WO2003082893A2 - Methodes therapeutiques et utilisations des sapogenines et de leurs derives - Google Patents

Methodes therapeutiques et utilisations des sapogenines et de leurs derives Download PDF

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WO2003082893A2
WO2003082893A2 PCT/GB2003/001380 GB0301380W WO03082893A2 WO 2003082893 A2 WO2003082893 A2 WO 2003082893A2 GB 0301380 W GB0301380 W GB 0301380W WO 03082893 A2 WO03082893 A2 WO 03082893A2
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Prior art keywords
alkyl
pharmaceutically acceptable
group
absent
acceptable salts
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PCT/GB2003/001380
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English (en)
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WO2003082893A3 (fr
WO2003082893A8 (fr
Inventor
Daryl Rees
Phil Gunning
Antonia Orsi
Zongqin Xia
Yaer Hu
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Phytopharm Plc
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Priority claimed from ARP020101170A external-priority patent/AR033079A1/es
Priority to EP03722713A priority Critical patent/EP1490071B1/fr
Priority to DE60326437T priority patent/DE60326437D1/de
Priority to KR1020047014567A priority patent/KR101130212B1/ko
Priority to AU2003229877A priority patent/AU2003229877B8/en
Priority to US10/507,000 priority patent/US20050130948A1/en
Priority to NZ535093A priority patent/NZ535093A/en
Priority to BR0308788-3A priority patent/BR0308788A/pt
Priority to IL16416103A priority patent/IL164161A0/xx
Priority to CN038071886A priority patent/CN1642558B/zh
Application filed by Phytopharm Plc filed Critical Phytopharm Plc
Priority to KR1020127008441A priority patent/KR20120128596A/ko
Priority to CA2477787A priority patent/CA2477787C/fr
Priority to MXPA04009321A priority patent/MXPA04009321A/es
Priority to JP2003580357A priority patent/JP4573157B2/ja
Publication of WO2003082893A2 publication Critical patent/WO2003082893A2/fr
Publication of WO2003082893A8 publication Critical patent/WO2003082893A8/fr
Publication of WO2003082893A3 publication Critical patent/WO2003082893A3/fr
Priority to NO20044468A priority patent/NO20044468L/no
Priority to HR20041009A priority patent/HRP20041009A2/xx
Priority to HK04110420.5A priority patent/HK1067546A1/xx
Priority to AU2008207565A priority patent/AU2008207565A1/en
Priority to US13/085,225 priority patent/US20110190249A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to therapeutic methods and uses of sapogenins, related compounds and their derivatives.
  • the uses of the sapogenins, related compounds and their derivatives are in the treatment of non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor- sensory neurodegeneration, or receptor dysfunction or loss.
  • the invention relates to compositions for use in such treatments.
  • Cognitive dysfunction is a characteristic of dementia conditions and syndromes, such as Alzheimer's disease (AD), senile dementia of the Alzheimer's type (SDAT), Lewy body dementia and vascular dementia.
  • a lesser degree of cognitive dysfunction is also a characteristic of certain non-dementia conditions and syndromes, such as mild cognitive impairment (MCI), age-associated memory impairment (AAMI), autism and neuroimpairment.
  • MCI mild cognitive impairment
  • AAMI age-associated memory impairment
  • autism neuroimpairment.
  • Non-cognitive neurodegeneration i.e. neurodegeneration in the absence of cognitive dysfunction
  • non-cognitive neuromuscular degeneration i.e. neuromuscular degeneration in the absence of cognitive dysfunction
  • motor-sensory neurodegeneration are characteristic of conditions and syndromes such as Parkinson's disease, muscular dystrophy including facioscapulohumeral muscular dystrophy (FSH), Duchenne muscular dystrophy, Becker muscular dystrophy and Bruce's muscular dystrophy, Fuchs' dystrophy, myotonic dystrophy, corneal dystrophy, reflex sympathetic dystrophy syndrome (RSDSA), neurovascular dystrophy, myasthenia gravis, Lambert Eaton disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis.
  • FSH facioscapulohumeral muscular dystrophy
  • Duchenne muscular dystrophy Becker muscular dystrophy and Bruce's muscular dystrophy
  • Fuchs' dystrophy myotonic dystrophy
  • Receptor dysfunction or loss - particularly dysfunction or loss of nicotinic and/or muscarinic acetylcholine receptors and/or dopamine receptors and/or adrenoceptors - is a characteristic of some or all of the above conditions and syndromes.
  • Receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment is also a characteristic of conditions and syndromes such as postural hypotension, chronic fatigue syndrome, asthma, susceptibility to heart failure and macular degeneration.
  • WO-A-99/16786 the disclosure of which is incorporated herein by reference, suggests the use of certain saponins and sapogenins in the treatment of dementia.
  • WO-A-99/48482, WO-A-99/48507, WO-A-01/23406, WO-A-01/23407, WO-A-01/23408, the disclosures of which are incorporated herein by reference, relate to the use of certain saponins, sapogenins and derivatives thereof in the treatment of cognitive dysfunction and allied conditions.
  • cognitive dysfunction is not a primary symptom, although it may be present as one of a number of possible secondary symptoms.
  • these conditions are not viral diseases or dementias.
  • a treatment for cognitive dysfunction e.g. dementia
  • the present invention is based upon our finding that certain sapogenins and their derivatives, including saponins, have a surprising disease-modifying activity against non- cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor-sensory neurodegeneration as well as against receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment, and thus actively prevent and reverse the conditions.
  • This finding enables improved treatment of certain non-viral, spectrum and non-spectrum, disorders in which cognitive dysfunction is not a primary symptom.
  • the active agents in the treatment or prevention of, or in the preparation of compositions (e.g. pharmaceutical compositions, foodstuffs, food supplements and beverages) for the treatment or prevention of, (i) non-cognitive neurodegeneration, (ii) non- cognitive neuromuscular degeneration, (iii) motor-sensory neurodegeneration (iv) receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment, in human and non-human animals suffering therefrom or susceptible thereto.
