WO2009023707A1 - Procédé de traitement de maladie impliquant la perte de myéline et/ou perte axonale - Google Patents

Procédé de traitement de maladie impliquant la perte de myéline et/ou perte axonale Download PDF

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Publication number
WO2009023707A1
WO2009023707A1 PCT/US2008/073007 US2008073007W WO2009023707A1 WO 2009023707 A1 WO2009023707 A1 WO 2009023707A1 US 2008073007 W US2008073007 W US 2008073007W WO 2009023707 A1 WO2009023707 A1 WO 2009023707A1
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alkyl
group
disease
oxyl
hydrogen
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PCT/US2008/073007
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English (en)
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Jacqueline A. Quandt
James B. Mitchell
Anastasia Sowers
Murali C. Krishna
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Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Priority to CA2696310A priority Critical patent/CA2696310A1/fr
Publication of WO2009023707A1 publication Critical patent/WO2009023707A1/fr
Priority to US12/706,068 priority patent/US20100168165A1/en

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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
    • A61K31/33—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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • MS multiple sclerosis
  • CNS central nervous system
  • therapies have been proposed to treat demyelinating diseases.
  • Some of the proposed therapies attempt to modulate the autoimmune and inflammatory components of the disease, but they are only moderately successful and afford little protection once subsequent damage to the nervous system has occurred. Accordingly, there is a desire for alternative therapies that modulate the autoimmune and inflammatory components and also provide protection against subsequent damage to the nervous system.
  • the invention provides a method of treating a disease involving myelin and/or axonal loss, specifically a demyelinating disease, in a mammal comprising administering a compound of formula I
  • the disease can be, for example, multiple sclerosis (MS), optic neuritis, Devic's disease (neuromyelitis optica), transverse myelitis, acute MS (Marburg variant), BaIo 's concentric sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis (ADEM), adrenoleukodystrophy, or adrenomyeloneuropathy.
  • MS multiple sclerosis
  • Devic's disease neuromyelitis optica
  • transverse myelitis acute MS (Marburg variant)
  • BaIo 's concentric sclerosis Guillain-Barre syndrome
  • ADAM acute disseminated encephalomyelitis
  • adrenoleukodystrophy or adrenomyeloneuropathy.
  • the invention further provides methods of using a compound of formula I to treat neurodegeneration associated with inflammation and to reduce myelin and/or axonal loss.
  • Figure 1 is a graph illustrating the assessed disease severity of actively induced chronic progressive experimental autoimmune encephalomyelitis (EAE) versus number of days post immunization in control- (•) and Tempol- (O) fed mice in an embodiment of the invention.
  • EAE actively induced chronic progressive experimental autoimmune encephalomyelitis
  • Figure 2 is a graph illustrating the assessed disease severity of passively induced chronic progressive EAE versus number of days post T cell transfer in control- (•) and
  • Figure 3 is a graph illustrating the EAE score versus number of days post T cell transfer in control-fed ( ⁇ ) mice and mice fed Tempol 2 weeks prior to T cell transfer (•), at
  • T cell transfer ( A ), and at disease onset ( ⁇ )in an embodiment of the invention.
  • Figure 4 is a graph illustrating the EAE score versus number of days post T cell transfer in control- ( ⁇ ) and Tempol- ( ⁇ ) fed mice in an embodiment of the invention.
  • Figure 5 is a bar graph illustrating the relative amount of spinal cord neurofilament H in control- (hatch marked bar) and Tempol- (solid bar) fed mice in an embodiment of the invention.
  • Figure 6 is a graph illustrating the cumulative disease score versus the relative amount of neurofilament H in control- ( ⁇ ) and Tempol- ( ⁇ ) fed mice in an embodiment of the invention.
