.
  • FIGURE 5 shows a 1 H-NMR spectrum of compound H.
  • FIGURE 6A shows an LC/MS Total Ion Chromatogram of compound H.
  • FIGURE 6B shows a mass spectrum of compound H.
  • FIGURES 7A-C illustrate LC chromatograms of compound H with UV monitoring at 254, 215, and 215 nm, respectively.
  • FIGURE 8 shows another mass spectrum of compound H.
  • FIGURE 9 shows a chiral liquid chromatographic separation of the two enantiomers of compound H, with UV monitoring at 208 nm.
  • FIGURES 10 and 11 show liquid chromatograms of the separated individual enantiomers of compound H, with UV monitoring at 208 nm.
  • FIGURE 12 shows a 1 H-NMR spectrum of compound CC.
  • FIGURE 13 shows a 13 C- NMR spectrum of compound CC.
  • FIGURES 14 and 15 show additional 1 H-NMR spectra of compound CC.
  • FIGURE 16 illustrates an embodiment of the present invention and the chemical structures of a number of novel, pharmacologically active compounds that exemplify the illustrated embodiment.
  • FIGURE 17 illustrates an embodiment of the present invention and the chemical structures of a number of novel, pharmacologically active compounds that exemplify the illustrated embodiment.
  • FIGURE 18 illustrates an embodiment of the present invention and the chemical structures of a number of novel, pharmacologically active compounds that exemplify the illustrated embodiment.
  • FIGURE 19 illustrates an embodiment of the present invention and the chemical structures of a number of novel, pharmacologically active compounds that exemplify the illustrated embodiment.
  • FIGURES 20A-20D illustrate observed neuroprotective/recovery effects of compound BX against oxidative damage in rat dopaminergic N27 cells.
  • FIGURES 21A-21D illustrate observed neuroprotective/recovery effects of compound B against oxidative damage in rat dopaminergic N27 cells.
  • FIGURES 22A-22D illustrate observed neuroprotective/recovery effects of compound M against oxidative damage in rat dopaminergic N27 cells.
  • FIGURES 23A-23D illustrate observed neuroprotective/recovery effects of compound N against oxidative damage in rat dopaminergic N27 cells.
  • FIGURES 24A-24D illustrate observed neuroprotective/recovery effects of compound AS against oxidative damage in rat dopaminergic N27 cells.
  • FIGURES 25A-25D illustrate observed neuroprotective/recovery effects of compound BY against oxidative damage in rat dopaminergic N27 cells.
  • FIGURES 26A-26E illustrate the measured effect of compound BX on rotenone-induced toxicity (26A-26C) and locomotion / time in motion (26D-26E) in a Drosophila model of sporadic Parkinson's disease.
  • FIGURES 27A-27C illustrate the effect of oral treatment of mice for two weeks with compound BX in an MPTP -induced Parkinson's disease model, which yielded a reduction of abnormal movement in the hindlimb clasping test (A), improved motor coordination in the crossbeam test (B), and improved grooming behavior in the coat grooming test (C).
  • FIGURES 28A and 28B illustrate that two weeks of oral treatment with compound BX was sufficient to induce recovery from MPTP-induced damage in striatum in mice.
  • FIGURE 29 illustrates the response of survival motor neuron 2 (SMN2) promoter reporter cells to exposure to a number of the novel, pharmacologically active compounds exemplified herein.
  • SSN2 survival motor neuron 2
  • FIGURE 30 illustrates the response of Exon 7 reporter cells to exposure to a number of the novel, pharmacologically active compounds exemplified herein.
  • FIGURES 31A-31C illustrate the localization of SMN protein to discrete intracellular structures called gems in response to exposure of spinal muscular atrophy fibroblast cells to a number of the novel, pharmacologically active compounds exemplified herein.
  • FIGURE 32 illustrates the fold change in FL-SMN mRNA levels in GM03813 type II SMA fibroblasts following exposure to various amounts of a number of the novel, pharmacologically active compounds exemplified herein.
  • FIGURE 33 illustrates the fold change in SMNA7 mRNA levels in GM03813 type II SMA fibroblasts following exposure to various amounts of a number of the novel, pharmacologically active compounds exemplified herein.
  • FIGURES 34A-34J are reproductions of representative images illustrating EGFP+ oligodendrocytes in mouse oligodendrocyte progenitor cells (OPCs) treated with a DMSO (34A), thyroid hormone T3 (34B), and various compounds of the present disclosure (34C-34J).
  • OPCs mouse oligodendrocyte progenitor cells
  • 34A DMSO
  • T3 thyroid hormone
  • 34C-34J various compounds of the present disclosure
  • FIGURES 35-38 are graphical representations of data quantified from Figures 34A-34J.
  • FIGURES 39A-39J are reproductions of representative images illustrating EGFP+ oligodendrocytes in mouse oligodendrocyte progenitor cells (OPCs) treated with DMSO (39 A), thyroid hormone T3 (39B), and various compounds of the present disclosure (39C-39J).
  • OPCs mouse oligodendrocyte progenitor cells
  • DMSO 39 A
  • T3 39B
  • 39C-39J various compounds of the present disclosure
  • FIGURES 40-43 are graphical representations of data quantified from Figures 30A-30J.
  • FIGURES 44A-44J are reproductions of representative images illustrating EGFP+ oligodendrocytes in mouse oligodendrocyte progenitor cells (OPCs) treated with DMSO (44A), thyroid hormone T3 (44B), and compounds of the present disclosure (44C-44J).
  • OPCs mouse oligodendrocyte progenitor cells
  • 44A thyroid hormone T3
  • 44C-44J compounds of the present disclosure
  • FIGURES 45-48 are graphical representations of data quantified from Figures 44A-44J. DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
  • the compounds of the invention and certain of their pharmacologically active analogs and congeners can be administered in vivo to effect a modulation of CNS activity. That is, these agents modulate CNS activity, by enhancing inhibitory, or decreasing excitatory, neurotransmission centrally, without complete suppression of all activity.
  • a subject who receives such an agent is not overtly sedated, anesthetized, or paralyzed in the context of, for example, decreasing seizures (no anesthesia), decreasing muscle tone (no paralysis), eliciting a calmative effect (no sedation), or ameliorating an ambulatory syndrome such as spasticity (no weakness or flaccidity).
  • a number of pathologies exemplified by convulsions (seizures), spasticity, affective mood disorders, such as bipolar mood disorder, headaches (chronic, cluster, migraine), restlessness syndromes, neuropathic pain, and movement disorders, have at least one symptom that is alleviated by a modulation of CNS activity. Accordingly, an individual who suffers from such a pathology is a candidate for therapy that entails, pursuant to the present invention, the individuals receiving a pharmaceutical formulation or composition containing the compounds of the invention or one of their structurally related analogs or congeners as one of the principal active ingredients.