  • compositions e.g. pharmaceutical compositions, foodstuffs, food supplements and beverages
  • active agents refers to compounds of the following general formulae I, II and HI, sapogenin derivatives as defined below by reference to derivatives bearing at least one defined X radical substituent, sugar-substituted derivatives of such compounds as defined below, all their stereoisomers and racemic mixtures, all their pharmaceutically acceptable pro-drugs and salts, and all mixtures and combinations thereof:
  • R 33 or R 14 alkyl group, and the stereochemistry of R 25 is in the ⁇ orientation;
  • sapogenin derivatives particularly but not exclusively steroidal spirostane sapogenin derivatives, bearing at least one X radical substituent, wherein X is chosen from the group consisting of :
  • the carbon atom at the 3-position i.e. the carbon to which R 3 is attached, or the corresponding position in the sapogenin derivatives defined above without a formula
  • the 3- position carbon atom, the 26-position i.e. the carbon to which R 34 is attached
  • each of the carbon atoms at the 3- and 26-positions carries an O-sugar moiety wherein the sugar group is a mono-, di- or tri-saccharide.
  • sugar-carrying derivative forms of sapogenin active agents are generally referred to in the art as saponins.
  • the expression "carbohydrate” used herein includes particularly such sugar groups.
  • the active agents used in the present invention are preferably the non-estrogenic steroidal sapogenins, saponins, and derivatives thereof within the terms of the above definition, including all physiologically acceptable pro-drugs and salts thereof.
  • the active agents may be naturally occurring or non-naturally occurring.
  • Non-naturally occurring active agents may suitably be prepared by modification of side groups and/or side atoms of naturally occurring compounds, as described below and as known in the art.
  • the invention also provides corresponding methods for the treatment of human and non- human animals, and compositions containing the active agents for use in the said treatment methods.
  • the active agents of the invention may, if desired, be co-administered with one or more additional active agent, for example one or more agent selected from, but not limited to, cholinesterase inhibitors, dopamine agonists (e.g. L-dopa), COMT inhibitors, MAO-B inhibitors, anti-cholinergics, acetylcholine agonists, serotonin agonists, AMPA receptor agonists, GABA receptor agonists, NMDA receptor agonists, ⁇ -adrenoceptor agonists, digoxin, dobutamine, anti-inflammatories, neurotrophic factors, statins, adenosine A2a receptor antagonists, aldose reductase inhibitors, immunomodulators, cannabinoid agonists, interferon ⁇ or tricyclic anti-depressants.
  • cholinesterase inhibitors e.g. L-dopa
  • COMT inhibitors e.g. L-dopa
  • the active agents may be applied therapeutically or prophylactically to human and non-human animals suffering from, or susceptible to, conditions and diseases that are characterised by non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor-sensory neurodegeneration, or receptor dysfunction or loss. Examples of such conditions and diseases are provided below.
  • the present invention therefore also provides the use of the active agents (as herein defined) in the treatment or prevention of, or in the preparation of compositions (e.g. pharmaceutical compositions, foodstuffs, food supplements and beverages) for the treatment or prevention of, one or more of said conditions and diseases in human and non- human animals suffering therefrom or susceptible thereto.
  • active agents as herein defined
  • compositions e.g. pharmaceutical compositions, foodstuffs, food supplements and beverages
  • R alkyl or acyl group
  • R 33 or R 14 alkyl group, and the stereochemistry of R 25 is in the ⁇ orientation;
  • R 33 or R i4 alkyl group, and the stereochemistry of R 25 is in the ⁇ orientation;
  • R 33 or R 14 alkyl group, and the stereochemistry of R 25 is in the ⁇ orientation;
  • R 33 or R 14 alkyl group, and the stereochemistry of R 25 is in the ⁇ orientation;
  • R 36 H or -OH represents a single bond
  • R 36 H or OH represents a single bond
  • Substituted sapogenins particularly but not exclusively steroidal spirostane sapogenins, wherein at least one OH-group of the sapogenin is substituted with X, chosen from the group consisting of :
  • Sapogenins defined above particularly but not exclusively steroidal spirostane sapogenins, wherein in the definition of X the halo atom is a fluoro atom;
  • Substituted sapogenins selected from :
  • Substituted sapogenins wherein the parent sapogenin which is then substituted with at least one X radical as defined above is selected from sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin, andmilarogenin-D;
  • group R is selected from hydrogen; alkylcarbonyl; alkoxycarbonyl; alkyl- carbamoyl; or arylcarbonyl; or sulpho (H0 3 S); phosphono ((HO) 2 P(0)-); or a mono-, di- or tri-saccharide; wherein any alkyl group is optionally substituted with aryl, amino, mono- or di-alkyl-amino, a carboxylic acid residue (-COOH), or any combination thereof;
  • Optional amino, mono-alkyl-amino and di-alkyl-amino substituents of alkyl groups, where present, are preferably a mono-substituent at the ⁇ position of the alkyl group.
  • Optional -COOH substituents of alkyl groups, where present, may be at the terminal or any other position of the alkyl group.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl” means about 1 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, t-propyl, M-butyl, t-butyl, _?-butyl, n-pentyl, 3-pentyl.
  • Aryl means any group comprising an aromatic ring or system of fused rings, and preferably contains up to 12 carbon atoms.
  • An exemplary aryl group is the phenyl group.
  • An aryl group may optionally be mono- or poly-substituted, for example by substituents independently selected from halo (e.g. chloro or bromo), alkyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, acylamino, carboxy and alkoxycarbonyl.
  • Carboxylic acid residue means the group -COOH.
  • acyl means an H-CO- or Alkyl-CO- group wherein the alkyl group is as defined below.
  • Preferred acyls contain a lower alkyl.
