[go: up one dir, main page]

WO2010128038A1 - Dérivés d'hydroquinone - Google Patents

Dérivés d'hydroquinone Download PDF

Info

Publication number
WO2010128038A1
WO2010128038A1 PCT/EP2010/056023 EP2010056023W WO2010128038A1 WO 2010128038 A1 WO2010128038 A1 WO 2010128038A1 EP 2010056023 W EP2010056023 W EP 2010056023W WO 2010128038 A1 WO2010128038 A1 WO 2010128038A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
hydrogen atom
alkyl group
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/056023
Other languages
English (en)
Inventor
Djalil Coowar
Emmanuel Couche
Eric Koncina
Aurélie DUBOIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AxoGlia Therapeutics SA
Original Assignee
AxoGlia Therapeutics SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AxoGlia Therapeutics SA filed Critical AxoGlia Therapeutics SA
Publication of WO2010128038A1 publication Critical patent/WO2010128038A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/11—Alkylated hydroxy benzenes containing also acyclically bound hydroxy groups, e.g. saligenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • the present invention relates to hydroquinone derivatives, to a process for preparing the hydroquinone derivatives, to a pharmaceutical composition comprising the hydroquinone derivatives and to the use of the hydroquinone derivatives in the treatment of neurodegenerative disease.
  • Neurodegenerative diseases result from deterioration of neurons or their myelin sheath which over time will lead to dysfunction and disabilities resulting from this.
  • Adult mammalian brain has limited capacity for regeneration. This makes the repair of any injuries hazardous and, consequently, CNS traumas are devastating.
  • Regulation, or production of microglia by the immune system, in a process of neuro inflammation, is currently being rigorously studied for its role in neurodegenerative diseases.
  • Alzheimer's Parkinson's, multiple sclerosis, amyotrophic later sclerosis (ALS) and Huntington's.
  • ALS amyotrophic later sclerosis
  • neurodegeneration also happens as a result of a stroke, a blow to the spinal cord or head, or bleeding in the brain.
  • AD Alzheimer's disease
  • a ⁇ amyloid beta
  • Parkinson's disease is a degenerative disorder of the central nervous system affecting more than 6 million people worldwide and that often impairs the sufferer's motor skills and speech.
  • the symptoms of Parkinson's disease result from the loss of dopamine-secreting cells in the region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement.
  • Multiple sclerosis is a neurological disease of the young adult which associates demyelination with inflammatory or even immunological elements.
  • MS is known to evolve initially by “relapsing and remitting", and then in a “progressive” form affecting more than 2.5 million people worldwide.
  • the most common initial symptoms reported are: changes in sensation in the arms, legs or face, complete or partial vision loss, weakness, unsteadiness when walking, and balance problems.
  • ALS Amyotrophic Lateral Sclerosis
  • SODl SODl
  • HD Huntington's disease
  • the normal huntingtin protein is present in all brain cells and is required for cell survival.
  • Affected areas include the cortex (which controls planning, thought, and memory) and the basal ganglia (which coordinates movement).
  • Stroke and traumatic brain injury can also cause neuronal loss and lead to cognitive decline. Stroke can be classified into two major categories: ischemic and hemorrhagic. Ischemia is due to interruption of the blood supply, while hemorrhage is due to rupture of a blood vessel or an abnormal vascular structure. Stroke can cause permanent neurological damage, complications and death if not promptly diagnosed and treated. It is the third leading cause of death and the leading cause of adult disability in the United States and Europe.
  • Prions diseases are fatal neurodegenerative diseases caused by an agent known as a "prion".
  • the disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen over time.
  • Prion diseases of humans include classic Creutzfeldt- Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia and kuru.
  • the degenerative tissue damage caused by human prion diseases is characterized by four features: spongiform change, neuronal loss, astrocytosis and amyloid plaque formation.
  • Frontotemporal Dementia accounts for 18% of dementias in people under 65 years old. It frequently manifests itself as a behavioral disturbance, and can progress to impair an individual's capacity for independent thought and function. Recent studies have uncovered genetic factors that contribute to this dementia; however no treatment yet exists to block the brain deterioration it causes.
  • NSCs neural stem/progenitor cells
  • SVZ subventricular zone
  • NSCs continue to divide and give rise to new functional neurons and glial cells [Zhao C et al., Cell. 2008, 132, 645]. It has been shown that a variety of factors can stimulate adult hippocampal neurogenesis ⁇ e.g. adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent learning and antidepressants).