  • the present invention can be used to treat convulsive disorders such as epilepsy. That is, the compositions and pharmaceutical formulations and compositions of the invention display "anticonvulsant activity," which is evidenced by a reduction of the severity, number, or duration of convulsions in animal models of epilepsy. To alleviate convulsions includes reducing the severity, number of duration of convulsions in a patient. Accordingly, the novel compositions and pharmaceutical formulations and compositions should be useful in treating conditions such as, but not limited to, generalized tonic-clonic seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures, secondarily generalized partial seizures, status epilepticus, and trauma-induced seizures, as occur following head injury or surgery.
  • SPASTICITY Spasticity is a disorder characterized by an increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks resulting from hyperexcitability of the stretch reflex.
  • Major disease states and conditions associated with spasticity include multiple sclerosis, cerebral palsy, stroke, trauma or injury to the spinal cord, and head trauma.
  • Symptoms that occur with spasticity include painful flexor and extensor spasms, increased or exaggerated deep-tendon reflexes, clonus, muscular weakness, fatigue, lack of dexterity, various degrees of loss of general motor function, paralysis, and impairment of sleep.
  • the pathological states observed in spasticity are fundamentally different at the physiological level from the commonly experienced acute muscular aches, strains, and sprains that occur from a localized external insult to a particular muscle, i.e., outside of or peripheral to the CNS. These pathological states also are different from the relatively common involuntary spasms or smooth muscle, such as vascular spasms, bladder spasms, and bronchial spasms. Such non-spastic (non-CNS), peripheral or localized symptoms are commonly treated with so-called “antispasmodic” or “spasmolytic” agents, but these generally are not useful in treating spasticity.
  • compositions of matter and pharmaceutical formulations and compositions employed in accordance with the present invention can cause a centrally mediated decrease in muscle tone and, hence, are useful for the acute or chronic alleviation of one or more symptoms or side effects of spasticity.
  • “spasticity” refers to a heightened tone of skeletal muscle with is manifested by symptoms such as, but not limited to, painful flexor or extensor spasms, increased or exaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity, muscular weakness, exaggerated tendon jerks, and clonus.
  • antispasticity agent refers here to a composition that is useful for the symptomatic treatment of spasticity, as demonstrated by the alleviation of at least one of the following manifestations or side effects of spasticity: painful flexor or extensor spasms, increased or exaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity, muscular weakness, exaggerated tendon jerks, and clonus, or the reduction of the frequency of these manifestations or side effects.
  • spasticity refers here to the lessening of one or more symptoms of spasticity, including, but not limited to, painful flexor or extensor spasms, increased or exaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity, muscle weakness, exaggerated tendon jerks, and clonus, or the reduction of the frequency of these manifestations or side effects.
  • [0079J AFFECTIVE MOOD DISORDERS include conditions ranging from depression to dysphoric mania, for example, mania, schizoaffective disorder, traumatic brain injury-induced aggression, post-traumatic stress disorder, bipolar mood disorder, panic states, and behavioral dyscontrol syndromes.
  • the novel compositions and pharmaceutical formulations and compositions according to the present invention are effective in the treatment of these diseases, disorders, and conditions, and should exhibit improved side effect profiles when compared to currently existing therapeutic agents in this therapeutic category.
  • NEUROPATHIC PAIN SYNDROMES Conditions in this category, involving "neuropathic pain," affect a significant number of patients suffering from disorders of the brain or spinal cord, such as stroke, trauma, multiple sclerosis, and diabetes. The use of anticonvulsants to treat various pain states has been documented extensively. Thus, a novel composition or pharmaceutical formulation or composition of the present invention can be applied in similar fashion to ameliorate neuropathic pain.
  • HEADACHES Headaches of the migraine type, the cluster type, and the chronic type have been treated with anticonvulsants.
  • the compositions and formulations of the present invention can therefore be used to alleviate the symptoms associated with each of these three headache types, without the adverse side effects of current existing therapies.
  • restlessness syndrome denotes a somatic (non-mental) restlessness characterized by involuntary movement of the limbs, as well as by a sense of physical (rather than mental) agitation, which is independent of mood and, hence, is distinguished from restlessness per se.
  • Restlessness syndromes can be observed in association with many organic and non-organic psychiatric illnesses.
  • drug-induced restlessness such as drug-induced extrapyramidal symptoms
  • restlessness-syndrome rubric are also within the restlessness-syndrome rubric.
  • restlessness-syndrome rubric are so-called “restless leg syndrome” and "sleep-related periodic leg movements,” pathologies that can be associated with head and/or spinal cord trauma and with lesions of the spinal cord.
  • Idiopathic restless leg syndrome follows an autosomal dominant inheritance, with a variable clinical expression of symptoms.
  • the present invention provides an effective therapy for restlessness syndromes with minimal side effects.
  • MOVEMENT DISORDERS Various agents are known to decrease the dyskinetic movement characterizing movement disorders such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, tardive dyskinesia, and stiff-man syndrome.
  • a therapy within the present invention alleviates one or more symptoms of a movement disorder.
  • SMA is an autosomal recessive genetic disorder caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. SMN is apparently selectively necessary for survival of motor neurons, as diminished abundance of the protein results in loss of function of neuronal cells in the anterior horn of the spinal cord and subsequent system-wide muscle wasting (atrophy). SMA affects about 1 in 6,000-10,000 live births and is a leading genetic cause of infant death. While SMA is almost always caused by a homozygous deletion of the SMN1 gene, almost all SMA patients have a functional SMN2, which is a nearly perfect duplicate of SMN1.
  • the SMN1 gene codes the survival of motor neuron protein (SMN) which, as its name says, plays a crucial role in survival of motor neurons.
  • the SMN2 gene on the other hand - due to a variation in a single nucleotide (840 C ⁇ T) - undergoes alternative splicing at the junction of intron 6 to exon 8, with only 10-20% of SMN2 transcripts coding a fully functional survival of motor neuron protein (SMN-fl) and 80-90% of transcripts resulting in a truncated protein compound (SMNA7) which is rapidly degraded in the cell.
  • SMN-fl motor neuron protein
  • SMNA7 truncated protein compound
  • SMN2 pre-mRNAs sometimes (-10-20%) leads to the production of full-length SMN2 mRNAs (termed FL-SMN), which leads to functional SMN2 protein that performs the same function as SMN1.
  • agents e.g., small molecule drugs
  • SMA may, for example, increase the activity of the SMN2 gene promotor and/or increase the inclusion of correct ⁇ 7 splicing.
  • the data presented herein demonstrates that many of the pharmacologically active compounds described in this application show promise as potential SMA therapeutics.
  • the compounds of the invention may also be useful as anxiety-reducing (anxiolytic) agents.