  • Nitroxide compounds that comprise or yield a stable radical, such as Tempol are anti-oxidants that can scavenge free radicals that can mediate tissue damage and destruction. It is contemplated that a nitroxide compound of formula I can serve therapeutically at both the autoimmune/inflammatory and neurodegenerative stages of a disease involving impaired myelin and/or axons, e.g., a demyelinating disease, thereby acting to limit (i) the generation of autoimmune responses and/or (ii) damage to the nervous system itself.
  • the present invention provides a method of treating a disease involving myelin and/or axonal loss in a mammal comprising administering to the mammal an effective amount of a compound of formula I
  • Z is selected from the group consisting Of C 1-12 alkyl, C 2-12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, and C 6-3O aryl;
  • R 2 , R 3 , R 4 , and R 5 are the same or different and are selected from the group consisting of hydrogen, C 1-12 alkyl, C 2-12 alkenyl, and C 2-12 alkynyl;
  • R and R 7 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, cyano, isothiocyanato (-NCS), C 1-12 alkyl, C 2-12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-30 aryl, C 1-I2 alkoxy, C 1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylcarbonylamino,
  • R 8 , R 9 , R 10 , and R 11 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, cyano, isothiocyanato (-NCS), C 1-12 alkyl, C 2 - 12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-30 aryl, C 1-12 alkoxy, C 1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoal
  • R 6 and R 7 and one of R 8 and R 9 can be absent such that a double bond joins the two carbon atoms to which the remaining of one of R 6 and R 7 and one of R 8 and R 9 are attached;
  • n 0 or 1 ;
  • the disease is not ataxia telangiectasia (AT).
  • the disease is a demyelinating disease and/or involves axonal loss, e.g., damage and/or impairment (via demyelination or other pathways).
  • the disease can involve a loss or defect of oligodendrocyte.
  • the disease can be an inflammatory disease (e.g., an inflammatory demyelinating disease and/or an inflammatory disease with myelin or axonal loss (e.g., damage and/or impairment)).
  • the method of treatment can include the aspect in which the autoimmune component of the inflammatory demyelinating disease is treated.
  • the disease is any disorder that involves myelin and/or axonal loss (e.g., damage, and/or impairment), regardless of the cause (e.g., a demyelinating disease).
  • a demyelinating disease is any disorder that results in deficient or abnormal myelination (e.g., destruction of myelin).
  • the pathology of the demyelinating disease can have autoimmune, inflammatory, neurodegenerative, or other components.
  • the disease is classified as an inflammatory demyelinating disease or an autoimmune/inflammatory demyelinating disease.
  • the disease can be, for example, multiple sclerosis (MS), optic neuritis, Devic's disease (neuromyelitis optica), transverse myelitis, acute MS (Marburg variant), Balo's concentric sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis (ADEM), adrenoleukodystrophy, or adrenomyeloneuropathy.
  • MS multiple sclerosis
  • MS multiple sclerosis
  • the hallmark characteristics of MS include the breakdown of the blood brain barrier, leukocytic infiltration, and demyelination often associated with axonal loss (e.g., damage and/or impairment).
  • treatment of the disease includes reduction (including complete or partial reduction) in the incidence and/or severity of the disease, including a reduction in a variety of symptoms, e.g., paresis, paralysis, spasticity, ataxia, and/or tremor.
  • the invention further provides a method of treating neurodegeneration associated with (e.g., induced by) inflammation, in a mammal comprising administering to the mammal an effective amount of a compound of formula I
  • Z is selected from the group consisting Of C 1-12 alkyl, C 2-12 alkenyl, C 3-S cycloalkyl, C 3-8 heterocycloalkyl, and C 6-30 aryl;
  • R 2 , R 3 , R 4 , and R 5 are the same or different and are selected from the group consisting of hydrogen, C 1-12 alkyl, C 2-12 alkenyl, and C 2-12 alkynyl;
  • R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, cyano, isothiocyanato (-NCS), C 1-12 alkyl, C 2 . 12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-30 aryl, C 1-12 alkoxy, C 1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylcarbonylamin
  • R 8 , R 9 , R 10 , and R 11 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, cyano, isothiocyanato (-NCS), C 1-12 alkyl, C 2-I2 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-30 aryl, C 1-12 alkoxy, C 1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalky
  • R 6 and R 7 and one of R 8 and R 9 can be absent such that a double bond joins the two carbon atoms to which the remaining of one of R and R and one of R and R 9 are attached;
  • n 0 or 1 ;
  • the neurodegeneration is not caused by ataxia telangiectasia (AT).