  • Exemplary acyl groups include formyl. acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl;
  • Optionally substituted means that the said group may be substituted with one or more substituents, which may be the same or different, preferably one or more substituents which individually have a size which is small (e.g. less than about 20% of the largest molecular dimension) in relation to the parent group being substituted; suitable substituents include halo (e.g. chloro or bromo), alkyl, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aryl, aroylamino, carboxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, and optionally substituted carbamoyl, preferably subject to the size limitation set out above ;
  • substituents include halo (e.g. chloro or bromo), alkyl, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aryl, aroylamino, carboxy, alkoxycarbonyl, aral
  • “Pharmaceutically acceptable” means it is, within the scope of sound medical and veterinary judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable prodrugs” means those prodrugs of the compounds which are, within the scope of sound medical and veterinary judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds.
  • prodrug means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood.
  • Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group. Because of the ease with which the metabolically cleavable groups of the compounds are cleaved in vivo, the compounds bearing such groups act as pro-drugs.
  • a thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K.
  • “Pharmaceutically acceptable salts” means the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds.
  • acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. See, for example S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 66: p.l- 19 (1977) which is incorporated herein by reference.
  • Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed.
  • Base addition salts include pharmaceutically acceptable metal and amine salts.
  • suitable acid addition salts are those formed with acids selected from hydrochloric, sulphuric, phosphoric and nitric acids.
  • suitable base addition salts are those formed with bases selected from sodium hydroxide, potassium hydroxide and ammonium hydroxide.
  • a particularly preferred class of active agents are the compounds of the general formula la.
  • the C 25 methyl group is in the S configuration; these compounds of the invention are sarsasapogenin and episarsasapogenin or derivatives thereof.
  • the C 25 methyl group is in the R configuration; these compounds of the invention are smilagenin and epismilagenin or derivatives thereof.
  • -OR may, for example, be selected from the following (unless excluded by proviso):, hydroxy, cathylatc (ethoxycarbonyloxy), acetate, succinate, cinnamate, ferulate, propionate, butyrate, valerate, isovalerate, caproate, isocaproate, diethylacetate, octanoate, decanoate, laurate, myristate, palmitate, stearate, benzoate, phenylacetate, phenylpropionate, cinnamate, p-nitrobenzoyloxy, 3,5-dinitrobenzoyloxy, p- chlorobenzoyloxy, 2,4-dichlorobenzoyloxy, p-bromobenzoyloxy, m-bromobenzoyloxy.
  • p- methoxybenzoyloxy phthalyl, glycinate, alaninate, valinate, phenylalaninate, isoleucinate, methioninate, argininate, asparaginate, aspartate, cysteinate, glutamate, histidinate, lysinate, prolinate, serinate, threoninate, tryptophanate, tyrosinate, fumarate or maleate.
  • suitable active agents include 16,22-epoxycoprostan-3 ⁇ -ol, smilagenone, coprosterol and pharmaceutically acceptable pro-drugs and salts thereof.
  • the present invention thus enables and provides a method for treating or preventing non- cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor-sensory neurodegeneration or receptor dysfunction or loss in the absence of cognitive, neural or neuromuscular impairment (particularly but not exclusively in relation to the specific disease states mentioned above) in a human or non-human animal in need thereof, which comprises administering to the said human or non-human animal an effective dosage of an active agent (as defined herein) or a pharmaceutically acceptable salt thereof.
  • an active agent as defined herein
  • the active agent may be administered in the form of a composition comprising the active agent and any suitable additional component.
  • the composition may, for example, be a pharmaceutical composition (medicament), a foodstuff, food supplement or beverage.
  • Such a composition may contain a mixture of the specified compounds, and/or of their pharmaceutically acceptable salts.
  • composition in the context of this invention means a composition comprising an active agent and comprising additionally pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • pharmaceutically acceptable carriers such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • the dosage of the active agent will vary widely, depending on the severity of the symptoms to be treated or prevented. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden.
  • the dosage of the active agent may, for example, be greater than about 0.1 mg/kg body weight, for example greater than about 0.3 mg/kg body weight, preferably administered once per day. More typically, the dosage will be between about 1 and about 25 mg/kg, e.g. between about 1 and about 10 mg/kg, preferably administered once per day. For human use, the dosage may conveniently be between about 70 and about 700 mg per day.
  • “Pharmaceutically acceptable dosage forms” means dosage forms of the compounds or compositions of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.
  • Techniques and formulations generally may be found in Remington, Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition. In general, reference herein to the presence of one of a specified group of compounds includes within its scope the presence of a mixture of two or more of such compounds.
  • This invention provides for the treatment of (i) non-cognitive neurodegeneration, (ii) non- cognitive neuromuscular degeneration, (iii) motor-sensory neurodegeneration, or (iv) receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment, in a human or non-human animal subject suffering from, or susceptible to, any of: Parkinson's disease, postencephalitic Parkinsonism, depression, schizophrenia, muscular dystrophy including facioscapulohumeral muscular dystrophy (FSH), Duchenne muscular dystrophy, Becker muscular dystrophy and Brace's muscular dystrophy, Fuchs' dystrophy, myotonic dystrophy, corneal dystrophy, reflex sympathetic dystrophy syndrome (RSDSA), neurovascular dystrophy, myasthenia gravis, Lambert Eaton disease, Huntington's disease, motor neurone diseases including amyotrophic lateral sclerosis (ALS), multiple sclerosis, postural hypotension, traumatic neurodegeneration e.g.
  • ALS amy
  • traumatic head injury or spinal cord injury Batten's disease, Cockayne syndrome, Down syndrome, corticobasal ganglionic degeneration, multiple system atrophy, cerebral atrophy, olivopontocerebellar atrophy, dentatorubral atrophy, pallidoluysian atrophy, spinobulbar atrophy, optic neuritis, sclerosing pan-encephalitis (SSPE), attention deficit disorder, post-viral encephalitis, post-poliomyelitis syndrome, Fahr's syndrome, Joubert syndrome, Guillain-Barre syndrome, lissencephaly, Moyamoya disease, neuronal migration disorders, autistic syndrome, polyglutamine disease, Niemann- Pick disease, progressive multifocal leukoencephalopathy, pseudotumor cerebri, Refsum disease, Zellweger syndrome, supranuclear palsy, Friedreich's ataxia, spinocerebellar ataxia type 2, Rhett syndrome, Shy
  • the invention therefore includes methods of treating or preventing the above diseases and conditions in a human or non-human animal suffering therefrom or susceptible thereto, which comprises administering to the said human or non-human animal an effective amount of an active agent as defined herein, as well as uses of the active agents in the preparation of compositions for said treatment or prevention.
