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WO1996025929A1 - Utilisation de l'helioxanthine comme activateur de facteurs induisant la differenciation cellulaire - Google Patents

Utilisation de l'helioxanthine comme activateur de facteurs induisant la differenciation cellulaire Download PDF

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Publication number
WO1996025929A1
WO1996025929A1 PCT/JP1996/000375 JP9600375W WO9625929A1 WO 1996025929 A1 WO1996025929 A1 WO 1996025929A1 JP 9600375 W JP9600375 W JP 9600375W WO 9625929 A1 WO9625929 A1 WO 9625929A1
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WO
WIPO (PCT)
Prior art keywords
helioxanthin
lactone
salt
form compound
open form
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/JP1996/000375
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English (en)
Inventor
Yukio Fujisawa
Masatoshi Hazama
Norihisa Iwakami
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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 Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to AU46774/96A priority Critical patent/AU4677496A/en
Publication of WO1996025929A1 publication Critical patent/WO1996025929A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones

Definitions

  • the present invention relates to an enhancer for a cell differentiation inducing factor, which is useful for treating or preventing bone diseases such as osteoporosis, fractures, etc., for bone regeneration, or for treating or preventing nerve diseases such as Alzheimer's disease, cerebrovascular dementia, amyotrophic lateral sclerosis, diabetic peripheral nerve disorders (neuropathy), etc.
  • bone diseases such as osteoporosis, fractures, etc.
  • nerve diseases such as Alzheimer's disease, cerebrovascular dementia, amyotrophic lateral sclerosis, diabetic peripheral nerve disorders (neuropathy), etc.
  • the bone morphogenetic proteins belong to the only protein factor family isolated from decalcified bones that is known to have ectopic bone-inducing ability. Therefore it is useful as a bone - morphogenesis promoting drug for treating fractures, bone regeneration, etc. (A. E. Wang, Trends Biotechnol., Vol. 11, p. 379-383 (1993)).
  • BMP directly promotes osteoblast differentiation
  • BMP is considered to play a role in bone remodeling as a coupling factor and be closely related with bone metabolism. It is reported that bone matrixes in aged animals have a considerably lowered BMP content (M. L. Urist, Bone and Mineral Research, vol. 6 (ed. by W.A. Peck), p. 57- 112, Elsevier, 1989), and BMP is likely to be closely related to the maintenance of bone quantity. This suggests that BMP is a promising candidate for a remedy against various bone diseases such as osteoporosis, etc. However, BMP normally exists in only a trace amount in the living body and is available from limited sources. In addition, because BMP is a protein, there are some problems in its administration, and its subject diseases are limited.
  • BMP has neurotrophic factor - like activity (V. M. Paralkar et al., J. Cell Biol., vol. 119, p. 1721-1728 (1992)). Furthermore, it is known that the BMP gene is highly expressed in brain tissues (E. Ozkaynak et al., Biochem. Biophys. Res. Commun., vol. 179, p. 116-123 (1991)). In addition, it is suggested that BMP plays an important role in neural tube formation at embryonal development (K. Basler et al.. Cell, vol. 73, p. 687-702 (1993)). Therefore, BMP is considered to be closely related to neuron differentiation or maintenance of neuron function.
  • Neurotrophic factors belong to a group of proteinaceous factors that play important roles in the life maintenance and function expression of neurons.
  • Neurotrophic factors include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), etc.
  • NGF nerve growth factor promotes the differentiation and maturation of sympathetic ganglia and dorsal root ganglia in the neural crest in the peripheral nervous system (A. M. Davies & R. M. Lindsay, Dev. Biol., vol. Ill, p. 62-72 (1985); R. Levi-Montalcini, EMBO J., vol. 6, p. 1145-1154 (1987)), and acts on cholinergic neurons of septa (the basal forebrain) in the central nervous system (H.
  • septa the basal forebrain
  • NGF is essential for neuron function maintenance after completion of neuron differentiation.