  • the term "associated with” includes instances in which neurodegeneration and inflammation are both detected.
  • the inflammation may or may not induce the neurodegeneration.
  • the inflammation induces the neurodegeneration.
  • the method includes treating neurodegeneration induced by an immune response that is also associated with demyelination.
  • the compound of formula I provides protection against onset and progression of neurodegeneration of the central nervous system (CNS).
  • the treatment of the neurodegradation associated with inflammation and/or an immune response that is also associated with demyelination includes reduction (including complete or partial reduction) in the incidence and/or severity of the disease, including a reduction in a variety of symptoms, e.g., paresis, paralysis, spasticity, ataxia, and/or tremor.
  • the treatment of neurodegeneration includes neurodegeneration that is caused by a disease such as multiple sclerosis (MS), optic neuritis, Devic's disease (neuromyelitis optica), transverse myelitis, acute MS (Marburg variant), Balo's concentric sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis (ADEM), adrenoleukodystrophy, or adrenomyeloneuropathy.
  • the neurodegeneration is caused by multiple sclerosis (MS).
  • EAE Experimental Autoimmune Encephalomyelitis
  • Tempol a compound of formula I, can both modulate the generation of disease-inducing autoimmune T cells and limit the damage that autoimmune T cells primed in other animals can cause when they access the nervous system.
  • Any suitable mammal can be used in the EAE model, such as mice, rats, guinea pigs, rabbits, macaques, rhesus monkeys, and marmosets. Rodents, such as mice and rats are particularly preferred given the resemblance of the induced disease to MS in humans.
  • proteins or parts of proteins can be used to induce EAE, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG).
  • MBP, PLP, and MOG can be synthesized by using, for example, standard 9-fluorenylmethoxycarbonyl (Fmoc) chemistry on a protein synthesizer and then purified by conventional techniques (e.g., high performance liquid chromatography (HPLC)).
  • Fmoc 9-fluorenylmethoxycarbonyl
  • HPLC high performance liquid chromatography
  • Literature methods are known (see, e.g., Fridkis-Hareli et al., J. Clin. Invest., 109: 1635-1643 (2002)).
  • these proteins are commercially available (e.g., AnaSpec, San Jose, CA; GenScript, Piscataway, NJ).
  • the present invention provides a method of reducing myelin and/or axonal loss in a mammal comprising administering to the mammal an effective amount of a compound of formula I
  • Z is selected from the group consisting Of C 1-12 alkyl, C 2-12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, and C 6-30 aryl;
  • R 2 , R 3 , R 4 , and R 5 are the same or different and are selected from the group consisting of hydrogen, C 1-12 alkyl, C 2-12 alkenyl, and C 2-12 alkynyl;
  • R and R 7 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, cyano, isothiocyanato (-NCS), C 1-12 alkyl, C 2-12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-30 aryl, C 1-12 alkoxy, C 1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylcarbonylamino, and
  • R , R 9 , R 1 ; and R are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, cyano, isothiocyanato (-NCS), C 1-12 alkyl, C 2-12 alkenyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-30 aryl, C 1-12 alkoxy, C 1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, al
  • R 6 and R 7 and one of R 8 and R 9 can be absent such that a double bond joins the two carbon atoms to which the remaining of one of R 6 and R 7 and one of R 8 and R 9 are attached;
  • n 0 or 1.
  • R 1 preferably is O- (a radical).
