WO2004067504A1 - Dérivé de vitamine d 2-substituée - Google Patents

Dérivé de vitamine d 2-substituée Download PDF

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Publication number
WO2004067504A1
WO2004067504A1 PCT/JP2004/001003 JP2004001003W WO2004067504A1 WO 2004067504 A1 WO2004067504 A1 WO 2004067504A1 JP 2004001003 W JP2004001003 W JP 2004001003W WO 2004067504 A1 WO2004067504 A1 WO 2004067504A1
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compound
group
mhz
cdc1
nmr
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PCT/JP2004/001003
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English (en)
Japanese (ja)
Inventor
Hiroaki Takayama
Atsushi Kittaka
Toshie Fujishima
Nozomi Saito
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Chugai Seiyaku Kabushiki Kaisha
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Publication of WO2004067504A1 publication Critical patent/WO2004067504A1/fr

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    • 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
    • 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
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel vitamin D derivatives, and more particularly, to novel 2-substituted-19-norvitamin D derivatives and 2-substituted vitamin D derivatives.
  • Active vitamin D 3 (l, 25-dihydroxy itamin D 3 ) is known to have many physiological activities, including calcium metabolism regulation, tumor cell growth suppression, differentiation induction, and immunomodulation. I have. However, active vitamin D 3 is liable to cause hypercalcemia due to long-term and continuous administration, so that it has been difficult to use it as an antitumor agent, an antirheumatic agent or the like. Therefore, the synthesis of a number of vitamin D derivatives has been studied for the purpose of separating these actions.
  • an object of the present invention is to synthesize and provide a novel 2-substituted -19-norubimin D derivative or a 2-substituted vitamin D derivative. Another object of the present invention is to evaluate the biological activity of the synthesized 2-substituted-19-norvitamin D derivative or 2-substituted vitamin D derivative.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a 19-norvitamin D derivative having a functional group of tricarbon or more at the 2-position and a vitamin D derivative having a spiro ring at the 2-position Having learned that the intended purpose was achieved, the present invention was completed.
  • R 2 represents a linear or branched C i-alkyl group which may be substituted with a hydroxyl group
  • a linear or may be substituted by a hydroxyl group or branched C 3 _ 5 alkyl group or a straight-chain may be substituted with a hydroxyl group or branched C represents 3 _ 5 alkenyl group
  • 'R 2 is a linear optionally substituted with a hydroxyl group or branched C 3 _. Represents an alkyl group.
  • 1 ⁇ is substituted by a hydroxyl group may linear or branched also C 3 _ 4 alkyl group linear substituted or with or hydroxyl branched C 3 _ 4 alkenyl It represents a group, R 2 represents a straight chain may be substituted with a hydroxyl group or branched C 5. 8 alkyl group.
  • R 3 and R 4 together a connexion to form optionally substituted C 3 _ 6 spirocyclic ⁇ alkyl group
  • R 5 represents a linear or branched alkyl group which may be substituted with a hydroxyl group
  • R 3 and R 4 together a connexion, a C 3 _ 5 spirocyclic alkyl groups of the non-replacement form, R 5 may be substituted by a hydroxyl group It represents a linear or branched C 5 _ 8 alkyl group.
  • a pharmaceutical composition comprising the compound represented by the general formula (1) or (2).
  • Such a pharmaceutical composition preferably contains a pharmaceutically acceptable carrier or diluent together with the compound represented by the general formula (1) or (2).
  • vitamin D derivative refers to 9,10-seco-5,7,10 9)-
  • 19-nor-1,2,5-dihydroxyvitamin D derivative refers to a compound having a 9,10-seco-5,7,10 (19) -cholestatriene structure and a 10 (19) -exomethylene A compound from which a group has been removed is meant.
  • a hydroxyl group branched c 3 - 8 alkyl refers to carbon unsubstituted or hydroxyl is substitution It means a linear or branched alkyl group of the number 3 to 8.
  • the number of carbon atoms is preferably from 3 to 5, more preferably from 3 to 4.
  • Examples of the unsubstituted linear or branched alkyl group having 3 to 8 carbon atoms include n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t.
  • straight-chain or branched-chain alkyl group having 3 to 8 carbon atoms substituted with a hydroxyl group refers to any hydrogen atom of the above-described unsubstituted straight-chain or branched-chain alkyl group having 3 to 8 carbon atoms.
