WO2016190871A1 - Composés 2,5-dialkyl-4-h/halo/éther-phénol - Google Patents

Composés 2,5-dialkyl-4-h/halo/éther-phénol Download PDF

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Publication number
WO2016190871A1
WO2016190871A1 PCT/US2015/032876 US2015032876W WO2016190871A1 WO 2016190871 A1 WO2016190871 A1 WO 2016190871A1 US 2015032876 W US2015032876 W US 2015032876W WO 2016190871 A1 WO2016190871 A1 WO 2016190871A1
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Prior art keywords
phenol
group
methyl
isopropyl
alkyl
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Max Baker
Rajesh Kumar Mishra
John J. Talley
Eduardo J. Martinez
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TANSNA THERAPEUTICS Inc
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TANSNA THERAPEUTICS Inc
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Priority to PCT/US2015/032876 priority Critical patent/WO2016190871A1/fr
Priority to ARP160101555A priority patent/AR104807A1/es
Priority to TW105116746A priority patent/TW201717922A/zh
Publication of WO2016190871A1 publication Critical patent/WO2016190871A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/055—Phenols the aromatic ring being substituted by halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/04—Phenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/06—Alkylated phenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/26—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/26—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms
    • C07C39/27—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms all halogen atoms being bound to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/26—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms
    • C07C39/27—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms all halogen atoms being bound to ring carbon atoms
    • C07C39/28—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms all halogen atoms being bound to ring carbon atoms the halogen being one chlorine atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/42—Halogenated derivatives containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This invention relates to compounds having beneficial effects in the central nervous system (CNS) of mammals. More specifically, this invention relates to compounds that prevent or halt ongoing seizures in mammals, and thus have antiepileptic/anticonvulsant activities that are useful for treating epileptics and other patients having seizures. In addition, the compounds described herein can have antiinflammatory properties. The compounds disclosed exert anticonvulsant effects while having low side effects. In addition, this invention relates to compounds useful for treating other pathological conditions of the CNS including anxiety, bipolar disorder, chronic or neuropathic pain, migraine headache, depression, schizophrenia, spasticity, tinnitus, and head trauma.
  • Epilepsy is a complex CNS condition involving excessive neuronal discharges that result in the occurrence of seizures (Stefan H, Feuerstein TJ, Pharmacol Therapeut 2007; 1 13 : 165-83).
  • Seizures may be localized (focal) or generalized within the brain. (Smith M, Wilcox KS, White HS, Neurotherapeutics 2007; 4: 12-17)
  • Seizures may be expressed outwardly as convulsions or they may be non- convulsive (Kwan P, Brodie MJ, Expert Opinion on Emerging Drugs 2007; 12:407-22). Focal (partial) seizures are the most common in humans.
  • Epilepsy occurs in approximately 0.5 to 1% of the human population (Smith M, Wilcox KS, White HS, Neurotherapeutics 2007; 4: 12-17).
  • Chronic, daily treatment with antiepileptic drugs (AEDs) continues to be the standard of care for these patients.
  • AEDs antiepileptic drugs
  • These existing AEDs have varying degrees of effectiveness in suppressing seizures in humans (Stefan H, Feuerstein TJ, Pharmacol Therapeut 2007; 1 13 : 165-83).
  • Refractory epilepsy is defined as failure of adequate trials of two tolerated and appropriately chosen and used AED (anti-epilepsy drug) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan P, Arzimanoglou A, Berg AT, et al. (vol 51, pg 1069, 2010). Epilepsia 2010; 51 : 1922).
  • Treatment of seizures with anticonvulsant drugs also has drawbacks due to the significant occurrence of side-effects.
  • Common side effects of AEDs include sedation, somnolence, depression and other neuropsychological deficits (Wuttke TV, Lerche H, Expert Opinion on Investigational Drugs 2006; 15: 1 167-77) that interfere with a patient's quality and functioning in daily life. Side effects also are a major limitation to escalating patient doses in attempts to suppress seizures.
  • antiseizure compounds are known to interact with a diversity of molecular targets that suppress nerve excitability and likely do so by exerting multiple mechanisms of action.
  • Known mechanisms include effects on voltage-gated ion channels, non-specific cation channels, ligand-gated ion channels, excitatory amino acid receptors, neurotransmitter transporters, and neurotransmitters.
  • GABAA receptor agonism/potentiation is also known to be a mechanism of some anticonvulsant compounds (Myhrer T, Nguyen NHT, Enger S, Aas V,Arch Toxicol 2006; 80:502-07).
  • GABAA receptor agonism/potentiation is presumed to be a component of propofol's anticonvulsant mechanism (Ragavendran JV, Sriram D, Kotapati S, Stables J, Yogeeswari P,. European Journal of Medicinal Chemistry 2008; 43:2650-55).
  • GABAA receptor stimulation depresses nerve conduction by hyperpolarizing the neuronal membrane and suppressing impulse conduction.
  • GABA receptors which exist as multiple isoforms with different sensitivities to agonists (Atack JR, Curr Top Med Chem 201 1; 1 1 : 1 176-202).
  • GABA receptors are known to be present in nerves that excessively fire causing seizures.
  • Other studies show that propofol can block sodium channels (Jones PJ, Wang YS, Smith MD, et al, J Pharmacol Exp Ther 2007; 320:828-36).
  • Propofol has also been reported to down-regulate glutamatergic synaptic transmission (Snyder GL, Galdi S, Hendrick JP, Hemmings HC, Neuropharmacology 2007; 53:619-30), other known anticonvulsant mechanisms. Unlike the barbiturate or benzodiazepine drug families, which have different members useful for anesthesia/sedation and anticonvulsant activity, propofol is the sole member of the alkyl phenolic class on the market.