  • R 2 , R 3 , R 4 , and R 5 preferably are C 1-12 alkyl, particularly a C 1-4 alkyl (e.g., methyl, ethyl, n- propyl, /-propyl, «-butyl, sec-butyl, /-butyl, t-butyl).
  • R 7 preferably is hydrogen, halogen, hydroxyl, or C 1-12 alkyl.
  • R 8 , R 9 , R 1 , and R 11 preferably are the same or different and each is hydrogen, halogen, hydroxyl, or C 1-12 alkyl. In a particular embodiment, R 7 , R 8 , R 9 , R 10 , and R 11 are hydrogen.
  • R 6 is hydrogen, hydroxyl, C 1-12 alkyl, C 1-12 alkoxy, cyano, isothiocyanato, amino, carboxy, alkylcarbonylamino, haloalkylcarbonylamino, or alkylsulfonyloxy.
  • n When n is 0, the compound of formula I is a 5-membered ring, and the substituents R 10 and R 11 are absent. When n is 1, the compound of formula I is a 6-membered ring. In a preferred embodiment, n is 1.
  • the compound of formula I is 4-hydroxy-2,2,6,6- tetramethylpiperidine-1-oxyl (Tempol, also known as 4-hydroxy-Tempo).
  • Examples of compounds of formula I also include 2,2,6,6-tetramethylpiperidine- 1-oxyl (Tempo), 4-methoxy-2,2,6,6-tetramethyl-l-piperidine-l-oxyl, 4-carboxy-2,2,6,6- tetramethyl- 1 -piperidine- 1 -oxyl, 4-oxo-2,2,6,6-tetramethyl- 1 -piperidine- 1 -oxyl, 4-amino- 2,2,6,6-tetramethyl- 1 -piperidine- 1 -oxyl, 4-cyano-2,2,6,6-tetramethyl- 1 -piperidine- 1 -oxyl, 4- isocyanato-2,2,6,6-tetramethyl- 1 -piperidine- 1 -oxyl, 4-acetamido-2,2,6,6-tetramethyl- 1 - piperidine- 1 -oxyl, 4-(
  • alkyl implies a straight or branched alkyl moiety containing from, for example, 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • moieties include methyl, ethyl, propyl, isopropyl, «-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.
  • alkenyl refers to a straight chain or branched non-cyclic hydrocarbon moiety having an indicated number of carbon atoms (e.g., C 2 -C 2O , C 2 -C 10 , C 2 -C 4 , etc.).
  • moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1- pentenyl, 2-pentenyl, 3-methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3- octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, and the like.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkynyl refers to a straight chain or branched non-cyclic hydrocarbon moiety having an indicated number of carbon atoms (e.g., C 2 -C 20 , C 2 -C 10 , C 2 -C 6 , etc.), and including at least one carbon-carbon triple bond.
  • moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl- 1- butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1- octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9- decynyl, and the like.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • cycloalkyl means a cyclic alkyl moiety containing from, for example, 1-3 rings (i.e., monocyclic, bicyclic, tricyclic, or spiro), 3 to 8 carbon atoms per ring, preferably from 5 to 8 carbon atoms, more preferably from 5 to 6 carbon atoms.
  • moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl means a cycloalkyl moiety having one or more heteroatoms, e.g., nitrogen, sulfur, and/or oxygen.
  • a heterocycloalkyl is a 5 or 6- membered monocyclic ring and contains one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and/or sulfur.
  • the heterocycloalkyl can be attached to the parent structure through a carbon atom or a heteroatom of the heterocycloalkyl moiety.
  • heterocycloalkyl moieties examples include pyrrolinyl, pyranyl, piperidyl, tetrahydrofuranyl, tetrahydrothiopheneyl, and morpholinyl.
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like.
  • halogen as used herein, means a substituent selected from Group
  • VIIA such as, for example, fluorine, bromine, chlorine, and iodine.
  • alkoxy embraces an alkyl group attached to an ether oxygen.
