WO2002066424A1

WO2002066424A1 - Vitamin d derivative having substituent in 2-position

Info

Publication number: WO2002066424A1
Application number: PCT/JP2002/001604
Authority: WO
Inventors: Hiroaki Takayama; Atsushi Kittaka; Yoshitomo Suhara; Toshie Fujishima
Original assignee: Chugai Seiyaku Kabushiki Kaisha
Priority date: 2001-02-23
Filing date: 2002-02-22
Publication date: 2002-08-29
Also published as: JPWO2002066424A1

Abstract

A novel vitamin D derivative having a specific substituent incorporated in the 2-position. The vitamin D derivative is represented by the general formula (1): (1) (wherein A represents linear or branched lower alkyl optionally substituted by hydroxy and m is a number of 0 to 2).

Description

Specification

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. Background art

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.

Among many 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).

Examples of the vitamin D derivative having a substituent at the 2-position 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).

However, there is no report on the synthesis of a vitamin D derivative having a phenyl group or a phenylalkyl group at the 2-position, and its physiological activity has not been studied.

Thus, 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.

That is, according to the present invention, general formula (1):

General formula (1)

(In the formula, 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.)

Is provided.

In the general formula (1), preferably, m is 0 to 2, and 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.

In the general formula (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 α-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, Α 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.)

Is preferably represented by

Further, according to the present invention, 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.

BEST MODE FOR CARRYING OUT THE INVENTION

The disclosure of Japanese Patent Application No. 2001-48486, which is the application on which the priority claimed by the present application is based, is entirely incorporated herein by reference.

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.

TBDMSOTf (4.75 eq)

2,6-lutidine (6 eq)

CH C

0 ^s & TBDMSO OTBDMS

(3Ϊ

(P ₃ P) ₄ Pd (0.3 eq)

Et ₃ N-/ toluene

Reflux

TBDMSO

In the method shown in the above reaction scheme, a binding-crystalline epoxide丄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. Oxyaltrose derivative ^ J Next, the benzylidene acetal moiety protecting the hydroxyl groups at the 4-position and the 6-position is cleaved while brominating with N-prosuccinimide or the like to obtain a promide. While forming olefins at the 5- and 6-positions of the bromide with zinc dust and sodium cyanoborohydride, the aldehyde thus obtained is reduced with a reducing agent (for example, sodium borohydride), leading to alcohol A. A leaving group is selectively introduced into the primary hydroxyl group of alcohol A (for example, by tosylation), and an ethynyl group is introduced at the 1-position via, for example, an epoxide to obtain enyne. After treating the enyne ___ with potassium carbonate or the like to silylate the two hydroxyl groups of the resulting enyne (e.g., tert-butyldimethylsilinolelation), 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.

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 ϋ_ 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 の 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. Then, after synthesizing an epoxide in which the configuration of the carbon functional group at the 3-position is inverted from that described above by the same reaction as in the above reaction scheme, the protecting group may be temporarily changed from a benzoyl group to a silyl group. For example, the benzoyl protecting group is removed under basic conditions, eg, with a catalytic amount of sodium methoxide, followed by silicidation. As the silyl group, for example, a tert-butyldimethylsilyl group can be used. Using an epoxide in which a benzoyl group has been converted to a silyl group, Similarly, by introducing an ethel group at the 1-position, 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.

In addition, 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. Specifically, by reacting the bromide ^ _ in the above reaction scheme with zinc powder without using sodium borohydride, the stereo configuration of the 2-position hydroxy group of the 5-hexenediol derivative A becomes R And a mixture of diastereomers that are S. Hereinafter, 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.

Here, as the compound of the CD ring portion of the vitamin D derivative, a known compound can be used. Alternatively, starting from a known CD ring compound, the side chain can be appropriately modified to obtain a desired CD ring compound. Alternatively, the CD ring compound can be obtained from a known vitamin D derivative having a corresponding side chain.

In the general formula (1), A represents a linear or branched lower alkyl group which may be substituted with a hydroxy group.

In this specification, 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. , N-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl, 4-methylpentyl, hexyl, 4-ethylhexyl Group, heptyl group, octyl group, nonyl group, decaninole group and the like.

Preferably, 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.

The term “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. In A, 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.

In the general formula (1), 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. Specifically, 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.

Among the compounds of the general formula (1) of the present invention, 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 R, 20 R)-2 benzene 9,10—Seco 5,7,10 (1 9) —Cholesta triene 1,3,25—triol, (5 Z, 7 E) 1 (IS , 2 R, 3 R, 2 OR) 1 2_phenethyl-9,10-Seco 1 5 7, 1 0 (1 9) -cholesta triene-1,3,25-triol, (5Z, 7E) -1 (1S, 2S, 3S, 2OR) —2-phenyl-1 9,10 —Seco 5, 7, 1 0 (1 9) -cholestatriene-1,3,25—triol, (5Z, 7E) one (1S, 2S, 3S, 20R) —2—benzyl — 9,10-1 Seco 5, 7, 1 0 (1 9) —Cholestatriene-1,3,25—Triol, (5 Z, 7 E)-(1 S , 2 S, 3 S, 20 R) — 2-phenethyl-1,9,10—Seco 5,7,10 (19) -cholestatriene-1,3,25-triol, (5 Z, 7 E ) 1 (IS, 2 R, 3 S, 20 R) _2_Fenrou 9,10—Seco-5,7,1 0 (1 9) —Cholestatriene 1,3,25—Triol, ( 5 Z, 7 E)-(1 S, 2 R, 3 S, 2 OR) —2—Benzyl 9,10—Seco _5,7,1 0 (1 9) —Cholestatriene 1,3,25 —Triol, (5 Z, 7 E)-(1 S, 2 R, 3 S, 20 R) — 2-phenethyl-9,10—seco-5,7,1 0 (1 9) —cholestatriene 1, 3, 25—triol.

