WO2000066548A1 - Derives 2-alkyles de vitamine d - Google Patents

Derives 2-alkyles de vitamine d Download PDF

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Publication number
WO2000066548A1
WO2000066548A1 PCT/JP1999/005778 JP9905778W WO0066548A1 WO 2000066548 A1 WO2000066548 A1 WO 2000066548A1 JP 9905778 W JP9905778 W JP 9905778W WO 0066548 A1 WO0066548 A1 WO 0066548A1
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WO
WIPO (PCT)
Prior art keywords
group
hydroxy
methyl
compound
ethyl
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Application number
PCT/JP1999/005778
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English (en)
Japanese (ja)
Inventor
Hiroaki Takayama
Toshie Fujishima
Zhaopeng Liu
Katsuhiro Konno
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Publication of WO2000066548A1 publication Critical patent/WO2000066548A1/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
    • 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

  • the present invention relates to a novel vitamin D derivative, and more particularly, to a vitamin D derivative having a lower alkyl group at the 2-position and -O- or 1-CH (CH 3 )-at the 22-position.
  • Other calcium metabolism regulating action, the growth inhibitory effect and differentiation inducing effect of tumor cells, to have many physiological activities such as immune regulatory effects intelligence Have been.
  • Some of activated vitamin D 3, long-term and by sequential administration, hypercalcemia present compounds have the disadvantage that straining force, such compounds antitumor agents, antirheumatic agents, etc. Not suitable for use. Therefore, the synthesis of many vitamin D derivatives has been studied for the purpose of separating the action of these vitamin Ds.
  • the present invention has a substituent at the 2-position, the 20-position is epoxidized, and the 22-position is 1- Or —
  • the present invention is also an object to be achieved by evaluating the raw material activity of the synthesized vitamin D 3 derivatives.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, synthesized a CD ring compound containing a desired side chain portion from vitamin D 2 and placed it in the (S)-or (R) -configuration.
  • Vitamin D derivatives having various configurations were successfully synthesized by coupling with the A-ring compound having a methyl group at the 2-position synthesized from methyl 3-hydroxy-2-methylpropionate as a starting material.
  • the present invention has been provided.
  • X represents — ⁇ — or —CH (CH 3 ) —
  • R 1 represents a saturated or unsaturated carbon atom having 1 to 15 carbon atoms which may be substituted with 1 to 3 hydroxyl groups or a protected hydroxyl group.
  • R 2 represents a lower alkyl group
  • R 2 is a methyl group.
  • X is —CH (CH 3 ) 1 and the configuration at the 22nd position is an R configuration, or X is —O—.
  • R 1 represents a saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms, which is substituted with one hydroxyl group or a protected hydroxyl group.
  • R 1 is a 4-ethyl-4-hydroxyhexyl group or a 3-hydroxy-3-methylbutyl group.
  • Particularly preferred compounds of the general formula (I) are (5Z, 7E)-(1S, 2S, 3R, 2OR) —2-methyl-22-oxa-24,26,27-trihomo-1,9— Seco 5, 7, 10 (19) —Kolles 1, 1, 3, 25—triol;
  • a pharmaceutical composition for example, a therapeutic agent for a disease associated with abnormal calcium metabolism, an antitumor agent or an immunoregulatory agent
  • a pharmaceutical composition comprising the above-mentioned biminmin D derivative of the present invention as an active ingredient.
  • X represents —O— or —CH (CH 3 ), and R 1 has 1 to 15 carbon atoms which may be substituted with 1 to 3 hydroxyl groups or protected hydroxyl groups. Represents a saturated or unsaturated aliphatic hydrocarbon group.
  • saturated aliphatic hydrocarbon group generally means a linear or branched alkyl group having 1 to 15 carbon atoms, such as a methyl group, an ethyl group, and an n-propyl group.
  • the unsaturated aliphatic hydrocarbon group generally indicates a linear or branched alkenyl group or alkynyl group having 2 to 15 carbon atoms, for example, a 2-propenyl group, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl Cenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-propynyl, 2-butynyl, 3-butynyl , 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-heptinyl, 3- A heptynyl group, a 4-heptyny
  • a 4-methyl-2-pentynyl group, a 4-ethyl-2-hexynyl group, a 4-methyl-2-pentenyl group, a 4-ethyl-2-hexenyl group and the like are exemplified.
  • the saturated or unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group is a group wherein any hydrogen atom of the above-mentioned saturated or unsaturated hydrocarbon group may be substituted with one or more hydroxyl groups.
  • the number of the substituted hydroxyl groups is 0, 1, 2 or 3, preferably 1 or 2, and more preferably 1.
