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WO2002066424A1 - Derive de vitamine d possedant un substituant en position 2 - Google Patents

Derive de vitamine d possedant un substituant en position 2 Download PDF

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Publication number
WO2002066424A1
WO2002066424A1 PCT/JP2002/001604 JP0201604W WO02066424A1 WO 2002066424 A1 WO2002066424 A1 WO 2002066424A1 JP 0201604 W JP0201604 W JP 0201604W WO 02066424 A1 WO02066424 A1 WO 02066424A1
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WO
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Prior art keywords
compound
vitamin
group
mmol
silica gel
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PCT/JP2002/001604
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English (en)
Japanese (ja)
Inventor
Hiroaki Takayama
Atsushi Kittaka
Yoshitomo Suhara
Toshie Fujishima
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Priority to JP2002565941A priority Critical patent/JPWO2002066424A1/ja
Publication of WO2002066424A1 publication Critical patent/WO2002066424A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Definitions

  • Vitamin D derivatives having a substituent at the 2-position
  • the present invention relates to a novel vitamin D derivative, and more particularly, to a vitamin D derivative having a phenyl group or a phenylalkyl group at the 2-position.
  • Vitamin D derivatives are known to exhibit a wide range of physiological activities, such as calcium metabolism regulation, growth suppression for tumor cells, differentiation induction, and immunomodulation.Renal bone disease, hypoparathyroidism Various vitamin D derivatives have been proposed as therapeutic agents for osteoporosis and the like.
  • vitamin D derivatives some of which have a substituent at the 2j3 position have physiological activities such as regulation of calcium in vivo, induction of differentiation on tumor cells, etc. It has been reported that it is useful as a therapeutic or antitumor agent for diseases based on abnormalities in calcium metabolism such as osteoporosis and osteomalacia (Japanese Patent Publication No. Hei 6-23185).
  • vitamin D derivative having a substituent at the 2-position examples include a vitamin D derivative having a 4-hydroxybutyl group and a hydroxy group at the 2-position (J. Org. Chem., Vol. 59, No. 25, 1994 and Tokuseki Sho 51-19752).
  • the present inventors have focused on vitamin D derivatives having a phenyl group or a phenylalkyl group at the 2-position, and have conducted various studies such as the physiological activity. Disclosure of the invention
  • the present invention provides a novel vitamin D derivative having a specific substituent introduced at the 2-position, preferably Aims to synthesize and provide a novel vitamin D derivative having a phenyl or phenylalkyl group introduced at the 2-position.
  • Another object of the present invention is to provide a novel vitamin D derivative exhibiting excellent vitamin D receptor binding ability.
  • the present inventors have conducted intensive studies in order to solve the above problems, and as a result, have found that by introducing a specific substituent at the 2-position, the vitamin D receptor binding ability is improved. It was completed.
  • A is a linear or branched lower alkyl group which may be substituted with a hydroxy group, and m represents a number of 0 to 2.
  • m is 0 to 2
  • A is a linear or branched alkyl group having 1 to 10 carbon atoms substituted with a hydroxy group. More preferably, m is from 0 to 2, and A is a linear or branched substituted with a hydroxy group It is a chain alkyl group having 5 to 10 carbon atoms. More preferably, m is 0 to 2, and A is a 4-hydroxy-4-methylpentyl group or a 4-ethyl-4-hydroxyhexyl group. Particularly preferably, A is a 4-hydroxy-4-methylpentyl group, and m is 0 or 1. More preferably, A is a 4-hydroxy-4-methylpentyl group and m is 1.