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. day _{0. 001 μ β ~0. 1 μ} g range, preferably 0. 0 1 M g before and after, the range for adult per day 1 00 ig~ 1 0000 μ g is the upper limit of the dose, preferably 200 tg The dose can be selected within the range of ~ 1 000 / ig, and can be administered in 1 to 3 times a day. Example

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples. Unless otherwise specified, commercially available reagents were used as they were.

For 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. Was measured at room temperature using. EIMS and HREIMS were measured using JMS-SX102A (JASCO).

(Example 1)

(1) Methyl 3-C-benzyl-4,6-0-benzylidene-3-deoxy-en-D-alto-pifunoside (Methyl 3-C-benzyl-4,6-0-benzylidene-3-deoxy- -Synthesis of D-altropyranoside, compound 2)

Methyl 2,3-anhydro-4,6-0- benzylidene- -D-mannoviranoside (Methyl

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 次いで 0

(200 mL) and then with saturated saline (200 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure on a rotary evaporator, and purified by silica gel ram chromatography (silica gel 150 g, 10% → 25% ethyl acetate / hexane) to give a colorless foamy compound 2. 3.77 g was obtained (91% yield).

_{¾ NMR (400 MHz, CDC1 3} ) δ 7.52-7.50 (2Η, m), 7.40-7.36 (3H, m), 7.29- 7.26 (5H, m), 7.21-7.18 (1H, m), 5.65 (1H, s), 4.61 (1H, s), 4.33 (1H, dd, J = 4.9, 10.2 Hz), 4.20 (1H, dd, J = 5.3, 10.2 Hz), 4.11 (1H, dt, J = 4 • 9, 10.2Hz), 3.82 (1H, t, J = 10.2 Hz), 3.79 (1H, brS), 3.47 (3H, s), 3. 08 (1H, dd, J = 5.1, 13.9 Hz), 2.44 (1H, m).

EIMS m / z: 356 (M ) +, 324 (M- CH 3 0H) +.

(2) Methyl 4-0-benzoyl-3-C-benzyl-6-promo-3,6-dideoxy- -D- anoretrohyphnoside (Methyl 4-0-benzoyl— 3—C benzyl-6_bromo—3 Synthesis of 6-dideoxy-a-D-altropyranoside conjugated product 3)

Compound 2 (2.29 g, 6.4 mmol), an alcohol, was dissolved in carbon tetrachloride (64 mL) through an alumina column, and N-promosuccinimide (1.37 g, 7.7 mmol) and barium carbonate (708 mg, 3.6 Ol) and heated to reflux at 80 ° C for 40 minutes under an argon atmosphere. The reaction solution was filtered, ethyl acetate (350 mL) was added to the filtrate, and the mixture was washed with a 0.1N aqueous sodium thiosulfate solution (50 mL). The organic layer was washed with saturated sodium hydrogen carbonate © anhydrous solution (50 mL), then H ₂ 0 was washed successively with (50 mL) further saturated brine (50 mL), dried over anhydrous sodium sulfate. After drying, the obtained organic layer is passed through a pad of silica gel, the eluate is concentrated under reduced pressure, and purified by silica gel column chromatography (silica gel 110 g, 10% → 25% ethyl acetate Z hexane) to give a white foam. 2.39 g of Compound 3 was obtained (yield: 85%).

¾ image _{R (400 MHz, CDC1 3)} δ 8.06-8.04 (2Η, m), 7.63-7.60 (1H, m), 7.50 - 7.46 (2Η, m), 7.28-7.10 (5H, m), 5.14 (1H , dd, J = 4.8, 6.2 Hz), 4.62 (1H, d, J = 3.7 Hz), 4.28-4.25 (1H, m), 3.83 (1H, s), 3.57-3.45 (5H, m), 3.22 (1H, dd, J = 7.8, 13.6 Hz), 2.78 (1H, dd, J = 7.7, 13.6 Hz), 2.51 (1H, ddd, J = 4.8, 7.7 Hz).

EIMS m / z: 436 (M) ⁺ , 404 (M-C0H) ⁺ .

(3) (2S, 3R, 4R) -4-Benzoyloxy_3-benzylhex-5-ene-1,2-diol ((2S, 3R, 4R) -4-Benzoyloxy-3-benzylhex-5- Synthesis of en-l, 2-diol, lig compound 4) Compound 3 (1.29 g, 2.97 mmol), a bromide, was dissolved in 1-propanol (50 mL), and distilled water (5.0 mL) was added. The obtained solution was heated to 95 ° C in advance, zinc dust (5.82 g, 89.1 mmol) and sodium cyanoborohydride (373 mg, 5.94 mmol) were added thereto, and the mixture was heated and refluxed at 110 ° C for 40 minutes. . After cooling, the mixture was filtered through a folded paper filter, sodium borohydride (224 mg, 5.94 mmol) was added to the filtrate at room temperature, and the mixture was stirred for 5 minutes. The insolubles were removed by filtration, and the filtrate was concentrated by adding silica gel (6 g). . The residue was purified by silica gel column chromatography (silica gel 95 g, 2% → 50% ethyl acetate / hexane) to obtain 727 mg of colorless oily compound 4 (yield 75%).

_{¾ NMR (600 MHz, CDC1 3} ) δ 8.04-8.03 (2Η, m), 7.58-7.50 (1H, m), 7.45 - 7.40 (2H, m), 7.26-7.23 (2H, m), 7.17-7.18 ( 3H, m), 5.91 (1H, ddd, J = 5.7, 10.7, 16.7 Hz), 5.59 (1H, t, J = 5.5 Hz), 5.35-5.27 (2H, in), 4.05 (1H, m), 3.63 (1H, dd, J = 8.5, 11.0 Hz), 3.54-3.52 (1H, m), 2.92 (1H, dd, J = 6.0, 14.5 Hz), 2.75 (1H, dd, J-6.0, 14.5 Hz), 2.24-2.12 (1H, m).