  • the present invention may be subject to the proviso that either symptoms of cognitive dysfunction are absent, or any symptoms of cognitive dysfunction presented by a subject to be treated are secondary or ancillary to the symptoms of non-cognitive neurodegeneration, non-cognitive neuromuscular degeneration, motor-sensory neurodegeneration or receptor dysfunction or loss in the absence of cognitive, neural and neuromuscular impairment.
  • Smilagenin, epismilagenin and sarsasapogenin are commercially available materials. Suppliers include, for example, Sigma Aldrich, Research Plus Inc. and Steraloids Inc. Preparative methods for these materials are also to be found in the literature (e.g. a preparation of episarsasapogenin is given in JACS p.5225 (1959)).
  • Sarsasapogenone can be prepared using the method of Lajis et al, Steroids, 1993, 58, 387-- 389.
  • unsubstituted saponins and sapogenins may occur naturally in a range of plant species, notably plants of the genus Smilax, Asparagus, Anemarrhena, Yucca or Agave.
  • smilagenin or sarsasapogenin is used in accordance with this invention, it may be in the form of a plant extract, or dry powdered plant material, derived from a plant . of the genus Smilax, Asparagus, Anemarrhena, Yucca or Agave.
  • the preferred reaction is a nucleophilic substitution reaction, in which a compound having OH at the 3-position is reacted with a compound of formula
  • R is selected from alkylcarbonyl; alkoxycarbonyl; alkylcarbamoyl; or arylcarbonyl; or wherein any alkyl group is optionally substituted with aryl, amino, mono- alkyl-amino, di-alkyl-amino, a carboxylic acid residue (-COOH), or any combination thereof; and L is a leaving group, under conditions suitable for nucleophilic substitution.
  • the compound L-R may, for example, be a carboxylic acid or, if appropriate, an anhydride, or an acyl halide (e.g. an acyl chloride).
  • R is a cathylate (ethoxycarbonyl) moiety
  • the compound L-R may suitably be ethyl chloroformate.
  • the reaction is suitably performed in a base such as pyridine, optionally in the presence of an acid such as hydrochloric acid.
  • Dihydrosarsasapogenin may be made using the method described in Marker and Rohrmann (1939), Sterols LIJI; The structure of the side chain of sarsasapogenin, J. Am. Chem. Soc. 61, pp 846-851. 16,22-Epoxycoprostan-3 ⁇ -ol may be made using the method described in Scheer et al, (1955), The C-25 isomerism of smilagenin and sarsasapogenin: J. Am. Chem. Soc. 77, pp 641-646.
  • an alkoxycarbonyl protecting group for protecting amino substituents in compounds of formula L-R wherein R is amino-substituted, it is preferred to use an alkoxycarbonyl protecting group, whereby the amino function is present as an alkoxycarbonylamino group (preferably t.-butoxycarbonylamino) during the synthetic steps, until deprotection in acid conditions in a dry solvent.
  • the compound thus prepared may be recovered from the reaction mixture by conventional means.
  • the compound may be recovered by distilling off the solvent from the reaction mixture or, if necessary after distilling off the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-miscible solvent and distilling off the solvent from the extract.
  • the product can, if desired, be further purified by various well known techniques, such as recrystallisation, reprecipitation, or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
  • the therapeutic uses underlying the present invention arise from a number of novel observations which are documented in detail in the Examples below. To understand the rationale of the invention, it is useful to summarise the observations and to explain how they predict the therapeutic activities claimed in this invention across the range of active agents defined above.
  • Smilagenin, epismilagenin, sarsaspogenin and episarsasapogenin restore the loss of muscarinic acetylcholine receptors and adrenoceptors in cells expressing such receptors in vitro. These results demonstrate that these compounds restore towards normal cellular receptor loss (Example 1). .
  • Sarsaspogenin, episarsasapogenin cathylate and smilagenin reduce the number of wrong responses in a cognitive ability test in vivo in aged rats, which correlates with an increase in muscarinic acetylcholine receptor density in the brains of aged rats following treatment with the compounds tested. These results demonstrate that the compounds reverse neuroimpairment in vivo (Example 9).
  • Episarsasapogenin cathylate, sarsasapogenin cathylate, episarsasapogenin and epismilagenin reduce the number of wrong responses in a cognitive ability test in vivo in young rats exposed to neurotoxic agents (ibotenic acid and amyloid D, and increase in muscarinic acetylcholine receptor density in the brains. These results demonstrate that the compounds reverse neuroimpairment in vivo (Example 10). Smilagenin and sarsasapogenin improve survival and motor-sensory neurodegeneration and neuroimpairment in a mouse model of amyotrophic lateral sclerosis (ALS) and Charcot- Marie-Tooth disease (Example 11).
  • ALS amyotrophic lateral sclerosis
  • Example 11 Charcot- Marie-Tooth disease
  • the compounds have been found to slow or reverse certain aspects of neuronal degeneration. These include the reversal of adverse changes in the cell body, atrophy of neuronal extensions (neurites), reduction in release of neurotrophic factors such as neurotrophins (e.g. BDNF, NGF, NT-3, NT4/5), TGF- ⁇ super-family neurotrophic factors (e.g. GDNF) and neurokines (e.g. CNTF, LIF), and neuronal toxicity or death (apoptosis).
