WO2013016411A1 - Nouveaux sulfamides cycliques fluorés présentant une action neuroprotectrice et leur procédé d'utilisation - Google Patents

Nouveaux sulfamides cycliques fluorés présentant une action neuroprotectrice et leur procédé d'utilisation Download PDF

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WO2013016411A1
WO2013016411A1 PCT/US2012/048120 US2012048120W WO2013016411A1 WO 2013016411 A1 WO2013016411 A1 WO 2013016411A1 US 2012048120 W US2012048120 W US 2012048120W WO 2013016411 A1 WO2013016411 A1 WO 2013016411A1
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fluoro
sulfonamide
phenyl
piperidine
methoxy
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PCT/US2012/048120
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English (en)
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Garry Robert Smith
Douglas E. Brenneman
Allen B. Reitz
Yan Zhang
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Garry Robert Smith
Brenneman Douglas E
Reitz Allen B
Yan Zhang
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Publication of WO2013016411A1 publication Critical patent/WO2013016411A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention describes compounds and methods useful as neuroprotective agents, useful for the treatment of epilepsy and related conditions.
  • the present invention further describes a novel chemotype useful for the treatment of neurodegenerative disease, epilepsy, multiple sclerosis, Alzheimer's disease and other diseases that involve the presence of excess glutamate.
  • Epilepsy is a common chronic neurological condition that affects over 50 million people worldwide, including approximately three million Americans. Although effective anticonvulsant drugs have been available since the early 1900's, significant unmet medical needs remain. Current estimates indicate that 25% of people suffering from epilepsy receive no effective treatment for their seizures from today's available drugs. Of those that do, approximately 15% report inadequate treatment and another 20% have intractable seizures. Serious toxicities (Stevens Johnson syndrome, metabolic acidosis, aplastic anemia), reduced bone mineral density and osteoporosis, and teratogenicity are concerns with currently marketed antiepileptic drugs. [0005] Frequently identified causes of epileptic seizures include stroke, injuries, poisoning (alcoholism), and systemic illnesses during pregnancy or brain injuries during childbirth.
  • the neurochemical rationale for treating epileptogenesis resides in our understanding of the multiple factors that contribute to neuronal cell death in this disease (Bengzon et al, 2002). These factors include genetic factors, glutamate- induced excitotoxicity, mitochondrial dysfunction, oxidative stress, growth factor loss and increases in cytokine concentration (Ferriero, 2005). Intense seizure activity produces large increases NMDA-mediated calcium influx (Van Den Pol et al., 1996). High levels of calcium lead to apoptotic cascades that result in acute neuronal cell death. Elevated calcium levels can also generate reactive oxygen species that can produce cell damage and death.
  • neuronal injury and death have been shown to occur in most epilepsy models and are widely considered both a prerequisite and a result of seizure-induced epilepsy.
  • Two of the processes that contribute to the neural losses are glutamate toxicity and oxidative stress.
  • An emerging concept is that neuroprotection by prevention of glutamate toxicity and oxidative stress will limit both neural damage associated with seizures and provide long-term antiepileptogenesis.
  • the same strategy has been suggested for the treatment of or preventing diseases with excess glutamate in their etiology, including, for example, Parkinson's disease, Alzheimer's disease, Multiple Sclerosis and Huntington's disease.
  • the present invention addresses the need to prevent glutamate toxicity and oxidative stress in addition to providing neurostabilization to treat acute seizures and epilepsy.
  • the present invention also addresses the long felt need for new treatments for and means of preventing diseases with excess glutamate in their etiology, including, for example, epilepsy, Parkinson's disease, Alzheimer's disease, Multiple Sclerosis and Huntington's disease.
  • the present invention is directed toward novel fluorinated cyclic sulfamide derivatives comprising compounds of formula (I),
  • R is selected from the group consisting of optionally substituted aryl, optionally substituted benzoisoxazole, and optionally substituted benzothiophene where R is substituted by 0-5 moieties;
  • R 1 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted Ci_ 6 alkyl.