  • BDNF acts on dorsal root ganglia and nodose ganglia, but not on sympathetic ganglia (R. M. Lindsay & H. Rohrer, Dev. Biol., vol. 112, p. 30-48 (1985); R. M. Lindsay et al., Dev.
  • BDNF acts on cholinergic neurons of septa and GABA ( ⁇ -aminobutyric acid)- ergic neurons, and dopa inergic neurons of midbrain (R. F. Alderson et al., Neuron, vol. 5, p. 297-306 (1990); C. Hyman et al., Nature, vol. 350, p. 230-232 (1991); B. Knusel et al., Proc. Natl. Acad. Sci. USA, vol.
  • NT-3 acts on the peripheral nervous system in a similar manner to NGF and BDNF, it is characterized by its potent action on neural placodes - derived sensory nerve cells (P. Ernfors et al., Proc. Natl. Acad. Sci. USA, vol. 87, p. 5454-5458 (1990); A. Rosenthal et al., Neuron, vol. 4, p. 767- 773 (1990)).
  • any neurons in the central nervous system that respond to NT-3 have not been known.
  • Alzheimer's dementia shows extensive disorders and loss of cerebral cortex neurons in addition to degeneration and loss of cholinergic neurons of the basal forebrain including septa, and NGF and neurotrophic factors are considered to be candidates for remedies for the disease (F. Hefti & W. J. Weiner, Annu. Neurol., vol. 20, p. 275-281 (1986)).
  • BDNF a trophic factor for dopaminergic neurons of midbrain, is expected to become a remedy for Parkinson's disease, in which dopaminergic neurons of midbrain are degenerated or lost.
  • these neurotrophic factors are proteins, there is a limit for their application.
  • BMP activity - enhancing substances reported so far include retinoic acid, vitamin D 3 , estrogen and glucocorticoid (V. Rosen & R. S. Thies, Trends Genet., vol. 8, p. 97-102 (1992); Y. Takuwa et al., Biochem. Biophys. Res. Commun. , vol. 174, p. 96-101 (1991)).
  • these substances when administered into the living body, promotes bone absorption or causes side effects such as hypercalcemia, ovary cancer formation, etc. They are not necessarily suitable for drugs for treating osteal diseases.
  • compounds that enhance NGF activity can enhance activity of NGF present in or administered into the living body, and are thus useful as drugs for treating dementia or peripheral nerve disorders.
  • sabeluzole i.e., 4-(2- benzothiazolylmethyl-amino)- ⁇ [ (p-fluorophenoxy) ]methyl]-l- piperidineethanol
  • New Current, vol. 4, No. 26, p. 14 (1993) has been reported (New Current, vol. 4, No. 26, p. 14 (1993)
  • sabeluzole has side effects such as headache, dizziness, fatigue, etc. Sabeluzole is thus not necessarily suitable for a drug for treating nerve diseases .
  • NGF secretion inducing activity As compounds having NGF secretion inducing activity, Experimental Neurology, vol. 124, p. 36-42 (1993) discloses steroids, catechols and cytokines, and USP 5059627 discloses idebenone. However, some of these compounds have adverse effects such as neurotoxicity, lowered immunity, hypercalcemia, promotion of bone absorption, etc. NGF secretion inducing activity cannot necessarily be separated from adverse effects on tissues other than the nervous system. Such compounds are thus unsatisfactory for practical use.
  • cell differentiation inducing factors represented by BMP or neurotrophic factors are proteins
  • the main object of the present invention is to find a low molecular weight compound that enhances activity of cell differentiation inducing factors represented by BMP or neurotrophic factors and to provide an enhancer for a cell differentiation inducing factor that is useful for treating or preventing various bone or nerve diseases.
  • Fig. 1 shows the neurite outgrowth promoting ability of helioxanthin in rat pheochromocytoma cells.