  • NSCs The differentiation of these NSCs is regulated by key factors involved in neurogenesis and stem cell development.
  • potent inducing agents for NSCs differentiation represent an innovative approach with good potential to treat or even cure neurological diseases by resupplying the central nervous system (CNS) with new functional nerve cells.
  • Some protein growth factors ⁇ e.g. , fibroblast growth factor (FGF) and epidermal growth factor (EGF)) are able to induce the differentiation of NSCs into mature neural cells [Caldwell MA et al., Nat Biotechnol. 2001, 19, 475].
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • few non-protein synthetic molecules have been shown to confer such effect. [Coowar D et al., J Med Chem. 2004, 47, 6270][Warashina M et al., Angew Chem M Ed. 2006, 45, 591][Saxe JP et al., Chem Biol. 2007, 14, 1019].
  • Notch signaling controls a wide variety of cell fate decisions, including the differentiation of NSCs during neurogenesis [Artavanis-Tsakonas, S, Science. 1999, 284, 770]. Hence, compounds inhibiting the Notch signaling pathway would increase the production of neurons from NSCs. Inhibition of Notch signaling pathway represents a promising drug discovery tool for the treatment of different kinds of neurological diseases and disorders, such as Alzheimer disease (Beher D et al, Exp Opin Investigat Drugs. 2005, 14, 1385); multiple sclerosis [John GR et al., Nat Med. 2002, 8, 1115]; brain tumours [Miele L et al., Curr MoI Med. 2006, 6, 905], and autoimmune disorders [Briend E et al., Curr Opin MoI Ther. 2005, 7, 56].
  • Alzheimer disease Beher D et al, Exp Opin Investigat Drugs. 2005, 14, 1385
  • multiple sclerosis John GR et al., Nat Med. 2002, 8, 11
  • inflammation is not strictly a CNS disorder, it is frequently associated with brain injury, neurodegenerative diseases, and radiation treatment for brain tumors, which often causes deficits in cognition.
  • Adult neurogenesis is also down-regulated by endotoxin-induced inflammation and can be restored by anti- inflammatory treatments [Ekdahl CT et al., PNAS. 2003, 100, 13632].
  • endotoxin-induced inflammation can be restored by anti- inflammatory treatments
  • cytokines like tumour necrosis factor- ⁇ (TNF- ⁇ ), interleukin-l ⁇ (IL- l ⁇ ) as well as free radicals like nitric oxide (NO) and superoxide anion (O 2 ).
  • TNF- ⁇ tumour necrosis factor- ⁇
  • IL- l ⁇ interleukin-l ⁇
  • free radicals like nitric oxide (NO) and superoxide anion (O 2 ).
  • a ⁇ amyloid beta
  • One theory involves neuroinflammation which is supported by studies showing clustering of microglial cells within A ⁇ depositions in human brain tissues. According to the neuro inflammatory hypothesis of neurodegenerative diseases, drugs with an antiinflammatory mode of action should slow the disease progression.
  • the complex nature of the pathogenesis of neurodegenerative disease may require simultaneous use of several drugs directed at various factors contributing to the disease pathogenesis, including neuroinflammatory reactions.
  • the urgent need for such combination therapies is being recognized due to the failure, or marginally protective effects, observed by using single anti- inflammatory and other neuroprotective agents.
  • anti- inflammatory compounds promoting neurogenesis and/or the differentiation of oligodendrocyte precursors are excellent agents for the treatment of neurodegenerative or demyelinating diseases.
  • these compounds modulate cell differentiation through inhibition of the Notch signaling pathway, they can be useful for the treatment of cancer where the Notch signaling is up-regulated.
  • n-hexacosanol a long chain primary alcohol containing 26 carbon atoms, confers neurotrophic activity. It has been shown that the length of the chain and the CO-hydroxyl function are essential for the biological activity [Borg J et al., FEBS Lett. 1987, 213, 406]. Besides, in order to take into account the presumed contribution of inflammatory and oxidative phenomena in neurodegenerative pathologies, small molecules bearing a co-alkanol side chain combined with a neuroprotective moiety were developed. Structure-activity relationship studies led to the identification of compounds, presenting even better neurotrophic activities with a shorter chain length. Moreover, some of these fatty alcohol derivatives were able to induce differentiation of neural stem cells into mature neurons or to induce the differentiation of oligodendrocyte precursors into mature oligodendrocytes.
  • Tocopherol [WO2005030748A1] and Resveratrol [WO2007099162A2] long-chain alcohol compounds are known to have these dual bioactivies, promoting the differentiation of neural progenitor cells and modulating neuroinflammation. Both types of compound are known to act through the Notch signaling pathway.