  • neurological disorder or disease is meant a disorder or disease of the nervous system including, but not limited to, epilepsy, anxiety, multiple sclerosis, strokes, head trauma, spinal cord injuries, and chronic neurodegenerative diseases such as Parkinson's and Huntington's diseases, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Also meant by “neurological disorder or disease” are those disease states and conditions in which an antispastic or anticonvulsant may be indicated, useful, recommended and/or prescribed.
  • neurodegenerative disease is meant diseases such as, but not limited to, Huntington's Disease, Parkinson's Disease, Alzheimer's Disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).
  • Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons.
  • Many neurodegenerative diseases including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's, Alzheimer's, and Huntington's occur as a result of neurodegenerative processes. Such diseases are believed to be incurable, resulting in progressive degeneration and/or death of neuron cells.
  • many similarities appear that relate these diseases to one another on a subcellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously.
  • Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
  • Alzheimer's disease has been hypothesized to be a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded beta-amyloid plaques.
  • Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane.
  • APP amyloid precursor protein
  • Parkinson's disease is the second most common neurodegenerative disorder and manifests as bradykinesia, rigidity, resting tremor and posture instability.
  • the crude prevalence rate of PD has been reported to range from 15 per 100,000 to 12,500 per 100,000, and the incidence of PD from 15 per 100,000 to 328 per 100,000, with the disease being less common in Asian countries.
  • Parkinson's disease is a degenerative disorder of the central nervous system. It results from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown.
  • Huntington's disease causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices.
  • the striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder.
  • Mutant Huntingtin is an aggregate-prone protein. During the cells' natural clearance process, these proteins are retrogradely transported to the cell body for destruction by lysosomes. It is a possibility that these mutant protein aggregates damage the retrograde transport of important cargoes such as BDNF by damaging molecular motors as well as microtubules.
  • Amyotrophic lateral sclerosis is a disease in which motor neurons are selectively targeted for degeneration.
  • SODl Cu/Zn superoxide dismutase 1
  • TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (C9orf72) is thought to be the most common known cause of sporadic ALS.
  • agents e.g., pharmaceutically active small molecule agents
  • neuroprotective and/or neuroregenerative effect may be effective treatments for neurodegenerative conditions.
  • Evidence presented herein demonstrates that many of the compounds of the present invention have a neuroprotective and/or neuroregenerative effect.
  • anticonvulsant is meant a compound capable of reducing the severity, number, or duration of convulsions produced, observed, or found in conditions such as generalized tonic-clonic seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures, secondarily generalized partial seizures, status epilepticus, and trauma-induced seizures as occur following head injury or surgery.
  • anticonvulsant activity is meant efficacy in reducing the severity, number, or duration of convulsions produced, observed, or found in conditions such as generalized tonic-clonic seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures, secondarily generalized partial seizures, status epilepticus, and trauma-induced seizures, as occur following head injury or surgery.
  • therapeutic dose is meant an amount of a compound that relieves to some extent one or more symptoms of the disease or condition of the patient. Additionally, by “therapeutic dose” is meant an amount that returns to normal, either partially or completely, physiological or biochemical parameters associated with or causative of the disease or condition. Generally, it is an amount between about 0.1- 15-20-30 mg/kg body weight, depending on the age, size, and disease associated with the patient. The dosing can be one to four times a day.
  • composition a therapeutically effective amount of a compound of the present invention in a pharmaceutically acceptable carrier, i.e., a formulation to which the compound can be added to dissolve or otherwise facilitate administration of the compound.
  • a pharmaceutically acceptable carrier include water, saline, and physiologically buffered saline.
  • Such a pharmaceutical composition is provided in a suitable dose.
  • Such compositions are generally those which are approved for use in treatment of a specific disorder by the FDA or its equivalent in non-U.S. countries.
  • certain of the compounds of the present invention have one or more chiral stereocenter(s). Such compounds may demonstrate preferred biological activity as a racemic (or diastereomeric) mixture, as a mixture of R and S enantiomers (or diastereomers), or as pure enantiomers (R or S) (or diastereomers). When one pure enantiomer shows preferred biological activity, it is this preferred enantiomer is referred to as the eutomer, whereas the less preferred, less biologically active enantiomer is referred to as the distomer.
  • useful pharmaceutical formulations and compositions of this invention may be used to treat neurological disorders or diseases. While these preparations will typically be used in therapy for human patients, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, domestic animals, farm animals such as swine, cattle, and poultry, and sports animals and pets such as horses, dogs, and cats.
  • the present invention also is directed to pharmaceutical formulations and compositions containing combinations of two or more of the active compounds described above.
  • the compounds of the present invention can be prepared (formulated) according to known methods for preparing pharmaceutically useful compositions, whereby active agents are combined in a mixture with a pharmaceutically acceptable carrier(s).
  • a compound and/or a composition is said to be in a "pharmaceutically acceptable carrier” if its administration can be tolerated by a recipient patient.
  • Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier.
  • Other suitable carriers e.g., saline and Ringer's solutions
  • the pharmaceutically acceptable carrier includes a suitable excipient and/or auxiliary whose administration is tolerated by the patient.
  • Pharmaceutically acceptable carriers which are known in the art include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, sucrose, dextrose, lactose, fructose, xylitol, sorbitol, starch, starch paste, cellulose derivatives, gelatin, polyvinylpyrrolidone, sodium chloride, dextrins, stearic acid, magnesium stearate, calcium stearate, vegetable oils, polyethylene glycol, sterile phosphate-buffered saline, saline, and Ringer's solutions, and mixtures thereof.
  • compositions of organic acids which have been approved by the U.S. Food and Drug Administration for commercial marketing include sodium, potassium, lithium, zinc, aluminum, calcium, and magnesium salts.
  • the compounds of the present invention and pharmaceutical compositions thereof are formulated as known in the art.
  • the compound(s) of the present invention may be combined with a pharmaceutically acceptable carrier(s) and processed into a desired dosage form.
  • the pharmaceutical compositions of the present invention may be produced or manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes which involve both the pharmaceutical composition of interest and its pharmaceutically acceptable carrier.
  • the dosages of the compounds, formulations, and compositions described herein will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition, and previous medical history.
  • a composition of the present invention and a pharmaceutically acceptable carrier are administered to a subject in need of such treatment in a therapeutically effective amount.
  • the combination of active agents and carrier is said to be administered in a "therapeutically effective amount” if the amount administered is physiologically significant.
  • a pharmaceutical composition is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient.
  • an anticonvulsant composition is physiologically significant if the presence of the composition results in the alleviation of one or more symptoms of epilepsy, such as seizures and/or convulsions. Further, the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • the compounds of the present invention can be administered orally using solid oral dosage forms such as, for example, enteric-coated tablets, caplets, gelcaps, sprinkles, or capsules, or via liquid oral dosage forms such as syrups or elixirs.