EIMS m / z: 326 (M ) +, 308 (M- H 2 0) +.

HREIMS calcd for [C ₂₀ H ₂₂ 0 ₄ ] 326.1518, found for 326.1521.

(4) (2S, 3R, 4R) -4-Benzoyloxy-3-benzyl-1-[(p-toluenesulfoninole) oxy] hexa-5-en-2-ol ((2S, 3R, 4R)-4- Benzoyloxy- 3-benzyl- 1- [-toluenesulfonyl) oxy] hex_5-en-2-ol

Compound 4 (59.7 mg, 0.183 mmol) was dissolved in methylene chloride (1.83 mL), and tosyl chloride (38.4 mg, 0.20 mmol) and 4_ (N, N-dimethylamino) pyridine (2.2 mg, 0.02 t ol) and phottriethylamine (38.0 mL, 0.275 marauder) 1), and stirred at room temperature for 14 hours under an argon atmosphere. The reaction mixture was partitioned between acetic acid Echiru (50 mL) one H ₂ 0 (20 mL). The organic layer was washed successively with H ₂ O (20 mL) and saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. And 10% to 20% ethyl acetate / hexane) to give Compound 5 as a colorless oil (72.0 mg, crude yield 82%). This compound was used for the next reaction without further purification.

EIMS m / z: 480 (M) +.

(5) (3R, 4R, 5R) -3 Benzoyloxy-4_benzyl-5,6_epoxyhex-1-ene ((3R, 4R, 5R) — 3 -Benzoyloxy_4 -benzyl-5, 6-epoxyhex -Synthesis of l_ene

Compound 5 (1.45 g, 3.01 mol), which is a tosylate, was dissolved in THF (30.1 mL), and the mixture was stirred at -78 ° C under an argon atmosphere at 1 M in lithium hexamethyldisilazide. Solution (3.62 mL, 3.62 mmol) was added and stirred for 20 minutes. The ice bath was removed, and the mixture was further stirred at room temperature for 90 minutes. The reaction solution was partitioned between ethyl acetate (500 mL) and a 10% aqueous solution of sodium chloride (200 raL). The organic layer was further 10% Shioi匕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). %).

_{¾ NMR (400 MHz, CDC1 3} ) δ 8. 10-8. 02 (2Η, m), 7. 63-7. 57 (1H, m), 7. 52- 7. 50 (3H, m), 7 30-7. 26 (3H, m), 7.22-7. 20 (3H, m), 5.90 (1H, dddd, J = 6.1, 10.6Hz), 5.53-5. 50 (1H, m), 5.29-5.27 (1H, m), 3.14-3.10 (1H, m), 3.00 (1H, dd, J = 5.3, 13.9 Hz), 2.93-2.84 (2H, m), 2.65 (1H, dd, J = 2.6, 5.0 Hz).

EIMS m / z: 308 (M) ⁺ ₀

(6) (4R, 5R, 6R) -6-Benzoyloxy-5-benzyl-1_ (trimethylsilyl) octo 7-en-1-yn-4-ol ((4R, 5R, 6R) -6-Benzoyloxy-5- Synthesis of benzyl— 1— (trimeth ylsilyl) oct-7- en- 1-yn-4- ol, lig compound 7)

Under an argon atmosphere, ethynyltrimethylsilane (908 mL, 6.43 mmol) was added to THF (15 mL), and a 1.6 M hexane solution of n-butyllithium was added at 3.78 ° C (3.19 mL). , 5.14 mmol) and stirred for 10 minutes. Next, a solution of compound 6 (793 mg, 2.57 mmol) as an epoxide in THF (15 mL) was added, and a boron trifluoride getyl ether complex (358 μm, 2.83 mmol) was added. The mixture was stirred at C for 4.5 hours. 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. After filtration and concentration of the filtrate, 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

) o

_{¾ NMR (400 MHz, CDC1 3} ) δ 8. 07-7. 96 (2Η, m), 7. 62-7. 58 (1H, m), 7. 49 one 7. 31 (2H, m), 7 30-7. 18 (5H, m), 5.90-5.82 (1H, m), 5.65-5.62 (1H, m), 5. 31-5.24 (2H, m), 4.25 (1H, t, J = 7.1 Hz), 2.98 (1H, dd, J = 4.6, 14.5 Hz), 2.73-2.41 (5H, m), 0.17 (9H, s) .

EIMS m / z: 406 (M) ⁺ , 388 (MH ₂₀ ) ⁺ .

_{_{HREIMS calcd for [C 25 H 30}} 0 3 Si] 406.1964, found 406.1963.

(7) (3R, 4R, 5S) -4 -Benzilotato-1_en-7-in-3,5-diol ((3R, 4R, 5S)-4-Benzyloct-1— en— 7 -yn-Synthesis of 3, 5-diol

Compound 7 (35.4 mg, 0.087 mmol), which was an enyne, was dissolved in methanol (3 mL), potassium carbonate (120 mg, 0.870 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with acetic acid (100 μl 1.74 mmol) and filtered. The filtrate was concentrated, it was partitioned acetate Echiru (50 mL) one H ₂ 0 (20 mL). The organic layer H ₂ 0 (20 mL), sequentially washed with saturated brine (20 mL), dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the concentrate was purified by preparatip thin-layer chromatography (33% ethyl acetate Z hexane) to obtain 10.3 mg of Compound 8 as a white powder (yield 51%).

_{¾ NMR (600 MHz, CDC1 3} ) δ 7.31-7.20 (5H, m), 5.84 (1H, ddd, J = 4.4, 10.7, 17.0 Hz), 5.32 (1H, d, J = 17.0 Hz), 5.22 (1H , D, J = 11.0 Hz), 4.2 6 (1H, t, J = 7.1 Hz), 4.21 (1H, m), 3.14 (1H, brS), 2.91 (1H, dd, J 10.4, 14.3 Hz ), 2.83 (1H, dd, J = 4.9, 14.3 Hz), 2.57 (1H, ddd, J = 2.7, 7.4, 17.0 Hz), 2.52 (1H, d, J = 3.3 Hz), 2.43 (1H, ddd, J = 2.7, 7.1, 17.0 Hz), 2.07 (1H, t, J = 2.7 Hz), 2.03-2.01 (1H, m)

EIMS m / z: 230 (M) ⁺ .