  • Fig. 2 shows the calcification - promoting activity of helioxanthin in mouse osteoblastic cells.
  • the calcium content is indicated as a mean ⁇ standard deviation (SD) for 3 wells per group.
  • SD standard deviation
  • the symbol * means that there was a statistically significant difference as compared to the BMP (alone)- treatment group (p ⁇ 0.05, t-test).
  • the symbol # means that there was a statistically significant difference as compared to the non-treated control group (p ⁇ 0.05, t-test).
  • Fig. 3 shows the promoting action of helioxanthin on the differentiation of rat bone marrow stromal cells to osteoblasts .
  • the alkaline phosphatase activity is indicated as a mean ⁇ S.D. for 3 wells per group.
  • ** and * means that there was a statistically significant difference as compared to the non-treated control group (**: p ⁇ 0.01, *: p ⁇ 0.05, t-test).
  • Fig. 4 shows the promoting action of helioxanthin on the differentiation of rat bone marrow stromal cells to osteoblasts.
  • the calcium content is indicated as a mean ⁇ S.D. for 3 wells per group.
  • ** and * means that there was a statistically significant difference as compared to the non-treated control group (**: p ⁇ 0.01, *: p ⁇ 0.05, t-test).
  • the present invention provides an enhancer for a cell differentiation inducing factor, particularly for a bone morphogenetic protein or a neurotrophic factor (e.g., a nerve growth factor family), which comprises helioxanthin, or its lactone-open form compound or its salt.
  • a cell differentiation inducing factor particularly for a bone morphogenetic protein or a neurotrophic factor (e.g., a nerve growth factor family), which comprises helioxanthin, or its lactone-open form compound or its salt.
  • the present invention also provides a composition for preventing or treating a bone disease or a nerve degenerative disease which comprises helioxanthin, or its lactone-open form compound or its salt.
  • the present invention also provides a composition which comprises helioxanthin, or its lactone-open form compound or its salt and a cell differentiation inducing factor.
  • the present invention also provides a method for enhancing a cell differentiation inducing factor which comprises using helioxanthin, or its lactone-open form compound or its salt.
  • the present invention also provides a method for preventing or treating a bone disease or a nerve degenerative disease in a mammal which comprises administering to said mammal in need thereof an effective amount of helioxanthin, or its lactone-open form compound or its salt.
  • the present invention also provides helioxanthin, or its lactone-open form compound or its salt for use as a medicine.
  • the present invention also provides use of helioxanthin, or its lactone-open form compound or its salt for the manufacture of an enhancer for a cell differentiation inducing factor, or a composition for preventing or treating a bone disease or a nerve degenerative disease.
  • the present invention also provides a method for preparing an enhancer for a cell differentiation inducing factor or a composition for preventing or treating a bone disease or a nerve degenerative disease which comprises admixing helioxanthin, or its lactone-open form compound or its salt with a pharmaceutically acceptable carrier, excipient or diluent therefor and then subjecting the mixture to molding .
  • the present invention also provides a method for
  • composition which comprises admixing helioxanthin, or its lactone-open form compound or its salt with a cell differentiation inducing factor and then subjecting the mixture to molding.
  • the present invention also provides an osteogenesis promoter which comprises helioxanthin, or its lactone-open form compound or its salt.
  • the present invention also provides use of helioxanthin, or its lactone-open form compound or its salt for the manufacture of an osteogenesis promoter.
  • the present invention also provides a method for preparing an osteogenesis promoter which comprises admixing helioxanthin, or its lactone-open form compound or its salt with a pharmaceutically acceptable carrier, excipient or diluent therefor and then subjecting the mixture to molding.
  • Helioxanthin i.e., l-(3,4-methylene-dioxyphenyl)-2- hydroxymethyl-7 , 8-methylenedioxy-3-naphthoic acid lactone
  • Onji polygala root
  • helioxanthin is represented by the formula (I) below, and is quite different from that of substances having activity of enhancing BMP or NGF activity.