  • Figure 1 shows the results of an experiment to measure the ability of test compounds to down- regulate iNOS, pro -inflammatory cytokines and S0CS3 gene expression in microglial cells
  • the present invention provides a compound of the general formula
  • each of Ri, R 2 , R3, R 4 , R5, R 6 , and R 7 independently represents a hydrogen atom, a hydroxyl group, a (Ci-C 6 ) alkyl group, a (C 2 -C 6 ) alkenyl group, a (C 2 -C 6 ) alkynyl group, a (Ci-C 6 ) alkoxy group, a hydroxy(Ci-C 6 ) alkyl group, a (Ci-C 6 ) alkoxy(Ci-C 6 ) alkyl group, a (Ci-C 6 ) alkanoyloxy group, a di(Ci-C 6 ) alkylaminoalkoxy group, a (Ci-C 6 ) alkanoyl group, a carboxyl group, a (Ci-C 6 ) alkoxycarbonyl group, a carbamoyl group, a (Ci-C 6 ) alkylaminocarbonyl
  • R 7 represents a bond
  • R9 represents a hydrogen atom, a (Ci-C 6 ) alkyl group, a (C 2 -C 6 ) alkenyl group, a (C 2 -C 6 ) alkynyl group, a (Ci-C 6 ) alkoxy(Ci-C 6 ) alkyl group, a (Ci-C 6 ) alkanoyloxy group, a (Ci-C 6 ) alkanoyl group, a (Ci-C 6 ) alkylcarbonyl group, a carbamoyl group, a (Ci-C 6 ) alkylaminocarbonyl group, a di(Ci-C 6 ) alkylaminocarbonyl group, a halo(Ci-C 6 ) alkyl group, a (N-(C i-C 6 )alkylamino)alkyl group, a (N,N-di(Ci-C 6 )alkylamino)
  • Z represents a hydrogen atom, a hydroxyl group, a (Ci-C 6 ) alkyl group, a (C 2 -C 6 ) alkenyl group, a (C 2 -C 6 ) alkynyl group, a (Ci-C 6 ) alkoxy group, a hydroxy(Ci-C 6 ) alkyl group, a (Ci-C 6 ) alkoxy(Ci-C 6 ) alkyl group, a (Ci-C 6 ) alkanoyloxy group, a (Ci-C 6 ) alkanoyl group, a carboxyl group, a (Ci-C 6 ) alkoxycarbonyl group, a carbamoyl group, a (Ci-C 6 ) alkylaminocarbonyl group, a di(Ci
  • n is an integer in the range of from 8 to 25.
  • Compounds according to the present invention can modulate the cellular fate of neural stem cells and promote the differentiation of these neural precursors to functional neurons and glial cells.
  • compounds according to the present invention are able to reduce the inflammatory component of neurological disorders by modulating the activation of microglia and/or by reducing reactive gliosis.
  • the compounds are useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, demyelinating diseases such as multiple sclerosis, Parkinson's disease, stroke (ischemic and hemorrhagic), traumatic brain injury and cancers, such as brain cancer.
  • (Ci-C 6 ) alkyl refers to an unbranched or branched alkyl group having from one to six carbon atoms.
  • An example of a (Ci-C 6 ) alkyl group is methyl.
  • (C 2 -C 6 ) alkenyl refers to an unbranched or branched alkenyl group having from two to six carbon atoms.
  • (C 2 -C 6 ) alkynyl refers to an unbranched or branched alkynyl group having from two to six carbon atoms.
  • (Ci-C 6 ) alkoxy group refers to an unbranched or branched alkoxy group having from one to six carbon atoms.
  • An example of a (Ci-C 6 ) alkoxy group is methoxy.
  • (Ci-C 6 ) alkanoyl group refers to an unbranched or branched alkanoyl group having from one to six carbon atoms.
  • An example of a (Ci-C 6 ) alkanoyl group is ethanoyl.
  • halogen atom refers to fluorine, chlorine, bromine and iodine.
  • halo(Ci-C 6 ) alkyl group and halo(Ci-C 6 ) alkoxy refer respectively to a (Ci-C 6 ) alkyl group and (Ci-C 6 ) alkoxy group in which one or more, for example one, two or three hydrogen atoms has been replaced with a halogen atom.
  • glucosidic group refers to a residue of glucose, that is attached to the phenolic oxygen atom in OR 9 at the anomeric position of the sugar.
  • pegylated group refers to a residue of a polyethylene glycol, for example having a molecular weight over 1000, in which a hydroxyl group has been replaced by a bond to the phenolic oxygen atom in OR9. It will be appreciated that certain compounds of formula (I) may form pharmaceutically acceptable salts with pharmaceutically acceptable bases or acids. It will also be appreciated that certain compounds of formula (I) contain a chiral center and may therefore be prepared and isolated in a stereochemically pure form.
  • n in a compound of formula (Ia) is an integer in the range of from 10 to 20.
  • Rs represents a hydrogen atom.
  • Such compounds may be represented by formula (Ib):
  • n in a compound of formula (Ib) is an integer in the range of from 8 to 18.
  • n can be, for example, 9, 10, 11, 12, 13, 14 or 15.
  • each of Ri, R 2 and R 3 independently represents a hydrogen atom or a (Ci- C 6 ) alkyl group.
  • An example of a particular value for each of Ri, R 2 and R3 is hydrogen.
  • each OfR 4 and R 5 independently represents a hydrogen atom or a (Ci-C 6 ) alkyl group.
  • An example of a particular value for each OfR 4 and R5 is hydrogen.
  • R 6 represents a hydrogen atom or a (Ci-C 6 ) alkyl group.
  • R 6 can represent a (Ci-C 6 ) alkyl group, such as methyl.
  • R 7 (when not forming a bond together with Rs) represents a hydrogen atom or a (Ci-C 6 ) alkyl group, such as a hydrogen atom.
  • Rg represents a hydrogen atom, a (Ci-C 6 ) alkyl group, a (Ci-C 6 ) alkanoyl group or a di(Ci-C 6 ) alkylaminocarbonyl group.
