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WO2006093290A1 - Dérivé de 19-norvitamine d substitué en position 9 - Google Patents

Dérivé de 19-norvitamine d substitué en position 9 Download PDF

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Publication number
WO2006093290A1
WO2006093290A1 PCT/JP2006/304149 JP2006304149W WO2006093290A1 WO 2006093290 A1 WO2006093290 A1 WO 2006093290A1 JP 2006304149 W JP2006304149 W JP 2006304149W WO 2006093290 A1 WO2006093290 A1 WO 2006093290A1
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compound
solution
mmol
added
ethyl acetate
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English (en)
Japanese (ja)
Inventor
Masato Shimizu
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Tokyo Medical and Dental University NUC
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Tokyo Medical and Dental University NUC
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Priority to JP2007506035A priority Critical patent/JP4887503B2/ja
Publication of WO2006093290A1 publication Critical patent/WO2006093290A1/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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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

Definitions

  • the present invention relates to a 9-substituted 19-nor vitamin D derivative effective for congenital vitamin dependence type II rickets.
  • Active vitamin D derivatives are widely used clinically as therapeutic agents for bone diseases such as osteomalacia, osteoporosis, and rickets.
  • vitamin D suppresses cell growth and induces differentiation and immune regulation, and is widely used as a specific drug for psoriasis of the skin, and is also being developed as a cancer therapeutic and immunomodulator.
  • Patent Document 1 shown below has a substituent at the 2a position represented by the following general formula (a), and the hydroxyl groups at the 1 and 3 positions are the a configuration and j8, respectively.
  • An arrangement, a vitamin D derivative, is disclosed.
  • This vitamin D derivative can be used as a medicine, for example, for the purpose of a therapeutic agent, an antitumor agent or an immunomodulator for a disease associated with abnormal calcium metabolism.
  • R 3 and R 4 may be substituted with a hydroxy group and may be a linear or branched lower alkyl group.
  • Patent Literature l WO0lZ062723 Disclosure of the invention
  • VDR type II rickets
  • W286R VDR 286th tryptophan (W) of VDR is mutated to an anoregine (R)
  • R anoregine
  • the present invention has been made in view of the problems as described above, and has transcriptional activity that activates the function of a mutant vitamin D receptor, and is a congenital vitamin dependence.
  • the present invention provides a 9-substituted 19-norvitamin D derivative, a method for producing the same, and a pharmaceutical composition containing them.
  • the compound of the present invention is a 9-substituted 19 norbitamine D derivative represented by the following general formula (1).
  • R 1 represents an alkyl group, an alkenyl group, or a hydroxyalkyl group
  • R 2 represents hydrogen or a hydroxyalkylidene group bonded through a double bond.
  • a 9-substituted 19-norvitamin D derivative represented by the following structural formula (3b) is preferable.
  • the compound of the present invention since it has a substituent at the 9-position, it can be adapted to the binding pocket of the mutant VDR (W286R VDR). This is because the mutant VDR has a larger ligand-binding pocket than the wild-type VDR. For this reason, a natural ligand creates a space at a large site, but according to the compound of the present invention, the 9-position substituent is compatible with this space, so that the mutant VDR can be compared. Can also show transcription activation ability.
  • the 9-substituted 19 norvitamin D derivative represented by the above general formula (2) comprises a ring A ketone body and a CZD ring phosphine oxide body having a substituent at the 9-position, Wittig-Horner coupling. Can be synthesized by the method.
  • the 9-substituted 19-norvitamin D derivative represented by the above general formula (3) is synthesized by a Julia coupling method by synthesizing A ring ketone body and CZD ring arylsulfone body having a substituent at the 9-position. can do.
  • the compound of the present invention can be used as a therapeutic agent for rickets or osteomalacia.
  • the compound of the present invention it is possible to provide a 9-substituted vitamin D derivative effective for congenital vitamin dependence type II rickets, a production method thereof and a pharmaceutical composition containing them. wear.