HREIMS calcd for [C ₁₅ H ₁₈ 0 ₂ ] 230.1307, found 230.1296.

(8) (3R, 4R, 5S) -4-benzyl-3,5-bis [(tert-butyldimethylsilyl) oxy] oct-1-ene-7-yne ((3R, 4R, 5S)- Synthesis of 4-Benzyl-3, 5-bis [(tert-butyldimethylsilyl) oxy] oct-1-en-7-yne 9)

Compound 8 (88.4 mg, 0.384 mmol) dissolved in methylene chloride (5 mL) was dissolved in tert-butyl dimethylsilyl trifluoromethanesulfonate (220 zL, 0.960 mmol) at 0 ° C under an argon atmosphere. 2,6-Lutidine (179 μm, 1.54 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. Then, tert-butyldimethylsilyl trifluoromethanesulfonate (110 μm, 0.480 mmol) was added again to 2,6 Lutidine (90 μm, 0.768 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (20 mL), and the organic layer was washed with ¾0 (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. Was. After filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (silica gel 10 g, 1% → 3% ethyl acetate Z hexane) to obtain 177.8 _mg of a colorless oily compound 9 (yield 99%). ).

_{¾ NMR (600 MHz, CDC1 3} ) δ 7.26-7.14 (5H, m), 5.83 (1H, ddd, J = 7.4, 10.4, 17.0 Hz), 5.17 (1H, dt, J = 1.1, 17.0 Hz), 5.08 (1H, dt, J = 1.1, 1 0.4 Hz), 4.18 (1H, dd, J = 6.0, 7.1 Hz), 4.07 (1H, ddd, J = 2.7, 6.0, 8.8 Hz), 2.70 (1H, dd, J = 8.2, 14.3 Hz), 2.62 (1H, dd, J = 6.0, 14.3 Hz), 2.30 (1H, ddd, J = 2.7, 6.0, 17.0 Hz), 2.27-2.24 (1H, m), 2.20 (1H, ddd, J = 2.7, 7.1, 17.0Hz), 1.94 (1H, t, J = 2.7Hz), 0.91 (9H, s), 0.89 (9H, s), 0.05 (3H, s), 0.03 ( 3H, s), 0.02 (3H, s), 0.01 (3H, s).

EIMS m / z: 458 (M) \

HREIMS calcd for [C ₂₇ H ₄₆ 0 ₂ Si ₂ ] 458.3036, found 458.3034.

(9) 1,3-bis (0-tert-butyldimethylsilyl) -2 -benzinole-1 a, 25 -dihydroxyvitamin D ₃ (1,3-Bis (O-tert-butyldimetylsilyl) -2 a -benzyl Synthesis of -1a, 25-dihydroxyvitamin D ₃

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. After cooling, the reaction mixture was diluted with ether (15 mL), filtered, and the filtrate was concentrated. Thus, 229.4 mg of compound 10 as a colorless oily substance was obtained (crude yield 92%). This compound was subjected to the next reaction without further purification.

(10) 2α-benzyl_1α, 25-dihydroxyvitamin D. (2 a— Benzyl- 1, 2 Synthesis of 5-dihydroxyvitamin D ₃ , lig compound 11)

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 ° /.). This compound was re-purified by reversed-phase HP LC (YMC-Pack ODS column 20 × 150 thigh, 9.9 mL / min, CH ₃ CN: H ₂₀ = 4: 1) to obtain a white powder. Using this product, a binding experiment to vitamin D receptor was performed.

_{¾ NMR (600 MHz, CDC1 3} ) δ 7.31-7.21 (5H, m), 6.42 (1Η, d, J = 11.0 Hz), 5.97 (1H, d, J - 11.0 Hz), 5.14 (1H, d, J = 1.7 Hz), 4.94 (1H, d, J = 2.2 Hz), 4.12 (2H, dd, J = 7.1, 14.3 Hz), 3.93 (1H, ddd, J = 4.4, 8.8, 13 • 2 Hz), 2.99 (1H, dd, J = 5.5, 13.7 Hz), 2.86-2.82 (2H, m), 2.73 (1H, dd, J = 4.4, 13.2Hz), 2.27 (1H, dd, J = 9.3, 12.6 Hz).

^{1 3 C NMR (100 MHz,} CDC1 3) d 146.37, 143.39, 140.43, 132.68, 129.27, 128.40, 125.95, 124.85, 116.85, 113.86, 72.87, 71.11, 70.11, 56.49, 56.30, 51.6 2, 45.90, 44.57, 44.38 , 40.48, 36.37, 36.08, 33.08, 29.35, 29.19, 29.06, 27.64, 23.51, 22.17, 20.80, 18.78, 12.02

EIMS m / z: 506 (M) ⁺ .

_{_{HREIMS calcd for [C 34 H 50}} 0 3] 506.3760, found 506.3773.

(Example 2) 2.beta. Hue sulfonyl - 1 a, 25 - synthesis of dihydric mud carboxymethyl vitamin D ₃

The steps performed in Example 2 are described below. 囊 OAV-:

εΗ.

(1) Methyl 3-C-phenyl-4,6-0-benzylidene-3-deoxy-a-D-mannobilanoside (Methyl 3-C-Pnenyl-4,6-0-benzylidene-3-deoxy- -D -mannopyranoside

Synthesis of compound 22).

