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WO2010041681A1 - Nouveau dérivé de sominone - Google Patents

Nouveau dérivé de sominone Download PDF

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Publication number
WO2010041681A1
WO2010041681A1 PCT/JP2009/067483 JP2009067483W WO2010041681A1 WO 2010041681 A1 WO2010041681 A1 WO 2010041681A1 JP 2009067483 W JP2009067483 W JP 2009067483W WO 2010041681 A1 WO2010041681 A1 WO 2010041681A1
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WO
WIPO (PCT)
Prior art keywords
compound
mmol
nmr
added
mhz
Prior art date
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Ceased
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PCT/JP2009/067483
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English (en)
Japanese (ja)
Inventor
英雄 根本
千尋 東田
裕二 松谷
昌司 山田
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Lead Chemical Co Ltd
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Lead Chemical Co Ltd
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Priority to JP2010509602A priority Critical patent/JPWO2010041681A1/ja
Publication of WO2010041681A1 publication Critical patent/WO2010041681A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • 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
    • A61P25/14—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

Definitions

  • the present invention relates to a novel sominone derivative useful as a prophylactic / therapeutic agent for neurological diseases.
  • Nerve cells have two types of neurites: dendrites that receive information from other neurons and axons that send information to other neurons.
  • Neural cell death and neurite atrophy due to various causes inhibit normal signal transmission between nerve cells, and therefore various diseases occur depending on the part of the damaged nervous system.
  • Specific diseases related to central nervous system (brain, spinal cord) disorders include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and other diseases caused by peripheral nervous system disorders such as multiple neuritis, For example, Valley syndrome.
  • central nervous system diseases are progressive, and there is still no effective treatment.
  • central nervous system diseases have been studied as therapeutic agents for central nervous system diseases, but all have a neuroprotective action, and the neurite extension action in a neurodegenerative environment has not been clearly shown.
  • the treatment of central nervous system diseases requires not only the suppression of neuronal cell death but also the extension of the neurites of the remaining neurons and normalization of information transmission between the neurons. Development of a therapeutic agent for central nervous system diseases is eagerly desired.
  • An object of the present invention is to provide a novel compound useful as a prophylactic / therapeutic agent for neurological diseases.
  • the present inventors have made various studies in order to find out a total synthesis method of a physiologically active substance contained in a plant represented by the above-mentioned sominone.
  • the compound was successfully synthesized.
  • the novel compound extends axons and / or dendrites in rat cerebral cortical neurons and spinal cord neurons, and is prominent in spinal cord injury models. Found to reduce symptoms. This indicates that this novel compound can treat neurological diseases caused by neurite atrophy. From the above knowledge, the present inventors have completed the present invention.
  • sominone derivative represented by these, its salt, and the pharmaceutical containing this are provided.
  • the compound (1) of the present invention is a novel compound that does not exist in nature, and is a compound synthesized for the first time by a completely new synthesis method found by the present inventors.
  • the compound (1) of the present invention extends neurites and is useful as a therapeutic agent for neurological diseases such as Alzheimer's disease.
  • FIG. 1 shows the hindlimb motor function recovery effect of compound (1-d) in spinal cord injury mice.
  • FIG. 2 shows the axonal outgrowth action of compounds (1-c) and (1-d) in rat spinal cord neurons.
  • FIG. 6 shows dendritic extension action and axonal extension action of compounds (1-b) and (1-d) in rat cerebral cortical neurons treated with A ⁇ (1-42). 2 shows the inhibitory effect of compound (1-d) and sominone on neuronal cell death in rat cerebral cortical neurons.
  • FIG. 5 shows the hindlimb motor function recovery effect of compound (1-d) in spinal cord injury mice.
  • the compound of the present invention is represented by the above formula (1), and specifically includes compounds represented by the following formulas (formula 1-a) to (1-g).
  • the compound (1) of the present invention may form a pharmaceutically acceptable salt or may exist in the form of a hydrate or the like.
  • the compound (1) of the present invention can be produced, for example, according to the following reaction formula.