  • the alkyl group is the same as described herein. Examples of such a group include methoxy, ethoxy, t-butoxy, and the like.
  • alkylthio refers to an alkyl group, as described herein, attached to a sulfur moiety.
  • An example of such substituent is ethylthio.
  • hydroxyalkyl and “mercaptoalkyl” refer to an alkyl group that is substituted with -OH or -SH, respectively.
  • the alkyl group is the same as described herein.
  • alkylamino and arylamino refer to groups with one hydrogen and one alkyl or aryl group, respectively, directly attached to a trivalent nitrogen atom.
  • dialkylamino and diarylamino refer to groups with two of the same or different alkyl or aryl groups, respectively, directly attached to a trivalent nitrogen atom.
  • aminoalkyl refers to an alkyl group substituted with -NH 2 .
  • alkylaminoalkyl and arylaminoalkyl refer to an alkyl group substituted with -NHR, in which R is an alkyl or aryl group, respectively, as described herein.
  • dialkylaminoalkyl refers to an alkyl group substituted with -NRR', in which R and R' are the same or different alkyl group, as described herein.
  • diarylaminoalkyl refers to an alkyl group substituted with NRR', in which R and R' are the same or different aryl group, as described herein.
  • Carboxy refers to the group -C(O)OH.
  • alkylcarbonyl and arylcarbonyl refer to the group -C(O)R, in which R is an alkyl or aryl group, as described herein.
  • carboxyalkyl and “carboxyaryl” refer to an alkyl or aryl group, respectively, substituted with -C(O)OH.
  • alkylcarbonylalkyl and “alkylcarbonylaryl” refer to an alkyl or aryl group, respectively, substituted with -C(O)R, in which R is an alkyl, as described herein.
  • alkylcarbonylamino refers to the group -NRC(O)R'.
  • R is a hydrogen or alkyl group and R' is an alkyl group, as described herein.
  • An example of an alkylcarbonylamino is acetamido.
  • haloalkylcarbonylarnino refers to the group -NRC(0)R'X, in which R is a hydrogen or alkyl group, R' is an alkylene, and X is a halogen, as described herein.
  • substituents include 2-bromoacetamido, 2-chloroacetamido, 2- iodooacetamido, 2-brorno-N-methyl-acetamido, 3-bromopropanamido, and the like.
  • alkylsulfonyloxy refers to the group -OSO 2 R, in which R is an alkyl group, as described herein. Examples of such substituent include methylsulfonyloxy and ethylsulfonyloxy.
  • any chemical group e.g., alkyl, alkylamino, etc.
  • any chemical group e.g., alkyl, alkylamino, etc.
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon
  • the compounds of formula I can be prepared by any suitable method.
  • compounds of formula I in which R 1 is O can be prepared by oxidation of 2,2,6,6- tetramethylpiperidine. See, e.g., Lebelev et al, Zhur. Obshch. Khim., 30: 1631 ff (1960).
  • certain compounds of formula I e.g., Tempol
  • are commercially available e.g., Sigma-Aldrich, St. Louis, MO).
  • Isolation and purification of the compound of formula I can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures.
  • the present inventive methods encompass administering a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical compositions; the compounds of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes or liposomes.
  • compositions described herein for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way limiting.
  • the compound of formula I or a composition thereof is administered to the mammal orally.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of formula I can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of formula I can be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).
  • the compounds of formula I can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Suitable carriers and their formulations are further described in A.R. Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995).
  • the compound of formula I or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid.
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0 0 C and 50 °C).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the term "mammal” includes, but is not limited to, the order Rodentia, such as mice, and the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs).
  • the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.
  • the amount or dose of a compound of formula I, a salt thereof, or a composition thereof should be sufficient to affect a therapeutic or prophylactic response in the mammal over a reasonable time frame.
  • the appropriate dose will depend upon the nature and severity of the disease or affliction to be treated or prevented, as well as by other factors. For instance, the dose also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular compound or salt.