  • R9 can represent a hydrogen atom, a methyl, an acetyl or a dimethylaminocarbonyl.
  • a particular example of a value for R 9 is a hydrogen atom.
  • the compounds of the general Formula (I) can be obtained by methods such as the following:
  • the chromanones 1 were synthesized by a tandem reaction.
  • the first step is the aldol condensation of 2',5'-dihydrohyacetophenones with the corresponding methylketones to afford the aldol adduct.
  • the second step is a ring-closing reaction when -OH phenolic group displaces the hydroxyl group in a nucleophilic substitution (Japp-Maitland condensation). Reduction of the chromanones 1 with sodium borohydride gave the corresponding chromanols 2.
  • the hydroxylamine derivatives 4 were obtained in two steps from chromanones 1 through the formation and the reduction of the oximes 3.
  • Amines 5 were synthesized from compounds 2 and were then substituted to derivatives 6 such as amides, carbamates, ureas etc.
  • the corresponding aryl-6-acetates, 6-carbamates or 6-methoxides 7 are obtained from chromanones 1 and are then reacted with hydroxylamine to give oximes 8. The latter are expected to demonstrate reduced or inhibited phase 1 metabolism of the 6-hydroxychromane moiety and ameliorated intestinal adsorption after oral administration.
  • Compounds of the present invention shown in Process B can be obtained by the following steps.
  • Compound 14 is obtained in seven steps. After aldol condensation of 2',5'- dihydrohyacetophenones with methylglyoxal- 1,1 -dimethyl acetal, the phenol 9 was protected with a benzyl group followed by deprotection of the acetal to give compounds 11.
  • Amino hydroquinones 16 and 18 were obtained by either the reduction of oximes 15 or by substitution of the benzyl alcohol of compounds 14 to the corresponding amines or derivatives 18.
  • the latter are expected to demonstrate reduced or inhibited phase 1 metabolism of the hydroquinone moiety and ameliorated intestinal adsorption after oral administration.
  • hydroquinones 28 obtained by catalytic hydrogenation were converted to their corresponding 4-hydroxyaryl-acetates, 4-hydroxyaryl-carbamates or 4-methoxyphenol 29 before deprotection of the hydroxyl group and the reduction of the ketone with sodium borohydride to give benzyl alcohol 31.
  • the present invention provides a process for the preparation of a compound of general formula (I), which comprises:
  • m represents n-2
  • Pi represents R9 or a hydroxyl protecting group, such as benzyl and P 2 represents a hydrogen atom or a hydroxyl protecting group, such as benzyl or tetrahydropyranyl
  • the present invention also provides novel intermediates useful in the preparation of the compounds of formula (I), including the compounds of formula (IV) and salts thereof.
  • the present invention provides a pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds may be formulated in any conventional manner, for example in a tablet, capsule, suppository, solution, syrup or powder, depending upon the intended route of administration.
  • the dose of the compound administered to the patient will depend upon many different factors to be considered by the attending physician, including the age, weight and sex of the patient, the route of administration and the nature of the condition being treated. In general, the compound will be administered at a dose equivalent to administering the compound in the range of from about 0.01 mg/kg to about 100 mg/kg body weight.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the compounds according to the present invention are useful in the treatment of neurodegenerative disease.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease.
  • the present invention provides a method of treating a neurodegenerative disease in a patient requiring treatment, which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinabove.
  • the compounds according to the present invention may be administered alone or coadministered with compounds working by a different mechanism, for example neuroprotectant agents.
  • the compounds are co-administered compounds with an acetylcholinesterase inhibitor [(e.g. Aricept) for Alzheimer's disease or L-DOPA for Parkinson disease]
  • Example synthesis of compounds of general Formula (I) Example 1 : synthesis of 6-hydroxy-2-(12-hydroxydodecyl)-2-methyl-chroman-4-one (Ia)
  • Example 12 synthesis of ⁇ /-(l-(2,5-dihydroxyphenyl)-15-hydroxy-3-methyl-pentadecyl)- acetamide
  • Example 13 synthesis of NN-dimethyl 4-hydroxy-3-[3-methyl-15-(tetrahydro-pyran-2- yloxy)-pentadecanoyl-phenyll- carbamate (19a)
  • Example 14 synthesis of Af.iV-dimethyl 4-hydroxy-3-(3-methyl-15-hydroxy-pentadecanoyl- phenyD-carbamate
  • microglial cells were cultured in DMEM-F 12 medium containing 2% heat-inactivated FBS in 48 well plates at a density of 20000 cells per well. Peripheral wells of the plate were discarded. After 72h, 400 ⁇ L out of 500 ⁇ L medium was replaced by 350 ⁇ L fresh medium. The cells were treated with each molecule to be tested by adding 50 ⁇ L of a 1OX solution to obtain a final concentration ranging from 0.1 ⁇ M to lO ⁇ M. Each treatment was done in duplicates. 10ng/ml LPS was added after lhour and the medium was collected after 48h and stored at -20 0 C until analysis.