  • the hydroxy group at the 1-position is preferably at the a-position.
  • the hydroxy group at the 3-position may be at the a-position or at the 3-position, but is preferably at the 8-position.
  • the substituent at the 2-position may be introduced at the para-position or at the -position, but is preferably at the ⁇ -position. That is, the vitamin D derivative represented by the general formula (1) is converted into the general formula (2):
  • Formula (2) (in the formula, ⁇ is a linear or branched lower alkyl group which may be substituted with a hydroxy group, and m represents a number of 0 to 2.)
  • the vitamin D derivative represented by the general formula (I) is effectively used.
  • a pharmaceutical composition for example, a therapeutic agent for a disease associated with abnormal calcium metabolism
  • provided as an ingredient is provided.
  • the vitamin D derivative represented by the general formula (1) of the present invention is a novel compound, and its synthesis method is not limited at all.For example, a method comprising the following steps and a method described in Examples described later are described. It can be manufactured according to the method described above.
  • a binding-crystalline epoxide ⁇ obtained from D- glucose and the like can be used as a common starting material for 2-substituted activated vitamin D 3 synthesis. That is, crystalline epoxide II is reacted with an organometallic reagent (eg, Grignard reagent, organocopper reagent, etc.) in an organic solvent, and a carbon functional group is regioselectively introduced at the 3-position, resulting in 3-substituted 3-de.
  • organometallic reagent eg, Grignard reagent, organocopper reagent, etc.
  • the desired CD ring-promolefin and palladium in a suitable solvent by reaction using a catalyst, to construct a 2-substituted activated vitamin D 3 skeleton.
  • the protected form J_Q_ After subjecting the obtained protected form J_Q_ to deprotection operation, it is purified by a conventional method such as reverse phase HPLC or thin layer chromatography to obtain the desired 2-substituted active vitamin D 3 derivative ⁇ _ Can be synthesized. Alternatively, the protected form JLQ_ may be subjected to deprotection after purification.
  • the 2j3-substituted product was obtained by reacting the crystalline epoxide ⁇ of the above reaction scheme with an organometallic reagent in the presence of copper ions, whereby the configuration of the carbon functional group at the 3-position was inverted from that of the above reaction scheme. It may be led to a 3-substituted 3-deoxyaltrose derivative.
  • the punishment ion may be a catalytic amount, for example, 0.3 equivalent of iodine punishment can be used.
  • the protecting group may be temporarily changed from a benzoyl group to a silyl group.
  • the benzoyl protecting group is removed under basic conditions, eg, with a catalytic amount of sodium methoxide, followed by silicidation.
  • a silyl group for example, a tert-butyldimethylsilyl group can be used.
  • a silyl-protected enyne (corresponding to an enyne whose configuration of the carbon functional group at the 4-position is inverted from A in the above reaction scheme) is synthesized.
  • the secondary hydroxyl group of the obtained enyne may be silylated in the same manner as in the above reaction scheme, and then reacted with a desired CD ring-promolefin.
  • a so-called 3 -epitamin of a vitamin D 3 skeleton in which the 3-position hydroxy group of the vitamin D 3 skeleton is located at the position, can also be synthesized as desired.
  • the stereo configuration of the 2-position hydroxy group of the 5-hexenediol derivative A becomes R
  • a mixture of diastereomers that are S eyne is synthesized by the same reaction as in the above reaction scheme and separated to give an epi-body (8-epi) relating to the 5-position of in the above reaction scheme.