  • a method for treating and/or improving a condition selected from the group consisting of Alzheimer's Disease, anxiety, bipolar disorder, convulsions, dementia, depression, epilepsy, fibromyalgia, Huntington's Chorea, mania, memory, migraine, multiple sclerosis, neuropathic pain, Parkinson's Disease, seizures, tinnitus, Tourette's Syndrome, and tremors comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula (I):
  • R 2 is selected from the group consisting of alkyl
  • R 4 is selected from the group consisting of H, halo, and alkoxy, wherein the alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and halo, and wherein R 4 is not methyl; and
  • R 5 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl.
  • Embodiment 2 is the method of Embodiment 1 wherein each of R 2 and R 5 has between one and five carbons.
  • Embodiment 3 is the method of Embodiment 1 wherein the condition epilepsy, seizures, or convulsions.
  • Embodiment 4 is the method of Embodiment 1 wherein the condition is neuropathic pain or fibromyalgia.
  • Embodiment 5 is the method of Embodiment 1 wherein the condition is a psychological disorder.
  • Embodiment 6 is the method of Embodiment 5 wherein the psychological disorder is anxiety, mania, bipolar disorder, or depression.
  • Embodiment 7 is the method of Embodiment 1, wherein the condition is Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis, Parkinson's disease, Tourette's Syndrome, tinnitus, and tremors.
  • Embodiment 8 is the method of Embodiment 1, wherein:
  • R 2 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl;
  • R 4 is halo
  • Embodiment 9 is the method of Embodiment 8, wherein:
  • R 4 is selected from the group consisting of Br, CI, and F.
  • Embodiment 10 is the method of Embodiment 9, wherein:
  • R 2 is alkyl
  • R 5 is alkyl having two or more carbons.
  • Embodiment 1 1 is the method of Embodiment 10, wherein the compound is selected from a group consisting of: 4-chloro-5-tert-butyl-2-methyl-phenol; 4-chloro-2- isopropyl-5-methyl-phenol; 4-fluoro-2-isopropyl-5-methyl-phenol; 4-chloro-2,5- diisopropyl-phenol; 4-bromo-5-isopropyl-2-methyl-phenol; 4-bromo-2-isopropyl-5- methyl-phenol; and 4-bromo-2-tert-butyl-5-isopropyl-phenol.
  • Embodiment 12 is the method of Embodiment 1, wherein the compound has the structure of Formula (II):
  • alkyl selected from the group consisting of alkyl, haloalkyl, and cycloalkyl
  • R 4 is selected from the group consisting of Br, CI, and F;
  • R 8 , R 9 and R 10 are each independently selected from the group consisting of H, alkyl, and haloalkyl.
  • Embodiment 13 is the method of Embodiment 1, wherein the compound has the structure of Formula (III): wherein:
  • R is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl;
  • R 5 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl; and R 7 is selected from the group consisting of alkyl and haloalkyl.
  • Embodiment 14 is the method of Embodiment 13, wherein:
  • R 2 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl;
  • R 5 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl; and R 7 is alkyl.
  • Embodiment 15 is the method of Embodiment 14, wherein the compound has the structure of Formula (IV):
  • R is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl
  • alkyl selected from the group consisting of alkyl, haloalkyl, and cycloalkyl.
  • Embodiment 16 is the method of Embodiment 15, wherein:
  • R 2 is selected from the group consisting of alkyl and cycloalkyl
  • R 5 is selected from the group consisting of alkyl and cycloalkyl.
  • a compound selected from the group consisting of: 4-bromo-5-ethyl-2-methyl-phenol; 4-fluoro-5- isopropyl-2-methyl-phenol; 4-bromo-5-tert-butyl-2-methyl-phenol; 4-bromo-5- cyclopropyl-2-methyl-phenol; 4-bromo-2-ethyl-5-isopropyl-phenol; 4-chloro-2-ethyl-5- isopropyl-phenol; 2-ethyl-4-fluoro-5-isopropyl phenol; 4-bromo-5-isopropyl-2-propyl- phenol, 5-isopropyl-2-propyl-phenol; and 4-bromo-2,5-isopropyl-phenol.
  • a compound is provided, selected from the group consisting of: 4-bromo-2-methyl-5-(2,2,2-trifluoro-l-methyl- ethyl)-phenol; 4-bromo-5-(2-fluoro-l-methyl-ethyl)-2-methyl -phenol; 4-bromo-2-methyl- 5-(2,2,2-trifluoro-l-trifluoromethyl-ethyl)-phenol; 4-bromo-2-trifluoromethyl-5-(2,2,2- trifluoro-l-methyl-ethyl)-phenol; 4-bromo-2-cyclopropyl-5-isopropyl-phenol; 4-bromo- 2,5-dicyclopropyl-phenol; 5-isopropyl-2-methyl-4-trifluoromethoxy -phenol; 2- cyclopropyl-5-isopropyl-4-trifluoromethoxy -phenol; 5-cyclopropyl-2-methyl-4- trifluoromethoxy -phenol; 5-cyclopropyl-2
  • haloalkyl selected from the group consisting of haloalkyl and cycloalkyl.
  • Embodiment 20 is the compound of Embodiment 19, wherein:
  • R 2 is selected from the group consisting of trifluoroalkyl and cycloalkyl
  • R 5 is selected from the group consisting of trifluoroalkyl and cycloalkyl.