  • FIG. 1 shows the transcriptional activity of 9-aryl derivatives (3b) and natural ligands.
  • the 9-substituted 19-norvitamin D derivative represented by the above general formula (2) comprises a ring A ketone and a CZD ring phosphine oxide having a substituent at the 9-position by the Wittig-Horner coupling method. Can be synthesized.
  • the 9-substituted 19-norvitamin D derivative represented by the above general formula (3) comprises a ring A ketone and a CZD ring arylsulfone having a substituent at the 9-position by the Julia coupling method. Can be synthesized.
  • the A ring ketone body (8) can be easily obtained by a synthesis method using (1) quinic acid described in DeLuca HF et. Al, Tetrahedron Lett, 1991, 32, 7663-7666. it can. (1) After introducing quinic acid to the methyl ester form, the hydroxyl group is regioselectively protected to obtain the silyl ether form (4). Subsequently, the hydroxyl group at the 4-position is removed by the Barton method to obtain a 4-deoxy body (6). Reduction of the ester followed by sodium periodate oxidation gives the 1-keto form (8).
  • the TMS ether form (9) can be obtained from glucose by the method described in Shimizu M et. Al, Bioorg Med. Chem. Lett, 2003, 13, 809-812.
  • the CZD ring aryl sulfone represented by structural formulas (22) and (23) can be synthesized in 7 steps by 6 steps.
  • the compound (10) is obtained by a known method using vitamin D as a starting material.
  • the 8-keto body (11) is synthesized by converting the compound (10) into a silyl enol ether body under kinetic conditions, followed by treatment with butyl iodide.
  • 9 Burylmagnesium bromide is attached to the butyl-8-keto body (11), which leads to the tertiary alcohol body (12), followed by PCC oxidation to obtain the allylaldehyde body (13).
  • the arylsulfone form is obtained by carrying out the benzothiazole salt of the aryl alcohol forms (19) and (21), followed by an oxidation reaction to obtain the arylsulfone forms (22) and (23). be able to.
  • a compound (26) is synthesized by a julia coupling method of a CZD ring aryl sulfone body (22) and a ring-ring ketone body (9). Subsequently, the TMS group is selectively removed, and the hydroxyl group at the 2-position is subjected to Swern oxidation, followed by cyanomylation with jetylcyanomethyl phosphonate to obtain the compound (27). The cyanide is converted to the aryl alcohol by -step reduction, and further deprotected with CSA to give the 9-aryl (3b). A 9-butylene compound (3c) is also obtained by the same method.
  • the 9-substituted 19 norvitamin D derivative of the present invention can be used as a therapeutic agent for rickets or a therapeutic agent for osteomalacia (hereinafter also referred to as “therapeutic agent”).
  • the therapeutic agent is formulated with necessary additives and solid oral preparations, oral liquid preparations, or injections according to conventional methods. It can be prepared as a parenteral preparation such as an agent. Most preferred is a solid oral formulation.
  • a solid oral preparation When a solid oral preparation is prepared, after adding an excipient such as lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, etc., tablets, granules, powders, capsules, etc. can do.
  • an excipient such as lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, etc.
  • binders such as hydroxypropyl cellulose and hydroxypropyl methylcellulose (HPMC)
  • lubricants such as magnesium stearate, polyethylene glycol, starch, and talc, calcium fibroglycolate, and carme as necessary.
  • disintegrants such as roast calcium, stabilizers such as ratatose, solubilizing agents such as dartamic acid or aspartic acid, plasticizers such as polyethylene glycol, and colorants such as titanium oxide, talc, and yellow iron oxide.
  • disintegrants such as roast calcium, stabilizers such as ratatose, solubilizing agents such as dartamic acid or aspartic acid, plasticizers such as polyethylene glycol, and colorants such as titanium oxide, talc, and yellow iron oxide.
  • tablets or pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
  • inert diluent taste-masking agents such as purified water and ethanol
  • buffering agents can be added to obtain internal liquids, syrups, jelly agents, elixirs, and the like.
  • the injection may be a sterile aqueous or non-aqueous solution, suspension, emulsion, etc., and may be a subcutaneous, intramuscular and intravenous injection.
  • aqueous solution and suspension diluent include distilled water for injection and physiological saline.
  • diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and the like.
  • pH adjusters e.g., buffers, preservatives, wetting agents, emulsifiers, dispersants, stabilizers ( For example, latatoses), isotonic agents, local anesthetics, solubilizing agents (eg, glutamic acid, aspartic acid), etc. may be added.