  • nitrites were measured using Griess reactive (sulfanilamide 1%, Sigma; N-(l-Naphthyl) ethylenediamine 0,1%, Sigma; phosphoric acid 2,5%). Briefly, lOO ⁇ L of medium was placed into a 96 well plate and lOO ⁇ L of Griess reactive was added. After lOmn incubation at r.t. in the dark, the OD was measured at 550nm.
  • the compound of Example 10 was revealed to be the most potent from the structure-activity relationship in this screening assay. Moreover, the presence of a side chain co-alkanol on position 2 of the hydroquinone moiety was found to be important. There was a loss of activity when no co-alkanol was present. The length of the side chain co-alkanol was also found to be important for this anti- inflammatory activity and the best one for compounds of Example 10 was that with fifteen carbon atoms with a methyl group on position 3 of the side chain.
  • Example 14 TNF-oc quantification by ELISA
  • the medium was collected 48h after treatment as described above.
  • the ELISA 96 well plate was incubated overnight with the capture antibody (0.8 ⁇ g/ml, R&D). lO ⁇ l of each sample was diluted with 90 ⁇ L of incubation buffer (PBS - BSA 1%, pH 7.2-7.4) and the plate was incubated for 2h at r.t. The plate was washed 3 times and incubated for 2h with the detection antibody (150ng/mL, R&D). After another washing step, the plate was incubated with streptavidine- HRP (20mn) and the peroxydase revealed with the R&D detection kit. After 20mn incubation at r.t., the reaction was stopped with an equal volume of a 10% solution of sulfuric acid and the OD was measured at 450nm.
  • Example 13 the best compounds inhibiting the release of pro-inflammatory cytokines like TNF- ⁇ were those of Example 10. Comparison of the test results for the compounds of the invention with that obtained for the hydroquinone or the 6-hydroxychromane moiety demonstrates that the presence of the co-alkanol side chain is important for the activity.
  • Example 15 RNA extraction, reverse transcription and real-time PCR
  • the reaction mixture contained 12.5 ⁇ l 2X SYBR Green mastermix (Biorad), l ⁇ l cDNA, l ⁇ l of each primer (12.5 ⁇ M) and 9.5 ⁇ l OfH 2 O.
  • the real-time PCR amplification was controlled by the MyIQ5 system (Biorad). After activation of the enzyme at 94°C for 3mn, the amplification was done by cycling 40 times between a denaturation step at 94°C and the annealing step at 54.5°C. Gene expression was analyzed using the provided software and normalized to beta-actin expression.
  • Fig. 1 Compound A inhibits microglial activation in vitro.
  • the experiments that were carried out concern the ability of these molecules to induce the differentiation of NSCs towards the neuronal lineage and the differentiation of human neuroblastoma cell line into neurons by inhibiting the Notch signaling pathway. Moreover, if these compounds modulate cell differentiation through inhibition of the Notch signaling pathway, they can be useful for the treatment of cancer where the Notch signaling is up- regulated.
  • the NSCs derived neurospheres culture was established from embryonic mouse cortices. Neurospheres were maintained in Neurobasal-A medium supplemented with B27 w/o retinoic acid, 2mM Glutamine, 20ng/ml EGF and antibiotics. The neurospheres were dissociated using a non enzymatic dissociation medium (Invitrogen) and the single cell suspension added to a flask with fresh medium. To differentiate the neurospheres into neurons, oligodendrocytes and astrocytes, 3 to 4 days old neurospheres were cultured in poly-ornithine treated 35mm dishes.
  • Test compounds (1 ⁇ M) or 0.1% DMSO vehicle as control in Neurobasal-A medium supplemented with B27 w/o retinoic acid, 2mM Glutamine, antibiotics, 2ng/ml EGF and 0.5% of heat inactivated FBS.
  • Compound A induces NSCs differentiation into neurons as observed qualitatively after immunostaining.
  • Neurospheres were fixed for 20 min in 4% paraformaldehyde in PBS (pH 7.4), washed in PBS, and permeabilized for 5 min with PBS/0.5% Triton X-IOO (Sigma). The neurospheres were incubated for 30 min in PBS containing 3% BSA and then for 2 h with the appropriate mixture of antibodies.
  • Warashina M., Min, K.H., Kuwabara, T., Huynh, A., Gage, F.H., Schultz, P.G., Ding, S., A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés de formule générale (I), dans laquelle R1, R2, R3, R4, R5, R6, R7, R8 et R9 ont les significations données dans la description, qui sont utiles dans le traitement d'une maladie neurodégénérative.
PCT/EP2010/056023 2009-05-04 2010-05-04 Dérivés d'hydroquinone Ceased WO2010128038A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LU91562 2009-05-04
LU91562A LU91562B1 (en) 2009-05-04 2009-05-04 Hydroquinone derivatives.