  • the attending physician will decide the dosage of the compound of formula I with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound or salt to be administered, route of administration, and the severity of the condition being treated.
  • Typical doses might be, for example, 0.1 mg to 1 g daily, such as 5 mg to 500 mg daily.
  • the dose can be administered via any suitable manner, as described herein, and including administration with food (e.g., prior to consuming food, concurrently administered with food (including combined with the food itself and/or maintained separately but co-administered), and/or subsequent to consuming food).
  • EAE induction all animals are female, 8-10 weeks of age at time of myelin protein immunization. Animals are immunized for active EAE induction with 200 ⁇ g of MOG35-55 peptide in 4 mg/ml H37Ra Mycobacterium/IFA with 200 ng pertussis toxin delivered intraperitoneally (IP) on days 0 and 2.
  • IP intraperitoneally
  • SJL animals are immunized with 75 ⁇ g of PLP139-151 peptide in 1 mg/ml H37Ra Mycobacterium/IFA (Difco, Detroit, MI).
  • the cumulative score represents the mean of the summation of single scores recorded in each mouse over days 0 (day of immunization) to day 30 post disease induction.
  • mice that are fed Tempol generate myelin antigen-specific T cells which are unable to cause paralytic disease in immunized mice.
  • Table 1 and Figure 1 The results indicate that Tempol reduces the incidence and severity of actively induced chronic progressive EAE.
  • the cumulative score represents the mean of the summation of single scores recorded in each mouse over days 0 (day of T cell transfer) to day 48 post disease induction.
  • PLP-specific T cells are capable of causing severe paralytic disease in the brain and spinal cord of control fed mice, yet Tempol-fed mice are protected showing decreased incidence of disease as well as reduced severity. Control animals on average reached a peak disease of complete hind limb paralysis with forelimb weakness, whereas animals on Tempol feed experienced hind limb paresis at peak disease.
  • Table 2 The results indicate that Tempol reduces the incidence and severity of passively induced chronic progressive EAE, thereby reducing the neurodegenerative effects of PLP-specific T cells.
  • SJL animals are induced for disease by the passive transfer of encephalitogenic T cells as described in Example 1.
  • Animals are placed on either Tempol or control feed at either (i) 2 weeks prior to transfer, (ii) at the time of transfer, or (iii) at the onset of disease.
  • Tempol reduces the severity of clinical symptoms and the cumulative disease score regardless of the time of administration.
  • a nitroxide compound of formula I reduces the degree of neuronal damage and/or loss as indicated by the preservation of neurofilament H in the CNS of EAE animals in an embodiment of the invention.
  • SJL animals are induced for disease by the passive transfer of encephalitogenic T cells as described in Example 1. Animals are placed on either Tempol or control feed. The spinal cords of the animals are analyzed 90 days post transfer.
  • Neurofilament staining is representative of the presence of axons. During autoimmune or demyelinating processes, the loss of neurofilament H has been associated with axonal loss. Animals on Tempol feed show a greater preservation of neurofilament H suggesting lesser axonal loss than animals on control feed ( Figure 5 and Table 3).
  • SJL animals are induced for disease by the passive transfer of encephalitogenic T cells as described in Example 1. Animals are placed on either Tempol or control feed. In a spinal cord histogram, T 2 relaxation times typically increase due to inflammation and edema during CNS autoimmunity/disease during EAE. In this experiment, the histogram shows that Tempol-fed animals have lower T 2 relaxation times, thereby indicating less edema, than control-fed animals. In the control-fed animals, the spinal cord T 2 relaxation times shifted to higher values due to edema and inflammation. [0078] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

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Abstract

La présente invention concerne un procédé de traitement de maladies impliquant la perte de myéline et/ou perte axonale telle que la maladie démyélisante chez les mammifères, et qui comprend l'administration d'un composé de formule I dans lequel R1-R11 et n sont définis ici. L'invention concerne également des procédés d'utilisation d'un composé de formula 1 destiné à traiter la neurodégénérescence associée à l'inflammation et à réduire la perte de myéline et/ou la parte axonale.