  • a hydroxyl group for example, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group, a hydroxyoctyl group and the like.
  • a hydroxyl group but it may also be substituted with a straight-chain or branched C 3 _ 8 alkenyl group
  • the number of carbon atoms which is substituted by unsubstituted or hydroxyl It means 3 to 8 linear or branched alkenyl groups having at least one double bond.
  • the number of carbon atoms is preferably from 3 to 5, more preferably from 3 to 4.
  • Examples of the unsubstituted linear or branched alkenyl group having 3 to 8 carbon atoms include an aryl group, an n-butenyl group, a sec-butenyl group, a pentenyl group, a heptenyl group and an octenyl group.
  • the straight-chain or branched alkenyl group having 3 to 8 carbon atoms substituted with a hydroxyl group is any of the unsubstituted straight-chain or branched alkynyl groups having 3 to 8 carbon atoms described above.
  • the hydrogen atom is substituted with a hydroxyl group, and examples thereof include a hydroxyaryl group, a hydroxybutenyl group, a hydroxypentenyl group, a hydroxyheptenyl group, and a hydroxyoctenyl group.
  • a hydroxyaryl group examples thereof include a hydroxyaryl group, a hydroxybutenyl group, a hydroxypentenyl group, a hydroxyheptenyl group, and a hydroxyoctenyl group.
  • n-propyl, n-butyl linear pentyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, aryl, n-butenyl, pentenyl, hydroxyaryl And n-propyl, n-butyl, hydroxypropyl, hydroxybutyl, aryl, n-butenyl and hydroxyaryl groups.
  • a hydroxybutenyl group examples thereof include
  • a straight-chain or branched-chain alkyl group which may be substituted with a hydroxyl group is a straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted with a hydroxyl group. Means Preferably it has 3 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, and even more preferably 7 carbon atoms.
  • Examples of the unsubstituted linear or branched alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, Examples thereof include an i-butyl group, a t-butyl group, a linear and branched pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decanyl group.
  • straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms substituted by a hydroxyl group means any hydrogen atom of the above-mentioned unsubstituted straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms.
  • hydroxyl group for example, hydroxymethyl group, hydroxyethyl group, hydroxybutyl group, hydroxypropyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, hydroxy Nonyl group, hydroxydecanyl group, 4-hydroxy-4-methylpentyl group, 1,4-dihydroxy-4-methylpentyl group, 4-ethyl-4-hydroxyhexyl group, 6-hydroxy-6-methyl-2 -Heptyl group, 7-hydroxy-7-methyl-2-octyl group, 5,6-dihydroxy-6-methyl-2-heptyl group and the like.
  • R 2 is a 4-hydroxy-4-methylpentyl group.
  • the configuration at the 2-position in the general formula (1) of the present invention may be an R configuration or an S configuration.
  • R 3 and R 4 of the "optionally substituted C 3 - 6 scan pyromellitic cyclic alkyl group" in the definitions refers to unsubstituted or substituted spirocyclic alkyl group 3-6 carbon atoms Means The number of carbon atoms is preferably from 3 to 5, more preferably from 3 to 4.
  • substituted spirocyclic alkyl group having 3 to 6 carbon atoms refers to an unsubstituted spirocyclic alkyl group having 3 to 6 carbon atoms in which at least one hydrogen atom is substituted,
  • the group include a halogen atom, a hydroxy group, an alkyl group, and a hydroxyalkyl group.
  • R 5 ' may be substituted by a hydroxyl group may linear or branched ⁇ 2 alkyl group "and, of has been C1-12 unsubstituted or substituted with a hydroxyl group linear or branched It means an alkyl group. Preferably it has 3 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, and even more preferably 7 carbon atoms.
  • Examples of the unsubstituted linear or branched alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, Examples thereof include an i-butyl group, a t-butyl group, a linear and branched pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decanyl group.
  • straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms substituted by a hydroxyl group means any hydrogen atom of the above-mentioned unsubstituted straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms.
  • hydroxyl group for example, hydroxymethyl group, hydroxyethyl group, hydroxybutyl group, hydroxypropyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, hydroxy Nonyl group, hydroxydecanyl group, 4-hydroxy-4-methylpentyl group, 1,4-dihydroxy-4-methylpentyl group, 4-ethyl-4-hydroxyhexyl group, 6-hydroxy-6-methyl- 2-heptyl group, 7-hydroxy-7-methyl-2-octyl group, 5,6-dihydroxy-6-methyl-2-heptyl group and the like.
  • R 5 is a 4-hydroxy-4-methylpentyl group.
  • the 1, 2, and 3 configuration may be R configuration or S configuration, respectively.