Publications (1)

Publication Number Publication Date
WO2010128038A1 true WO2010128038A1 (fr) 2010-11-11

Family

ID=41162291

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/056023 Ceased WO2010128038A1 (fr) 2009-05-04 2010-05-04 Dérivés d'hydroquinone

Country Status (2)

Country Link
LU (1) LU91562B1 (fr)
WO (1) WO2010128038A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172090A1 (fr) 2011-06-17 2012-12-20 Ludwig Aigner Prénylflavonoïdes cycliques de chromane pour intervention médicale lors de troubles neurologiques
CN109336935A (zh) * 2018-11-29 2019-02-15 雷逸鸥 二羟基苯甲酸酯葡萄糖苷的制备方法及其药用用途
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6140236A (ja) * 1984-08-02 1986-02-26 Yamanouchi Pharmaceut Co Ltd ハイドロキノン誘導体
WO2005030748A1 (fr) * 2003-09-26 2005-04-07 Universite Louis Pasteur Derives de tocopherol a longue chaine hydroxylee utiles comme neurotrophiques
US20060193797A1 (en) * 2005-02-25 2006-08-31 Galileo Pharmaceuticals, Inc Chroman derivatives as lipoxygenase inhibitors
EP1854777A1 (fr) * 2005-02-28 2007-11-14 Meiji Dairies Corporation Derive a longue chaine d hydroquinone et/ou derive a longue chaine de phenoxy, et preparation pharmaceutique composee de ces derives
WO2009040423A1 (fr) * 2007-09-26 2009-04-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de dérivés de tocophérol comme inhibiteurs de la voie de signalisation notch

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6140236A (ja) * 1984-08-02 1986-02-26 Yamanouchi Pharmaceut Co Ltd ハイドロキノン誘導体
WO2005030748A1 (fr) * 2003-09-26 2005-04-07 Universite Louis Pasteur Derives de tocopherol a longue chaine hydroxylee utiles comme neurotrophiques
US20060193797A1 (en) * 2005-02-25 2006-08-31 Galileo Pharmaceuticals, Inc Chroman derivatives as lipoxygenase inhibitors
EP1854777A1 (fr) * 2005-02-28 2007-11-14 Meiji Dairies Corporation Derive a longue chaine d hydroquinone et/ou derive a longue chaine de phenoxy, et preparation pharmaceutique composee de ces derives
WO2009040423A1 (fr) * 2007-09-26 2009-04-02 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de dérivés de tocophérol comme inhibiteurs de la voie de signalisation notch