  • neurotrophins e.g. BDNF, NGF, NT-3, NT4/5
  • TGF- ⁇ super-family neurotrophic factors e.g. GDNF
  • neurokines e.g. CNTF, LIF
  • apoptosis neuronal toxicity or death
  • the compounds have also been found to slow or reverse decreases in cholinergic and dopaminergic function, for example, decreases in muscarinic acetylcholine and dopamine receptor density. Furthermore, we have found that the neuroprotective and the reversal of receptor loss effects are actively regulated effects, in which past deterioration is reversed towards the normal or young state with protection against continued deterioration. Still further, we have found that the reversal of apoptotic effect of the compounds appears to be regulated in the non-neoplastic domain of cell life, and does not appear likely to trigger neoplasia.
  • the above data indicate activity against the disease states already listed in this application. Furthermore, the above data indicates a likely absence of severe or life- threatening side effects such as cancer.
  • the active agents are typically non-oestrogenic.
  • side group substituents in a wide range of forms, can be present in a complex carbon skeleton without substantially adversely affecting the pharmacological activity of the structure, particularly when the side groups are small in comparison with the overall size of the molecule.
  • one physiological effect of the active agents is the ability to increase the synthesis, or release of, or to reduce the rate of degradation of, neurotrophic factors such as brain derived neurotrophic factor and/or nerve growth factor or their receptors.
  • neurotrophic factors such as brain derived neurotrophic factor and/or nerve growth factor or their receptors.
  • These effects on growth factors might be due to an effect of the compound on a cytosolic or nuclear receptor, or the binding of a compound to a promoter region with a consequent effect directly on the rate of production of mRNA for the growth factor, or as a consequence of increasing the production of another material factor.
  • the compounds appear to regulate receptors. For example, some of these compounds have been found to prevent or reverse the loss of muscarinic acetylcholine or dopamine receptors in the brain. It is believed that the compounds function by rectifying a deficiency in receptor number or function or turnover.
  • Figure 1 shows the effect of epismilagenin acetate on m3 and ⁇ 2 adrenoceptor density at day 5 in a CHO- ⁇ 2/m3 co-transfected cell line;
  • Figure 2 shows the effects of sarsasapogenin, episarsasapogenin cathylate and smilagenin on glutamate induced neurodegeneration in rat primary cortical neurons;
  • Figure 3 shows the effects of sarsasapogenin, episarsasapogenin cathylate and smilagenin on the learning ability and memory of aged rats;
  • Figure 4 shows the effects of sarsasapogenin, episarsasapogenin cathylate and smilagenin on muscarinic receptor number;
  • Figure 5 shows the survival profile of SOD-1 mice following oral administration of smilagenin
  • Figure 6 shows the survival profile of pmn mice following oral administration of sarsasapogenin.
  • epismilagenin cathylate sarsasapogenin cathylate, episarsasapogenin cathylate, episarsasapogenin succinate, epismilagenin acetate and sarsasapogenin on the expression of muscarinic acetylcholine receptor (m) in CHO cells or ⁇ 2 and m3 receptors in CHO cells transfected with either a vector for the m receptor or co-transfected with the vector for ⁇ 2 and m3 receptors were investigated.
  • m muscarinic acetylcholine receptor
  • Table 1 Effect of epismilagenin cathylate, sarsasapogenin cathylate, episarsasapogenin cathylate, episarsasapogenin succinate and sarsasapogenin on restoration of m acetylcholine receptor density.
  • the objective of this study was to examine the effects of sarsasapogenin, episarsasapogenin cathylate, episarsasapogenin, epismilagenin and smilagenin on the survival of rat primary cortical neurones exposed to glutamate, which is known to induce neurodegeneration.
  • Rat cortical neurones were cultured for 10 days; at day 10 the medium was changed to a serum-free defined medium. On day 12, 24 hours before glutamate exposure, cultures were washed a d medium was replaced with fresh medium containing positive .control ( ⁇ - oestradiol)j test compounds (sarsasapogenin, episarsasapogenin - cathylate, episarsasapogenin, epismilagenin and smilagenin) or vehicle control (DMSO, 0.25%) or diosgenin as negative control.
  • LDH lactate dehydrogenase
  • the objective of this study was to examine the anti-apoptotic effect of smilagenin on the caspase-3 activity, a marker of apoptosis, in rat primary cortical cultures exposed to glutamate
  • Rat cortical neurones were cultured for 6 days. At day 6, glutamate (100 microM, 10 min) was added. Then the cultures were washed and medium was replaced with fresh medium containing smilagenin or vehicle control (DMSO, 0.25%) for 6 h. After 6 h treatment, apoptosis was evaluated by measuring caspase 3 activity. Caspase 3 activity was detected by the cleavage of p-nitroaniline from a colorimetric caspase-3 substrate, acetyl-Asp-Glu- Val-Asp p-nitroanilide. p-Nitroalanine has a high absorbance at 405 nM. Relative caspase- 3 activity was measured as optical density.
  • Neurodegenerative disorders are characterised by a progressive loss of neurones and degradation of neuronal processes (neurites).
  • Agents that induce neurite outgrowth may promote the formation of new connections between neurones and ameliorate the symptoms of neurodegenerative conditions (Katzman et al, Faseb J., 5, 278-286, 1991).
  • MPP + a metabolite of l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine (MPTP) mimics the degeneration of nigrostriatal dopaminergic neurones observed in neurodegenerative disorders such as Parkinson's disease (Mytinlineou et al, Science, 225, 529-531, 1984).
  • biochemical changes induced by this toxin include decreased levels of dopamine and its metabolites in the substantia nigra pars compacta and in the caudate nucleus (Burns et al, Proc Natl Acad Sci U.S.A., 80, 4546- 4550, 1983) and a reduction in dopamine uptake in nigrostriatal synaptosomal preparations (Heikkila et al, J Neurochem., 44, 310-313, 1985).
  • Pre-treatment with smilagenin and sarsasapogenin produced a significant increase in the neuronal survival compared to neurones exposed to MPP + alone, suggesting a significant neuroprotective effect (Table 7).