  • a compound is provided, selected from the group consisting of: 5-(l,2-dimethyl-propyl)-2-methyl-phenol; 5- isobutyl-2-methyl-phenol; 5-cyclopentyl-2-methyl-phenol; 5-sec-butyl-2-ethyl-phenol; 5- butyl-2-propyl-phenol; 5-isopropyl-2-propyl-phenol; 5-sec-butyl-2-propyl-phenol; 5-tert- butyl-2-propyl-phenol; 2-butyl-5-isopropyl-phenol; 2-butyl-5 -sec-butyl-phenol; 5-(tert- butyl)-2-butylphenol; 2-isopropyl-5-propyl-phenol; 5-sec-butyl-2-isopropyl-phenol; 2-sec-butyl-5-ethyl
  • R 2 is selected from the group consisting of methyl, cycloalkyl, and -CF 3 ;
  • R 4 is halo
  • R 5 is selected from the group consisting of fluoroalkyl and a three, four, or five carbon cycloalkyl.
  • Embodiment 23 is the compound of Embodiment 22, wherein: selected from the group consisting of Br, CI, and F.
  • R 2 and R 5 are each independently selected from the group consisting of alkyl and cycloalkyl; wherein at least one of R 2 and R 5 is cycloalkyl.
  • R 7 is selected from the group consisting of isopropyl, tert-butyl, and haloalkyl.
  • Embodiment 25 is the compound of Embodiment 24, wherein:
  • R 7 is selected from the group consisting of isopropyl and tert-butyl.
  • Embodiment 26 is the compound or pharmaceutically acceptable salt of the compound of Embodiment 22, wherein the compound has the structure of Formula (IV):
  • R 2 is selected from the group consisting of alkyl, and cycloalkyl
  • R 5 is selected from the group consisting of alkyl, and cycloalkyl.
  • a method for treating epilepsy, seizures, or convulsions comprising administering a therapeutically effective amount of a compound or of a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula (I), wherein R 2 and R 5 are each independently selected from the group consisting of methyl, isopropyl, and tert-butyl; and R 4 is selected from the group consisting of Br, CI, and F.
  • R 2 and R 5 are each independently selected from the group consisting of methyl, isopropyl, and tert-butyl
  • R 4 is selected from the group consisting of Br, CI, and F.
  • Embodiment 28 is the method of any one of Embodiments 1-16 or 27, wherein the compound is deuterated.
  • Embodiment 29 is the compound or pharmaceutically acceptable salt of any one of Embodiments 17-26, wherein the compound is deuterated.
  • Embodiment 30 provides a method for treating a neurological or an inflammatory condition comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the compound, wherein the compound has a structure of Formula (V):
  • R 1 is selected from the group consisting of an ester, a carbonate, a phosphate, a carbamate, a sulfamate, and an acylmethylester;
  • R 2 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl
  • R 4 is selected from the group consisting of H, halo, and alkoxy, wherein the alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and halo, and wherein R 4 is not methyl;
  • R 5 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl.
  • Embodiment 31 is the method of Embodiment 30,
  • heteroalkyl heteroaryl, heteroaralkyl, carbonylalkyl, or
  • alkyl carboxylate, heteroalkyl, monocyclic ring
  • substituent may be either (1) not substituted or (2) substituted on a substitutable position. If a substitutable position is not substituted, the default substituent is H.
  • the number of carbon atoms in a substituent can be indicated by the prefix "CA-B" where A is the minimum and B is the maximum number of carbon atoms in the substituent.
  • halo refers to fluoro (-F), chloro ( ⁇ C1), bromo (-Br), or iodo (-1).
  • alkyl denotes a linear or branched acyclic alkyl radical containing from 1 to about 15 carbon atoms. In some embodiments, alkyl is a Ci-ioalkyl, Ci- 7 alkyl, Ci-
  • alkyl or Ci-salkyl radical.
  • alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentan-3-yl and the like.
  • heteroatom denotes an atom other than carbon or hydrogen, found in the context of an organic compound.
  • Non-limiting exemplary heteroatoms include N, O, P, and S.
  • heteroalkyl denotes an alkyl that comprises one or more heteroatoms. A heteroatom in a heteroalkyl can be found in the middle and/or at the distal terminus of the alkyl chain.
  • alkylcarbonyl denotes an alkyl radical attached to carbonyl.
  • hydroxyalkyl embraces a radical wherein any one or more of an alkyl carbon is substituted with a hydroxyl radical as defined above, for example, monohydroxyalkyl, dihydroxyalkyl and trihydroxyalkyl. More specific examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl and hydroxypropyl.
  • Hydroxyalkyl may be substituted with, for example, alkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, amino, aminoalkyl, aryl, aralkyl, and heterocyclyl. Further non- limiting examples include hydroxyalkyl substituted with methyl, isobutyl, benzyl, isopropyl, benzyl and sec-butyl.
  • hydroxyalkoxy denotes a hydroxy radical attached to an alkoxy radical.
  • hydroxyalkoxyalkyl denotes a hydroxyalkoxy radical attached to an alkyl radical.
  • Non-limiting examples include hydroxyethyl-O-ethyl and hydroxylmethyl- O-ethyl.
  • Hydroxyalkoxyalkyl may, for example, be substituted with alkyl, hydroxyalkyl, hydroxyalkoxy, amino, aminoalkyl, aryl, aralkyl, and heterocyclyl. Further non-limiting examples include hydroxyalkoxyalkyl substituted with methyl, isobutyl, benzyl, isopropyl and sec-butyl. More specific non-limiting examples of substituted hydroxyalkoxyalkyl include hydroxyethyl-O-ethyl substituted with methyl, isobutyl, benzyl, isopropyl and sec- butyl.
  • haloalkyl embraces an alkyl radical wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • monohaloalkyl, dihaloalkyl and trihaloalkyl may have either a bromo, chloro or a fluoro atom within the radical.