  • the raw material compound (A) is reacted with a silylating agent such as tert-butyldimethylsilyloxytriflate to obtain a compound (2), which is reacted with an alkyltriphenylphosphonium halide such as ethyltriphenylphosphonium bromide to give a compound (3 )
  • a silylating agent such as tert-butyldimethylsilyloxytriflate
  • an alkyltriphenylphosphonium halide such as ethyltriphenylphosphonium bromide
  • compound (3) Compound (3) is reacted with a hydroxymethylating agent such as paraformaldehyde to obtain compound (4), which is reduced by hydrogenation or the like to obtain compound (5), and then dehydrating agents such as pyridinium dichloride and molecular sieves.
  • dehydrating agents such as pyridinium dichloride and molecular sieves.
  • This compound (6) is reacted with an asymmetric allylating agent such as diisopinocinfylallylborane (IpC 2 B (allyl)) or a Grignard reagent to obtain a compound (16), which is then treated with 2- (4- (Methoxyphenoxymethyl) acrylic acid is reacted to give compound (17).
  • This compound (17) is reacted with an oxidizing agent such as (NH 4 ) 2 Ce (NO 3 ) 6 to obtain a compound (18), and this is subjected to metathesis using a Grubbs catalyst or Hoveyda-Grubbs catalyst to obtain a compound (19).
  • the compound (1-a) is obtained by removing the protecting group and then removing the protecting group.
  • reaction from compound (6) to compound (1-a) in the above reaction formula can also be applied to the synthesis method of compound (1-b) to compound (1-g). Accordingly, other compounds of the present invention can be produced according to the following reaction formula.
  • the reaction from the compound (6) to the compound (7B) or the compound (7A) may usually be a Grignard reaction.
  • the compound (1) of the present invention produced by the above steps can be isolated and purified by using generally known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, various chromatography and the like.
  • a compound that not only suppresses neuronal cell death but also extends the neurites of the remaining neuronal cells to normalize information transmission between the neuronal cells 1) has a neurite extension action and is useful as an active ingredient of a medicament for the prevention and / or treatment of neurological diseases caused by neuronal cell death or neurite atrophy.
  • a neurological disease to which the pharmaceutical of the present invention is applied for example, Alzheimer's disease, cerebrovascular dementia, senile dementia, frontotemporal dementia, Lewy body dementia, Parkinson's disease, Huntington's chorea, Neurogenic bladder, overactive bladder, urinary frequency, urge incontinence, reflex incontinence, overflow urinary incontinence, amyotrophic lateral sclerosis, cerebral hemorrhage, cerebral infarction, brain tumor, brain trauma, spinal cord injury , Down syndrome, hyperactivity disorder and the like.
  • Alzheimer's disease cerebrovascular dementia, senile dementia, frontotemporal dementia, Lewy body dementia, Parkinson's disease, Huntington's chorea
  • Neurogenic bladder overactive bladder, urinary frequency, urge incontinence, reflex incontinence, overflow urinary incontinence, amyotrophic lateral sclerosis, cerebral hemorrhage, cerebral infarction, brain tumor, brain trauma, spinal cord injury , Down syndrome, hyperactivity disorder and the like.
  • the medicament of the present invention As an active ingredient of the medicament provided by the present invention, a substance selected from the group consisting of compound (1) and physiologically acceptable salts thereof, and hydrates and solvates thereof may be used. it can.
  • the medicament of the present invention is provided in the form of a pharmaceutical composition comprising the active ingredient and a pharmaceutical additive (carrier, excipient, etc.).
  • the route of administration of the medicament of the present invention is not particularly limited, and oral administration or parenteral administration (for example, intramuscular administration, intravenous administration, subcutaneous administration, intraperitoneal administration, mucosal administration to nasal cavity, inhalation administration, etc.) Either may be used.
  • the pharmaceutical form of the present invention is not particularly limited, and examples of the preparation for oral administration include tablets, capsules, fine granules, powders, granules, liquids, syrups and the like, and parenteral administration Examples of preparations for injection include injections, drops, suppositories, inhalants, transmucosal absorbents, transdermal absorbents, nasal drops, ear drops, eye drops and the like.
  • the dosage of the medicament of the present invention may be appropriately selected in consideration of the patient's sex, age or weight, severity of symptoms, administration purpose such as prevention or treatment, or the presence or absence of other complications. it can.
  • the dose of compound (1) is about 0.05 mg to 2 g, preferably about 0.1 mg to 1 g per day for an adult, divided into 1 to 5 doses. That's fine.
  • about 0.01 mg to 1 g, preferably about 0.05 mg to 0.5 mg per day for an adult can be administered in 1 to 5 divided doses.