  • saturated or unsaturated aliphatic hydrocarbon group substituted by a hydroxyl group include 2-hydroxy-2-methylpropyl group, 3-hydroxy-2-methylpropyl group, and 2,3-dihydroxy-2-methyl Propyl group, 2-ethyl-2-hydroxybutyl group, 2-ethyl-3-hydroxybutyl group, 2-ethyl-2,3-dihydroxybutyl group, 2-hydroxy-2- (n-propyl) pentyl group, 3-hydroxy-2 — (N-propyl) pentyl group, 2,3-dihydroxy-2- (pentyl) pentyl group, 2-hydroxy-3-methylbutyl group, 3-hydroxy xy-3-methylbutyl group, 4-hydroxy-3-methylbutyl group, 2,3-dihydroxy-3-methylbutyl group, 2,4-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl , 3-Ethyl-2-hydroxypentyl group, 3-Ethyl-3-
  • 6-hydroxyheptyl group 5-ethyl-4,5-dihydroxyheptyl group, 5-ethyl-4,6-dihydroxyheptyl group, 5-ethyl-5,6-dihydroxyheptyl group, 4-hydroxy-5- (n-propyl) Octyl group, 5-hydroxy-1- (n-propyl) octyl group, 6-hydroxy-5- (n-propyl) octyl group, 4,5-dihydroxy-5- (n-propyl) octyl group, 4, 6-dihydroxy-1- (n-propyl) octyl group, 5,6-dihydroxy-5- (n-propyl) octyl group, 5-hydroxy-6-methylheptyl group, 6-hydroxy-6-methylheptyl group, 7 —Hydroxy-6-methylheptyl group, 5,6-dihydroxy-1-6-methylheptyl group, 5,7-dihydroxy-6-methylheptyl group, 6,7
  • Cypentyl group 3-ethyl-4-hydroxy Methyl, 3-ethyl-3,4-dihydroxypentyl, 4-hydroxy-4-methylpentyl, 5-hydroxy-1-methylpentyl, 4,5-dihydroxy-4-methylpentyl, 4-ethyl 4-hydroxyhexyl, 4-ethyl-5-hydroxyhexyl, 4-ethyl-4,5-dihydroxyhexyl, 4-hydroxy-4-methyl-2-pentenyl, 5-hydroxy-1-methyl-2- Pentenyl group, 4,5-dihydroxy-4-methyl-2-pentenyl group, 4-ethyl-4-hydroxy-12-hexenyl group, 4-ethyl-5-hydroxy-2-hexenyl group, 4-ethyl-4-, 5- Dihydroxy-2-hexenyl group, 4-hydroxy-4-methyl-1-pentynyl group, 5-hydroxy-4-methyl-2-pentynyl group, 4,5-dihydroxy — 4-methyl-2-pentyny
  • Examples of the hydroxyl-protecting group in the general formula (I) include an acyl group, a substituted silyl group, and a substituted alkyl group, and are preferably an acyl group or a substituted silyl group.
  • acyl group '' means a substituted carbonyl group
  • ⁇ substituent of carbonyl group '' as used herein means a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent.
  • the acyl group is a formyl group, a lower alkyl group.
  • the substituted silyl group means a silyl group substituted by a lower alkyl group which may have one or more substituents or an aryl group which may have a substituent, and is preferably 3-substituted.
  • Preferred examples of the substituted silyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldiphenylsilyl group, a t-butyldimethylsilyl group, and the like.
  • the substituted alkyl group refers to an alkyl group substituted with one or more substituents.
  • preferred examples of the substituent include an alkyloxy group which may have a substituent and an alkyloxy group which may have a substituent. Examples include good aryl groups, and in particular, an alkyloxy group which may have a substituent.
  • Examples of the substituted alkyl group substituted with an alkyloxy group which may have a substituent such as an alkyloxy group include, for example, a methoxymethyl group, a 2-methoxyethoxymethyl group, and a tetrahydropyran-1-yl group.
  • substituents include a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, an alkyl group, an alkyloxy group, an acyloxy group, and a sulfonyl group.
  • R 2 represents a lower alkyl group.
  • the lower alkyl group means, for example, an alkyl group having 1 to 6 carbon atoms.
  • R 2 is preferably methyl, E Ji Le, propyl, particularly preferably methyl.
  • any of the compounds having a steric configuration of a hydroxyl group at the 1-position and 3-position and a lower alkyl group at the 2-position is included in the present invention.
  • R 1 in the general formula (I) represents an unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group, and when a double bond is contained, cis or trans is generated thereby.
  • R 1 in the general formula (I) represents an unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group, and when a double bond is contained, cis or trans is generated thereby.
  • particularly preferred specific compounds include (5 Z, 7 E) ⁇ (IS, 2 S, 3R, 20 R) — 2-methyl-22-oxa
  • the method for synthesizing the compound of the general formula (I) of the present invention is not limited at all.
  • the A ring portion and the CD ring portion of the bimin D derivative are separately synthesized.
  • Ring A compounds having a lower alkyl group at the 2-position are known, for example, LKonno et al., Bioorg. Med. Chem. Lett., 8 (1998), P.151-156; or ⁇ ⁇ Fujishima et al., Bioorg. M ed. Chem. Lett., 8 (1998), pp. 215-2148. Specifically, it can be synthesized according to the following reaction scheme. When a compound other than a methyl group at the 2-position is synthesized, the compound can be synthesized in the same manner using the corresponding starting material.
  • Ph 3 P CH 2 , THF, 0 to room temperature
  • CD ring part of vitamin D derivatives can be obtained by various methods.
  • R 1 group as a side chain wherein R 1 is a saturated or unsaturated aliphatic hydrocarbon having 1 to 15 carbon atoms which may be substituted by 1 to 3 hydroxyl groups or protected hydroxyl groups.
  • a CD ring compound having the following formula: can be synthesized, for example, by the following reaction.
  • Hal represents a halogen atom.
  • the starting compounds used in the above reaction are known compounds or compounds that can be easily synthesized from known compounds.