  • a dihalo radical may have two of the same halo radicals or a combination of different halo radicals.
  • a trihaloalkyl radical may have three of the same halo radicals or a combination of different halo radicals.
  • Non- limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, iodomethyl, diiodomethyl and triiodomethyl.
  • alkoxy is RO- where R is alkyl as defined above.
  • alkoxy radicals include methoxy, ethoxy and propoxy.
  • alkyloxy and “alkoxy” and “alkyl-O-” may be used interchangeably.
  • phosphonooxyalkyl is -RO-P(0)(OH) 2 , where R is alkyl as defined above.
  • phosphonooxyalkyl should also be understood to include salts.
  • Non- limiting examples of phosphonooxyalkyl radicals include
  • alkoxyalkyl refers to an alkyl moiety substituted with an alkoxy radical.
  • alkoxyalkyl radicals include methoxymethyl, methoxyethyl, methoxypropyl and ethoxyethyl.
  • alkoxycarbonyl refers to an carbonyl radical substituted with alkoxy.
  • Non-limiting examples include methoxycarbonyl and ethoxycarbonyl.
  • alkoxycarbonylalkyl refers to an alkoxycarbonyl radical substituted with alkyl.
  • carbonyl denotes a carbon radical having two of four covalent bonds shared with a single oxygen atom.
  • alkylcarbonyl denotes an alkyl radical attached to a carbonyl radical.
  • carbonylalkyl denotes a carbonyl radical attached to an alkyl radical.
  • carbonylalkylcarbonyl denotes a carbonylalkyl radical attached to a carbonyl radical.
  • cyclic ring embraces any aromatic or non-aromatic cyclized carbon radical (e.g., aryl and cycloalkyl respectively) which may contain one or more ring heteroatoms (e.g., heteroaryl and heterocyclyl).
  • a cyclic ring may be unsaturated, partially unsaturated, or saturated.
  • cycloalkyl embraces any monocyclic, bicyclic or tricyclic cyclized carbon radical of 3 to about 15 carbon atoms that is fully or partially saturated. Cycloalkyl may be attached to an aryl, cycloalkyl or a heterocyclyl radical in a fused or pendant manner.
  • Cycloalkyl may be substituted with alkyl, alkoxy, carboxyalkyl, hydroxyalkyl, amino, acylamino, amido, alkylamino, nitrooxyalkyl, nitrooxy, carbonyl, acyl, aralkyl, aryl, heterocyclyl or cycloalkyl.
  • aryl refers to any monocyclic, bicyclic or tricyclic cyclized carbon radical, wherein at least one ring is aromatic. An aromatic radical may be attached to a non-aromatic cycloalkyl or heterocyclyl radical in a fused or pendant manner. Examples of aryl radicals include, but are not limited to, phenyl and naphthyl.
  • aralkyl embraces aryl attached to an alkyl radical and may be used interchangeably with arylalkyl. Examples of aralkyl include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms “benzyl” and “phenylmethyl” may be used interchangeably.
  • aralkoxy embraces an arylalkyl radical attached through an oxygen atom to the parent molecular scaffold.
  • arylalkoxy and “aralkoxy” may be used interchangeably.
  • aryloxy is RO-, where R is aryl.
  • aryloxyalkyl embraces an aryloxy radical attached to an alkyl radical.
  • pharmaceutically-acceptable means suitable for use in pharmaceutical preparations, generally considered as safe for such use, officially approved by a regulatory agency of a national or state government for such use, or being listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • pharmaceutically-acceptable salt refers to a salt which is suitable for use in pharmaceutical preparations.
  • therapeutically-effective amount refers to an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect treatment for the disease. "Therapeutically effective amount” can vary depending on the compound, the disease and its severity, the age, the weight, etc. of the subject to be treated.
  • solvate denotes a molecular or ionic complex of molecules or ions of solvent with those of a compound of the present invention.
  • solvate embraces the term “hydrate”.
  • hydrate denotes a compound of the present invention containing water combined in the molecular form.
  • Some of the compounds described contain one or more stereocenters and are meant to include R, S and mixtures of R and S forms for each stereocenter present.
  • AED refers to "Anti-Epileptic Drug.”
  • AED can be used interchangeably with “ASD,” which means “Anti-Seizure Drug.”
  • B. Compounds
  • the present disclosure further provides methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds as described above; such compounds may optionally include one or more deuterium or tritium atoms.
  • the treatment is preventative treatment.
  • the treatment is palliative treatment.
  • the treatment is restorative treatment.
  • the conditions that can be treated in accordance with the present invention include, but are not limited to Alzheimer's Disease, anxiety, atherosclerosis, bipolar disorder, celiac sprue, convulsions, dementia, depression, epilepsy, fibromyalgia, glomerulonephritis, Huntington's Chorea, inflammation disorders, inflammatory bowel disease, mania, memory, migraine, multiple sclerosis, neuropathic pain, Parkinson's Disease, pelvic inflammatory disease, rheumatoid arthritis, seizures, tinnitus, Tourette's Syndrome, and tremors.
  • the compounds described herein can be administered prophylactically to prevent one or more of the above listed conditions.
  • the compounds described herein can be administered prophylactically to individuals such as soldiers, sailors, biohazard remediation professionals, and the like, who are particularly susceptible to one or more of the above listed conditions as a result of exposure to their work environments.
  • the compounds of the present invention may be administered as adjunctive therapy in the treatment of partial onset seizures in adults and children with epilepsy. In certain embodiments the compounds of the present invention may be administered as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents with juvenile myoclonic epilepsy. In certain embodiments the compounds of the present invention may be administered as adjunctive therapy in the treatment of primary generalized tonic -clonic seizures in adults and children with idiopathic generalized epilepsy.