  • R 2 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted Ci_ 6 alkyl.
  • R 1 and R 2 are taken together with atoms to which they are bound to form an optionally substituted bridging ring having from 5 to 7 ring atoms.
  • the compounds of the present invention include compounds of formula (II):
  • R is selected from the group consisting of optionally substituted aryl, optionally substituted benzoisoxazole, and optionally substituted benzothiophene where R is substituted by 0-5 moieties.
  • the present invention further relates to compositions comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing diseases that involve excess glutamate in their etiology, including, for example, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease and Multiple Sclerosis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing diseases that involve excess glutamate in their etiology, including, for example, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease and Multiple Sclerosis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with epilepsy, Parkinson's disease, Alzheimer's disease, Multiple Sclerosis, Huntington's disease, and diseases that involve excess glutamate in their etiology.
  • Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, Multiple Sclerosis and diseases that involve excess glutamate in their etiology, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with neuronal cell death or damage from glutamate toxicity. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with neuronal cell death or damage from glutamate toxicity, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with neuronal cell death or damage from oxidative stress. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with neuronal cell death or damage from oxidative stress, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention further relates to a process for preparing the neuroprotective agents of the present invention.
  • the neuroprotective agents of the present invention are capable of treating and preventing diseases associated with glutamate toxicity and oxidative stress including, for example epilepsy, Parkinson's disease, Alzheimer's disease, Multiple Sclerosis and Huntington's disease. It has been discovered that prevention of glutamate toxicity and oxidative stress will limit neural damage associated with seizures, provide long-term antiepileptogenesis, and prevent neuronal cell death. Without wishing to be limited by theory, it is believed that neuroprotective agents can ameliorate, abate, or otherwise cause to be controlled, diseases associated with glutamate toxicity, oxidative stress, and neuronal cell death.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • compositions comprising specific components are open to additional unspecified components; compositions consisting essentially of specific components are open to additional unspecified components that have no material effect on the compositions; and compositions consisting of specific components are closed to additional unspecified components.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl and “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Designated numbers of carbon atoms e.g. Ci_ e shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, and the like.
  • Alkyl groups can be optionally substituted.
  • Non- limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2 -hydroxy ethyl, 1 ,2-difluoroethyl, 3- carboxypropyl, and the like.
  • substituent groups with multiple alkyl groups such as (Ci_ 6 alkyl) 2 amino, the alkyl groups may be the same or different.
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain.
  • Alkenyl and alkynyl groups can be optionally substituted.
  • Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like.
  • Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chloro vinyl), 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7- hydroxy-7-methyloct-3,5-dien-2-yl, and the like.
  • Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-l-yl, and 2-methyl- hex-4-yn-l-yl.
  • Nonlimiting examples of substituted alkynyl groups include, 5- hydroxy-5 -methylhex-3 -ynyl, 6-hydroxy-6-methylhept-3 -yn-2-yl, 5 -hydroxy-5 - ethylhept-3-ynyl, and the like.
  • cycloalkyl refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond.
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted.
  • Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3- dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5- dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5- trimethylcyclohex-l-yl, octahydropentalenyl, octahydro-lH-indenyl, 3a,4,5,6,7,7a- hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicy clo [3.3.3 ]undecany 1.
  • bridged bicycle refers to a non-aromatic carbon-containing ring structure that creates a bridged bicycle.
  • bridged bicycle includes non limiting examples 8-aza- bicyclo[3.2.1]octane, 6-aza-bicyclo[3.1.1]heptane, 9-aza-bicyclo[3.3.1]nonane, 10- aza-bicyclo[4.3. l]decane, 3-aza-bicyclo[3.2. ljoctane, 3-aza-bicyclo[3.1.l]heptane, 3-aza-bicyclo[3.3.1]nonane, and 8-aza-bicyclo[4.3.1]decane.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., - CF 3 , CF 2 CF 3 ).
  • Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
  • alkoxy refers to the group -O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted.
  • C 3 -C 6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C 3 -C 6 cyclic alkoxy groups optionally may be substituted.
  • aryl wherein used alone or as part of another group, is defined herein as an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic poly eye lie ring of from 10 to 14 carbon members.
  • Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms.
  • Non-limiting examples of aryl groups include: phenyl, naphthylen-l-yl, naphthylen-2-yl, 4- fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N- diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8- hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-l-yl, and 6-cyano-naphthylen-l- yl.
  • Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • arylalkyl refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein.
  • Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.
  • heterocyclic and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic.
  • the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl).
  • heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocycle group can be oxidized.
  • Heterocycle groups can be optionally substituted.
  • Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin- 2-onyl (valerolactam), 2,3,4,5-tetrahydro-lH-azepinyl, 2,3-dihydro-lH-indole, and 1,2,3,4-t
  • Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-lH-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-lH- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-lH-indolyl, 1,2,3,4- tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro- 1 H-cycloocta[b]pyrrolyl.
  • heteroaryl whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non- heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H- cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl).
  • heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted.
  • heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, lH-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2- phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl.
  • Non- limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H- purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3- d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, lH-indolyl, 4,5,6,7-tetrahydro-l-H- indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy- quinolinyl, and isoquinolin
  • heteroaryl group as described above is C1-C5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • C1-C5 heteroaryl examples include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-l-yl, lH-imidazol-2-yl, lH-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin- 5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
  • the ring when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 taken together with the carbon and nitrogen to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • the ring can be saturated or partially saturated and can be optionally substituted.
  • fused ring units as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1, 2,3, -tetrahydroquino line having the formula:
  • l,2,3,4-tetrahydro-[l,8]naphthyridine having the formula:
  • substituted is used throughout the specification.
  • substituted is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below.
  • the substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • substituted is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced.
  • difluoromethyl is a substituted Ci alkyl
  • trifluoromethyl is a substituted Ci alkyl
  • 4-hydroxyphenyl is a substituted aromatic ring
  • (N,N-dimethyl- 5-amino)octanyl is a substituted C 8 alkyl
  • 3-guanidinopropyl is a substituted C 3 alkyl
  • 2-carboxypyridinyl is a substituted heteroaryl.
  • variable groups defined herein e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.
  • the substituents are selected from:
  • -OR 4 for example, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 ; ii) -C(0)R 4 ; for example, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 ; iii) -C(0)OR 4 ; for example, -C0 2 CH 3 , -C0 2 CH 2 CH 3 , - C0 2 CH 2 CH 2 CH 3 ;
  • -S0 2 R 4 for example, -S0 2 H; -S0 2 CH :
  • each R 4 is independently hydrogen, optionally substituted Ci-C 6 linear or branched alkyl (e.g., optionally substituted C 1-C4 linear or branched alkyl), or optionally substituted C 3 -C 6 cycloalkyl (e.g optionally substituted C 3 -C 4 cycloalkyl); or two R 4 units can be taken together to form a ring comprising 3-7 ring atoms.
  • each R 4 is independently hydrogen, Ci-C 6 linear or branched alkyl optionally substituted with halogen or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.
  • substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci_ 6 alkyl” is specifically intended to individually disclose d, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-C 6 , Ci-C 5 , C1-C4, Ci-C 3 , Ci-C 2 , C 2 - C 6 , C 2 -C5, C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C5, C 3 -C 4 , C 4 -C 6 , C4-C5, and Cs-C 6 , alkyl.
  • composition of matter stand equally well for the neuroprotective agent described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.
  • Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • asymmetric atom also referred as a chiral center
  • the present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
  • compositions of the present teachings which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts
  • ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,
  • inorganic bases include NaHC0 3 , Na 2 C0 3 , KHC0 3 , K 2 C0 3 , Cs 2 C0 3 , LiOH, NaOH, KOH, NaH 2 P0 4 , Na 2 HP0 4 , and Na 3 P0 4 .