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
ARTAVANIS-TSAKONAS, S, SCIENCE, vol. 284, 1999, pages 770
ARTAVANIS-TSAKONAS, S.; RAND, M.D.; LAKE, R.J.: "Notch signaling: cell fate control and signal integration in development", SCIENCE, vol. 284, no. 5415, 1999, pages 770 - 776
BEHER D ET AL., EXP OPIN INVESTIGAT DRUGS, vol. 14, 2005, pages 1385
BEHER, D.; GRAHAM, S.L.: "Protease inhibitors as potential disease-modifying therapeutics for Alzheimer's disease", EXPERT OPIN INVESTIG DRUGS., vol. 14, no. 11, 2005, pages 1385 - 1409
BORG J ET AL., FEBS LETT., vol. 213, 1987, pages 406
BORG, J.; TOAZARA, J.; HIETTER, H.; HENRY, M.; SCHMITT, G.; LUU B.: "Neurotrophic effect of naturally occurring long-chain fatty alcohols on cultured CNS neurons", FEBS LETT., vol. 213, no. 2, 1987, pages 406 - 410, XP025598501, DOI: doi:10.1016/0014-5793(87)81531-4
BRIEND E ET AL., CURR OPIN MOL THER., vol. 7, 2005, pages 56
BRIEND, E.; YOUNG, L.L.; MCKENZIE, G.J.; TUGAL, T.; RAGNO, S.; CHAMPION, B.R.: "Modulation of the notch pathway for immunotherapy", CURR OPIN MOL THER., vol. 7, no. 1, 2005, pages 56 - 61, XP009122588
CALDWELL MA ET AL., NAT BIOTECHNOL., vol. 19, 2001, pages 475
CALDWELL, M.A.; HE, X.; WILKIE, N.; POLLACK, S.; MARSHALL, G.; WAFFORD, K.A.; SVENDSEN, C.N.: "Growth factors regulate the survival and fate of cells derived from human neurospheres", NAT BIOTECHNOL., vol. 19, no. 5, 2001, pages 475 - 479
COOWAR D ET AL., JMED CHEM., vol. 47, 2004, pages 6270
COOWAR, D.; BOUISSAC, J.; HANBALI, M.; PASCHAKI, M.; MOHIER, E.; LUU, B.: "Effects of indole fatty alcohols on the differentiation of neural stem cell derived neurospheres", JMED CHEM., vol. 47, no. 25, 2004, pages 6270 - 6282
EKDAHL CT ET AL., PNAS., vol. 100, 2003, pages 13632
EKDAHL, C.T.; CLAASEN, J.H.; BONDE, S.; KOKAIA, Z.; LINDVALL, 0.: "Inflammation is detrimental for neurogenesis in adult brain", PROC NATL ACAD SCI USA., vol. 100, no. 23, 2003, pages 13632 - 13637
HANBALI M ET AL: "Quinol fatty alcohols as promoters of axonal growth", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 10, 15 May 2006 (2006-05-15), pages 2637 - 2640, XP025106811, ISSN: 0960-894X, [retrieved on 20060515] *
ICHIMIYA, S.; NIMURA, Y.; SEKI, N.; OZAKI, T.; NAGASE, T.; NAKAGAWARA, A.: "Downregulation of HASH is associated with the retinoic acid-induced differentiation of human neuroblastoma cell lines", MED PEDIATR ONCOL., vol. 36, no. 1, 2001, pages 132 - 134
ITO, H.; NAKAJIMA, A.; NOMOTO, H.; FURUKAWA, S.: "Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix- loop-helix transcription factors Mash1 and Mathl", J NEUROSCI RES., vol. 71, no. 5, 2003, pages 648 - 658
JANERO D A ET AL: "Novel 6-hydroxychroman-2-carbonitrile inhibitors of membrane peroxidative injury", BIOCHEMICAL PHARMACOLOGY, vol. 40, no. 3, 1 August 1990 (1990-08-01), pages 551 - 558, XP025515600, ISSN: 0006-2952, [retrieved on 19900801] *
JOHN GR ET AL., NAT MED., vol. 8, 2002, pages 1115
JOHN, G.R.; SHANKAR, S.L.; SHAFIT-ZAGARDO, B.; MASSIMI, A.; LEE, S.C.; RAINE, C.S.; BROSNAN, C.F.: "Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation", NAT MED., vol. 8, no. 10, 2002, pages 1115 - 1121
KLEGERIS A ET AL., CURR OPIN NEUROL., vol. 20, 2007, pages 351
KLEGERIS, A.; MCGEER, E.G.; MCGEER, P.L.: "Therapeutic approaches to inflammation in neurodegenerative disease", CURR OPIN NEUROL., vol. 20, no. 3, 2007, pages 351 - 357
MAHER, P.; AKAISHI, T.; ABE, K.: "Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory", PROC NATL ACAD SCI USA., vol. 103, no. 44, 2006, pages 16568 - 16573
MANTHEY, J.A.; GROHMANN, K.; GUTHRIE, N.: "Biological properties of citrus flavonoids pertaining to cancer and inflammation", CURR MED CHEM., vol. 8, no. 2, 2001, pages 135 - 153, XP009086464
MARTINO G ET AL., NAT REV NEUROSCI., vol. 7, 2006, pages 395
MARTINO, G.; PLUCHINO, S.: "The therapeutic potential of neural stem cells", NAT REV NEUROSCI., vol. 7, no. 5, 2006, pages 395 - 406, XP002587341
MIDDLETON, E. JR; KANDASWAMI, C.; THEOHARIDES, T.C.: "The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer", PHARMACOL REV., vol. 52, no. 4, 2000, pages 673 - 751
MIELE L ET AL., CURR MOL MED., vol. 6, 2006, pages 905
MIELE, L.; GOLDE, T.; OSBORNE, B.: "Notch signaling in cancer", CURR MOL MED., vol. 6, no. 8, 2006, pages 905 - 918
MULLER T ET AL: "Improved synthesis of tocopherol fatty alcohols and analogs: microglial activation modulators", TETRAHEDRON, vol. 62, no. 51, 18 December 2006 (2006-12-18), pages 12025 - 12040, XP025003017, ISSN: 0040-4020, [retrieved on 20061218] *
MULLER T ET AL: "Tocopherol long chain fatty alcohols decrease the production of TNF-alpha and NO radicals by activated microglial cells", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 24, 20 December 2004 (2004-12-20), pages 6023 - 6026, XP004645147, ISSN: 0960-894X *
NAGASE, H.; YAMAKUNI, T.; MATSUZAKI, K.; MARUYAMA, Y.; KASAHARA, J.; HINOHARA, Y.; KONDO, S.; MIMAKI, Y.; SASHIDA, Y.; TANK, A.W.: "Mechanism of neurotrophic action of nobiletin in PC12D cells", BIOCHEMISTRY, vol. 44, no. 42, 2005, pages 13683 - 13691
SAXE JP ET AL., CHEM BIOL., vol. 14, 2007, pages 1019
SAXE, J.P.; WU, H.; KELLY, T.K.; PHELPS, M.E.; SUN, Y.E.; KORNBLUM, H.I.; HUANG, J.: "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation", CHEM BIOL., vol. 14, no. 9, 2007, pages 1019 - 1030, XP022259057, DOI: doi:10.1016/j.chembiol.2007.07.016
WARASHINA M ET AL., ANGEW CHEM INT ED., vol. 45, 2006, pages 591
WARASHINA, M.; MIN, K.H.; KUWABARA, T.; HUYNH, A.; GAGE, F.H.; SCHULTZ, P.G.; DING, S.: "A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells", ANGEW CHEM INT ED ENGL., vol. 45, no. 4, 2006, pages 591 - 593
ZHAO C ET AL., CELL, vol. 132, 2008, pages 645
ZHAO, C.; DENG, W.; GAGE, F.H.: "Mechanisms and functional implications of adult neurogenesis", CELL, vol. 132, no. 4, 2008, pages 645 - 660