  • the effective dose of the 9-substituted 19-norvitamin D derivative of the present invention varies depending on the patient's body weight, age, sex, administration method, physical condition, symptoms, dosage form, etc. It is preferably not less than ⁇ g and not more than 50 ⁇ g, more preferably not less than 0.01 ⁇ g and not more than 10 ⁇ g, and is preferably taken once or divided into two to several times.
  • Ozone gas was introduced for 8 hours. Next, oxygen gas was introduced for 1 hour, dimethyl sulfide (0.6 ml) was added at 78 ° C., the temperature was gradually raised, and the mixture was stirred until it reached room temperature. After concentrating the solvent, ice water was added and the mixture was extracted with ethyl acetate Z-hexane (1: 1). The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (180 g, 5% ethyl acetate Z-hexane) to obtain Compound 30 (6.8 g) quantitatively.
  • n-Butyllithium (2.32 ml, 3.67 mmol, 1.58 M hexane solution) was added to a solution of diisopropylamine (594 ⁇ 1, 4. 24 mmol) in anhydrous tetrahydrofuran (10 ml) cooled to 20 ° C. The mixture was further stirred for 15 minutes. Lithium diisopropylamide (LDA) was cooled to ⁇ 78 ° C., and a solution of compound 10 (917. Omg, 2.83 mmol) in anhydrous tetrahydrofuran (10 ml) was charged.
  • LDA Lithium diisopropylamide
  • Buresumagnesium bromide (3.37 ml, 3.37 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of the compound 33 (761.4 mg, 2.25 mmol) cooled to 0 ° C in anhydrous tetrahydrofuran (8 ml). After stirring for 3 hours, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (30 g) to obtain Compound 34 (766.6 mg, 93%) from the eluate of 5% ethyl acetate Z hexane.
  • n -Butyllithium (104 1, 0.165 mmol, 1.58M hexane solution) was added to a solution of phosphine oxide 37 (90.6 mg, 0.165 mmol) in anhydrous tetrahydrofuran (lml) cooled to 78 ° C. After stirring for 15 minutes, a solution of ketone body 8 (29.6 mg, 0.083 mmol) in anhydrous tetrahydrofuran (lml) was slowly added. After stirring at 78 ° C for 1.5 hours, the temperature was gradually raised and the mixture was stirred at 0 ° C for 2.5 hours.
  • the compound 46 (338.3 mg, 60%) was obtained from the elution part of 10% ethyl acetate Z hexane, and the protecting group was removed from the elution part of 25% ethyl acetate Z hexane. 46 ′ (9 1.5 mg, 18%) was obtained.
  • aldehyde compound 48 (198. lmg, 0.490 mmol) cooled to 0 ° C in ethanol (2 ml) was added sodium borohydride (18.5 mg, 0.490 mmol) and stirred for 1 hour. . Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated.
  • reaction A saturated aqueous solution of ammonium chloride was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (8 g) to obtain Compound 29 (97.5 mg, 96%, approximately 1: 1 mixture) from the eluate of 1% ethyl acetate Z-hexane.
  • UV Imax (EtOH): 247nm, 255nm, 264nm.
  • UV Imax (EtOH): 247nm, 255nm, 264nm.
  • n-Butyllithium (710 1, 1. 12 mmol, 1.58M hexane) in a solution of aranolenoreconole isomer 19 (400.6 mg, 1.02 mmol) in anhydrous tetrahydrane-furan (lml) cooled to 0 ° C Solution) and tosyl chloride (252.9 mg, 1.33 mmol) in anhydrous tetrahydrofuran (500 1) were added and stirred for 7 minutes.
  • Hexamethylphosphorustriamide (66 1, 0.377 mmol) and n-butyllithium (237 1, 0.377 mmol, 1.59 M hexane solution) were added to the (2 ml) solution and stirred for 15 minutes.
  • a solution of (120. Omg, 0.335 mmol) in anhydrous tetrahydrofuran (lml) was charged. After stirring at 78 ° C for 1 hour, the temperature was gradually raised over 2 hours, followed by stirring at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • UV Imax (EtOH): 245nm, 253nm, 262nm.
  • Camphorsulfonic acid (9.9 mg, 42.4 / zmol) was added to a methanol (250 1) solution of 19-nor 25, (5.2 mg, 7.07 mol), and the mixture was stirred at room temperature for 2 hours. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (3 g) to obtain Compound 2d (2.4 mg, 73%) from the eluate of 3% methanol Z ethyl acetate.
  • UV Imax (EtOH): 247nm, 255nm, 264nm.
  • 19-Nonole isomer 51a (E isomer, 13. lmg, 0.0147 mmol) in methanol (300 / z 1) solution was added with nephrosulfonic acid (34. lmg, 0.147 mmol, 10. Oeq) at room temperature The mixture was stirred for 2 hours. To the reaction solution was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (5 g) to obtain compound 3d (5.7 mg, 77%) from the 5% methanol / ethyl acetate eluate.
  • UV Imax (EtOH): 246nm, 254nm, 264nm.
  • Evaluation was performed using E-form (3b-2E) of 9-aryl derivative (3b) and 1, 25- (OH) D which is a natural ligand as a comparative example. Measurements were taken in COS-7 cells, 9-substituents.