  • Internal salts also can be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.
  • any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R 2 ) 2 , each R 2 may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • treat and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
  • terapéuticaally effective and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.
  • neuroprotective agent shall mean a compound that provides neuroprotection.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
  • the neuroprotective agents of the present invention are substituted fluorinated cyclic sulfamides, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):
  • R is selected from the group consisting of optionally substituted aryl, optionally substituted benzoisoxazole, and optionally substituted benzothiophene where R is substituted by 0-5 moieties;
  • W is 1 or 2;
  • R 1 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted Ci_ 6 alkyl.
  • R 2 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted Ci_ 6 alkyl.
  • R 1 and R 2 are taken together with atoms to which they are bound to form an optionally substituted bridging ring having from 5 to 7 ring atoms.
  • the compounds of the present invention include compounds having formula
  • R is selected from the group consisting of optionally substituted aryl, optionally substituted benzoisoxazole, and optionally substituted benzothiophene where R is substituted by 0-5 moieties.
  • R is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from Ci- 6 alkyl, halogen, Ci- 6 alkoxy, OH, NH 2 , NH(Ci_6 alkyl), N(Ci_ 6 alkyl) 2 , N0 2 , Ci_ 3 haloalkyl, Ci_ 3 haloalkoxy, SH, SCi_ 6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S.
  • R is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, methyl and methoxy.
  • R is benzothiophene optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci- 6 alkyl, halogen, Ci- 6 alkoxy, OH, NH 2 , NH(Ci_6 alkyl), N(Ci_ 6 alkyl) 2 , N0 2 , Ci_ 3 haloalkyl, Ci_ 3 haloalkoxy, SH, SCi_6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S.
  • substituents independently selected from Ci- 6 alkyl, halogen, Ci- 6 alkoxy, OH, NH 2 , NH(Ci_6 alkyl), N(Ci_ 6 alkyl) 2 , N0 2 , Ci_ 3 haloalkyl, Ci_ 3 haloalkoxy, SH, SCi_6 alkyl, CN, and 3-10 membered cycloheteroalky
  • R is benzothiophene optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, methyl and methoxy.
  • R is benzisoxazole optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci- 6 alkyl, halogen, Ci- 6 alkoxy, OH, NH 2 , NH(Ci_6 alkyl), N(Ci_ 6 alkyl) 2 , N0 2 , Ci_ 3 haloalkyl, Ci_ 3 haloalkoxy, SH, SCi_ 6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, O and S.
  • substituents independently selected from Ci- 6 alkyl, halogen, Ci- 6 alkoxy, OH, NH 2 , NH(Ci_6 alkyl), N(Ci_ 6 alkyl) 2 , N0 2 , Ci_ 3 haloalkyl, Ci_ 3 haloalkoxy, SH, SCi_ 6 alkyl, CN, and 3-10 membered cycloheteroalky
  • R is benzisoxazole optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from fluorine, chlorine, trifluoromethyl, trifluoromethoxy, methyl and methoxy.
  • R is phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 2- chloro-6-fluorophenyl, 2-fluoro-6-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 2- chloro-6-methoxyphenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, or 2,4- difluorophenyl.
  • R is benzothiophene.
  • R is benzisoxazole.
  • R 1 is optionally substituted Ci_ 6 alkyl.
  • R 1 is methyl or hydrogen.
  • R 1 is H.
  • R 2 is optionally substituted Ci_ 6 alkyl.
  • R 2 is methyl or ethyl.
  • R 1 is H.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having from 5 to 7 ring atoms.
  • R 1 and R 2 are taken together with the atom to which they are bound to form an optionally substituted ring having from 5 ring atoms.
  • m is 1 or 2.
  • n 1 or 2.
  • n 3.
  • W is CH 2 .
  • W is CH 2 CH 2 .
  • Y is CH 2 .
  • Y is CH 2 CH 2 .