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172090A1 (fr) 2011-06-17 2012-12-20 Ludwig Aigner Prénylflavonoïdes cycliques de chromane pour intervention médicale lors de troubles neurologiques
US9527860B2 (en) 2011-06-17 2016-12-27 Ludwig Aigner Chromane-like cyclic prenylflavonoids for the medical intervention in neurological disorders
EP3202398A1 (fr) 2011-06-17 2017-08-09 Ludwig Aigner Chromane-similaires prénylflavonoïdes cycliques pour l'intervention médicale lors de troubles neurologiques
US9956199B2 (en) 2011-06-17 2018-05-01 Ludwig Aigner Chromane-like cyclic prenylflavonoids for the medical intervention in neurological disorders
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US10981855B2 (en) 2015-12-17 2021-04-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US11680034B2 (en) 2015-12-17 2023-06-20 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
CN109336935A (zh) * 2018-11-29 2019-02-15 雷逸鸥 二羟基苯甲酸酯葡萄糖苷的制备方法及其药用用途

Also Published As

Publication number Publication date
LU91562B1 (en) 2010-11-05

Similar Documents

Publication Publication Date Title
US20110144194A1 (en) Chromenone derivatives useful for the treatment of neurodegenerative diseases
US9527860B2 (en) Chromane-like cyclic prenylflavonoids for the medical intervention in neurological disorders
US20100048731A1 (en) Hydroxylated Long-Chain Resveratrol Derivatives Useful as Neurotrophic Agents
KR900001511B1 (ko) 카테콜 유도체 및 그것을 함유하는 중추신경계 퇴행성질환의 진행방지 및 치료제
US10676438B2 (en) KCNQ2-5 channel activator
Kwon et al. Total synthesis of naturally occurring 5, 7, 8-trioxygenated homoisoflavonoids
JPH10502336A (ja) ナフタレン誘導体、製造方法および使用
WO2010128038A1 (fr) Dérivés d'hydroquinone
JP2006507357A (ja) プロシアニジンｂ２の単離、精製および合成ならびにその使用
CN110790739B (zh) 用于治疗神经系统疾病的化合物及其应用
EP3447045B9 (fr) Dérivés 1-(1-hydroxy-2,3-dihydro-1h-indèn-5-yl)-urée et composés similaires en tant qu'activateurs des canaux kcnq 2-5 pour le traitement de la dysurie
Tadtong et al. Effects of oxyresveratrol and its derivatives on cultured P19-derived neurons
JP5150807B2 (ja) ハイドロキノン長鎖誘導体及び／又はフェノキシ長鎖誘導体及びこれらを含有する医薬
US9884836B2 (en) 2-substituted-5-hydroxy-4H-chromen-4-ones as novel ligands for the serotonin receptor 2B (5-HT2B)
US7691900B2 (en) Tocopherol derivatives with a long hydroxylated chain, which can be used as neurotrophics
US20080070951A1 (en) Non-Nucleotide Reverse Transcriptase Inhibitors
US20230139975A1 (en) Arylcyclohexylamine derivatives and process for preparing same
JP4354585B2 (ja) シクロヘキセノール誘導体及びこれを含有する医薬
US20250333392A1 (en) Synthesis of (-)-trans-delta-9-tetrahydrocannabivarin (delta-9 thcv) and analogs thereof
JP2021512958A (ja) 神経変性疾患を治療するための医薬及びその使用
CN119100931A (zh) 一种玉米木脂素类化合物及其应用和制备方法
Mousavi et al. Synthesis of novel 3-benzylidene chromane-2-one derivatives
JP2021514350A (ja) 神経変性疾患を予防・治療するための新規な化合物及びその応用
JPWO1992015543A1 (ja) 新規アリルアルコール誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10721384

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10721384

Country of ref document: EP

Kind code of ref document: A1