  • the compound represented by the general formula (1) or (2) of the present invention can also be used as an active ingredient of a pharmaceutical composition (for example, a calcium metabolism regulator or the like).
  • a pharmaceutical composition for example, a calcium metabolism regulator or the like.
  • the compound of the present invention is preferably formulated into an appropriate dosage form together with a pharmaceutically acceptable carrier, excipient, disintegrant, lubricant, binder, flavor, coloring agent and the like, and used in such a form.
  • dosage forms include tablets, granules, 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, patient condition, body weight, constitution, age, sex, administration route, dosage form, and the like. Range of 0.000 l g-0.lg per day, preferably 0.0 1 ⁇ g, the upper limit of the dose is lOO g- 100 per adult per day
  • the dose can be selected within the range of 0,000 g, preferably within the range of 200 g-1000 g, and can be administered in 1 to 3 times a day.
  • the compound represented by the general formula (1) of the present invention is a novel compound, and its synthesis method is not limited. For example, it can be synthesized as shown in the following schemes 1 to 3.
  • the A ring precursor of the compound of the general formula (1) can be synthesized by a method as shown in Scheme 1.
  • (-)-Quinic acid is used as a starting material in order to obtain final compounds having the desired stereochemical configuration at the 1- and 3-positions, respectively.
  • the hydroxyl group at the starting material is esterified, and both hydroxyl groups at the 3- and 5-positions of quinic acid are protected with bulky silyl-type protecting groups (tert-butyldimethylsilyl group, triethylsilyl group, etc.).
  • the 4-position hydroxyl group is imidazolylthiocarbonylated (or even if it is phenoxythiocarbonylated).
  • a C 4 carbon radical is generated by a tin radical (heating AIBN-aryl tributyltin), and an aryl group is introduced at the 4-position by a radial coupling with the aryl tin.
  • the resulting compound is subjected to a high-end portation to convert the 4-position to a hydroxypropyl group.
  • resulting 1-position of the functional groups in the compounds and diol was reduced with N a BH 4 (or not good even L i A 1 H 4), then oxidatively cleaved with sodium periodate
  • the aryl group at the 4-position may be hydrogenated to be converted to a propyl group.
  • the CD ring precursor of the compound of the general formula (1) can be synthesized from a 25-hydroxygrandmanketone compound by a method as shown in Scheme 2. That is, the hydroxyl group at the 25-position of the 25-hydroxygrandmanketone is methoxymethylated (or may be trimethylsilylated), and the 8-position is ethoxylated with ethylethyl phosphonoacetate.
  • the obtained ester was reduced by DI BAL-H, and the obtained aryl alcohol was dehydrated and condensed with 2-mercaptobenzothiazole by Mitsunobu reaction, and then subjected to an oxidation reaction using Mo catalyst-hydrogen peroxide water.
  • a CD ring precursor is obtained.
  • the 25-hydroxygrandmanketone compound can be synthesized by ozonolysis of a known vitamin D derivative having a desired CD ring (Sandina, FJ, Mourino, S., Castedo, L., J. Org. Chem., 1986, 51, 1264-1269 .: Kiegiel, J., Wovkulic, PM, Uskokovic, M.R.Tetrahedron Lett., 1991, 32, 6057-6060 .: Fernadez, B., Pe rez , J. A. Grana, J. R., Castefo, L., Mourino, A., J. Org.
  • the desired compound of the present invention can be obtained by coupling the synthesized A-ring precursor and CD-ring precursor with a Ju1ia-type coupling by the method shown in Scheme 3.
  • the hydroxyl group at position 25 of the CD ring precursor is replaced with an acyl group, a substituted silyl group, or a substituted alkyl group. It is preferable to protect with a suitable protecting group such as a triethylsilyl group and a methoxymethyl group.
  • the CD ring precursor is treated with a strong base (such as butyl lithium) and reacted with the A ring precursor.
  • the obtained protected product is subjected to a deprotection operation, and purified by a conventional method such as reverse phase HPLC or thin layer chromatography to obtain the desired compound. Alternatively, the protected product may be subjected to deprotection after purification, and then further purified.
  • the compound represented by the general formula (2) of the present invention is a novel compound and its synthesis method is not limited at all. For example, it can be synthesized as shown in the following scheme 4 or schemes 5 and 6. it can.
  • Starting materials include commercially available 1,1-bis (hydroxymethyl) cyclopropane (Aldrich, etc.) ⁇ Jetyl 1,1-cycloalkanecarboxylate, for example, getyl 1,1-cyclobutanecarboxylate (4-membered ring, Wako Pure Chemical Industries, Ltd.) Medicine) Ethyl 1,1-cyclopentanecarboxylate (5-membered ring), getyl 1,1-cyclohexanecarboxylate (6-membered ring, Wako Pure Chemical Industries) and the like can be used.