  • Y is CH 2 CH 2 CH 2 .
  • Exemplary embodiments include compounds having the formula (I) or a pharmaceutically acceptable salt form thereof:
  • Exemplary embodiments include compounds having the formula (II) or a pharmaceutically acceptable salt form thereof:
  • a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.
  • the present invention further relates to a process for preparing the neuroprotective agents of the present invention.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • HPLC high pressure liquid chromatography
  • GC gas chromatography
  • GPC gel-permeation chromatography
  • TLC thin layer chromatography
  • Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al, Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
  • Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of these teachings can be prepared by methods known in the art of organic chemistry.
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes below.
  • the reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds in the genus may be produced by one of the following reaction schemes.
  • R-X (II) a suitably substituted compound, a known compound or compound prepared by known methods, wherein X is a halogen
  • a strong base such as butyllithium or isopropylmagnesium chloride and the like in an organic solvent like tetrahydrofuran, diethyl ether and the like
  • PG is a protecting group
  • a compound of formula (VI) can then be converted into a sulfamide compound of formula (I) via multiple pathways.
  • a compound of formula (VI) can be treated with a suitable protected chlorosulfonylcarbamate (VII), wherein PG is a protecting group formed in situ by the reaction of chlorosulfonylisocyanate and an alcohol such as tert-butyl alcohol, benzyl alcohol, ethanol and the like in an organic solvent like dichloromethane, chloroform and the like to yield the carbamate of a compound of formula (VIII).
  • VII protected chlorosulfonylcarbamate
  • the protecting group can be remove by treatment under suitable conditions such as 1) with acid, such as hydrogen chloride, trifluoroacetic acid, and the like in organic solvent such as 1,4-dioxane, dichloromethane, and the like, or 2) hydrogen in the presence of a catalyst such as palladium on activated carbon, platinum oxide and the like in an organic solvent such as ethyl acetate, methanol, ethanol or 3) base such as sodium hydroxide, potassium carbonate and the like in a solvent like water, methanol, tetrahydrofuran and the like to give a sulfamide of formula (I).
  • suitable conditions such as 1) with acid, such as hydrogen chloride, trifluoroacetic acid, and the like in organic solvent such as 1,4-dioxane, dichloromethane, and the like, or 2) hydrogen in the presence of a catalyst such as palladium on activated carbon, platinum oxide and the like in an organic solvent such as ethyl acetate, methanol,
  • Examples 1 through 3 provide methods for preparing representative compounds of formula (I). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.
  • Example 1 Synthesis of 4-Fluoro-4-(2-fluoro-phenyl)-piperidine-l- sulfonamide.
  • l-bromo-2-fluorobenzene (2g, 11.4 mmol) in tetrahydrofuran (30 mL) at -70 °C under nitrogen was added a solution of n- butyllithium (5.0 mL, 12.6 mmol, 2.5 M in hexane).
  • the reaction mixture was diluted with dichloromethane (50 mL) and poured into saturated aqueous sodium hydrogen carbonate (50 mL). The layers were separated, the aqueous layer was extracted with dichloromethane (30 mL) and the organic layers were combined, washed with saturated aqueous sodium chloride and concentrated at reduced pressure to give the crude product.
  • the crude product was purified through a plug of silica (4g), eluting with ethyl acetate/hexane (1 : 1) to give the product as a white solid (1.27g, 97%).
  • the reaction mixture was diluted with dichloromethane (50 mL) and poured into saturated aqueous sodium hydrogen carbonate (50 mL). The layers were separated, the aqueous layer was extracted with dichloromethane (25 mL) and the organic layers were combined, washed with saturated aqueous sodium chloride and concentrated at reduced pressure to give the crude product.
  • the crude product was purified through a plug of silica (4g), eluting with ethyl acetate/hexane (1 : 1) to give the product as a white solid (355 mg, 41%).