  • the present invention also relates to compounds having microbial-static and microbicidal effects in mammals or on inanimate objects.
  • Compounds of the present invention are useful for sanitizing objects, and therefore are useful for preventing the spread of microorganisms causing infectious disease.
  • Compounds of the present invention are also useful for preserving food, beverage, pharmaceutical and cosmetic preparations at antimicrobial concentrations. They are furthermore useful to prevent and treat infections in mammals, such as the treatment of skin ulcers or periodontal disease, by causing antimicrobial effects on mammalian tissue.
  • the compounds of the present invention cause antimicrobial effects while not causing sedation in animals or humans, regardless of whether exposure is deliberate (such as during treatment of a mammalian subject), or inadvertant (such as exposure resulting from application of compounds of the present invention to inanimate objects in the environment of a mammalian subject).
  • the compounds of the present invention can be used to kill or prevent the growth of microorganisms, such as Enterobacteriaceae (such as Escherichia coli), Firmicutes (such as Staphylococcus aureus, Listeria monocytogenes, and Bacillus spp.), Archaebacteria, Protozoans (such as Giardia lamblia) and Yeasts (such as Candida spp.).
  • microorganisms such as Enterobacteriaceae (such as Escherichia coli), Firmicutes (such as Staphylococcus aureus, Listeria monocytogenes, and Bacillus spp.), Archaebacteria, Protozoans (such as Giardia lamblia) and Yeasts (such as Candida spp.).
  • Disclosed compounds may be used alone, in combination with other compounds of this invention, or in combination with other substances to cause antimicrobial effects.
  • Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, human, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, including humans, and the like, and encompass mammals in utero. Subjects may be of either gender and at any stage of development, including infancy, childhood, adolescence, young adulthood, adulthood, and senescence.
  • the compounds of the present invention are generally administered in a therapeutically effective amount.
  • the compounds of the present invention may be administered in amounts ranging from about 1 mg to about 100 mg per kilogram of body weight per day, for example about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, or about 90 mg/kg per day.
  • the total daily dosage may run from 10 to 1000 mg, such as from 30 to 500 mg, or even from 50 to 250 mg per day.
  • the dosage regimen may be adjusted to provide the optimum therapeutic response and is preferably administered one to three times a day.
  • the active compound may be administered in any convenient manner such as by oral, intraveneous, intramuscular, or subcutaneous routes.
  • Oral administration includes pills, tablets, capsules, syrups, powders, tonics, and the like
  • Parenteral administration includes enemas, suppositories, and the like.
  • Topical administration includes lotions, creams, salves, ointments, patches, and the like
  • the compounds of the present invention may be synthesized and/or administered as prodrugs.
  • Propofol and certain other phenol containing drugs can have short duration of action in vivo or poor oral absorption by virtue of their susceptibility to extensive first pass metabolism.
  • Prodrugs of propofol have been prepared to increase aqueous solubility for intravenous administration.
  • prodrugs are well known in the art (see, e.g., US 6,362,234, US 201 1/257587, US 2010/087536, US 2009/005352, US 2006/287525, US 2006/205969, US 2005/234050, US 2005/090431, US 2005/004381, and US 2003/176324, all incorporated by reference in their entireties herein).
  • There are numerous approaches for protecting phenols including but not limited to the formation of esters, carbonates, phosphates, carbamates, sulfamates, and acylmethylesters.
  • the rate of esterase hydrolysis is known to be highly sensitive to the steric environment about the ester carbonyl.
  • many prodrugs are designed to take advantage of this fact allowing the release kinetics to be adjusted. Other release mechanisms can be similarly affected by the steric environment.
  • the compounds of the present invention can be used, alone or in combination with other pharmaceutically active compounds, to treat conditions such as those previously described above.
  • a compound according to Formula (I) can be administered simultaneously with a second agent (either in the same dosage form or in separate dosage forms) or sequentially with a second agent.
  • the present invention comprises methods for treating a condition by administering to the subject a therapeutically-effective amount of one or more compounds according to Formula (I) and one or more additional pharmaceutically active compounds.
  • the second agent can comprise one or more anticonvulsants, for example selected from acetylpheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitoin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, fosphenytoin, gabapentin, ganaxolone, lamotrigine, levetiracetam, lorazepam, mephenyloin, mephobarbital, metharbital, methetoin, methsuximide, midazolam, narcobarbital, nitrazepam,
  • anticonvulsants for example selected from
  • the second agent can comprise an analgesic or anti-inflammatory drug, for example selected from the group consisting of acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dipyrone (metamizol), eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fent
  • the present invention also relates to methods of manufacturing the compounds of the present invention for use in treatment of nervous conditions such as seizure or convulsion disorders.
  • the compounds of the present invention can be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. These general synthetic schemes and experimental procedures are presented for purposes of illustration and are not intended to be limiting.
  • the starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using routine methods known in the art.
  • Compounds embraced by Formula I may be prepared in accordance with Schemes I-IV, which follow, wherein the R substituent are as defined herein.
  • Conversion B' Silver mediated coupling of aryl tributylstannane I 2 with tris dimethyl ammonium sulfonium trifluoromethoxide (TAS.OCF 3 ) at -30 °C in THF: acetone to afford Scheme IV 4-trifluoromethoxy aryl silyl ether, intermediate I3.
  • TAS.OCF 3 tris dimethyl ammonium sulfonium trifluoromethoxide
  • Conversion C The silyl ether of intermediate I3 is cleaved by treating it with TBAF in THF to afford 4-trifluoromethoxy phenol, Scheme IV intermediate I 4 .