  • Helioxanthin can be chemically synthesized as described in J. of Natural product, vol. 52(2), p. 367-375 (1989) .
  • lactone-open form compound of helioxanthin having the formula (II):
  • the salt of the lactone-open form compound (II) is preferably a physiologically acceptable salt.
  • the salts include salts with inorganic bases, organic bases, inorganic acids, organic acids, basic or acidic amino acids, etc.
  • Preferred examples of the salts with inorganic bases include salts with alkaline metals such as sodium, potassium, etc.; salts with alkaline earth metals such as calcium, magnesium, etc.; salts with aluminium; etc.
  • Preferred examples of the salts with organic bases include ammonium salts, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N' -dibenzylethylenediamine, etc.
  • Preferred examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • Preferred examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.
  • Preferred examples of the salts with basic amino acids include salts with arginine, lysine, ornithine, etc.
  • Preferred examples of the salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. These salts can be obtained by conventional methods.
  • the cell differentiation inducing factors in the present invention include bone morphogenetic proteins, neurotrophic factors, factors belonging to transforming growth factor (TGF) - ⁇ superfamily such as TGF- ⁇ , activin, etc., factors belonging to fibroblast growth factor (FGF) superfamily such as basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), etc., factors belonging to neuropoietic cytokine family such as leukemia inhibitory factor (LIF) (also referred to as cholinergic differentiation factor (CDF)), cilialy neurotrophic factor (CNTF), etc., factors that induce characters characteristic of the step where cells maintaining living function differentiate from indifferent precursors in specific tissues such as osteoblasts or neurons, such as interleukin-1 (IL-1, hereinafter abbreviated likewise) , IL-2, IL-3, IL-5, IL-6, IL- 7, IL-9, IL-11, tumor necrosis factor - ⁇ (TNF- ), interferon -
  • the bone morphogenetic proteins include proteins that promote bone and cartilage formation, such as BMP family (e.g., BMP-2, -4, -5, -6, -7, -8, -9, -10, -11, -12, etc), in particular, BMP-2, -4, -6, and -7.
  • BMP may be in the form of homodimers of each factor described above or heterodimers of possible combinations of the above factors .
  • the neurotrophic factors include nerve growth factor
  • NGF brain-derived neurotrophic factor
  • BDNF brain-derived neurotrophic factor
  • NT-3 glia derived neurotrophic factor (GDNF), NT-4/5, etc.
  • Preferred examples thereof are factors belonging to a nerve growth factor family, such as NGF, BDNF, and NT-3.
  • the enhancer of the invention can be used alone or in combination with substances having cell differentiation inducing activity (e.g., BMP, neurotrophic factors) to promote fracture healing and bone regeneration and treat or prevent various bone diseases such as osteoporosis, etc., nerve degenerative disorders in cerebrovascular dementia, senile dementia, Alzheimer's disease, etc., various cerebral function disorders or nerve diseases such as amyotrophic lateral sclerosis, diabetic peripheral nerve disorders (neuropathy), etc.
  • the enhancer of the invention can also be used as a therapeutic or prophylactic drug against diseases associated with BMP, neurotrophic factors, etc.
  • the enhancer of the invention can be applied to the above diseases in humans and other mammals (e.g., mice, rats, rabbits, dogs, cats, cattle, swine, etc.).
  • the enhancer of the invention can be administered orally or parenterally to humans.
  • the enhancer of the invention can be prepared by known methods in the art except that helioxanthin or its lactone-open form compound or its salt is formulated.
  • helioxanthin or its lactone-open form compound or its salt can be used alone or In combination with a physiologically acceptable carrier.
  • the amount of helioxanthin or its lactone-open form compound or its salt can be appropriately selected depending on the kind of preparation.
  • the amount of helioxanthin or its lactone-open form compound or its salt contained in the composition of the invention is normally about 0.3 to 100% by weight, preferably about 0.5 to 20% by weight.