  • the reaction mixture was diluted with dichloromethane (100 mL) and poured into saturated aqueous sodium hydrogen carbonate (100 mL). The layers were separated, the aqueous layer was extracted with dichloromethane (50 mL) and the organic layers were combined, washed with saturated aqueous sodium chloride and concentrated at reduced pressure to give the crude product.
  • the crude product was purified by column chromatography through a silica cartridge (40g), eluting with ethyl acetate/hexane (1 : 1) to give the product, semi-pure, as an oil.
  • Example 4 Synthesis of 4-(2,6-difluoro-phenyl)-4-fluoro-piperidine-l- sulfonamide.
  • Example 8 Synthesis of 4-(2-Chloro-6-fluoro-phenyl)-4-fluoro-piperidine-l- sulfonamide:
  • the present invention also relates to compositions or formulations which comprise the neuroprotective agents according to the present invention.
  • the compositions of the present invention comprise an effective amount of one or more fluorinated cyclic sulfamides and salts thereof according to the present invention which are effective for providing neuroprotection; and one or more excipients.
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington 's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials.
  • the compounds can be formulated in conventional manner, for example, in a manner similar to that used for known neuroprotective agents.
  • Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • the carrier in powders, can be a finely divided solid, which is an admixture with a finely divided compound.
  • a compound disclosed herein in tablets, can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets can contain up to 99 % of the compound.
  • Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
  • pharmaceutically acceptable diluents including
  • Surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time -release formulations to alter the absorption of the compound(s).
  • the oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery.
  • a compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition.
  • the liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser.
  • the solvents can be, for example, isotonic saline or bacteriostatic water.
  • the solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation.
  • the aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device.
  • the propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.
  • compositions described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms .
  • the pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form can sterile and its viscosity permits it to flow through a syringe.
  • the form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in- water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable.
  • occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound.
  • Other occlusive devices are known in the literature.
  • Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.
  • a compound can be combined with other agents effective in the treatment of the target disease.
  • other active compounds i.e., other active ingredients or agents
  • the other agents can be administered at the same time or at different times than the compounds disclosed herein.
  • Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject.
  • the present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings inclding its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers.
  • Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.
  • compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more fluorinated cyclic sulf amides according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more fluorinated cyclic sulfamides according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more fluorinated cyclic sulfamides according to the present invention; and one or more excipients.
  • hippocampal tissue was obtained commercially through Brain Bits (Springfield, IL) and cultures prepared as previously described (Brewer, 1995). The hippocampal neurons were platted at low density (10,000 cell /well) in a 96-well format and maintained in serum-free medium consisting of Neurobasal Medium supplemented with B27 and GlutaMAX (Gibco). Pre-coated poly-L-lysine coated plates will be used because of the preferential adherence and survival of hippocampal neurons on this matrix support.
  • Carboxyfluorescein CFDA was used a vital stain for all cell toxicity and neuroprotection studies. With the use of the CytoFluor fluorimeter, the CFDA assay was employed to assess the viability of neurons.
  • CFDA is a dye that becomes fluorescent upon cell entry and cleavage by cytosolic esterases (Petroski and Geller, 1994). Neuronal specificity is obtained relative to astrocytes because the cleaved dye is extruded extracellularlly by glia with time, while dye in neurons remains intracellular. Previous experience with this assay showed a good correlation with neuronal cell counts stained immunocytochemically with neuron specific enolase antibodies, a reference marker for neuronal identity in complex cultures.
  • a propidium iodide method was used as previously described (Sarafian et al, 2002) to measure the number of dead cells. Propidium iodide becomes fluorescent when binding to the DNA of dead cells.
  • Cultures were treated on day 2 with the test agent and then the two assays were conducted after a four day test period. For all assays, a 96-well format was used. For the screen, log concentration-effect studies were conducted from 10 nM to lmM with 8 replications. The duration of the test period was five days. Cultures were given a complete change of medium prior to the initiation of the treatment period.
  • PI Propidium iodide
  • PI stock solution 1 mg/ml (1.5 mM) was obtained from Sigma.