  • Unit solid oral dosage forms preferably contain appropriate amounts of active compounds per tablet or capsule such that they can be taken 1-2 at a time for a maximum of two times per day.
  • Liquid formulations can also be employed with active compounds so as to provide 1-2 teaspoonfuls per dose.
  • corresponding reduced dosage pediatric chewable and liquid oral dosage forms can also be prepared and administered. These compounds can also be added to foods and beverages in the form of drops (with a dropper from a "concentrate" preparation) for oral administration.
  • the compounds of the present invention may also be formulated into chewing gum to facilitate oral delivery and absorption. Appropriate dosages for each of the compounds used in the formulations and compositions of the present invention can be discerned from the foregoing descriptions by those skilled in the art.
  • the compounds of the present invention can be administered by injection or other systemic routes, such as transdermal or transmucosal administration, for example, nasally, sublingually, buccally, vaginally, or rectally, via suppositories.
  • Other routes of administration include intestinal and parenteral delivery, including intramuscular, subcutaneous, and/or intramedullary injections, as well as intrathecal, direct intracerebroventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Oral administration is much more convenient, however, and therefore is preferred.
  • the present invention thus contemplates a variety of compounds that are suitable for oral, parenteral, transdermal, transmucosal, intranasal, sublingual, buccal, or rectal administration. It is further understood that the compounds of the present invention can be used in combination with other pharmaceutically active ingredients to prepare still other novel pharmaceutical compositions.
  • the white precipitate (ammonium chloride) was filtered and washed with THF (100 mL). The filtrate and wash-solution were combined and evaporated under reduced pressure. The resulting white solid was re-dissolved in ethyl acetate (300 mL). The ethyl acetate layer was washed with H 2 0, 1.0 M HCl, a saturated solution of sodium bicarbonate, and brine solution. The ethyl acetate solution was then dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting white solid was triturated with a chilled solution of diethyl ether and hexane (50:50).
  • the white precipitate (ammonium chloride) was filtered and washed with THF (100 mL). The filtrate and wash-solution were combined and evaporated under reduced pressure. The resulting white solid was re-dissolved in ethyl acetate (300 mL). The ethyl acetate layer was washed with H 2 0, 1.0 M HC1, a saturated solution of sodium bicarbonate, and brine solution. The ethyl acetate solution was then dried over magnesium sulfate, filtered, and evaporated under reduced pressure. Crude material was purified using a Biotage SP4 System (Column Si 40+M 0344-1, 95 :5, CH 2 C1 2 : MeOH).
  • the mixture was cooled to ambient temperature and then treated with a solution of 3'-fluoroacetophenone (1.0 eq. 10 g, 72.4 mmol) in DMF (50 mL).
  • the reaction mixture was stirred for 2 hours at ambient temperature and a 1-mL aliquot was removed and quenched in water ( ⁇ 2 mL). Diethyl ether ( ⁇ 2 mL) was added to this and the mixture was equilibrated. Analysis of the organic layer by GC/MS showed complete consumption of the starting benzophenone. As a result, the reaction mixture was quenched by the addition of water.
  • the mixture was transferred to a large round-bottomed flask and the majority of the solvents were removed using a rotary evaporator.
  • the white precipitate (ammonium chloride) was filtered and washed with THF (200 mL). The filtrate and wash-solution were combined and evaporated under reduced pressure. The resulting white solid was re-dissolved in ethyl acetate (350 mL). The ethyl acetate layer was washed with H 2 0, 1.0 M HCl, a saturated solution of sodium bicarbonate, and brine solution. The ethyl acetate solution was then dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting white solid was triturated with a chilled solution of diethyl ether and hexane (50:50).
  • the white precipitate (ammonium chloride) was filtered and washed with CH 2 C1 2 (100 mL). The filtrate and wash-solution were combined and evaporated under reduced pressure. The resulting white solid was re-dissolved in ether (250 mL). The ether layer washed with H 2 0, 1.0 M HC1, a saturated solution of sodium bicarbonate, and brine solution. The ether solution was then dried over magnesium sulfate, filtered, and evaporated under reduced pressure. Crude material was purified using a Biotage SP4 System (Column Si 40+M 0344-1, 95:5, CH 2 Cl 2 :MeOH).
  • the reaction mixture was evaporated under reduced pressure and the resulting residue re-dissolved in an ethyl acetate/water mixture.
  • the mixture was transferred to a separately funnel using H 2 0 (60 mL) and ethyl acetate (100 mL).
  • the mixture was equilibrated and the aqueous phase was removed.
  • the organic layer was washed with 1.0 M HC1 (10 mL), H 2 0 (70 mL), and brine (75 mL), consecutively.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered, and [the] excess solvent was removed under reduced pressure.
  • the reaction mixture was evaporated under reduced pressure and the resulting residue was re-dissolved in an ethyl acetate/water mixture.
  • the mixture was transferred to a separatory funnel using H2O (50 mL) and ethyl acetate (80 mL).
  • the mixture was equilibrated and the aqueous phase was removed.
  • the organic layer was washed with 1.0 M HC1 (20 mL), H 2 0 (90 mL), and brine (120 mL), consecutively.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered, and the excess solvent was removed under reduced pressure.
  • the ether extracts and ether-wash are combined and washed with saturated sodium bicarbonate solution and brine. Then the ether extracts are dried over magnesium sulfate and the excess diethyl ether is removed under reduced pressure at 30°C. This affords 1 -(1-bromom ethyl - cyclopropyl)-4-methoxybenzene.
  • the crude material is converted into the corresponding nitrile without further purification.
  • a stirred suspension of lithium aluminum hydride (0.211 mol) in anhydrous ether (200 mL) is treated with 2-(4-chlorophenoxy)-2-methylpropanic acid (0.1406 mol) in 100 mL of ether at 0 °C.
  • the reaction mixture is stirred at room temperature under nitrogen overnight.
  • the reaction mixture is quenched by the drop- wise addition of 100 mL of deionized H2O.
  • the mixture is filtered and the cake solid is washed with diethyl ether (1 L).
  • the filtrate mixture (ether and water) is transferred into a separatory funnel.
  • the organic layer is separated from the aqueous layer and washed with brine solution.
  • the filtrate is transferred into a separatory funnel using 150 mL of water and 200 mL of diethyl ether.
  • the mixture is equilibrated and the aqueous layer is extracted one more time with 200 mL of diethyl ether.
  • the ether extracts and ether-wash are combined and washed with saturated sodium bicarbonate solution and brine. Then the ether extract is dried over magnesium sulfate and the excess diethyl ether is removed under reduced pressure at 30 °C. This affords 1 -(2 -bromo- 1, 1- dimethylethoxy)-4-chlorobenzene.