Under an argon atmosphere, methyl 2,3-anhydro-4,6-0-benzylidene-α-D-mannopifunoside (methyl 2,3—anhydro—4,6—0—benzylidene—hiichi D_mannopyranoside, compound 21) 2.87 g (10.9 s Awakening ol) was dissolved in Et ₂ 0 were distilled (Jeffrey chill ether) (108.6 mL), copper iodide (620 mg, 3.56謹ol) and chloride phenylpropyl magnesium TH F solution (2.0 M, 27.2 mL, 54.3 mmol), and the mixture was heated under reflux at 50 ° C for 7.5 hours, and then stirred at room temperature for 16 hours. The reaction solution was partitioned between ethyl acetate (500 mL) and a saturated aqueous NH ₄ C1 solution (150 mL). The organic layer was washed with saturated _{NH 4 C1 (150 mL),} H 2 0 (150 mL), sequentially washed with saturated NaCl (150 mL), dried putting Na ₂ S0 _4, The filtrate was concentrated and filtered, the residue The product was purified by silica gel column chromatography (silica gel 150 g, ethyl hexanoacetate = 3/1) to give 1.51 g of pale yellow oily compound 22 (yield 41 ° / ₀ ) ¾ NMR (400 MHz, CDC1 ₃ ) δ 7.39-7.34 (6Η, m), 7.31-7.26 (4H, m), 5.64 (1H, s), 4.75 (1H, d, J = 1.5 Hz), 4.43 (1H, dd, J = 9.8, 11.2 Hz), 4.34 (1H, dd, J = 4.5, 9.8 Hz), 4.03 (1H, dt, J = 4.5, 9.8 Hz), 3.94 (1H, t, J = 9.8 Hz), 3.92 (1H, br s ), 3.49 (3H, s), 3.48 (1H, J = 2.9, 11.2 Hz), 1.71 (1H, J-3.4 Hz).

EIMS m / z: 342 (M) ⁺ .

HREIMS calcd for [C ₂₀ H ₂₂ 0 ₅ ] 342.1467, found for 342.1440.

(2) Methyl 4--0-benzoyl-3-C-phenyl-6-bromo-3,6-dideoxy-hi 4) -mannopyranoside (Methyl 4--0-benzoy 3--C-phenyl-6_bromo- 3,6 _-dideoxy- a - D -mannopyrano si de Λ I匕合article 23) synthesis of

Compound 22 (2.84 g, 8.30 tmol), which is an alcohol, was dissolved in carbon tetrachloride (83 mL) through an alumina column, and N-promosuccinimide (1.63 g, 9.13 mmol) and barium carbonate (barium carbonate) were dissolved. 917 mg, 4.65 nmol) under an argon atmosphere. The mixture was heated and refluxed at C for 60 minutes. The reaction solution was filtered, the filtrate acetate Echiru (500 mL) - was partitioned with saturated Na _₂ S ₂ 0 ₃ solution (100 mL). 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 organic layer was passed through a pad of silica gel, and the eluate was concentrated and purified by silica gel column chromatography (silica gel 150 g, hexane Z ethyl acetate = 3/1) to obtain 2.24 g of compound 23 as a colorless oil. (Yield 64%).

_{¾ NMR (400 MHz, CDC1 3} ) δ 7.80-7.78 (2Η, m), 7.50-7.47 (1H, m), 7.37- 7.25 (6H, m), 7.20-7.17 (1H, m), 5.81 (1H, dd, J = 9.8, 11.2 Hz), 4.83 (1H, s), 4.17 (1H, dt, J = 3.2 Hz), 3.89 (1H, brS), 3.58 (3H, s), 3.55-3.50 (3H , M), 1.85 (1H, brd, J = 5.1 Hz).

EIMS m / z: 420 (M) ⁺ .

HREIMS calcd for [C ₂₀ H ₂₁ BrO ₅ ] 420.0572, found for 420.0558.

(3) (2S, 3R, 4R) -4-Benzoyloxy-3-phenylhexyl-5-ene-1,2-diol ((2S, 3S, 4R)-4-Benzoyloxy_3-phenylhex-5_en-1 Compound 23 (967 mg, 2.30 mmol) as a bromide was dissolved in 1-propanol (23 mL), and distilled water (2.3 mL) was added. The obtained solution was heated to 95 ° C in advance, and zinc dust (4.51 g, 69.0 mmol) and NaB¾CN (289 mg, 4.60 mol) were added thereto, and the mixture was heated to 105 and refluxed for 60 minutes. After cooling, the mixture was filtered through a folded paper filter, NaBH ₄ (87 mg, 2.30 raraol) was added to the filtrate at room temperature, and the mixture was stirred for 1 hour.The unnecessary substances were removed by filtration, and 10 g of silica gel was added to the filtrate and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, hexane Z ethyl acetate = 2/1) to obtain 257 mg of Compound 24 as a colorless oil (yield 36%).

¾ NMR '(400 MHz, CDC1 3) δ 8.11-8.09 (2Η, m), 7.65-7.61 (1H, m), 7.52- 7.48 (2H, m), 7.34-7.28 (3H, m), 7.21-7.19 (2H, m), 6.19 (1H, brd, J = 6.4 Hz), 5.68 (1H, ddd, J = 6.4, 10.7, 17.1 Hz), 5.26 (1H, brd, J = 17.1 Hz), 5.11 ( 1H, brd, J = 10.7 Hz), 3.96 (1H, ddd, J = 2.9, 6.8, 10.5 Hz), 3.37 (1H, dd, J = 2.9, 11.5 Hz), 3.27 (1H, dd, J = 6.8, 11.5 Hz), 2.96 (1H, dd, J = 2.7, 10.5 Hz).