  • compositions for oral administration include solid or liquid dosage forms such as tablets (including sugar-coated tablets and film-coated tablets), granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions, etc.
  • Such compositions can be prepared by per se known methods and contain carriers commonly used in the art.
  • Such carriers include physiologically acceptable carriers that are organic or inorganic materials commonly used for pharmaceutical carriers.
  • the carriers include excipients, lubricants, binders, disintegrators, etc. for solid preparations; and suspending agents for liquid preparations. If necessary, appropriate additives such as antiseptics, antioxidants, colorants, sweetening agents, etc. can be used in appropriate amounts.
  • excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc.
  • Preferred examples of the lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, etc.
  • binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.
  • Preferred examples of the disintegrators include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, etc .
  • suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl ⁇ cellulose , etc.
  • Preferred examples of the antiseptics include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • Preferred examples of the antioxidants include sulfites, ascorbic acid, etc.
  • compositions for parenteral administration include, for example, injections, suppositories, etc.
  • the injections include subcutaneous, intradermal (or intracutaneous) , or intramuscular injections.
  • Such injections can be prepared as aqueous solutions by per se known methods, for example, by dissolving, suspending or emulsifying helioxanthin or its lactone-open form compound or its salt in sterile aqueous or oily liquids commonly used for injections.
  • the aqueous liquids for injections include physiological saline, isotonic solutions, etc. which can optionally be used in combination with appropriate suspending agents such as carboxymethylcellulose sodium, nonionic surfactants, etc. in appropriate amounts.
  • the oily liquids include sesame oil, soybean oil, etc. which can optionally be used in combination with solution adjuvants such as benzyl benzoate, benzyl alcohol, etc. Normally, the liquid for injection thus prepared is filled into an appropriate ampule.
  • the dose for a particular patient can be determined depending on the age, body weight, physical conditions, sex, diets, administration period, administration methods, clearance, combinations of drugs, severity of the disease to be treated, or other factors.
  • the dose of the enhancer of the invention can appropriately be selected depending on the kind or severity of disease, etc.
  • the enhancer containing about 0.1 to 500 mg, preferably about 1 to 50 mg, more preferably about 3 to 50 mg, of helioxanthin or its lactone open form compound or its salt is administered per day.
  • the unit dose can be determined, considering such a daily dose, dosage forms, etc.
  • the frequency of administrations is not specifically limited, and is preferably 1 to 5 times a day, more preferably 1 to 3 times a day.
  • helioxanthin is known as a component of a galenical and has low toxicity.
  • the enhancer of the invention Since the enhancer of the invention has potent bone formation - promoting activity, it can be mixed with a carrier for bone regeneration to prepare a bone formation - promoting drug for bone repair or bone implantation.
  • the enhancer of the invention may be attached or added to artificial bones, etc., made from metals, ceramics or polymers.
  • the artificial bones preferably have many pores on the surface so as to release the enhancer of the invention in living tissues when they are implanted in a bone - defective part.
  • the fixing agent for artificial bones can be prepared by mixing the active ingredient helioxanthin with a physiologically acceptable dispersion, binder, diluent, other ingredients effective for bone regeneration (e.g., calcium), etc.
  • the fixing agent for artificial bones can also be used so as to fill the gaps between the artificial bones to be implanted in the bone - defective part and the bone - defective part in the host without attaching or incorporating it into artificial bones.
  • bone morphogenesis - promoting proteins such as BMP family may be attached to or contained in the above parenteral compositions.
  • the mouse-derived osteoblast strain MC3T3-E1 was inoculated (8000/well) in a 96-well plate in an ⁇ -minimum essential medium (MEM) containing 10% fetal calf serum (FCS). Two days later, the sample diluted to the concentrations described in Table 1 with a medium containing or not containing BMP-4/7 heterodimer (described in Japanese Patent Application No. 6-111255) (3 ng/ml) was added to cells that had been confluent all over the surface, and the mixture was incubated for 72 hours. After the plate was washed with physiological saline once, the substrate solution was added, and the mixture was incubated at room temperature for 15 minutes.