  • the compound of the CD ring portion of the vitamin D derivative a known compound can be used.
  • the side chain can be appropriately modified to obtain a desired CD ring compound.
  • the CD ring compound can be obtained from a known vitamin D derivative having a corresponding side chain.
  • A represents a linear or branched lower alkyl group which may be substituted with a hydroxy group.
  • a straight-chain or branched lower alkyl group generally indicates a straight-chain or branched-chain alkyl group having 1 to L0 carbon atoms, such as a methyl group or an ethyl group.
  • A is a linear or branched C1-C10 alkyl group substituted with a hydroxy group. More preferably, A is a linear or branched C5-C10 alkyl group substituted with a hydroxy group.
  • linear or branched lower alkyl group substituted with a hydroxy group means a group in which any hydrogen atom of the above-mentioned lower alkyl group is substituted with one or more hydroxy groups.
  • the number of substituted hydroxy groups is 1, 2 or 3, preferably 1 or 2, and more preferably 1.
  • Non-limiting specific examples of A include a 4-hydroxy-14-methylpentyl group, a 4-ethyl-4-hydroxyhexyl group, and the like.
  • m is 0 to 2, preferably m is 0 to 1, and more preferably m is 1.
  • A is a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms substituted with a hydroxy group, preferably a straight-chain or branched-chain alkyl group having 5 to 10 carbon atoms substituted with a hydroxy group. And more preferably a straight-chain or branched alkyl group having 5 to 8 carbon atoms, more preferably a branched-chain alkyl group having 5 to 8 carbon atoms, which is substituted with a hydroxy group.
  • A includes a 4-hydroxy-4-methylpentyl group, a 4-ethyl-4-hydroxyhexyl group and the like, and a 4-hydroxy-14-methylpentyl group is particularly preferred.
  • preferred compounds include (5Z, 7E)-(IS, 2S, 3R, 20R) -12-phenyl-19,10-seco 5, 7,1 0 (1 9) -Cholesta Trien-1,3,25—Triol, (5 Z, 7 E) 1 (IS, 2 S, 3 R, 20 R) —2—Benzyl 9,10 0— Seco_5,7,1 0 (1 9) -cholestatriene 1,3,25-triol, (5 Z, 7 E)-(1 S, 2 S, 3 R, 2 OR) 1-2-phenethyl _ 9,10—Seco 5,7,1 0 (1 9) -Cholestatriene 1,3,25—Triol, (5 Z, 7 E)-(1 S, 2 R, 3 R, 2 OR) 1-Phenyl _9, 10—Seco 5, 7, 10 (1 9) -cholestatriene 1, 3, 25—triol, (5 Z, 7 E) 1 (1 S, 2 R, 3
  • the vitamin D derivative of the present invention can also be used as a medicament, for example, as a therapeutic agent for a disease associated with calcium metabolism abnormality.
  • the vitamin D derivative of the present invention can also be used as a reagent in the study of the metabolism of active tenamin vitamin D 3. (Ie, 1 ", 25-dihydroxyvitamin D 3 ). It is preferable to formulate into an appropriate dosage form together with an acceptable carrier, excipient, disintegrant, lubricant, binder, fragrance, coloring agent and the like, and to use such dosage forms as tablets, granules Preparations, fine granules, capsules, powders, injections, solutions, suspensions, emulsions, transdermal absorbers, suppositories and the like.
  • the administration route of the compound of the present invention is not particularly limited, and may be oral administration or parenteral administration (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, etc.).
  • the dose of the compound of the present invention can be appropriately selected depending on the target disease, the condition of the patient, body type, constitution, age, sex, administration route, dosage form, and the like.
  • the dose can be selected within the range of ⁇ 1 000 / ig, and can be administered in 1 to 3 times a day.
  • silica gel column chromatography Merck silica gel (Silica Gel 60) was used, and for silica gel thin layer chromatography, Merck silica gel TLC plate (Precaate silica GelPlateF F 254) was used.
  • the NMR spectrum uses JE JL GSX-400 (JEOL) and J EOL EC P-600 (JEOL), and in tetrachloroform solvent, tetramethyl ⁇ / lesilane (0 ppm) as an internal standard.