  • the objective of this study was to examine the effects of sarsasapogenin and smilagenin on the survival of rat primary spinal motor neurones exposed to glutamate, which is known to induce neurodegeneration in this model of motor neurodegeneration. 17 ⁇ -oestradiol and BDNF were used as positive controls.
  • Rat motor neurones were prepared according to the method described by (Martinou et al, Neuron, 8, 737-744, 1992). On day 10, medium was removed and the cultures were exposed to glutamate (4 microM) for 10 min at 37°C in defined medium. After the glutamate exposure, cultures were washed with Dulbecco modified Eagle medium at 37°C then placed in fresh culture medium containing test compounds. After 48 h, the extent of spinal motor neurone degeneration was determined by measuring the amount of lactate dehydrogenase (LDH) released into the culture medium as above.
  • LDH lactate dehydrogenase
  • BDNF brain derived neurotrophic factor
  • acetylcholine receptor density muscarinic and nicotinic
  • a decrease in their coupling function in cortical areas Rosci., 18, 223-253, 1995
  • muscarinic acetylcholine receptor binding is significantly reduced in the hippocampus (Narang, N, Mech. Ageing Dev., 78, 221-239, 1995) and striatum of older rats (Biegon et al, Neurobiol.
  • a Y-maze apparatus was used for the learning and memory test.
  • On the floor of each arm of the Y-maze is an array of copper rods to which electric current is applied whenever needed, with adjustable voltage.
  • Each arm is 45 cm long and has a 15 W lamp at the end, which is turned on when needed.
  • each rat was trained for 7 consecutive days, as follows. For each training session, the rat was put into one arm of the Y-maze, after two minutes rest, an electrical current was applied to the copper rods and the lamp of the clockwise arm was illuminated to indicate the non-stimulation area. If the rat went into that arm, one correct response was recorded, otherwise, one wrong response was recorded.
  • This stimulation-response test was repeated 20 times each day, with a pause of 5 sec between each two consecutive tests.
  • the number of correct responses following the twenty tests on the seventh day was used to express learning ability, (the higher the number the better the learning ability).
  • the rats were then left resting for 30 days and the procedure was repeated once more.
  • the number of correct responses of the 20 tests after the 30 day rest period was used to represent the memory ability
  • Muscarinic acetylcholine receptor density in the brain was measured. Tissue was prepared as follows: brains were removed quickly after decapitation, frozen in dry ice, and transferred to a freezer. The brains were homogenised and the pellet was finally suspended in buffer.
  • the dual-site competitive ligand binding assay was used to measure muscarinic acetylcholine receptor density.
  • the compounds reverse the neuroimpairment, the decline in BDNF levels, and the decline in the muscarinic acetylcholine and dopamine receptor density that occur in aged rats.
  • Alzheimer's disease model as a model of neurodegeneration
  • Alzheimer's disease An in vivo model of Alzheimer's disease was used to model neurodegeneration.
  • the neurotoxic agents amyloid ⁇ and ibotenic acid
  • amyloid ⁇ and ibotenic acid are injected into the brain of the rat. This leads to neuronal loss, receptor loss and cognitive impairment.
  • Previous studies showed that local injection of amyloid ⁇ in the nucleus vasalis of the rat brain caused cholinergic hypofunction and behavioural impairment up to two months post surgery (Giovannelli et al., 1995: Neuroscience, 66, 781-792.).
  • the dose for each rat was amyloid ⁇ M0 (4 ⁇ g) and ibotenic acid (1 ⁇ g) in 1 ⁇ l of saline. The injection was completed in 20 min, and the needle was withdrawn 10 min later. Then the skin was sutured.
  • the 8 groups were:
  • Episarsasapogenin cathylate, sarsasapogenin cathylate, episarsasapogenin ethylsuccinate (comparison compound), episarsasapogenin, epismilagenin and diosgenin (all at a dosage of 18 mg/kg/day) were administered to animals as stable suspensions in CMC-Na (0.5%) once daily through a gastric tube.
  • the control and the model group were given the same volume of CMC-Na (0.5%) once daily.
  • the drugs and vehicles were given for a period of two months, starting 20 days before operation.
  • Muscarinic acetylcholine receptor density was assessed.
  • the brain samples were homogenised, centrifuged, and the pellet of centrifugation at 27000xg was re-homogenised and used for measurement.
  • the concentration of 3 H-QNB was chosen at the saturation range. After incubation and separation, the bound portion was measured by liquid scintillation counter.
  • Step-Through Test learning and memory. The effect of test compounds on learning and memory was assessed using the step-through test.
  • the experiment is carried out for each rat on two consecutive days. The first day is for training; when the rat is adapted in the box for the first 3 min, then put in the light room, with its back toward the hole, and the copper rods of the dark room are charged for 5 min. The second day is for testing, when the number of crosses in 5 min are recorded. Improvements in memory are signalled by a reduction in the number of crosses.
  • the muscarinic acetylcholine receptor density in the neurodegeneration model brains was significantly lower than control.
  • Episarsasapogenin cathylate, sarsasapogenin cathylate, episarsasapogenin and epismilagenin produced a significant elevation in brain muscarinic acetylcholine receptor density, whereas diosgenin and episarsasapogenin ethylsuccinate did not significantly change the muscarinic acetylcholine receptor density.
  • the compounds of this invention act to normalise receptor number, i.e. they tend to restore receptor number to normal levels when given to animals in which the receptor level is depressed.
  • ALS Amyotrophic lateral sclerosis
  • SOD-1 Cu Zn superoxide dismutase
  • Animal models of this disease include the SOD-1 transgenic mice over-expressing SOD-1 gene and the progressive motor neuropathy (pmn, a model of Charcot-Marie-Tooth) mice.
  • SOD superoxide dismutase
  • pmn mouse
  • ALS amyofrophic lateral sclerosis
  • Charcot-Marie-Tooth disease two models of amyofrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease.