PCT/US2008/073007 2007-08-14 2008-08-13 Procédé de traitement de maladie impliquant la perte de myéline et/ou perte axonale WO2009023707A1 (fr)

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CA2696310A CA2696310A1 (fr) 2007-08-14 2008-08-13 Procede de traitement de maladie impliquant la perte de myeline et/ou perte axonale
US12/706,068 US20100168165A1 (en) 2007-08-14 2010-02-16 Method of treating disease involving myelin and/or axonal loss

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US60/955,731 2007-08-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103111A1 (fr) * 2010-02-16 2011-08-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthode de traitement d'une maladie impliquant la perte de myéline et/ou d'axones

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2377381B1 (es) 2010-05-17 2013-03-14 Fundació Institut De Investigació Biomèdica De Bellvitge (Idibell) Uso de una combinación de n-acetil-cisteína y ácido lipoico para la preparación de un medicamento útil para el tratamiento de una enfermedad con daño axonal y lesiones oxidativas concomitantes.

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005084677A1 (fr) * 2004-03-01 2005-09-15 Medestea Research & Production S.P.A. Utilisation de derives de n-piperidine dans le traitement des pathologies neurodegeneratives
WO2006014968A2 (fr) * 2004-07-27 2006-02-09 Teva Pharmaceutical Industries, Ltd. Nitroxydes propargyle et nitroxydes indanyle et leur utilisation pour traiter les maladies et les troubles neurologiques
WO2006027785A1 (fr) * 2004-09-09 2006-03-16 Yissum Research Development Company Of The Hebrew University Of Jerusalem Formules liposomales comprenant une base faible amphipathique telle que la tempamine pour le traitement des affections neurodegeneratives
WO2006084198A2 (fr) * 2005-02-02 2006-08-10 Mitos Pharmaceuticals, Inc. Oxydes d'azote destines a etre utilises pour le traitement ou la prevention de maladies immunologiques
WO2006105215A2 (fr) * 2005-03-28 2006-10-05 Acucela, Inc. Methodes permettant de renforcer la survie des cellules neuronales et de traiter les maladies neurodegeneratives
WO2008112647A2 (fr) * 2007-03-09 2008-09-18 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Radical nitroxyde en tant que traitement pour la neurodégénération

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005084677A1 (fr) * 2004-03-01 2005-09-15 Medestea Research & Production S.P.A. Utilisation de derives de n-piperidine dans le traitement des pathologies neurodegeneratives
WO2006014968A2 (fr) * 2004-07-27 2006-02-09 Teva Pharmaceutical Industries, Ltd. Nitroxydes propargyle et nitroxydes indanyle et leur utilisation pour traiter les maladies et les troubles neurologiques
WO2006027785A1 (fr) * 2004-09-09 2006-03-16 Yissum Research Development Company Of The Hebrew University Of Jerusalem Formules liposomales comprenant une base faible amphipathique telle que la tempamine pour le traitement des affections neurodegeneratives
WO2006084198A2 (fr) * 2005-02-02 2006-08-10 Mitos Pharmaceuticals, Inc. Oxydes d'azote destines a etre utilises pour le traitement ou la prevention de maladies immunologiques
WO2006105215A2 (fr) * 2005-03-28 2006-10-05 Acucela, Inc. Methodes permettant de renforcer la survie des cellules neuronales et de traiter les maladies neurodegeneratives
WO2008112647A2 (fr) * 2007-03-09 2008-09-18 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Radical nitroxyde en tant que traitement pour la neurodégénération

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103111A1 (fr) * 2010-02-16 2011-08-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthode de traitement d'une maladie impliquant la perte de myéline et/ou d'axones

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