  • the crude 1 -(2 -bromo- 1,1 -dimethyl ethoxy)-4- chlorobenzene is converted into the corresponding nitrile without further purification.
  • CH2CI2 was added methanesulfonyl chloride followed by dropwise addition of TEA. The resulting white slurry was allowed to stir for 1 hour and then diluted with H2O (200 mL). The suspension was extracted with CH2CI2 (2 x 100 mL). The CH2CI2 layers were combined and with water (2 x 100 mL) and a 5% H OH solution (100 mL). The CH2CI2 layer was then washed with additional H2O (200 mL) and dried over MgS04. The CH2CI2 layer was concentrated to an oily residue which was dissolved in anhydrous DMF (50 mL). This solution was treated with NaCN and stirred at 60 °C for 14 hours.
  • the reaction was cooled to room temperature and diluted with H2O (100 mL).
  • the solution was extracted with ethyl acetate (2 x 100 mL), dried over MgS0 4 , and concentrated to an oily residue which was chromatographed on silica gel (90% Hex, 10% EtOAc) to give 3-(2-fluoro-biphenyl-4-yl)butyronitrile as an oil which slowly solidified on standing at room temperature (2.05 g, 49% yield).
  • Example 25 Preparation of Compound AY [3-(4-Morpholin-4-yl-phenyl)- butyramide].
  • Example 26 Preparation of Compound Q-l [trans-2-Phenylcyclopropane- carboxylic acid-((S)-l-carbamoyl-propyl)amide].
  • reaction mixture was evaporated under reduced pressure and resulting residue re-dissolved in ethyl acetate/water mixture.
  • the mixture was transferred into a separatory funnel using H2O (50 mL) and ethyl acetate (80 mL).
  • the mixture was equilibrated and the aqueous phase was removed.
  • the organic layer was washed with 1.0M HC1 (20 mL), H 2 0 (90 mL) and brine (120 mL) consecutively.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered, and excess solvent was removed under reduced pressure.
  • FIGS. 4A-40 illustrate additional examples of the syntheses of various compounds and key intermediates (Schemes 1-15), drawn from the literature of synthetic organic chemistry, from which skilled artisans will be able to envision the preparation of various additional compounds of the present invention.
  • Example 28 Baseline Separation of Racemic Compound H into its Enantiomers, Compounds BX and BY, by Means of Chiral Liquid Chromatography (LC).
  • Feed solubility was 15g/L in the mobile phase. Stirring and heating were required to dissolve the feed. The feed solution was filtered through a 0.2- ⁇ filter before use. A total of 37.7g of racemate was processed. Injection volume was 20ml every 14.5 min.
  • Example 42- 59 The secondary and tertiary amides listed in the Table 4 (Examples 42- 59) were prepared using the corresponding acid chlorides and amines by the method of Example 2. In certain cases (i.e., when the amines used were amino acids), the amine hydrochlorides were first rendered as free bases using excess tri-ethylamine.
  • Example Weight % Corresponding
  • Example 63 Demonstration of Biological Activity in Rodent Anticonvulsant Models of Epilepsy.
  • the following compounds also show activity in the MES test at 100 mg/kg: C, Q-2, Q-3, X, Y, AA, AE, AL, AM, AN, AO, AQ, AS, BD, BE, BG, BJ, BL, BR, BU and BV; and at 300 mg/kg: D, L, N, P, Q-l, AP, AR, AW, BF, BM, BN, and BS.
  • the following compound also shows activity in the s.c. MET test at 100 mg/kg: Y; and at 300 mg/kg: D, J, L, Q-l, Q-2, X, AA, AO, AP, AQ, AR, BC, BD, BF, BH, BI, and BM.
  • [00191 j In addition to the compounds shown in Table 5 above, the following compounds also show activity in the 6 Hz (minimal clonic seizure) model at 100 mg/kg: Y, Q-l, Q-2, AA, AN, AX, AY, BB, BL, BK, and CA; at 200 mg/kg: AE and AW; and at 300 mg/kg: Q.
  • mice administered compound BE at 300 mg/kg i.p. exhibited tremors 30 minutes after injection, and those given compound BH exhibited vocalization and hyperactivity on injection lasting for 5-6 minutes.
  • two further tertiary amide compounds, BJ and BT produced diarrhea in the mice 30 minutes after i.p. injection of 100 mg/kg of each.
  • compound G also shows activity in the s.c. MET test at 30 mg/kg.
  • Example 64 Demonstration of Biological Activity in Rat Anticonvulsant Models of Status Epilepticus.
  • Example 65 Demonstration of Lack of Toxicity in In Vitro (LDH and Cell Proliferation) Assays.
  • Compounds A, I, H, and F were tested by Stem Cell Innovations, Inc. (Houston, TX) in their ACTIVTox ® Human Liver Cell-based assays (using C3A hepatocyte cells). Specifically, the compounds were tested in the LDH release assay, which determines the release of Lactate Dehydrogenase (an indicator of cell death) at various concentrations of test compound.
  • Compounds A and I were also tested in the ACTIVTox Cell Proliferation Assay and were found to be non-toxic to proliferating cells at a concentration of 100 ⁇ , with mean fold control values of 1.15 and 1.25, respectively.
  • Example 66 Demonstration of Analgesic Activity in the Mouse Formalin Pain Model and the Sciatic Nerve Ligation Model in Rats.
  • Compounds of the present invention are active in the mouse formalin pain model, significantly decreasing the animals' pain response in both the acute and inflammatory phases. Furthermore, such compounds have also been shown to exhibit significant analgesic effects against both: a) inflammatory (formalin-induced) pain, and
  • neuropathic (sciatic nerve-ligation) pain b) neuropathic (sciatic nerve-ligation) pain.
  • racemic compound H is active in the formalin pain model (mouse i.p.), significantly decreasing the animals' pain response in both the acute (to 63% of the control) and inflammatory (also to 63% of the control) phases at 76 mg/kg i.p. (at 0.5 hours). In the sciatic nerve-ligation model in rats, compound H also significantly increases the allodynic threshold to 455% of the control at a dose of 62 mg/kg at 0.5 hours.
  • One of the active enantiomers of H i.e., BX, is also active in the mouse formalin pain model, significantly decreasing the animals' pain response in both the acute (to 84% of the control) and inflammatory (to 41% of the control) phases at 76 mg/kg i.p. (at 0.5 hours).
  • the other active enantiomer of H i.e., BY
  • BY is also active in the mouse formalin pain model, significantly decreasing the animals' pain response in both the acute (to 53%) of the control) and inflammatory (to 24% of the control) phases at 76 mg/kg i.p. (at 0.5 hours). It thus appears that BY is the more potent and effective analgesic enantiomer of H, although both of the enantiomers exhibit significant activity in the mouse formalin pain model.