  • Conversion D' Scheme I intermediate 4-bromo phenol I 1 on treatment with Cul and sodium alkoxide in DMF at 110 °C, affords the 4-alkoxy phenol I 5 .
  • the reaction was allowed to warm to room temperature and stirred for 24 hour.
  • the mixture was poured on to ice-water (50 mL) and quenched with NaHC0 3 .
  • the organic layer was removed and the aqueous layer was extracted with CH2CI2 (3 x 50 mL).
  • the combine organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the residue was purified by column chromatography using hexanes and ethyl acetate, giving 3 g (86 %) of the desired phenol as an oil.
  • reaction mixture was allowed to warm to room temperature over 1 h, quenched cautiously with ice and water. It was then extracted with CH2CI2 (3 x 50 mL). The organic extract was washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography using hexanes and ethyl acetate to afford 3.5 g (74 %) of the title compound as an yellow oil.
  • the reaction mixture was stirred at room temperature for 8 h. Water (50 mL) and CH2CI2 (50 mL) are added. The aqueous layer is separated and extracted with CH2CI2 (3 x 50 mL). The combined organic extracts is washed with brine and dried over anhydrous Na 2 S0 4 , filtered, and concentrated under vacuo. The residue was purified by column chromatography using hexanes and ethyl acetate to afford 1.5 g (85 %) the title phenol as an yellow oil.
  • Scheme I Conversion C A suspension Intermediate I 3 and catalytic amount of 5% Pd/C in methanol under hydrogen atmosphere is stirred for 12 hours. The reaction mixture is carefully filtered over a plug of Celite and the solvent is removed in vacuo. The residue is purified by column chromatography to yield the 5-ethyl-2-methyl phenol, Scheme I intermediate I4.
  • Scheme III conversion A The intermediate I4, obtained above is brominated at 4-position using «-BuNBr 3 in a mixture of CH ⁇ C ⁇ MeOH (3:2), following the procedure described for the synthesis of compound 9 to obtain compound 5.
  • Scheme I Conversion G A suspension of intermediate I 7 and catalytic amount of 5% Pd/C in methanol is agitated under hydrogen atmosphere using a hydrogen balloon for 12 hours. The reaction mixture is filtered through a plug of Celite. The filtrate is concentrated under vacuo and the residue is purified by column chromatography to afford the intermediate phenol I 8 .
  • Scheme III Conversion A The intermediate phenol I 8 is brominated at 4-position with in CH 2 Cl2:MeOH using a procedure described for the synthesis of compound 9, to afford the compound 41.
  • Scheme II Conversion F' To a solution of phenol I 5 (1 equivalent) in anhydrous THF at 0 °C is added a solution of methylmagnesium bromide in ether (5 equivalent). The reaction mixture is allowed to warm to room temperature and stirred till the completion of reaction. The reaction mixture is quenched slowly with aqueous NH 4 C1 solution then extracted with ether. The organic layer is dried over sodium sulfate, filtered, and concentrated under vacuo. The residue is then purified by column chromatography to afford Scheme II intermediate phenol I 7 .
  • Scheme II Conversion G' A suspension of phenol I 7 and catalytic amount of 5% Pd/C in methanol under hydrogen atmosphere is stirred at room temperature for 12 hours, Scheme II, conversion G'. The reaction mixture is filtered through a plug of Celite and the filtrate concentrated under reduced pressure. The residue is purified by column chromatography to afford Scheme II intermediate phenol I 8.
  • Scheme III Conversion A" The intermediate phenol I 8 is brominated at 4-position, according to the procedure described for the synthesis of compound 9, to afford compound 148.
  • Scheme I Conversion E Thionyl chloride (2 equivalent) is added drop wise to a solution of intermediate phenol I 5 (1 equivalent) in toluene and pyridine (few drops) at 0 °C. The reaction mixture is allowed to warm to room temperature and stirred for 12 hours. The reaction mixture is poured on to water and extracted with ethyl acetate. The combined ethyl acetate extracts is washed with aqueous NaHC0 3 solution, dried over sodium sulfated, filtered, and concentrated under vacuo. The residue is purified by column chromatography to afford the tert-chloro derivative.
  • a suspension of tert-chloro derivative (1 equivalent) and sodium borohydride (15 equivalent) in anhydrous THF is stirred at room temperature. After completion of reaction, the reaction is quenched with water and extracted with ethyl acetate. The combined ethyl acetate layers are dried over sodium sulfate, filtered, and concentrated under vacuo. The residue is purified by column chromatography to afford the de-chlorinated derivative.
  • a solution of the de-chlorinated derivative (1 equivalent) and TBAF (5 equivalent) in THF is stirred at room temperature. After completion of reaction, the solvent is removed under vacuo. The residue is dissolved in water and extracted with ethyl acetate.
  • Scheme II conversion H' A mixture of intermediate phenol le (1 equivalent), KIO 3 (0.2 equivalent), iodine (0.5 equivalent) in acetic acid is stirred at room temperature for 3 days. The solvent is removed under vacuo. The residue is dissolved in ether and washed with aqueous NaHCC ⁇ , Na 2 S 2 0 3 , and brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under vacuo. The residue is purified by column chromatography to yield the Scheme II intermediate iodinated phenol I9.