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  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
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Abstract

l'invention concerne un dérivé de vitamine D à capacité d'activation de transcription qui peut solliciter la fonction d'un récepteur de vitamine D mutée (w286R VDR), une méthode d'obtention du dérivé de vitamine D, et un agent pharmaceutique comprenant ledit dérivé de vitamine D. Ce dérivé, qui comporte un substituant en position 9, peut donc s'inscrire dans une poche de liaison du récepteur de vitamine D mutée. Le substituant en position 9 est de préférence un groupe allyle. L'exemple idéal de dérivé de vitamine D est un dérivé de 2-hydroxyéthylidène-9-allyle-19-norvitamine D possédant un groupe hydroxyl éthylidène en positon 2. Etant doté d'une capacité améliorée d'activation de transcription, le dérivé peut être utilisé comme agent thérapeutique, par exemple dans le cas de rachitisme ou d'ostéomalacie.
PCT/JP2006/304149 2005-03-04 2006-03-03 Dérivé de 19-norvitamine d substitué en position 9 Ceased WO2006093290A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107501317A (zh) * 2017-09-13 2017-12-22 上海皓元医药股份有限公司 一种帕立骨化醇中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02262555A (ja) * 1988-05-04 1990-10-25 Ire Medgenix Sa 新しいビタミンｄ誘導体、治療への適用とビタミンｄの代謝生成物の検定への適用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02262555A (ja) * 1988-05-04 1990-10-25 Ire Medgenix Sa 新しいビタミンｄ誘導体、治療への適用とビタミンｄの代謝生成物の検定への適用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOUILLON R. ET AL.: "Structure function analysis of vitamin D analogs with C-ring modifications", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 267, no. 5, 1992, pages 3044 - 3051, XP003001259 *
D'HALLEWEYN C. ET AL.: "Synthesis of (C-11)-substituted analogs of 1alpha,25-dihydroxyvitamin D3", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 2, no. 5, 1992, pages 477 - 480, XP003001258 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107501317A (zh) * 2017-09-13 2017-12-22 上海皓元医药股份有限公司 一种帕立骨化醇中间体的制备方法

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JP4887503B2 (ja) 2012-02-29

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