  • JEOL JE JL GSX-400
  • JEOL J EOL EC P-600
  • tetrachloroform solvent tetramethyl ⁇ / lesilane (0 ppm)
  • 2,3-anhydro_4,6-0-benzylidene-H-D-mannopyranoside conjugate 1 3.08 g (11.7 marl ol) of tetrahydrofuran (THF) (117 mL) solution was added under argon atmosphere. A solution of 06 M benzylmagnesium chloride in THF (65.9 mL) was added, and the mixture was heated and refluxed at 80 ° C for 14 hours. After cooling, the reaction solution was separated with ethyl acetate (500 mL) -0.5N hydrochloric acid (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (200 mL) and then ⁇ ⁇ ⁇ 0
  • the organic layer was further 10% Shioi ⁇ Anmoniumu solution (200 mL), H 2 0 (200 mL), washed with saturated brine (200 raL), and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (silica gel 150 g, 5./. ⁇ 10% ethyl acetate Z hexane) to obtain 793 mg of a colorless oily compound 6 (yield 86). %).
  • the reaction solution was separated with ethyl acetate (300 mL) and a 10% aqueous solution of ammonium chloride (100 raL).
  • the organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL), washed with H 2 0 (100 mL) further brine AOO mL), and dried over anhydrous sodium sulfate.
  • the residue was purified by silica gel column chromatography (silica gel 50 g, 2% ⁇ 7% ethyl acetate Z hexane) to obtain 816 mg of a colorless oily compound 7 78% yield
  • tert-butyldimethylsilyl trifluoromethanesulfonate 110 ⁇ m, 0.480 mmol
  • 2,6 Lutidine 90 ⁇ m, 0.768 mmol
  • the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (20 mL), and the organic layer was washed with 3 ⁇ 40 (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate.
  • compound 9 In an argon atmosphere, compound 9 (156.0 mg, 0.340 mmol), which is a quinine, and bromoolefin (CD ring portion in which the group corresponding to A in general formula (1) is a 4-hydroxy-1-methylpentyl group, 243.0 mg , 0.682 mmol) were dissolved in toluene (1 mL), and triethylamine (3 mL) was added. Tetrakis (triphenylphosphine) palladium (0) complex (118 mg, 0.102 mmol) was added, and the mixture was stirred at room temperature for 15 minutes, heated to 90 ° C, and heated under reflux for 2 hours.
  • Tetrakis (triphenylphosphine) palladium (0) complex 118 mg, 0.102 mmol
  • Bissilyl ether compound 10 (229.4 mg, 0.312 ol) was dissolved in THF (5 mL), and tetrabutylammonium fluoride 1.0 M THF solution (1.56 mL, 1.56 t ) was added and the mixture was stirred at room temperature for 48 hours.
  • the reaction mixture was concentrated on a rotary evaporator under reduced pressure, and purified by silica gel column chromatography (silica gel 20 g, 10% ⁇ 14 ° / ethyl acetate Z hexane) to obtain 54.8 mg of compound 11 as a white powder. (Yield 35 ° /.).
  • Example 2 The steps performed in Example 2 are described below. ⁇ OAV-: ⁇ .
  • the organic layer was washed with saturated NaHC0 3 (100 mL), then H 2 0 (10 0 mL) and then with saturated saline (100 mL), and the organic layer was dried over Na 2 SO 4 .
  • the reaction solution was partitioned between ethyl acetate (150 mL) and a saturated aqueous solution of NH 4 C1 (40 mL).
  • the organic layer was washed with a saturated aqueous solution of NH 4 C1 (40 mL), then with H 20 (40 mL) and then with a saturated saline solution (40 mL), and dried over Na 2 SO 4 .
  • Compound 25 (22.3 mg) as a raw material was recovered (recovery rate: 7%).
  • the reaction solution was partitioned between ethyl acetate (50 mL) and saturated NH 4 C1 (20). The organic layer was washed with saturated NaHC0 3 (20 mL), followed by 3 ⁇ 40 (20 mL), then washed with saturated brine (20 mL), dried putting Na 2 S0 4. After filtration, the filtrate was concentrated and purified by preparative thin-layer chromatography (hexane / ethyl acetate-20/1). 36.7 mg of a colorless oily compound 29 was obtained (yield 47%). 23.7 mg of the compound 28 was recovered (recovery rate 40%).