  • the reaction is carried out using metal alkoxides, metal hydrides, alkyl lithium, metal hydroxides, metal amides, carbonates, amines and other bases (preferably metal hydrides such as sodium hydride, potassium hydride, calcium hydride) In a suitable solvent (18-crown-16, THF, etc.).
  • an alcohol compound is obtained by removing the protecting group for the hydroxyl group at the 8-position of the obtained compound, and this is oxidized with an appropriate oxidizing agent to obtain a ketone compound having an oxo group at the 8-position.
  • a CD ring compound that can be coupled to the A ring compound can be obtained.
  • —CH CHJ—R 1 group (where R 1 is 1 to 3 hydroxyl groups) Or a saturated or unsaturated aliphatic hydrocarbon group having 1 to 15 carbon atoms which may be substituted with a protected hydroxyl group.)
  • the starting compound used in the above reaction is a known compound or a compound which can be easily synthesized from a known compound.
  • the reaction is carried out using metal alkoxides, metal hydrides, alkyl lithium, metal hydroxides, metal amides, carbonates, amines and other bases (preferably sodium amide, potassium pistrimethylsilylamide, sodium bistrimethylsilylamide, lithium diisopropyl
  • the reaction can be carried out in a suitable solvent (eg, THF) in the presence of an amide (metal amide such as LDA).
  • THF a suitable solvent
  • an amide metal amide such as LDA
  • vitamin D derivatives with the desired side chains can be used to obtain CD ring compounds.
  • known vitamin D derivatives having various side chains include, for example, JP-A-61-265550, JP-A-6-72994, JP-A-6-256930, Vitamin D derivatives described in Japanese Patent Application Laid-Open Nos. 510-36569 and 415-5733 are listed. That is, after protecting a hydroxyl group of such a vitamin D derivative with a protecting group, and Ozon'norishisu (ozone decomposition), then it is possible to obtain the alcohol compound having a hydroxyl group at the 8-position by reduction N a BH 4 .
  • a CD ring compound having a desired side chain can be obtained by obtaining a ketone compound having an oxo group and further converting the oxo group at the 8-position into a promethylene group.
  • the force coupling reaction between the A ring compound and the CD ring compound can be performed by a known conventional method. That is, a CD ring compound having a bromoethylene group at the bonding point with the A ring portion obtained by the above method, and an A ring compound having a triple bond at one end and a double bond at the other end, Coupling can be achieved by reacting with a palladium catalyst (for example, Pd 2 (db a) 3 and triphenylphosphine (also abbreviated as PPh 3 )) in a suitable solvent.
  • a palladium catalyst for example, Pd 2 (db a) 3 and triphenylphosphine (also abbreviated as PPh 3 )
  • the product is purified by a conventional method such as thin-layer chromatography, and the hydroxyl-protecting group is removed to obtain the desired biminamine D derivative having a methyl group at the 3-position. it can.
  • the compound of the present invention is preferably formulated into an appropriate dosage form together with a pharmaceutically acceptable carrier, excipient, disintegrant, lubricant, binder, flavoring agent, coloring agent and the like, and used.
  • 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 type, constitution, age, sex, administration route, dosage form, and the like.
  • the lower limit of the dose per adult per day In the range of 0.001 / g to 0., preferably 0.0
  • the upper limit of the dose is about 1 g, and the upper limit of the dose can be selected from 100 g to 10,000 g per adult per day, preferably from 200 zg to l000 / zg, and should be administered once to three times a day. Can be. (Example)
  • Compound 12 was synthesized from compound 6 according to the following reaction scheme.
  • UV (EtOH) A mai 265 nm, A mjn 226 nm.
  • n-butyllithium (1.54 ⁇ ) (4.26 ml, 2 eq, 6.56 mmol) was added to 5 ml of a THF solution of diisopropylamine (o.92 ml, 2 eq, 6.56 mmol), and the mixture was stirred for 0.5 hours.
  • n-butyllithium (1.54 ⁇ ) (4.26 ml, 2 eq, 6.56 mmol) was added to 5 ml of a THF solution of diisopropylamine (o.92 ml, 2 eq, 6.56 mmol), and the mixture was stirred for 0.5 hours.
  • UVA BaY 264nm A min 228nm A 228 / A 264 0.62
  • UV ⁇ thigh 263MI A min 227nm A 228 / A 264 0.56
  • ⁇ thymus 1 h 25-dihydroxyvitamin D 3 receptor purchased from Yamasa Biochemcal (Choshi, Chiba, Japan), 0.05 M phosphate buffer containing 0.3 M KC 1 and 5 mM dithiothreitol (PH 7.4) was.
  • Receptor solution 500 1, 0. 23 mg protein
  • [ 3 H] -la 25-dihydroxyvitamin D 3 was added to the receptor mixture to a concentration of 0.1 nM, and the mixture was allowed to stand at 4T:- ⁇ .
  • the binding property of the compound of the present invention was determined by a ratio where the binding property of 1 ⁇ , 25-dihydroxyvitamin D 3 was 100.
  • the compounds tested were the eight vitamin D derivatives synthesized in the examples. The results obtained are shown below.
  • 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.
  • the compounds of the present invention have the potential to be useful reagents in the study of the metabolism of active vitamin D 3 (ie, 1,25-dihydroxyvitamin D 3 ).