  • MEM ⁇ -minimum essential medium
  • FCS fetal calf serum
  • PC 12 cells (rat pheochromocytoma; 2000/well) suspended in Dulbecco MEM containing 10% FCS were mixed with the sample containing varying concentrations of NGF and helioxanthin shown in Fig. 1, inoculated in a 96-well plate, and then cultivated for 3 days .
  • the culture solution was removed, and hematoxylin-eosin staining was conducted using a commercially available kit (Diff-Quik R, International Reagents Corporation, Kobe, Japan). The cells were observed with a microscope to evaluate the neurite outgrowth. The results are shown in Fig. 1.
  • the mouse osteoblastic cell line, MC3T3-E1 was inoculated (10 /well) in a 24-well plate. From the next day, the cells were cultivated in ⁇ -MEM medium that contains 10% FCS containing various concentrations of helioxanthin, 10 mM ⁇ -glycerophosphate and 50 ⁇ g/ml ascorbic acid in the presence or absence of 3 ng/ml of BMP for 10 days. The cells were rinsed once with phosphate-buffered saline (PBS), and then 6N hydrochloric acid (0.2 ml) was added.
  • PBS phosphate-buffered saline
  • helioxanthin increased alkaline phosphatase activity in a dose-dependent manner. The increase in alkaline phosphatase activity became significant as the cultivation term became longer.
  • Fig. 4 in the helioxanthin-treatment groups, calcification was suddenly promoted from the 11th day from the beginning of the cultivation. The results show that helioxanthin acts on precursor cells of osteoblasts in the living body to promote its maturation and differentiation. This action of helioxanthin is considered to result from the enhancement of stimulation of a low concentration of endogenous BMP.
  • the enhancer of the invention has, for example, potent BMP action - enhancing activity and bone morphogenesis - promoting activity, and acts on bone tissues to increase bone weight and strength.
  • the enhancer is, therefore, useful for treating or preventing various bone diseases such as osteoporosis, or promoting fracture healing or bone regeneration, etc.
  • the enhancer of the invention enhances the activity of neutrophilic factors, and is useful for treating or preventing various nerve diseases such as Alzheimer's dementia, senile dementia, mononeuron disorders (e.g., amyotrophic lateral sclerosis, etc.), diabetic peripheral nerve disorders, etc.

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Abstract

La présente invention concerne un activateur pour un facteur qui provoque la différenciation des cellules, une composition servant à prévenir ou à traiter une maladie des os ou de dégénérescence des nerfs, et un promoteur de l'ostéogénèse, chacun de ces produits comprenant de l'hélioxanthine ou son composé ayant la forme de la lactone ouverte, ou son sel.