  • alcohol 30 (82.7 mg, 0.250 t) was dissolved in dry CH 2 C 12 (3 mL), and 2,6-lutidine (111 ⁇ , 0.950 bandol) and TBDMSOTf (103 ⁇ ) were dissolved. , 0.450 mmol) and stirred at 0 ° C for 1.5 hours.
  • the reaction mixture was partitioned acetate Echiru (50 mL) and saturated NaHC0 3 (20 mL). The organic layer was washed with 0 (20 mL) and then with saturated saline (20 mL), and dried over Na 2 SO 4 .
  • Example 3 Synthesis of 3 -Epi-2 ⁇ -benzyl-1 ⁇ , 25-dihydroxyvitamin D 3 The steps performed in Example 3 are shown below.
  • Dissolve 45 mix (57.8 mg, 0.12 mmol) of the compound tosylate in THF (3 mL), and add a 1.0 M THF solution of lithium hexamethyldisilazide (0.144 mL, 0.14 iranol) and stirred for 20 minutes. The cooling bath was removed, and the mixture was further stirred at room temperature for 90 minutes. The reaction solution was separated with ethyl acetate (50 mL) -saturated aqueous ammonium chloride solution (20 mL).
  • the organic layer was further washed with a saturated aqueous solution of ammonium chloride (20 mL), then with 0 (20 mL), and further with a saturated saline solution (20 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, the product is purified by silica gel gel chromatography (silica gel 150 g, 10% ethyl acetate / hexane), and is a colorless oil containing two diastereomers of R configuration and S configuration at the 5-position. 31.5 mg of 46 mi was obtained (yield: 85%).
  • the compound 47 mix (322.5 mg, 0.793 mmol), which was a enein, was dissolved in methanol (16 mL), potassium carbonate (1.10 g, 7.93 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was neutralized by adding an ion exchange resin (IR-120 (H + )). After filtration and concentration, the residue was purified by silica gel column chromatography (silica gel 50 g, 25% ethyl acetate / hexane) to obtain 66.6 mg of a colorless oily compound 48 epi having R configuration at the 5-position (yield 37 °). /.). 91.8 mg of 47 mixes were recovered (recovery rate 51 ° /.).
  • reaction solution was separated with ethyl acetate (50 mL) -saturated aqueous sodium hydrogen carbonate solution (20 mL).
  • organic layer H 2 0 (20 mL), Tsugire, in dried with anhydrous sodium sulfate and saturated brine (20 raL).
  • the residue was purified by silica gel column chromatography (silica gel 6 g, 10% ethyl acetate hexane) to obtain 123.4 mg of a colorless oily compound 49 epi having the R configuration at the 5-position (yield (93% rate)
  • compound 49 epi (38.0 mg, 0.083 mmol), which is a enein, and bromoolefin (CD in which the group corresponding to A in the general formula (1) is a 4-hydroxy-14-methylpentyl group) Ring portion, 32.7 mg, 0.092 mmol) was dissolved in 0.5 mL of toluene, and triethylamine (1.5 mL) was added. Tetrakis (triphenylphosphine) palladium (0) complex (28.7 mg, 0.025 mmol) was added, and the mixture was stirred at room temperature for 15 minutes and then at 90 ° C for 2 hours.
  • reaction solution was separated and purified by preparative TLC (17% ethyl acetate Z-hexane), and 32.3 rag of 5 O epi, a pale yellow oily compound in which the 3-hydroxy group of the vitamin D skeleton is located at the 3-position was obtained (crude yield 53%). This compound was used for the next reaction without further purification.
  • Example 2 3 compounds were synthesized in 1 1 (2 a -Benzyl- 1 a , 25- dihydr oxyvitamin D 3), Compound 33 (2 ⁇ -Phenyl-1, 25-dihydroxyvitamin D 3) Contact 5 lepi (3-epi-2a-Benzyl-1, 25-dihydroxyvitamin D 3 ) was tested for its ability to bind to the thymus-derived vitamin D receptor (VDR).
  • VDR thymus-derived vitamin D receptor
  • Compound 1 1, 33 or 51epi is, [3 H] 1 ⁇ , 25 - capable of use on-dihydroxy vitamin D 3 and the density industry to bind 50% inhibition of the VD R great collection
  • the vitamin D derivative represented by the general formula (I) of the present invention is a novel compound and may be useful as a medicine.