  • reaction mixture After completion of reaction, the reaction mixture is cooled to room temperature. A saturated aqueous solution of NH 4 C1 is added and the reaction mixture is extracted with ether. The organic layer is washed with aqueous NaHC0 3 and brine, and dried over sodium sulfate. The solvent is removed under vacuo. The residue was purified by column chromatography to afford the 3-trifluoromethyl substituted intermediate aryl triflate. To a solution of aryl trifate (1 equivalent) in dioxane is added 10 % aqueous Et4NOH solution (2 equivalent) at room temperature and the reaction is stirred till completion of reaction. The reaction mixture is diluted with CHCI 3 , washed with 1M HCl, water, and brine.
  • Compound 269 is derived from 5 -bromo-2 -methyl phenol according to the procedure described for the synthesis of compound 216, using CHF 2 COCH 3 instead of CH 3 COCF 3 in the second step of the synthesis.
  • reaction mixture is stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (1.20 equivalent) and silver hexafluorophosphate (2.00 equivalent) in dry acetone is added by cannula.
  • the reaction mixture is stirred for 2.5 hours in the dark, then warmed to 23 °C.
  • the reaction mixture is filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo at 5 °C.
  • the residue is purified via column chromatography on silica gel to afford Scheme IV intermediate I 2 .
  • 253 is synthesized from compound 240, according to the procedure described for the synthesis of compound 251.
  • Phenols are excellent nucleophiles known to condense with a wide variety of acid chlorides.
  • compound 9 can be treated with acid chloride in the presence of base to provide the 4-bromo-5-isopropyl-2-methyl phenol alkyl/aryl esters (Scheme V).
  • Scheme V 4-bromo-5-isopropyl-2-methyl phenol alkyl/aryl esters
  • Prodrugs containing a phosphate moiety have been successfully employed for increasing oral absorption and modulation of duration of action in vivo. Shown below are potential phosphate containing analogs of compound 9 and 11 (Scheme VIII).
  • Ether prodrug approach has been used to enhance lipophilicity, favoring the permeation into cellular membranes and the blood brain barrier, and/or to improve the pharmacokinetic properties of the parent drug.
  • Many phenolic group-containing drugs cannot be administrated orally due to their rapid metabolism by the enzymes in the intestinal tract and liver.
  • Ether prodrugs undergo chemical hydrolysis and are not always enzyme dependent for their cleavage.
  • O-(saccharinylmethyl) prodrug can protect the drug from first pass metabolism and increase the drugs oral potency. It can be synthesized by treating the phenol with saccharinyl methyl chloride (Scheme IX).
  • Glycosides derivatives of dopamine have shown high stability in plasma and a sustained release of dopamine in brain extract through an activation mechanism catalyzed by glycosidase.
  • a glycosyl derivative can be prepared by coupling the phenol with glucose penta acetate (Scheme X).
  • N-alkyloxycarbonylaminomethyl and alkylcarbonyloxymethyl prodrugs have been used for the topical delivery of the phenol drug and increase its biphasic stability.
  • the synthesis can be achieved as described in Scheme XI.
  • Sulfamate ester pro-drugs have been employed to mitigate hepatic first-pass metabolism of selected phenol drugs. Once these molecules reach systemic circulation they are converted by hydrolysis to the corresponding phenols by esterases and amidases. Shown in Scheme XII is a sulfamate ester of compound 9. A variety of substituents can be incorporated into the sulfamate moiety to modulate kinetics of parent molecule release.
  • the minimal clonic seizure (6Hz) test is used to assess a compound's efficacy against electrically induced seizures but uses a lower frequency (6Hz) and longer duration of stimulation (3 s) than the MES test (Barton ME KB, Wolf HH, White HS: Pharmacological characterization of a 6 HZ psychomotor seizure model of partial epilepsy. Epilepsy Res 2001; 47:217-27). Test compounds are pre-administered to mice via i.p. injection.
  • mice are challenged with sufficient current delivered through corneal electrodes to elicit a psychomotor seizure in 97% of animals (32 mA or 44 mA for 3s) (Toman JEP, Everett GM, Richards RK: The Search for New Drugs against Epilepsy. Texas Reports on Biology and Medicine 1952; 10:96-104). Untreated mice will display seizures characterized by a minimal clonic phase followed by stereotyped, automatistic behaviors described originally as being similar to the aura of human patients with partial seizures. Animals not displaying this behavior are considered protected. The test compounds are evaluated quantitatively by measuring the responses at varying doses at a determined time of peak effect (TPE).
  • TPE time of peak effect
  • mice are kindled electrically with 3 sec stimulation, 8 mA, 60 Hz, and corneal electrodes to a criterion of 10 consecutive Stage 5 seizures (facial clonus and head nodding progressing to forelimb clonus, and finally rearing and falling accompanied by a generalized clonic seizure as described by Racine (Racine RJ: Modification of Seizure Activity by Electrical Stimulation. II. Motor Seizure. Electroen Clin Neuro 1972; 32:281— 94).
  • Stage 5 is generally reached after twice daily stimulation for 8 days. With continued stimulation once a day, animals usually progress to a reproducible Stage 5 after 10-14 additional days.
  • the test substance is administered either intraperitoneal (i.p.) or per os (p.o.) and, at the previously determined TPE, each animal is given the electrical stimulus indicated above. Following stimulation, the animals are observed for the presence or absence of the rearing and falling criteria of a Stage 5 seizure. Treated animals not displaying a Stage 3, 4, or 5 seizure are considered protected.
  • the dose of the test substance is varied between the limits of 0 and 100% efficacy, and the ED5 0 and 95% confidence intervals calculated by probit analysis. Mean values and the S.E.M. are calculated for the length of clonus and seizure duration and p values are determined by the Student's t-test.
  • MES test is performed as in the Minimal Clonic Seizure (6 Hz) test, but the MES test utilizes a current of 50 mA (mice) or 150 mA (rats), frequency of 50-60 Hz, and a stimulation time of 0.2 seconds.