(4) (2S, 3R, 4R) -4-Benzoyloxy-3-phenyl-1-[(p-toluenesulfinoloxy) oxy] hexa-5-en-2-ol ((2S, 3S, Synthesis of 4R)-4-Benzoyloxy- 3-phenyl "1-[(p-toluenesulfonyl) oxyJhex-5 en-2- ol, Under an argon atmosphere, a Orefin compound 24 (213 mg, 0.682 negation ol) was dissolved in _{_{CH 2 C1 2 (6.82 mL)}} , Toshirukurori de (143 mg, 1.08 mmol) and 4-(N, N-dimethyl Chiruamino) Pyridine (8.3 mg, 0.07 tmol) and triethylamine (375 μL, 1.02 mmol) were added, and the mixture was stirred at room temperature for 4.5 hours. Further, tosyl lip (39 mg, 0.20 ol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was partitioned acetate Echiru (50 mL) and H ₂ 0 (20 mL). The organic layer was washed with H ₂ 0 (20 mL) then brine (20 mL), dried putting Na ₂ S0 _4, filtered and concentrated the filtrate, the residue silica gel column chromatography (silica gel Purification with 15 g, hexane Z ethyl acetate = 4/1) gave Compound 25 (304.6 mg) as a pale yellow oil (yield 96%).

EIMS m / z: 466 (M) ⁺ .

_{_{HREIMS calcd for [C 26 H 26}} 0 6 S] 466.1450, found for 466.1429.

(5) (3R, 4R, 5R) -3-Benzoyloxy_4-phenyl-5,6-epoxyhex-1-ene ((3R, 4R, 5R) -3-Benzoyloxy-4-phenyl-5, 6 -Synthesis of oxyhex-1-ene, compound 26) .Dissolve Compound 25 (304 mg, 0.652 tmol) as a tosylate in THF (6.5 mL) under an argon atmosphere. A 1 M solution of lithium hexamethyldisilazide in THF (0.782 mL, 0.782 liter) was added, and the mixture was stirred at the same temperature for 20 minutes, then returned to room temperature and stirred for 90 minutes. 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 . After filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (silica gel 20 g, hexane Z ethyl acetate = 6/1) to obtain 110.6 mg of a colorless oily compound 26 (yield 57%). Compound 25 (22.3 mg) as a raw material was recovered (recovery rate: 7%).

_{¾ NMR (600 MHz, CDC1 3} ) δ 7.93-7.85 (2Η, m), 7.54-7.46 (1H, m), 7.37 - 7.34 (2H, m), 7.28-7.24 (4H, m), 7.22-7.18, (1H, m), 5.94-5.92 (1H, m), 5.85 (1H, ddd, J = 6.6, 10.4, 17.1 Hz), 5.33 (1H, dd, J = 1.1 Hz), 5.30 (1H, dt, J = 1.1 Hz), 3.29 (1H, ddd, J = 2.8, 4.4, 8.3 Hz), 2.69 (1H, dd, J = 4.4, 4.9 Hz), 2.63 (1H, dd, J = 6.0, 8.3 Hz), 2.44 (1H, dd, J = 2.8, 4.9 Hz). EIMS ra / z: 294 (M) ⁺ .

HREIMS calcd for [C ₁₉ H ₁₈ 0 ₃ ] 294.1256, found for 294.1263.

(6) (31?, 4¾510—4-phenyl-5,6-epoxyhexan-3-ene ((3R, 4R, 5R) -4-Phenyl-5,6-epoxyhex-toen) -Synthesis of 3-ol compound 27)

Under an argon atmosphere, the epoxide compound 26 (68.5 mg, 0.233 mmol) was dissolved in dry methanol (15 mL), a 28% NaOCH ₃ methanol solution (0.13 mL) was added, and the mixture was stirred at room temperature with stirring. Further, a methanol solution (0.13 mL) of 28% NaOCH ₃ was added, and the mixture was stirred at room temperature for one hour. Silica gel was added to the reaction mixture, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (silica gel 5 g, hexane Z ethyl acetate = 4/1) to give 40.8 mg of compound 27 as a colorless oil. Was obtained (yield 92%). ¾ title _{R (600 MHz, CDC1 3)} δ 7.34-7.31 (2H, m), 7.28-7.24 (3H, m), 5.88 (1H, ddd, J = 6.1, 10.4, 17.1 Hz), 5.28 (1H, d , J = 17.1 Hz), 5.16 (1H, d, J = 10.4 Hz), 4.57-4.56 (1H, m), 3.37 (1H, ddd, J = 2.8, 3.3, 8.3 Hz), 2.76 (1H, dd, J = 3.3, 5.5 Hz), 2.51 (1H, dd, J = 2.8, 4.4 Hz), 2.41 (1H, dd, J = 5.5, 8.3 Hz), 1.96 (1H, brd, J = 3.9 Hz).

(7) (3R, 4R, 5R) -3- (tert-butyldimethylsilyloxy) _4-phenyl-5,6-epoxyhex-1-ene ((3R, 4R, 5R) -3- ( (tert-Butyldimethylsilyloxy) -4-pheny 1-5, 6-epoxyhex-l-ene, lig compound 28)

Under an argon atmosphere, alcohol 27 (147 rag, 0.773 t) was dissolved in dry CH ₂ C ₁₂ (7.8 mL), and 2,6-lutidine (342 μΐ, 2.94 mmol) and TBDMSOTf (tert-butylinole) were dissolved. Dimethinoresilinoletriflate) (320 μL, 1.39 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was partitioned acetate Echiru (0.99 mL) and saturated NaHC0 ₃ (30 mL). The organic layer was washed with H ₂ O (30 mL) and then with saturated saline (30 mL), and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated, and purified by silica gel column chromatography (silica gel 10 g, 10% ethyl acetate Z hexane) to obtain 213 mg of compound 28 as a pale yellow oil (yield) 91%).

_{¾ NMR (600 MHz, CDC1 3} ) δ 7.28-7.21 (5Η, m), 5.64 (1H, ddd, J = 6.9, 10., 17.3 Hz), 5.14 (1H, d, J = 17.3 Hz), 5.01 ( 1H, d, J = 10.4 Hz), 4.57 (1H, dd, J = 4.9, 6.6 Hz), 3.34 (1H, m), 2.73 (1H, t, J = 4.7 Hz), 2. 46 (1H, dd, J = 2.7, 4.9 Hz), 2.18 (1H, dd, J = 4.7, 8.5 Hz), 0.86 (9H, s), 0.01 (3H, s), 0.00 (3H, s).