  • compound G At a dose of 100 mg/kg, compound G also exhibited a significant analgesic effect in the sciatic nerve-ligation model in rats, shown by a statistically significant increase of the allodynic threshold (to 275% of the control), especially at 1 hour post-administration. [The response (threshold for foot withdrawal) was measured in grams.] The allodynic threshold was observed to decrease in a time- dependent manner, with the analgesic effect (i.e., an increased allodynic threshold) still evident in the rats at 2 hours ⁇ 219% of the control) and 4 hours (175%) of the control) post-administration.
  • This unique profile (including protective activity against both convulsive and non-convulsive seizures induced in the resistant status epilepticus models) further implicates a novel mechanism of action exerted by a unique target (which has not yet been identified) that explains its activity.
  • a unique target which has not yet been identified
  • tramadol (Nucynta ® )
  • acts in part as a weak, but fast-acting serotonin and norepinephrine reuptake inhibitor traditionally antidepressant mechanisms
  • opioids such as methadone
  • CNS-active compounds which have shown analgesic properties as well as NMDA antagonist activity include the psychotropic agent ketamine, the centrally active potassium-channel opener, flupirtine (with weak NMDA antagonist properties), dextromethorphan, ketobemidone, and possibly piritramide.
  • carbamazepine and oxcarbazepine act principally on sodium channels
  • tricylic antidepressants may also work on sodium channels in peripheral nerves
  • gabapentin and pregabalin work by blocking specific calcium channels on neurons.
  • Example 68 Demonstration of Activity in the Lamotrigine-Resistant Amygdala- Kindled Rat Model of Partial Epilepsy and the Gender Neutral Test
  • Lamotrigine Resistance to Lamotrigine can be induced in rats by treating them with the drug during the kindling acquisition phase (i.e., during kindling development in the epileptogenesis phase). Subsequently, the fully kindled Lamotrigine-refractory rats (i.e., now fully manifesting seizures) are also resistant (cross-tolerant) to carbamazepine, phenytoin, and topiramate, but not to valproate (or diazepam or the clinical Phase III drug candidate, retigabine).
  • the Lamotrigine-resistant amygdala-kindled rat model may thus serve as an early model of drug-resistant (i.e., pharmacoresistant, refractory) epilepsy to identify novel AEDs for further evaluation in more extensive model systems, including the phenytoin-resistant kindled rat
  • the LRM thus serves to identify novel broad- spectrum AEDs which may be effective in the treatment of drug-resistant epilepsies.
  • AEDs such as lamotrigine (Lamictal ), carbamazepine (Tegretol ), phenytoin (Dilantin ® ), and topiramate (Topamax ® ).
  • the Gender Neutral test demonstrates the differences between the genders in the way that they respond to AEDs.
  • compound H was found to be equally efficacious in both genders, unlike, e.g., phenytoin (Dilantin ® ) which is significantly less effective in male kindled rats than it is in female kindled rats.
  • Example 69 In Vitro Human CYP-450 Studies.
  • compound H has either no or only a remote possibility of inhibiting four of the tested enzymes (3A4, 2E1, 2B6 and 1A2). On the other hand, it is an inhibitor for 2C19, 2D6, 2A6 and 2C9.
  • the Ki values range from 29 to 174 ⁇ .
  • Example 70 Demonstration of Biological Activity in Rodent Anticonvulsant Models of Epilepsy.
  • MID50 median minimal motor impairment dose
  • ED50 median effective dose
  • AGS Audiogenic Seizure susceptible
  • 6 Hz seizures induced through low-frequency (6 Hz), long-duration (e.g., 3 sec) stimulus delivered through corneal electrodes
  • Corneal Kindled seizures induced through high-frequency, long-duration (e.g., 3 mA, 60Hz, 3 seconds) stimulus delivered through corneal electrodes
  • Example 71 Neuroprotective/recovery effects of various compounds of the invention against oxidative damage as demonstrated in rat dopaminergic N27 cells
  • FIGS 20A-25D data are shown illustrating neuroprotective and neuroregenerative effects observed in rat dopaminergic N27 cells.
  • Rat dopaminergic N27 cells are commonly used in in vitro and in vivo model systems for studying Parkinson's disease. Parkinson's disease is a neurodegenerative disorder of the central nervous system that affects more than 6 million people worldwide. The motor symptoms of Parkinson's disease result from the death of dopamine generating cells in the substantia nigra, a region of the midbrain.
  • the N27 rat dopaminergic neuron cell line was harvested from E12 rat mesencephalic tissue and was transfected with SV40 to immortalize the cell line.
  • the N27 cell line when injected into the striata of 6-hydroxydopamine-lesioned rats (an animal model of PD) caused a time-dependent improvement in neurological deficits.
  • This immortalized cell line has been carefully characterized in studies of dopamine biosynthesis, neurotoxicity and used as a dopaminergic neuron model studies.
  • a number of compounds described herein were tested to identify and develop potential therapeutics for Parkinson's disease and other neurodegenerative disorders. Such therapeutics may not only be able to relieve the devastating symptoms of neurodegenerative diseases like Parkinson's Disease (PD) symptoms, but also to slow, halt, or even reverse the pathology neurodegenerative diseases.
  • PD Parkinson's Disease
  • the N27 in vitro Parkinson's disease model included a test of cell viability and cell toxicity in response to exposure to oxidative stress (e.g., either 200 ⁇ H 2 0 2 or 640 ⁇ MPP+).
  • the MTT assay is a colorimetric analysis based on the activities of mitochondrial NAD(P)H-dependent cellular oxidoreductase enzymes. These enzymes are capable of reducing the tetrazolium dye, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] bromide, to an insoluble formazan (purple).
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] bromide
  • LDH lactose dehydrogenase
  • Figures 20A-25D present data from two types of assays: protection and recovery assays.
  • the drug candidate was applied to the cells at various concentrations for 24 hours, followed by the exposure to oxidative stress (either 200 ⁇ H 2 0 2 or 640 ⁇ MPP+) for measuring neuroprotective effect.
  • H 2 0 2 provides a broad measure of oxidative stress
  • MPP+ gives a more specific oxidative stress to dopaminergic neurons.
  • Example 72 The effect of compound BX on rotenone-induced toxicity in a Drosophila model of sporadic Parkinson 's disease
  • FIGS 26A-26C illustrate the effect of compound BX in another Parkinson's disease model.
  • Chronic infusion of rotenone to fruit flies reproduces many features of Parkinson disease.
  • Rotenone is a pesticide that inhibits mitochondrial complex I activity, thus creating an environment of oxidative stress in the cell.
  • Many studies have employed rotenone to generate an experimental animal model of Parkinson's disease (PD) that mimics and elicits PD-like symptoms, such as motor and cognitive decline.