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  • Chemical & Material Sciences (AREA)
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  • Nutrition Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne de nouveaux dérivés de la vitamine D3, qui sont substitués en position 2, épimérisés en position 20, qui présentent un -O- ou un -CH(CH3)- en position 22, et qui sont représentés par la formule générale (I) ci-après : dans laquelle X désigne -O- ou -CH(CH3)- ; R1 représente un groupe hydrocarbure C¿1?-C15 aliphatique saturé ou insaturé, pouvant être substitué par un à trois groupes hydroxyle éventuellement protégés ; et R?2¿ représente un alkyle inférieur.
PCT/JP1999/005778 1999-04-28 1999-10-20 Derives 2-alkyles de vitamine d WO2000066548A1 (fr)

Applications Claiming Priority (2)

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JP11/121589 1999-04-28
JP12158999 1999-04-28

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WO2000066548A1 true WO2000066548A1 (fr) 2000-11-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1219599A1 (fr) * 1999-08-27 2002-07-03 Chugai Seiyaku Kabushiki Kaisha Derives de vitamine d ayant des substituants a la position 2 alpha
WO2013180881A1 (fr) * 2012-05-30 2013-12-05 Wisconsin Alumni Research Foundation Cristallisation de (20r,22r)-2-méthylène-19-nor-22-méthyl-1α,25-dihydroxyvitamine d3 et précurseurs correspondants

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010351A1 (fr) * 1988-04-21 1989-11-02 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis Nouveaux analogues de vitamine d
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
US5877168A (en) * 1995-02-10 1999-03-02 Chugai Seiyaku Kabushiki Kaisha Vitamin D derivative with substituent at the 2β-position

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010351A1 (fr) * 1988-04-21 1989-11-02 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis Nouveaux analogues de vitamine d
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
US5877168A (en) * 1995-02-10 1999-03-02 Chugai Seiyaku Kabushiki Kaisha Vitamin D derivative with substituent at the 2β-position

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1219599A1 (fr) * 1999-08-27 2002-07-03 Chugai Seiyaku Kabushiki Kaisha Derives de vitamine d ayant des substituants a la position 2 alpha
EP1219599A4 (fr) * 1999-08-27 2002-09-11 Chugai Pharmaceutical Co Ltd Derives de vitamine d ayant des substituants a la position 2 alpha
WO2013180881A1 (fr) * 2012-05-30 2013-12-05 Wisconsin Alumni Research Foundation Cristallisation de (20r,22r)-2-méthylène-19-nor-22-méthyl-1α,25-dihydroxyvitamine d3 et précurseurs correspondants
JP2015518044A (ja) * 2012-05-30 2015-06-25 ウイスコンシン アラムニ リサーチ ファンデーション （２０Ｒ，２２Ｒ）−２−メチレン−１９−ノル−２２−メチル−１α，２５−ジヒドロキシビタミンＤ３および関連前駆体の結晶化
US9212137B2 (en) 2012-05-30 2015-12-15 Wisconsin Alumni Research Foundation Crystallization of (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D3 and related precursors
AU2013267872B2 (en) * 2012-05-30 2017-07-13 Wisconsin Alumni Research Foundation Crystallization of (20R,22R)-2-methylene-19-nor-22-methyl-1alpha,25-dihydroxyvitamin D3 and related precursors

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