  • One of the hydroxyl groups of 1,1-bis (hydroxymethyl) cycloalkane is protected to form a protected P-methoxybenzyl ether, which is then subjected to TPAP oxidation to form an aldehyde.
  • This aldehyde is reacted with vinylmagnesium bromide to produce an aryl alcohol derivative.
  • the protecting group on the primary hydroxyl group is deprotected to give an alcohol.
  • This alcohol is subjected to TPAP oxidation or the like to form an aldehyde, which is then reacted with arenylmagnesium bromide to form a desired eneine form, and its secondary hydroxyl group is silylated to form an A ring part precursor.
  • a compound having a vitamin D skeleton having a cycloalkane at the 2-position can be obtained by reacting the obtained A-ring part precursor with a CD-ring promoter in a suitable solvent using palladium. .
  • the obtained compound is subjected to a deprotection operation, and is separated and purified by a conventional method such as reverse phase HPLC or thin layer chromatography to obtain a target vitamin D derivative.
  • the compound of the CD ring portion of the vitamin D derivative a known compound such as (E) -de-A, B-8- (bromomethylene) cholestan-25-ol can be used.
  • the desired A CD ring compound may be obtained.
  • it can be synthesized from a known vitamin D derivative having a side chain corresponding to a desired CD ring compound.
  • TBSC1 tert-butyresimetizoresilizolechloride
  • DIBAL-H diisobutyl aluminum hydride
  • L1HMDS lithium bis (trimethylsilyl) amide
  • NMO N-methylmorpholine N-oxide
  • TPAP Tetrapropylammonium Pearl Tenate
  • TBSOTf tert-butyldimethylsilyl trifluoromethanesulfonate DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
  • Nuclear magnetic resonance spectra were measured using J EOL AL-400 or J E ⁇ L EC P-600.
  • EIMS and HREIMS were measured by the £ 1 method using JEOL JMS-SX 1028.
  • Infrared absorption was measured with JASCO FT-IR 8000.
  • UV Ultraviolet absorption
  • Silica gel column chromatography used Merck silica gel 60 (Merck sili ca gel 60 70-230 mesh). For preparative thin-layer chromatography, Merck silica gel 5744 was used.
  • Example 12 (1R, 2E, 6R, 7R) _7-[(R) -6-methoxymethoxy-6-methylheptane-2-yl] -6-methyl-2- [2- (benzothiazole- 2-sulfonyl) ethylidene] bicyclo [4.3.0] nonane ((1R, 2E, 6R, 7) -7- [(R) -6-Me t hoxyme t hoxy-6-me t hy 1 hep tan-2_yl] -6-metlr ⁇ -2 [2_ (benzothiazole_2-sulfoiiyl) ethylideiie] bicyclo [4.3 .OJ bandage ane, compound 15)
  • compound Tbl was synthesized from compound Sbl.
  • Compound P 3 (1.38 g, 3.41 thigh ol) was dissolve in a mixture of a and CH 2 Cl 2 a9 mL) and water (2 mL). The resulting solution was treated with DDQ (1.29 g, 1.5 eq) at 0 ° C. with stirring. After stirring at 0 ° C. for 40 minutes, the reaction mixture was diluted with ether and filtered through celite. The organic layer was washed with saturated NaHCO 3 solution and brine, dried over magnesium sulfate, filtered and evaporated.
  • compound Tb3 was synthesized from compound Sb3.
  • CDCI3) ⁇ 12.1, 18.9, 20.9, 20.9, 21.5, 22.5, 23.8, 26.1, 27.7, 29.2, 29.3, 29.4, 30.3, 32.3, 36.1, 36.4, 40.5, 40.6,
  • vitamin D derivative of the present invention The ability of the vitamin D derivative of the present invention to bind to human thymus VDR was tested.
  • the vitamin D derivatives of the present invention include the compounds 1a, 1b, 2a, 2b, 3a, 3b, Ja synthesized in Examples 13, 14, 15, 24, 34, 44, 54 described above. , Jb, Jc, Jd, Ual, Ubl, Ucl, Udl, Ua2, Ub2, Uc2, Ud2, Ua3, Ub3, Uc3, Ud3.
  • ⁇ ishi thymus VDR is Yamasa Shoyu Co., Ltd.
  • the ethanol solution 50111 of the vitamin D derivative or 1-, 25-dihydroxyvitamin D 3 of the present invention and the receptor solution 5001 are placed in a test tube, and after precipitating at room temperature for 1 hour, [ 3 H] 50/1 of 1,25-dihydroxyvitamin D 3 solution was added to a final concentration of 0.1 InM, and the mixture was incubated at 4 ° C. Dextran-coated carcoa 1 was added to the reaction solution, mixed, left to stand at 4 for 30 minutes, and centrifuged at 3000 rpm for 10 minutes to bind [ 3 H] to the receptor. ] 1 a, 25 Hydroxyvitamin D 3 and free [ 3 H] la, 25 dihydroxyvitamin D 3 were separated. The supernatant (500 1) was mixed with ACS-II (9.5 ml) (Amersham, Eng 1 and), and the radioactivity was measured.
  • y concentration at which 1 a, 25-dihydroxyvitamin D 3 inhibits the binding of [ 3 H] 1,25-dihydroxyvitamin D 3 to VDR by 50%
  • the compound represented by the general formula (1) or (2) of the present invention is a novel compound. It is expected to be useful as a drug such as a calcium metabolism regulator.