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Abstract

L'invention concerne des méthodes thérapeutiques et les utilisations de certaines sapogénines stéroïdiques, des composés analogues et des dérivés de ce celles-ci, pour le traitement de la neurodégénérescence non cognitive, de la dégénérescence neuromusculaire non-cognitive, de la neurodégénérescence senso-motrice ou des dysfonctions ou des pertes des récepteurs, en l'absence de troubles cognitifs, neurologiques et neuromusculaires.
PCT/GB2003/001380 2002-03-27 2003-03-27 Methodes therapeutiques et utilisations des sapogenines et de leurs derives WO2003082893A2 (fr)

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KR1020127008441A KR20120128596A (ko) 2002-03-27 2003-03-27 사포게닌 및 그 유도체의 치료 방법 및 용도
CA2477787A CA2477787C (fr) 2002-03-27 2003-03-27 Methodes therapeutiques et utilisations des sapogenines et de leurs derives
DE60326437T DE60326437D1 (de) 2002-03-27 2003-03-27 Therapeutische verwendung von sapogeninen
AU2003229877A AU2003229877B8 (en) 2002-03-27 2003-03-27 Theraputic methods and uses of sapogenins and their derivatives
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NZ535093A NZ535093A (en) 2002-03-27 2003-03-27 Therapeutic methods and uses of sapogenins and their derivatives
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IL16416103A IL164161A0 (en) 2002-03-27 2003-03-27 Therapeutic methods and uses of sapogenins and their derivatives
MXPA04009321A MXPA04009321A (es) 2002-03-27 2003-03-27 Metodos y usos terapeuticos de sapogeninas y sus derivados.
EP03722713A EP1490071B1 (fr) 2002-03-27 2003-03-27 Utilisations therapeutiques des sapogenines
JP2003580357A JP4573157B2 (ja) 2002-03-27 2003-03-27 治療方法ならびにサポゲニンおよびその誘導体の使用
KR1020047014567A KR101130212B1 (ko) 2002-03-27 2003-03-27 사포게닌 및 그 유도체의 치료 방법 및 사용법
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NO20044468A NO20044468L (no) 2002-03-27 2004-10-20 Anvendelse av sapogeniner samt derav ved fremstilling av medikamenter
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AU2008207565A AU2008207565A1 (en) 2002-03-27 2008-08-27 Therapeutic methods and uses of sapogenins and their derivatives
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2868700A1 (fr) * 2004-04-09 2005-10-14 Michel Coisy Utilisation de la dopamine ou de ses precurseurs biologiques contre l'algoneurodystrphie.
WO2007049932A1 (fr) 2005-10-28 2007-05-03 Sun-Yeou Kim Extrait de la famille dioscoreaceae et composition le comprenant pour prevenir ou traiter la neuropathie peripherique
JP2008519020A (ja) * 2004-11-05 2008-06-05 フィトファーム・パブリック・リミテッド・カンパニー サルササポゲニンの多形相
WO2010084356A1 (fr) 2009-01-24 2010-07-29 Phytopharm Plc Traitement de troubles médiés par un facteur neurotrophique
EP2402362A2 (fr) 2004-04-28 2012-01-04 Phytopharm PLC Formes cristallines de la smilagénine
WO2012010896A1 (fr) 2010-07-20 2012-01-26 Phytopharm Plc Traitement de troubles induits par la l-dopa, un agoniste de dopamine et/ou un activateur de dopamine
WO2013097835A1 (fr) * 2011-12-27 2013-07-04 Centro De Investigacion Y Desarrollo De Los Medicamentos (Cidem) Systèmes spiro-stéroïdiens ayant des effets neuroactifs et anti-inflammatoires
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US6861788B2 (en) * 2003-06-03 2005-03-01 Motorola, Inc. Switchable display/mirror method and apparatus
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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0162330A1 (fr) * 1984-04-30 1985-11-27 Roecar Holdings (Netherlands Antilles) N.V. Utilisation de stérolines et de spirokétalines dans la fabrication de médicaments pour traiter le psoriasis
US4680289A (en) * 1985-06-05 1987-07-14 Progenics, Inc. Treatment of obesity and diabetes using sapogenins
DE4303214A1 (de) * 1993-02-04 1994-08-11 Wolfgang Marks Behandlung von Erkrankungen viraler, viroidaler oder onkogener Genese durch Steroid-Saponine oder deren Aglykone
EP0659762A2 (fr) * 1993-12-24 1995-06-28 Mitsubishi Chemical Corporation Amides de l'acide sialique avec les dérivés 3-amino-sterols
WO1998002450A2 (fr) * 1996-07-11 1998-01-22 Inflazyme Pharmaceuticals Ltd. Steroides oxygenes en position 6, 7 et leurs utilisations
WO1999048507A2 (fr) * 1998-03-26 1999-09-30 Phytopharm Plc Recepteurs membranaires et leur fonction, dysfonctionnement cognitif et traitements correspondants, et compositions pour de tels traitements
EP1024146A1 (fr) * 1997-09-26 2000-08-02 Institute of Radiation Medicine Academy of Military Medical Sciences of the Pla Utilisation de composes de saponine et de steroides pour prevenir la senilite et nouveaux composes de saponine steroide
WO2001023408A1 (fr) * 1999-09-29 2001-04-05 Phytopharm Plc Derives 5-hydroxysapogenine actifs contre la demence
WO2001023407A1 (fr) * 1999-09-29 2001-04-05 Phytopharm Plc Derives de sapogenine et leur utilisation dans le traitement de dysfonctionnement cognitif
WO2001023406A1 (fr) * 1999-09-29 2001-04-05 Phytopharm Plc Derives de 5-beta-sapogenine et de pseudosapogenine et leurs utilisations dans le traitement de la demence