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Abstract

L'invention concerne un dérivé de vitamine D possédant un substituant spécifique en position 2. Ce dérivé est représenté par la formule générale (1): (dans laquelle A représente un alkyle inférieur linéaire ou ramifié éventuellement substitué par un groupe hydroxy et m est un nombre prenant une valeur de 0 à 2).
PCT/JP2002/001604 2001-02-23 2002-02-22 Derive de vitamine d possedant un substituant en position 2 WO2002066424A1 (fr)

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JP2002565941A JPWO2002066424A1 (ja) 2001-02-23 2002-02-22 ２位に置換基を有するビタミンｄ誘導体

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JP2001-48486 2001-02-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006019169A1 (fr) * 2004-08-17 2006-02-23 Teijin Pharma Limited Dérivé de l’épimère en 3 alpha de la vitamine d3 et agent thérapeutique contenant ce composé
WO2006051106A1 (fr) 2004-11-12 2006-05-18 Bioxell Spa Emploi combiné de dérivés de vitamine d et d'agents antiproliférants pour le traitement de cancers de la vessie
WO2022269768A1 (fr) * 2021-06-22 2022-12-29 学校法人神奈川大学 Composé de type vitamine d3

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184206A2 (fr) * 1984-12-05 1986-06-11 Chugai Seiyaku Kabushiki Kaisha Dérivés de vitamine D3 avec un substituant en position 2
JPH0834802A (ja) * 1994-07-21 1996-02-06 Gun Ei Chem Ind Co Ltd バクテリアセルロース、その製造方法及び該バクテリアセルロースを用いた加工物
EP0806413A1 (fr) * 1995-01-23 1997-11-12 Chugai Seiyaku Kabushiki Kaisha Derives de vitamine d 3? de 2-substitution
JPH10251183A (ja) * 1997-03-07 1998-09-22 Chugai Pharmaceut Co Ltd ビタミンｄ誘導体のａ環部分の合成に有用な合成中間体、その製造方法およびその使用方法
EP0957088A1 (fr) * 1997-05-02 1999-11-17 Teijin Limited Derives de vitamine d3 et procede de production

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184206A2 (fr) * 1984-12-05 1986-06-11 Chugai Seiyaku Kabushiki Kaisha Dérivés de vitamine D3 avec un substituant en position 2
JPH0834802A (ja) * 1994-07-21 1996-02-06 Gun Ei Chem Ind Co Ltd バクテリアセルロース、その製造方法及び該バクテリアセルロースを用いた加工物
EP0806413A1 (fr) * 1995-01-23 1997-11-12 Chugai Seiyaku Kabushiki Kaisha Derives de vitamine d 3? de 2-substitution
JPH10251183A (ja) * 1997-03-07 1998-09-22 Chugai Pharmaceut Co Ltd ビタミンｄ誘導体のａ環部分の合成に有用な合成中間体、その製造方法およびその使用方法
EP0957088A1 (fr) * 1997-05-02 1999-11-17 Teijin Limited Derives de vitamine d3 et procede de production

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006019169A1 (fr) * 2004-08-17 2006-02-23 Teijin Pharma Limited Dérivé de l’épimère en 3 alpha de la vitamine d3 et agent thérapeutique contenant ce composé
WO2006051106A1 (fr) 2004-11-12 2006-05-18 Bioxell Spa Emploi combiné de dérivés de vitamine d et d'agents antiproliférants pour le traitement de cancers de la vessie
WO2022269768A1 (fr) * 2021-06-22 2022-12-29 学校法人神奈川大学 Composé de type vitamine d3
WO2022270443A1 (fr) * 2021-06-22 2022-12-29 学校法人神奈川大学 Composé de type vitamine d3

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