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Abstract

L'invention concerne un nouveau dérivé de vitamine D. Il s'agit d'un composé représenté par la formule générale (1), dans laquelle R1 représente un alkyle C3-8 éventuellement hydroxylé, linéaire ou ramifié ou un alcényle C3-8 éventuellement hydroxylé, linéaire ou ramifié et R2 représente un alkyle C1-12 éventuellement hydroxylé, linéaire ou ramifié.
PCT/JP2004/001003 2003-01-31 2004-02-02 Dérivé de vitamine d 2-substituée WO2004067504A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
JP2012524091A (ja) * 2009-04-17 2012-10-11 ヴィダシム，エルエルシー ビタミンｄ受容体アゴニストとその使用
CN107698580A (zh) * 2017-09-28 2018-02-16 上海彩迩文生化科技有限公司 一种苯并噻唑砜类化合物、其制备方法及应用
WO2023068322A1 (fr) * 2021-10-20 2023-04-27 学校法人帝京大学 Dérivé de vitamine d substitué par chaîne latérale de cycle cd

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641059A (ja) * 1991-11-01 1994-02-15 Chugai Pharmaceut Co Ltd ２β位に置換基を有するビタミンＤ誘導体
WO1998041500A1 (fr) * 1997-03-17 1998-09-24 Wisconsin Alumni Research Foundation Derives 2-alkyle-19-nor- de la vitamine d
WO2001092221A1 (fr) * 2000-05-31 2001-12-06 Wisconsin Alumni Research Foundation Composes de 2-ethyle et 2-ethylydene-19-nor-vitamine d

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641059A (ja) * 1991-11-01 1994-02-15 Chugai Pharmaceut Co Ltd ２β位に置換基を有するビタミンＤ誘導体
WO1998041500A1 (fr) * 1997-03-17 1998-09-24 Wisconsin Alumni Research Foundation Derives 2-alkyle-19-nor- de la vitamine d
WO2001092221A1 (fr) * 2000-05-31 2001-12-06 Wisconsin Alumni Research Foundation Composes de 2-ethyle et 2-ethylydene-19-nor-vitamine d

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
JP2012524091A (ja) * 2009-04-17 2012-10-11 ヴィダシム，エルエルシー ビタミンｄ受容体アゴニストとその使用
CN107698580A (zh) * 2017-09-28 2018-02-16 上海彩迩文生化科技有限公司 一种苯并噻唑砜类化合物、其制备方法及应用
WO2023068322A1 (fr) * 2021-10-20 2023-04-27 学校法人帝京大学 Dérivé de vitamine d substitué par chaîne latérale de cycle cd

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