  • untreated test subjects display immediate severe tonic seizure (including maximal extension of legs) and the body becomes stiffened for roughly 10-15 seconds.
  • clonic seizures start (including shaking of body and paddling movements of the hind limbs) and may last 20-30 seconds (Castel-Branco MM, Alves GL, Figueiredo IV, Falcao AC, Caramona MM: The Maximal Electroshock Seizure (MES) Model in the Preclinical Assessment of Potential New Antiepileptic Drugs. Methods and Findings in Experimental and Clinical Pharmacology 2009; 31 : 101-06). Test subjects that display reduced or eliminated symptoms of MES- type seizures during and/or after stimulation are considered protected.
  • MES Maximal Electroshock Seizure
  • mice are monitored for overt signs of impaired neurological or muscular function.
  • the rotorod (Dunham NW, Miya TS: A Note on a Simple Apparatus for Detecting Neurological Deficit in Rats and Mice. Journal of the American Pharmaceutical Association 1957; 46:208-09), procedure is used to disclose minimal muscular or neurological impairment.
  • a mouse is placed on a rod that rotates at a speed of 6 rpm, the animal can maintain its equilibrium for long periods of time. The animal is considered toxic if it falls off this rotating rod three times during a 1-min period.
  • minimal motor deficit is indicated by ataxia, which is manifested by an abnormal, uncoordinated gait.
  • Rats used for evaluating toxicity are examined before the test drug is administered, since individual animals may have peculiarities in gait, equilibrium, placing response, etc., which might be attributed erroneously to the test substance. In addition to minimum motor impairment, animals may exhibit a circular or zigzag gait, abnormal body posture and spread of the legs, tremors, hyperactivity, lack of exploratory behavior, somnolence, stupor, catalepsy, loss of placing response, and changes in muscle tone.
  • Phenol derivatives with known GABAnergic activity and structurally similar phenol derivatives were tested for lipophilic parameters because GABA receptors are present in cell membranes in Reiner et al., Colloids and Surfaces, B: Biointerfaces, 101 :61-67 (2013). Reiner et al. considered 4-chloro-2-isopropyl-5-methylphenol to be structurally related to the compound thymol, which has known GABAnergic activity, so 4- chloro-2-isopropyl-5-methylphenol was tested for membrane interaction. All five phenol derivatives tested were shown to interact with membranes.
  • a method for treating a neurological or an inflammatory condition comprising administering a therapeutically effective amount of a compound or
  • R 2 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more cycloalkyl substituents;
  • R 4 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more cycloalkyl substituents, and wherein R 4 is not methyl;
  • R 5 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl.
  • Phenol derivatives with known GABAnergic activity and structurally similar phenol derivatives were tested for lipophilic parameters because GABA receptors are present in cell membranes in Reiner et al., Colloids and Surfaces, B: Biointerfaces, 101 :61-67 (2013).
  • Reiner et al. considered 4-chloro-2-isopropyl-5-methylphenol to be structurally related to the compound thymol, which has known GABAnergic activity, so 4- chloro-2-isopropyl-5-methylphenol was tested for membrane interaction. All five phenol derivatives tested were shown to interact with membranes.
  • a method for treating a neurological or an inflammatory condition comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula (I): wherein:
  • R 2 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more cycloalkyl substituents;
  • R 4 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more cycloalkyl substituents, and wherein R 4 is not methyl;
  • R 5 is selected from the group consisting of halo, and alkoxy, wherein the alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and halo.
  • Phenol derivatives with known GABAnergic activity and structurally similar phenol derivatives were tested for lipophilic parameters because GABA receptors are present in cell membranes in Reiner et al., Colloids and Surfaces, B: Biointerfaces, 101 :61-67 (2013).
  • Reiner et al. considered 4-chloro-2-isopropyl-5-methylphenol to be structurally related to the compound thymol, which has known GABAnergic activity, so 4- chloro-2-isopropyl-5-methylphenol was tested for membrane interaction. All five phenol derivatives tested were shown to interact with membranes.
  • a method for treating a neurological or an inflammatory condition comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the compound, wherein the compound has a structure of Fo
  • R 2 is selected from the group consisting of alkyl, haloalkyl, and cycloalkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more cycloalkyl substituents;
  • R 4 is selected from the group consisting of H, halo, alkyl, alkoxy, haloalkyl, haloalkoxy and cycloalkyl, wherein alkyl or haloalkyl is optionally substituted with one or more cycloalkyl substituents, wherein the alkyl portion of the alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and halo, and wherein R 4 is not methyl;
  • R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halo, and alkoxy, wherein the alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl and haloalkyl; and
  • R 6 is halo

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Abstract

L'invention concerne des composés phénoliques utiles dans le traitement de pathologies neurologiques telles que les convulsions et les tremblements. Ces composés présentent la structure de formule (I), dans laquelle R2, R4, R5, & R6sont tels que définis dans la description détaillée. L'invention concerne également des compositions pharmaceutiques comprenant au moins un desdits composés, et des méthodes de traitement d'états neurologiques.
PCT/US2015/032876 2015-05-28 2015-05-28 Composés 2,5-dialkyl-4-h/halo/éther-phénol Ceased WO2016190871A1 (fr)

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CN112812126A (zh) * 2021-01-28 2021-05-18 天津全和诚科技有限责任公司 一种双通道荧光探针的制备方法
JP2023552699A (ja) * 2020-11-17 2023-12-19 ハー・ルンドベック・アクチエゼルスカベット パーキンソン病の治療に使用するための新規なカテコールアミンプロドラッグ

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