  • reaction solution was diluted with CH 2 Cl 2 , and the organic layer washed successively with 10% hydrochloric acid and saturated aqueous sodium hydrogen carbonate was dried over MgSO 4 and filtered, and then the solvent was distilled off.
  • reaction solution was diluted with CH 2 Cl 2 , and the organic layer washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine was dried over MgSO 4 , filtered and the solvent was distilled off. The residue was separated by silica gel column chromatography (CH 2 Cl 2 ) to obtain the compound (30) as a white solid material (6.53 g, 97%, mp 151-153 ° C.).
  • Example 8 Cerebral cortical neurons of SD rats (embryonic 19 days old) were primarily cultured. Cells were seeded on an 8-well culture slide at a density of 2.0 5 10 5 cells / cm 2 , 10 days later, the compound was treated at a concentration of 1 ⁇ l, and 4 days later, immunostaining was performed.
  • the primary antibodies are a rabbit polyclonal antibody against MAP2a2b, a dendritic marker protein (dilution factor 500 times; Chemicon, Temecula, USA), and a mouse monoclonal antibody against phosphorylated NF-H, an axon marker protein (dilution factor). 500 times; Sternberger Monoclonals, Lutherville, USA).
  • Alexa Fluor 488-labeled goat anti-mouse IgG and Alexa Fluor 568-labeled goat anti-rabbit IgG were used (dilution ratio 300 times; Molecular Probes, Carlsbad, USA). Cells were observed with a fluorescence microscope AX-80 (Olympus, Tokyo, Japan) to obtain a fluorescence image. The average length of dendrites and axons per neuron was measured with Neuroocyte Ver. 1.5 (Toyobo, Osaka Japan).
  • the compound was treated with 1 ⁇ l 10 days after the start of culture of rat cerebral cortical neurons, and the length of dendrites 4 days later was measured.
  • the dendrite (Dendrite) was significantly extended as compared with the control group (Cont) by treatment with the compound (1-d) and the compound (1-g).
  • An extension tendency was also observed in the compound (1-f). Further, when the length of the axon was measured by the same treatment, the compound (1-f) and the compound (1-d) showed significant extension activity (FIG. 1).
  • Example 9 Spinal nerve cells of SD rats (embryonic day 18) were primary cultured. Cells were plated on an 8-well culture dish at a density of 3.6 10 5 cells / cm 2 , 3 days later, the compound was treated at a concentration of 1 ⁇ l, and 4 days later, immunostaining was performed.
  • the primary antibody used was a mouse monoclonal antibody (dilution factor 500 times; Sternberger Monoclonals) against phosphorylated NF-H, which is an axon marker protein.
  • Alexa Fluor 488-labeled goat anti-mouse IgG was used (dilution ratio 300 times; Molecular Probes).
  • Example 10 Cerebral cortical neurons of SD rats (embryonic day 18) were primary cultured. Cells were seeded on 8 well culture slides at a density of 2.6 ⁇ 10 5 cells / cm 2 and treated 5 days later with 5 ⁇ M A ⁇ (1-42), 3 days later with compound (1 ⁇ M) and further 5 Immunostaining was performed one day later.
  • the primary antibody is a rabbit polyclonal antibody against MAP2 which is a dendritic marker protein (dilution factor 500 times; Chemicon, Temecula, CA, USA) and a mouse monoclonal antibody against phosphorylated neurofilament H which is a marker protein of axon (diluted) Magnification 500 times; Sternberger Monoclonals, MD, USA) was used.
  • MAP2 dendritic marker protein
  • phosphorylated neurofilament H which is a marker protein of axon (diluted) Magnification 500 times; Sternberger Monoclonals, MD, USA
  • Alexa Fluor 568-labeled goat anti-rabbit IgG and Alexa Fluor 488-labeled goat anti-mouse IgG were used (dilution ratio 300 times; Molecular Probes, Carlsbad, CA, USA).
  • Example 11 Cerebral cortical neurons of SD rats (embryonic day 18) were primary cultured. On the fourth day of culture, 20 ⁇ M A ⁇ (25-35) was treated, and 0.01 ⁇ M compound (1-d) and sominone were added simultaneously. Two days after the addition treatment, the number of viable cells was measured using Cell Titer-Glo Luminescent Cell Viability Assay (Promega). The group in which A ⁇ i 25-35) treatment and test compound addition were not performed was defined as a control group (Cont), and the group in which A ⁇ i 25-35) treatment was performed but no test compound addition was performed was determined as Vehicle. Group (Veh).
  • Example 12 The tenth thoracic vertebral arch of a ddY mouse (male 7 weeks old) was excised and the exposed spinal cord was damaged by crushing. One hour after injury, compound (1-d) was orally administered at 10 ⁇ mol / kg, and thereafter, the same amount was orally administered once a day for 7 days. Every day from the day after injury, hindlimb motor function was assessed by Basso Mouse Scale (BMS score) (J Neurotrauma. 2006 May; 23 (5): 635-59.). The group in which spinal cord injury treatment and test compound addition were not performed was defined as a control group, and the group in which spinal cord injury treatment was performed but no test compound addition was defined as a vehicle group.
  • BMS score Basso Mouse Scale