  • the PI stock was diluted 1 :30 in DPBS for a final working concentration of 50 ⁇ .
  • 50 ⁇ of the 50 ⁇ PI solution was added to cultures and allowed to incubate in the dark at room temperature for 15 min.
  • the cultures were then assessed for fluorescence intensity at Ex536/Em590 nm in a CytoFluor fluorimeter. Results were expressed in relative fluorescent units and as a % of control values.
  • CFDA 5,6-Carboxyfluorescein diacetate
  • Potent neuroprotection is the distinguishing characteristic that separates this program's anticonvulsants from all other commercial drugs for epilepsy.
  • the experimental details and the rationale for the implemented assays are essential in differentiating these compounds from that of others.
  • the central objective of all neuroprotective assays was their relevancy to excitotoxicity and oxidative stress related to epilepsy. Both the amount of glutamate and hydrogen peroxide used in the assays, as well as the time of treatment and duration of the experiment, were designed to be relevant to epilepsy. Further, all time parameters employed in these studies were empirically determined to be within the limits of reversible toxic events, yet using amounts of glutamate and hydrogen peroxide that were relevant to the disease.
  • glutamate toxicity a critical feature was the duration of treatment of the hippocampal neurons.
  • the rational for using a short 5 min treatment with glutamate was based on the observation of Randall and Thayer (1992). Their study demonstrated that a short-term treatment with glutamate produced a delayed but substantial increase in intracellular calcium that overloaded the neurons and produced cell death. The rationale is that this intense burst of glutamate and resulting calcium overload is relevant to seizures and therefore was important data to capture in the screening assay.
  • the amount of glutamate (30 ⁇ ) employed in our screening was based on the basal levels of glutamate observed in microdialysis measurements of hippocampus from epileptogenic patients (Cavus et al, 2008).
  • PI Propidium iodide
  • PI stock solution 1 mg/ml (1.5 mM) was obtained from Sigma.
  • the PI stock was diluted 1 :30 in DPBS for a final working concentration of 50 ⁇ .
  • 50 ⁇ of the 50 ⁇ PI solution was added to cultures and allowed to incubate in the dark at room temperature for 15 min.
  • the cultures were then assessed for fluorescence intensity at Ex536/Em590 nm in a CytoFluor fluorimeter. Results were expressed in relative fluorescent units and EC50's calculated from the dose response of the test compound.
  • the test compound was then added to the hippocampal cultures for a 4 hour test period in concentrations that ranged from 1 pM to 300 ⁇ . At the conclusion of the test period, the cultures were tested for the amount of cell death by the propidium iodide method.
  • Propidium iodide (PI) stock solution of 1 mg/ml (1.5 mM) was obtained from Sigma.
  • the PI stock was diluted 1 :30 in DPBS for a final working concentration of 50 ⁇ .
  • 50 ⁇ of the 50 ⁇ PI solution was added to cultures and allowed to incubate in the dark at room temperature for 15 min.
  • the cultures were then assessed for fluorescence intensity at Ex536/Em590 nm in a CytoFluor fluorimeter. Results were expressed in relative fluorescent units and EC50's calculated from the dose response of the test compound.
  • test compounds were dissolved to 10 mM in Dulbecco's phosphate buffered saline (DPBS; Sigma:D-5780) prior to testing.
  • DPBS Dulbecco's phosphate buffered saline
  • day 11 hippocampal cultures were given a complete change of medium containing 100 ⁇ of Neurobasal medium with B27 that contained no antioxidants. Twenty four hours after the change in medium, the hydrogen peroxide neuroprotection studies were started. The test compound was added to the day 12 hippocampal cultures for a 4 hour test period in concentrations that ranged from 1 nM to 300 ⁇ . Concurrent with the treatment of test compound, 10 ⁇ hydrogen peroxide was added for the 4 hour test period.