PCT/JP1996/000375 1995-02-21 1996-02-20 Utilisation de l'helioxanthine comme activateur de facteurs induisant la differenciation cellulaire Ceased WO1996025929A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46774/96A AU4677496A (en) 1995-02-21 1996-02-20 Use of helioxanthin as an enhancer of cell differentiation inducing factors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP7/32703 1995-02-21
JP3270395 1995-02-21
JP7/248994 1995-09-27
JP24899495 1995-09-27

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998007705A1 (fr) * 1996-08-20 1998-02-26 Takeda Chemical Industries, Ltd. Naphtolactames et lactones utilises en qualite d'agents actifs pour les proteines morphogenetiques des os
WO1998049155A1 (fr) * 1997-04-25 1998-11-05 Takeda Chemical Industries, Ltd. Derives amides induisant la differenciation cellulaire, leur production et leur utilisation
WO2000009100A3 (fr) * 1998-08-12 2000-08-24 Takeda Chemical Industries Ltd Renforçateur du facteur d'induction de la differenciation cellulaire
WO2001064239A1 (fr) * 2000-03-03 2001-09-07 The Walter And Eliza Hall Institute Of Medical Research Methode de traitement
EP1107961A4 (fr) * 1998-08-25 2002-01-30 Univ Yale Inhibition et traitement du virus de l'hepatite b et de flavivirus par l'helioxanthine et ses analogues
AU2001237132B2 (en) * 2000-03-03 2006-04-27 Amrad Corporation Limited A method of treatment
JP2009506982A (ja) * 2005-06-23 2009-02-19 ティシュージーン，インク 神経保護効果のある化合物
US10413633B2 (en) 2008-09-10 2019-09-17 The University Of Manchester Peripheral nerve growth conduit

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JPH02300124A (ja) * 1989-02-28 1990-12-12 Takeda Chem Ind Ltd 骨粗鬆症予防治療剤
JPH04211609A (ja) * 1990-03-22 1992-08-03 Takeda Chem Ind Ltd 骨吸収抑制剤およびナフタレン誘導体
WO1994027614A1 (fr) * 1993-05-28 1994-12-08 Conpharm Ab Utilisation de derives de lignane pour la preparation de compositions pharmaceutiques destinees au traitement de l'amyloïdose
JPH06340528A (ja) * 1993-05-28 1994-12-13 Suntory Ltd ナフタレン誘導体を有効成分とする骨疾患の予防及び治療剤

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JPH02300124A (ja) * 1989-02-28 1990-12-12 Takeda Chem Ind Ltd 骨粗鬆症予防治療剤
JPH04211609A (ja) * 1990-03-22 1992-08-03 Takeda Chem Ind Ltd 骨吸収抑制剤およびナフタレン誘導体
WO1994027614A1 (fr) * 1993-05-28 1994-12-08 Conpharm Ab Utilisation de derives de lignane pour la preparation de compositions pharmaceutiques destinees au traitement de l'amyloïdose
JPH06340528A (ja) * 1993-05-28 1994-12-13 Suntory Ltd ナフタレン誘導体を有効成分とする骨疾患の予防及び治療剤

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Publication number Priority date Publication date Assignee Title
WO1998007705A1 (fr) * 1996-08-20 1998-02-26 Takeda Chemical Industries, Ltd. Naphtolactames et lactones utilises en qualite d'agents actifs pour les proteines morphogenetiques des os
US6030967A (en) * 1996-08-20 2000-02-29 Takeda Chemical Industries, Ltd. Naphtholactams and lactones as bone morphogenetic protein active agents
WO1998049155A1 (fr) * 1997-04-25 1998-11-05 Takeda Chemical Industries, Ltd. Derives amides induisant la differenciation cellulaire, leur production et leur utilisation
US6340704B1 (en) 1997-04-25 2002-01-22 Takeda Chemical Industries, Ltd. Cell differentiation inducing amide derivatives, their production and use
WO2000009100A3 (fr) * 1998-08-12 2000-08-24 Takeda Chemical Industries Ltd Renforçateur du facteur d'induction de la differenciation cellulaire
EP1107961A4 (fr) * 1998-08-25 2002-01-30 Univ Yale Inhibition et traitement du virus de l'hepatite b et de flavivirus par l'helioxanthine et ses analogues
WO2001064239A1 (fr) * 2000-03-03 2001-09-07 The Walter And Eliza Hall Institute Of Medical Research Methode de traitement
AU2001237132B2 (en) * 2000-03-03 2006-04-27 Amrad Corporation Limited A method of treatment
JP2009506982A (ja) * 2005-06-23 2009-02-19 ティシュージーン，インク 神経保護効果のある化合物
EP1904113A4 (fr) * 2005-06-23 2009-03-04 Tissuegene Inc Composé neuroprotecteur efficace
US10413633B2 (en) 2008-09-10 2019-09-17 The University Of Manchester Peripheral nerve growth conduit

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