WO2001049703A2 (fr) * 2000-01-06 2001-07-12 Phytopharm Plc Sapogenines substituees et leur utilisation
JP2002030096A (ja) * 2000-07-11 2002-01-29 Kyorin Pharmaceut Co Ltd 神経細胞突起再生剤及びその製造方法
WO2003077869A2 (fr) * 2002-03-15 2003-09-25 Samaritan Pharmaceuticals, Inc Compositions pharmaceutiques neuroprotectrices a base de spirostenol

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246866A (ja) * 1992-03-06 1993-09-24 Ruibosuteii Japan:Kk 脳代謝促進・脳機能改善剤
JPH092956A (ja) * 1995-06-22 1997-01-07 Mitsubishi Chem Corp 神経障害の治療、予防薬
JPH092957A (ja) * 1995-06-22 1997-01-07 Mitsubishi Chem Corp 末梢性神経障害の治療、予防薬

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0162330A1 (fr) * 1984-04-30 1985-11-27 Roecar Holdings (Netherlands Antilles) N.V. Utilisation de stérolines et de spirokétalines dans la fabrication de médicaments pour traiter le psoriasis
US4680289A (en) * 1985-06-05 1987-07-14 Progenics, Inc. Treatment of obesity and diabetes using sapogenins
DE4303214A1 (de) * 1993-02-04 1994-08-11 Wolfgang Marks Behandlung von Erkrankungen viraler, viroidaler oder onkogener Genese durch Steroid-Saponine oder deren Aglykone
EP0659762A2 (fr) * 1993-12-24 1995-06-28 Mitsubishi Chemical Corporation Amides de l'acide sialique avec les dérivés 3-amino-sterols
WO1998002450A2 (fr) * 1996-07-11 1998-01-22 Inflazyme Pharmaceuticals Ltd. Steroides oxygenes en position 6, 7 et leurs utilisations
EP1024146A1 (fr) * 1997-09-26 2000-08-02 Institute of Radiation Medicine Academy of Military Medical Sciences of the Pla Utilisation de composes de saponine et de steroides pour prevenir la senilite et nouveaux composes de saponine steroide
WO1999048507A2 (fr) * 1998-03-26 1999-09-30 Phytopharm Plc Recepteurs membranaires et leur fonction, dysfonctionnement cognitif et traitements correspondants, et compositions pour de tels traitements
WO2001023408A1 (fr) * 1999-09-29 2001-04-05 Phytopharm Plc Derives 5-hydroxysapogenine actifs contre la demence
WO2001023407A1 (fr) * 1999-09-29 2001-04-05 Phytopharm Plc Derives de sapogenine et leur utilisation dans le traitement de dysfonctionnement cognitif
WO2001023406A1 (fr) * 1999-09-29 2001-04-05 Phytopharm Plc Derives de 5-beta-sapogenine et de pseudosapogenine et leurs utilisations dans le traitement de la demence
WO2001049703A2 (fr) * 2000-01-06 2001-07-12 Phytopharm Plc Sapogenines substituees et leur utilisation
JP2002030096A (ja) * 2000-07-11 2002-01-29 Kyorin Pharmaceut Co Ltd 神経細胞突起再生剤及びその製造方法
WO2003077869A2 (fr) * 2002-03-15 2003-09-25 Samaritan Pharmaceuticals, Inc Compositions pharmaceutiques neuroprotectrices a base de spirostenol

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 199343 Derwent Publications Ltd., London, GB; Class B04, AN 1993-339641 XP002157713 & JP 05 246866 A (KATO K), 24 September 1993 (1993-09-24) *
INOUE K ET AL: "Cholestanol induces apoptosis of cerebellar neuronal cells." BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. UNITED STATES 5 MAR 1999, vol. 256, no. 1, 5 March 1999 (1999-03-05), pages 198-203, XP001188107 ISSN: 0006-291X *
KYOUNG SOOK KIM, ET AL.: "Effects of cholestanol feeding on corneal dystrophy in mice." BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1085, 1991, pages 343-349, XP008027217 *
PATENT ABSTRACTS OF JAPAN vol. 1997, no. 05, 30 May 1997 (1997-05-30) & JP 09 002956 A (MITSUBISHI CHEM CORP), 7 January 1997 (1997-01-07) *
PATENT ABSTRACTS OF JAPAN vol. 1997, no. 05, 30 May 1997 (1997-05-30) & JP 09 002957 A (MITSUBISHI CHEM CORP), 7 January 1997 (1997-01-07) *
PATENT ABSTRACTS OF JAPAN vol. 2002, no. 05, 3 May 2002 (2002-05-03) & JP 2002 030096 A (KYORIN PHARMACEUT CO LTD), 29 January 2002 (2002-01-29) *
See also references of EP1490071A2 *
SUN, HUI ET AL: "Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease" JOURNAL OF BIOLOGICAL CHEMISTRY (1999), 274(12), 8269-8281 , XP001165795 *

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FR2868700A1 (fr) * 2004-04-09 2005-10-14 Michel Coisy Utilisation de la dopamine ou de ses precurseurs biologiques contre l'algoneurodystrphie.
WO2005102299A1 (fr) * 2004-04-09 2005-11-03 Michel Coisy Utilisation de la dopamine ou de ses precurseurs biologiques contre l’algoneurodystrophie
EP2402362A2 (fr) 2004-04-28 2012-01-04 Phytopharm PLC Formes cristallines de la smilagénine
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WO2007049932A1 (fr) 2005-10-28 2007-05-03 Sun-Yeou Kim Extrait de la famille dioscoreaceae et composition le comprenant pour prevenir ou traiter la neuropathie peripherique
US8202554B2 (en) 2005-10-28 2012-06-19 Sun-Yeou Kim Extract of the family dioscoreaceae and composition for preventing or treating peripheral neuropathy comprising the same
WO2010084356A1 (fr) 2009-01-24 2010-07-29 Phytopharm Plc Traitement de troubles médiés par un facteur neurotrophique
WO2012010896A1 (fr) 2010-07-20 2012-01-26 Phytopharm Plc Traitement de troubles induits par la l-dopa, un agoniste de dopamine et/ou un activateur de dopamine
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TW200400042A (en) 2004-01-01
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