  • PD Parkinson's disease
  • Evidence suggests that mitochondrial dysfunction and oxidative stress-dependent apoptotic pathways contribute to dopaminergic neuron degeneration in PD.
  • FIG. 26D Figure 26E is a scatter plot of data shown in Figure 26D.
  • Compound BX therefore, protects Drosophila from the neurotoxic effects of rotenone and may prevent oxidative stress in dopaminergic neurons.
  • Example 73 The effect of oral treatment of mice for two weeks with compound BX in an MPTP-induced Parkinson's disease model, which yielded a reduction of abnormal movement in the hindlimb clasping test, improved motor coordination in the crossbeam test, and improved grooming behavior in the coat grooming test.
  • FIG. 27A-27C data are illustrated showing the effect of oral treatment of mice for two weeks with compound BX in an MPTP-induced Parkinson's disease model.
  • MPTP l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine
  • MPP+ a neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animal studies.
  • mice 9 month-old C57/B16 male mice were treated for 7 days of MPTP injection at a rate of 25 mg/kg dose: once a day. Mice in the treatment group were subsequently treated with 14 days of gavage with compound BX at a rate of 50 ⁇ g/gram dose: once a day. Treatment was followed with 5 days of behavioral assays
  • mice were tested on their ability to cross a 20 inch beam with four progressively narrower sections - in the experimental design employed in these data, the beam starts out at 2 inches wide and decreases to 0.5 inches wide in four equal sections. Mice were scored on the number of legs slips per crossing. MPTP treatment significantly reduced the physical dexterity of the mice and increased the number of leg slips. Oral treatment with compound BX for two weeks significantly improved the motor coordination and reduced the number of leg slips.
  • Example 74 Histological analysis: oral treatment with compound BX induced recovery from MPTP-induced damage in striatum in mice.
  • FIGs 28A and 28B illustrate immunohistochemical analysis of the brains of mice treated with MPTP.
  • MPTP causes Parkinson' s- like symptoms by destroying dopaminergic neurons in the substantia nigra of the brain. Loss of dopaminergic neurons leads to the loss of the neurotransmitter dopamine and the onset of Parkinson's symptoms.
  • tyrosine hydroxylase (TH) levels were measured in the Striatum (St) (Fig. 28A) and TH+ dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) were counted (Fig. 28B) to assess the recovery effect of compound BX treatment from chronic MPTP-induced damage.
  • TH tyrosine hydroxylase
  • Pilocarpine-induced SE results in marked cell loss in the hippocampus, when compared to the naive vehicle-treated rats, as evidenced by increased FluoroJade B fluorescence in the dentate gyrus (DG), CA1, and CA3 cell layers.
  • Administration of compound BX, 30 minutes after the first stage 3 convulsive seizure protected the hippocampal neurons against SE-induced cell death in a majority of the animals (11/15; complete neuroprotection), while, 2 of the rats showed partial neuroprotection, where CA3 and hilar neurons of DG are preserved.
  • Pilocarpine-induced SE results in impaired spatial learning and memory in the water maze task.
  • Compound BX at 200 mg/kg halted the convulsive SE, when administered 30' after the first stage 3 seizure.
  • Compound BX preserved spatial learning and memory in pilocarpine-induced SE rats.
  • compound BX offered neuroprotection in a majority of the rats.
  • the ability to protect against learning defects and provide neuroprotection may be generally applicable to neurodegenerative diseases. Particularly, these results may demonstrate that compound BX and compounds related to it may be potential therapeutics that can protect cognitive function in Alzheimer's patients and possibly prevent and/or reverse neural damage.
  • Table 10 illustrates preliminary protein profiling data using Mass spectrometry to identify up/down- regulation by compound BX treatment among numerous identified target proteins.
  • SOD superoxide dismutase
  • SOD protein which is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (0 2 " ) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2), is strongly associated with amyotrophic lateral sclerosis (ALS).
  • SOD1 SOD1 Mutations in the first SOD enzyme (SOD1) can cause familial ALS. Onset of ALS is strongly associated with oxidative stress in the neural tissue of affected individuals. These data indicate that Compound BX may, for example, be effective for reducing the oxidative stress that may lead to the onset of ALS.
  • Tables 1 1 and 12 illustrate PCR array data using real-time PCR to track mRNA levels for various potential targets of compound BX.
  • the upregulated genes shown in Table 1 1 are genes that are associated with ALS: Als2 and catalase enzyme. It should be noted that while Als2 and catalase mRNA levels are significantly upregulated (i.e., approx. 100 fold), this does not necessarily mean that protein levels will be as highly increased.
  • Prdx2 9.66 process, transcription initiation
  • Solute carrier family 6 (DAT), member 3/Dopamine & protein
  • Gclc 5.79 apoptotic mitochondrial changes, response to oxidative stress
  • Atp2b2 ATPase Ca ++ transporting, plasma membrane 2/ ATP binding -5.85
  • Example 76 The response of survival motor neuron 2 (SMN2) promoter reporter cells to exposure to various compounds
  • SMA spinal muscular atrophy
  • SMN1 transcripts contain exon 7 and produce fully functional SMN protein. Because of the transition in exon, most of the mRNAs derived from the transcription of SMN2 lack exon 7 and produce an unstable protein (SMNA7) that is not fully functional.
  • SMNA7 unstable protein
  • the severity of motor neuron degeneration depends on the copy number of SMN2 and the levels of SMN protein in SMA patients. In transgenic mouse models for SMA, SMN2 copy number also modulates phenotypic severity. Taken together, these observations in mice and men suggest that SMN2 is a phenotypic modifier of disease and, therefore, a strong target for therapeutics development.
  • FIG. 30 illustrates a screen for SMN2 expression of a number of compounds described herein.
  • the data illustrated in Figure 29 shows that compounds AY, BB, BX, AA, AW, AX, AM, AN, AS, BU, BZ, CA, Y, AJ, CX, AZ, DA, DB, DC, DD, A, L, M, K, AL, BH, X, BM, and BK were able to increase activity of the SMN2 promoter in SMA Fibroblasts.
  • SMN2 promoter activity was measured using NSC34 motor neuron-like cells stably transfected with a ⁇ -lactamase (BLA) reporter gene under the control of a 3.4- kilobase fragment of the SMN2 promoter. D 156844 was used as a positive control for this assay.
  • BLA ⁇ -lactamase
  • Compounds AA, AX, and K yielded particularly strong hits.