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

Abstract

La présente invention concerne un nouveau composé qui est un dérivé de sominone représenté par la formule (1) ou un sel de celui-ci et qui est utile en tant qu'agent pour la prévention et le traitement d'une maladie neurologique.
PCT/JP2009/067483 2008-10-09 2009-10-07 Nouveau dérivé de sominone Ceased WO2010041681A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2010509602A JPWO2010041681A1 (ja) 2008-10-09 2009-10-07 新規ソミノン誘導体

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2008-263236 2008-10-09
JP2008263236 2008-10-09
JP2009176369 2009-07-29
JP2009-176369 2009-07-29

Publications (1)

Publication Number Publication Date
WO2010041681A1 true WO2010041681A1 (fr) 2010-04-15

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PCT/JP2009/067483 Ceased WO2010041681A1 (fr) 2008-10-09 2009-10-07 Nouveau dérivé de sominone

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WO (1) WO2010041681A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014112145A1 (fr) * 2013-01-21 2014-07-24 レジリオ株式会社 Agent thérapeutique et procédé thérapeutique concernant 1,25d3-marrs pour une maladie neurologique telle que la maladie d'alzheimer

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006176428A (ja) * 2004-12-22 2006-07-06 Toyama Univ 神経回路網再構築剤および神経回路網の再構築方法
WO2007094166A1 (fr) * 2006-02-14 2007-08-23 Meiji Dairies Corporation Agent therapeutique aidant la guerison de l'epine dorsale
WO2008136199A1 (fr) * 2007-04-26 2008-11-13 Meiji Dairies Corporation Procédé de fabrication de withanolide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006176428A (ja) * 2004-12-22 2006-07-06 Toyama Univ 神経回路網再構築剤および神経回路網の再構築方法
WO2007094166A1 (fr) * 2006-02-14 2007-08-23 Meiji Dairies Corporation Agent therapeutique aidant la guerison de l'epine dorsale
WO2008136199A1 (fr) * 2007-04-26 2008-11-13 Meiji Dairies Corporation Procédé de fabrication de withanolide

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Dai 38 Kai Book of Abstracts, Congress of Heterocyclic Chemistry, 10 October 2008 (10. 10.2008)", article YAMAKAWA ET AL.: "Ninchisho Chiryoyaku Kaihatsu o Mezashita sominone Oyobi Ruien Kagobutsu no Gosei", pages: 213 - 214 *
MASASHI ONO ET AL.: "Withanolide-rui no Gosei Kenkyu:Sominone Model Kagobutsu no Gosei", DAI 127 NENKAI THE PHARMACEUTICAL SOCIETY OF JAPAN TOYAMA2007 YOSHISHU 4, 5 March 2007 (2007-03-05), pages 87 *
YUICHIRO YAMAKAWA ET AL.: "Withanolide-rui no Kanben Goseiho no Kaihatsu", DAI 128 NENKAI THE PHARMACEUTICAL SOCIETY OF JAPAN YOKOHAMA 2008 YOSHISHU 2, 5 March 2008 (2008-03-05), pages 153 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014112145A1 (fr) * 2013-01-21 2014-07-24 レジリオ株式会社 Agent thérapeutique et procédé thérapeutique concernant 1,25d3-marrs pour une maladie neurologique telle que la maladie d'alzheimer

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