EIMS m / z: 304 (M) ⁺ , 247 (M—tBu) ⁺ .

HREIMS calcd for [C ₁₈ H ₂₈ 0 ₂ Si] 304.1859, found for 304.1860.

(8) (4R, 5S, 6R) -6- (tert-butyldimethylsilyloxy) -5-phenyl-tri (trimethylsilinole) otato-7-ene-1-in-4--4-ol ((4R , 5S, 6R) -6- (tert-Butyl dimethylsilyloxy)-5-phenyl-1-(trimethylsilyl) oct-7-en-1-yn-4 ol

Under argon atmosphere, add ethynyltrimethylsilane (68 ports iL, 0.483 mmol) to THF (3 mL), and add 1.6 M hexane solution of n-butyllithium at -78 ° C (0.243 mL, 0.389 mmol). Was added and stirred for 10 minutes. Next, a solution of compound 28 (58.8 mg, 0.193 mmol), which is an epoxide, in THF (3 mL) was added, and further, boron trifluoride getyl ether complex (27D 0.212 mmol) was added, and the mixture was stirred at -78 ° C for 2.5 hours. Then, the mixture was stirred at room temperature for 20 hours. 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 ¾0 (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%).

_{¾ NMR (600 MHz, CDC1 3} ) δ 7.27-7.16 (5H, m), 5.73 (1Η, ddd, J = 6.6, 10.4, 17.1 Hz), 5.10 (1H, d, J = 17.3 Hz), 5.06 (1H , D, J = 10.4 Hz), 4.61 (1H, dd, J = 2.8, 6.8 Hz), 4.25 (1H, dddd, J = 3.3, 6.3, 10.2 Hz), 3.45 (1H, brd, J = 2.8 Hz), 2.91 (1H, dd, J = 3.0, 10.2 Hz), 2.31 (1H, dd, J = 3.6, 17.1 Hz), 2.04 (1H, dd, J = 6.1, 17.3 Hz), 0.93 (9H , S), 0.14 (3H, s), 0.03 (3H, s).

EIMS m / z: 402 (M) ⁺ .

HREIMS calcd for [C ₂₃ H ₃₈ 0 ₂ Si ₂ ] 402.2410, found for 402.2404.

(9) (4R, 5S, 6R) -6- (tert-butyldimethylsilyloxy) -5-phenyl-7-en-1-yn-4-ol ((4R, 5S, 6R) -6- (tert-Butyl dimethvlsilyloxy) -5-phen Synthesis of yloct-7-en-1-yn-4-ol, lig compound 30)

Compound 29 (28.1 mg, 0.070 t ol), which was the starting compound, was dissolved in methanol (3 mL), and K ₂ CO ₃ (29 mg, 0.210 awake ol) was added, followed by stirring at room temperature for 2.5 hours. Acetic acid (24 μΐ, 0.42 tmol) was added to the reaction solution to neutralize it. The reaction was filtered, the filtrate was concentrated, acetic acid Echiru (50 mL) and was H ₂ 0 (20 mL) was added for liquid separation. The organic layer was washed with 0 (20 mL) and then with saturated saline (20 mL), and dried over Na ₂ SO ₄ . After filtration and concentration of the filtrate, the residue was separated and purified by preparative thin-layer chromatography (hexane Z ethyl acetate = 15Z1) to obtain 20.3 mg of a colorless oily compound 30 (yield: 88%).

_{¾ NMR (400 MHz, CDC1 3} ) δ 7.29-7.18 (5Η, m), 5.72 (1H, ddd, J = 6.8, 10.3, 17.3 Hz), 5.11 (1H, t, J = 1.5 Hz), 5.09 (1H , T, J = 1.5 Hz), 4.64

(1H, dd, J = 3.2, 6.8 Hz), 4.31 (1H, ddt, J = 3.1, 6.6, 10.1 Hz), 3.48 (1H, d, J = 3.7 Hz), 2.89 (1H, dd, J = 3.2 , 10.3 Hz), 2.28 (1H, m), 2.03

(1H, m), 0.95 (9H, s), 0.15 (3H, s), 0.05 (3H, s).

EIMS m / z: 330 (M) ⁺ .

HREIMS calcd for [C ₂₀ H ₃₀₀ ₂ Si] 330.2015, found for 330.2015.

(10) (3R, 4S, 5R) -3,5_bis [(tert-butyldimethylsilyl) oxy] _4-phenylotato-11-en-7-yne ((3R, 4S, 5R) -3, Synthesis of 5-Bis [(tert-butyldimethylsilyl) oxy] -4-phenyloct-l-en-7-yne _N compound 31)

Under an argon atmosphere, alcohol 30 (82.7 mg, 0.250 t) was dissolved in dry CH ₂ C ₁₂ (3 mL), and 2,6-lutidine (111 βΐ, 0.950 bandol) and TBDMSOTf (103 μΐ) 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 . After filtration and concentration of the filtrate, the residue was separated and purified by preparative thin-layer chromatography (hexane / ethyl acetate = 16/1) to obtain 89.6 mg of a colorless oily compound 31 (81% yield).

EIMS m / z: 444 (M) ⁺ , 387 (M-tBu) ⁺ .

_{_{HREIMS calcd for [C 26 H 44}} 0 2 Si 2] 444.2880, found for 444.2877.