  • Example 77 The response of Exon 7 reporter cells to exposure to various compounds
  • Example 78 SMN protein localization in response to exposure to various compounds
  • GM03813 fibroblasts were treated with different doses (100 nM - 10 ⁇ ) of compounds H, H (acid form), AY, F, BX, and BY for 5 days. SMN immunostaining was then completed on these cells and the number of gems was counted in 100 randomly-selected nuclei. As shown in Figures 31A-31C, compounds H, H (acid form), AY, F, BX, and BY increase gem counts in a dose-dependent manner with compound H (and its acid form) being the most potent. In fact, the gem counts at the highest dose of compound H approach those observed for carrier fibroblasts (GM03814).
  • Example 79 SMN2 expression in response to exposure to various compounds
  • GM03813 type II SMA fibroblasts were treated with 26 hit compounds (100 nM to 10 ⁇ ) for 5 days.
  • Total RNA was extracted from each sample and analyzed for full-length SMN (FL-SMN) and SMNA7 transcript levels by quantitative RT-PCR.
  • FL-SMN and SMNA7 transcript levels in GM03814 carrier fibroblasts was also measured.
  • 9 showed increased FL-SMN transcript levels relative to DMSO treated SMA samples ( Figure 32). Of these 9 hits, 8 hits also increased SMNA7 transcript levels ( Figure 33).
  • tier I greater than 2-fold increase in FL-SMN: Compounds H, BX, M and K;
  • tier II between 1.5- and 2-fold increase in FL-SMN
  • ⁇ tier III between 1.0- and 1.5-fold increase in FL-SMN
  • Compounds F and X Compounds F and X.
  • Example 80 Duchenne muscular dystrophy
  • DMD Duchenne muscular dystrophy
  • DMD is a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and premature death.
  • DMD is thought to be a mitochondrial disorder in which changes in the dystrophin gene lead to dysfunction of muscle cell mitochondria.
  • mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive-oxygen species (ROS) production.
  • ROS reactive-oxygen species
  • MS Multiple sclerosis
  • OPCs mouse oligodendrocyte progenitor cells
  • OLs oligodendrocytes
  • Renovo's high content screening system was investigated.
  • OPCs were derived from plp-EGFP expressing mice. Compounds were tested at luM in a 96-well plates (6 wells per concentration). Negative and positive controls (0.1% DMSO and 10 ng/ml thyroid hormone T3, respectively) were included in each plate. At the end of the 5-day treatment, cells were fixed and imaged on Cellomics ArrayScan Reader in two channels. Computer algorithms were used to count nuclei and EGFP+ oligodendrocytes.
  • Figures 34A-34J are reproductions of representative images illustrating
  • EGFP+ oligodendrocytes in OPCs treated with DMSO 34A
  • thyroid hormone T3 34B
  • Compound B 34C
  • Compound M 34D
  • Compound N 34E
  • a commercial or tool compound 34F
  • Compound H 34G
  • Compound G 34H
  • Compound AV (341)
  • Compound AA 34J
  • Figures 35-38 are graphical representations of the data quantified from Figures 34A-34J, with #2 corresponding to Compound B, #9 corresponding to Compound M, #10 corresponding to Compound N, #23 corresponding to a commercial (or tool) compound, #26 corresponding to Compound H, #27 corresponding to Compound G, #36 corresponding to Compound AV, and #37 corresponding to Compound AA.
  • Figures 39A-39J are reproductions of representative images illustrating
  • Figures 40-43 are graphical representations of the data quantified from Figures 39A-39J, with #39 corresponding to Compound AE, #40 corresponding to Compound AX, #44 corresponding to trans-diastereomer compounds having formulas
  • Figures 44A-44J are reproductions of representative images illustrating
  • EGFP+ oligodendrocytes in OPCs treated with DMSO 44A
  • thyroid hormone T3 44B
  • Compound BK 44C
  • Compound BX 44D
  • Compound BY 44E
  • Compound CA 44F
  • Compound AH 44G
  • Compound AJ 44H
  • Compound DA 391
  • Compound DD 39J
  • Figures 45-48 are graphical representations of the data quantified from Figures 44A-44J, with #75 corresponding to Compound BK, #79 corresponding to Compound BX, #80 corresponding to Compound BY, #82 corresponding to Compound CA, #89 corresponding to Compound AH, #90 corresponding to Compound AJ, #95 corresponding to Compound DA, and #98 corresponding to Compound DD.

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Abstract

La présente invention concerne une série de nouveaux amides présentant une large activité pharmaceutique. Les composés décrits ici sont efficaces en tant qu'anticonvulsants, contre-mesures chimiques et analgésiques. Ces composés présentent également des effets neuroprotecteurs/neuroréparateurs et une activité contre l'amyotrophie spinale. Ces composés pharmaceutiquement actifs présentent une utilité dans le traitement de maladies et de troubles du système nerveux central ("SNC") tels que l'anxiété, la dépression, l'insomnie, les maux de tête migraineux, la schizophrénie, les maladies neurodégénératives (maladie de Parkinson, maladie d'Alzheimer, SLA et malade d'Huntington), la spasticité et les troubles bipolaires. De plus, ces composés peuvent également être utiles en tant qu'analgésiques (par exemple pour le traitement d'une douleur chronique ou neuropathique) et en tant qu'agents neuroprotecteurs utiles dans le traitement d'un ou de plusieurs accidents vasculaires cérébraux et/ou de lésions cérébrales traumatiques et/ou de lésions de la moelle épinière.
PCT/US2016/056152 2015-10-16 2016-10-07 Nouveaux composés bénéfiques dans le traitement de maladies et de troubles du système nerveux central WO2017066103A1 (fr)

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US14/938,341 US10793515B2 (en) 2008-03-19 2015-11-11 Compounds advantageous in the treatment of central nervous system diseases and disorders
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7312214B2 (en) * 2002-05-10 2007-12-25 Bristol-Myers Squibb Company 1, 1-disubstituted cycloalkyl derivatives as factor Xa inhibitors
US20110046128A1 (en) * 2008-03-19 2011-02-24 Aurimmed Pharma, Inc. Novel compounds advantageous in the treatment of central nervous system diseases and disorders
US20120083495A1 (en) * 2006-03-17 2012-04-05 The United States Of America, As Represented By The Secretary, Compounds for the treatment of spinal muscular atrophy and other uses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7312214B2 (en) * 2002-05-10 2007-12-25 Bristol-Myers Squibb Company 1, 1-disubstituted cycloalkyl derivatives as factor Xa inhibitors
US20120083495A1 (en) * 2006-03-17 2012-04-05 The United States Of America, As Represented By The Secretary, Compounds for the treatment of spinal muscular atrophy and other uses
US20110046128A1 (en) * 2008-03-19 2011-02-24 Aurimmed Pharma, Inc. Novel compounds advantageous in the treatment of central nervous system diseases and disorders

Non-Patent Citations (1)

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DATABASE Pubchem 19 August 2012 (2012-08-19), Database accession no. 59019947 *

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