  • CFDA 5,6- Carboxyfluorescein diacetate
  • the test compound was then added to the hippocampal cultures for a 4 hour test period in concentrations that ranged from 1 pM to 300 ⁇ At the conclusion of the test period, the cultures were tested for the amount of neuronal viability by the CFDA method.
  • CFDA 5,6-Carboxyfluorescein diacetate
  • 100 ⁇ CFDA dye solution was added for 15 min of incubation at 37 degrees in the dark.
  • the dye was removed from the cultures and washed once with 100 ⁇ of DPBS. After removal of the first wash, a second wash of DPBS was added to the culture and then incubated for 30 min to allow the efflux of dye out of glia in the cultures. At the conclusion of the 30 min efflux period, the culture efflux medium was removed and 100 ⁇ of 0.1% triton-X in water 100 was added to the cultures to before reading at Ex490/Em517 in a CytoFluor fluorimeter. Results were expressed in relative fluorescent units (RFU) and ECso's calculated from the dose response of the test compound. Results were expressed in relative fluorescent units and EC 5 o's calculated from the dose response of the test compound.
  • This stock solution of CDFFDA was diluted a 1 : 1000 in DPBS and added to the cultures for one hour AT 37 °C. After the one hour loading of the dye, the cultures were washed two times with DPBS. The cultures loaded with the ROS-sensitive dye were then placed back into B27 medium neural basal medium without antioxidants before treatment with test compounds. The cultures were treated with a dose response to test compounds and then placed back into the incubator for re- equilibration of the medium (10 minutes). The cultures were then treated with 30 ⁇ hydrogen peroxide for three hours and the fluorescence measured at Ex/Em 485/508. Background fluorescence was subtracted from values obtained from wells without cells.
  • Seizure-related assays Maximal electroshock test: The most definitive assay for antiseizure activity is the maximal electroshock (MES) test (Swinyard, E.A. Laboratory evaluation of antiepileptic drugs: review of laboratory methods, Epilepsia, 1969, 10, 107-119.).
  • MES maximal electroshock
  • This model which is highly predictive of efficacy in human epilepsy, is utilized to demonstrate antiseizure activity in mice after i.p. administration and in rats after oral administration. With both rodent assays, the duration of action is of high importance as well as the potency of the response.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques qui comprennent des dérivés sulfamides cycliques fluorés ayant une action de modification de maladie dans le traitement de maladies associées à une excitotoxicité et accompagnant un stress oxydatif. Les maladies concernées comprennent l'épilepsie, la sclérose en plaques, la maladie d'Alzheimer et toute maladie neurodégénérative impliquant la toxicité du glutamate.
PCT/US2012/048120 2011-07-28 2012-07-25 Nouveaux sulfamides cycliques fluorés présentant une action neuroprotectrice et leur procédé d'utilisation WO2013016411A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014275A2 (fr) * 2000-08-11 2002-02-21 Eli Lilly And Company Derives sulfonamides heterocycliques
US20040049038A1 (en) * 2000-11-02 2004-03-11 Collins Ian James Sulfamides as gamma-secretase inhibitors
WO2007101116A2 (fr) * 2006-02-24 2007-09-07 The Trustees Of Columbia University In The City Of New York Modulateurs du récepteur glur2
US20100311714A1 (en) * 2009-06-04 2010-12-09 Pascal Furet 1H-IMIDAZO[4,5-c]QUINOLINONE COMPOUNDS

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014275A2 (fr) * 2000-08-11 2002-02-21 Eli Lilly And Company Derives sulfonamides heterocycliques
US20040049038A1 (en) * 2000-11-02 2004-03-11 Collins Ian James Sulfamides as gamma-secretase inhibitors
WO2007101116A2 (fr) * 2006-02-24 2007-09-07 The Trustees Of Columbia University In The City Of New York Modulateurs du récepteur glur2
US20100311714A1 (en) * 2009-06-04 2010-12-09 Pascal Furet 1H-IMIDAZO[4,5-c]QUINOLINONE COMPOUNDS

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