(1 1) 1,3-bis (0-tert-butyldimethylsilyl) `` 2β-phenyl-1a, 25-dihydroxyvitamin D ₃ (1,3-Bis (O-tert-butyldimetylsilyl) -2 j3 -phenyl-1 a, 2 Synthesis of 5-dihydroxyvitamin D ₃

Under argon atmosphere, compound 31 (87.8 mg, 0.198 tmol), which was a quinine, was dissolved in toluene (1 mL), and triethylamine (3 mL) was added. Next, bromorefin (CD ring part in which the group corresponding to A in the general formula (1) is a 4-hydroxy-1-methylpentyl group, 106.3 mg, 0.298 tmol) and tetrakis (triphenylphosphine) palladium (0) The complex (68.6 mg, 0.060 tmol) was added, and the mixture was heated under reflux at room temperature for 15 minutes and then at 90 ° C for 2 hours. After cooling, the reaction mixture was diluted with getyl ether (15 mL), filtered, and the filtrate was concentrated. The residue was separated and purified by preparative thin-layer chromatography (hexane Z ethyl acetate = 5/1) to give a pale yellow oil. 69.5 mg of Compound 32 was obtained (yield 49%).

This danjido product was subjected to the following reaction without further purification.

EIMS m / z: 721 (Μ) + ·

HREIMS calcd for [C ₄₅ H _y6 0 ₃ Si ₂ ] 720.5333, found for 720.5560.

(1 2) 2; Synthesis of 3-phenyl-1,25-dihydroxyvitamin D ₃ (2 β-Phenyl-1, 25-dihydroxyvitamin D ₃ , compound 33)

Compound 32 (69.5 mg, 0.097 t) was dissolved in THF (5 mL), and a 1.0 M THF solution (0.483 mL, 0.483 mmol) of tetrabutylammonium fluoride was dissolved in an argon atmosphere. The mixture was stirred at room temperature for 2 days. It was separated and purified by preparative thin-layer chromatography (hexane / ethyl acetate = 2/1) to obtain 14.8 mg of compound 33 as a white powder (yield 31%).

This compound was re-purified by reversed-phase HP LC (YMC-Pack 0DS column 20 × 150 ■, 9.9 mL / min, CH ₃ CN: H ₂₀ = 8: 2) to obtain a white powder. Using this product, a binding experiment to vitamin D receptor was performed.

_{¾ NMR (400 MHz, CDC1 3} ) δ 7.53-7.40 (5Η, m), 6.53 (1H, d, J = 11.2 Hz), 6.27 (1H, d, J = 11.2 Hz), 5.67 (1H, s), 5.26 (1H, s), 4.93 (1H, d, J-11.0 Hz), 4.23 (1H, m, J = 2.0 Hz), 3.85 (1H, dd, J = 7.0, 14.0 Hz), 3.03 (1H, dd , J = 2.0, 11.0 Hz), 2.99 (1H, dd, J = 3.7, 12.0 Hz), 3.84 (1H, brd, J = 13.9 Hz), 2.67 (1H, dd, J = 3.2, 13.9 Hz), 1.40 - 0.19 (m) EIMS m / z:. 492 (M) +, 474 (M + - H 2 0), 456 (M + - 2H 2 0). HREIMS calcd for [C ₃₃ H ₄₈ 0 ₃ ] 492. 3603, found for 492. 3589.

Example 3 Synthesis of ₃ -Epi-2α-benzyl-1α, 25-dihydroxyvitamin D ₃ The steps performed in Example 3 are shown below.

TBDMSOTf (3.75 eq)

2,6-lutidine (6 eq)

CH ₂ CI ₂ , 0 ° C

48epi 49epi (93%)

itamin D ₃

(1) (2RS, 3R, 4R) -4-Benzoyloxy-3-benzylhex-5-ene-1,2-diol ((2RS, 3R, 4R)-4-Benzoyloxy_3-benzylhex-5 -en-1, 2-diol, compound 44 mix)

Compound 43 (1.85 g, 4.24 mmol), a bromide, was dissolved in 1-propanol (70 mL) and distilled water (7 mL) was added. The solution was heated to 95 ° C in advance, zinc dust (8.3 g, 127 mmol) was added thereto, and the mixture was heated under reflux at 100 ° C for 40 minutes. After cooling, the solution was filtered through a foldable filter paper, sodium hydrogenborohydride (320 mg, 8.5 mmol) was added to the filtrate at room temperature, and the mixture was stirred for 5 minutes. The insolubles were removed by filtration, and the filtrate was added with silica gel (10 g) and concentrated. The residue was purified by silica gel column chromatography (silica gel 95 g, 2% → 50% ethyl acetate / hexane) to give a colorless oily compound containing two diastereomers, R-configuration and S-configuration at the 2-position 44 1.03 g of mix was obtained (yield 74 ° /.).

¾ negation R (600顧_{z, CDC1 3) δ 8.04-8.03 (} 2.8Η, m), 7.58-7.50 (1. H, m), 7.45-7.40 (2.8H, m), 7.26-7.23 (2.8H, m), 7.17-7.18 (4.2H, m), 6.03 (0.4H, ddd, J = 5.5, 10.7, 16.7 Hz), 5.91 (1H, ddd, J = 5.7, 10.7, 16.7 Hz), 5.79-5.78 ( 0.4H, m), 5.59 (1H, t, J = 5.5 Hz), 5.35-5.27 (2.8H, m), 4.05 (1H, m), 3.83 (0.4H, m), 3.63 (1.4H, dd, J = 8.5, 11.0 Hz), 3.54- 3.52 (1H, m), 2.92 (1H, dd, J = 6.0, 14.5 Hz), 2.83 (0.4H, dd, J = 6.6, 14.0 Hz), 2.75 (1H, dd, J = 6.0, 14.5 Hz), 2.73 (0.4H, dd, J = 6.6, 14.0 Hz), 2.39-2.35 (0.4H, m), 2.24-2.12 (1H, m).

EIMS m / z: 326 (M) +.

(2) (2RS, 3R, 4R) -4- Benzoyloxy-3_benzyl-1-[(p-toluenesulfonyl) oxy] hex-5-en-2-ol ((2RS, 3R, 4R Synthesis of)-4- Benzoyloxy- 3— benzyl-1- [(p-"oluenesulfonyl) oxy" hex-5-en- 2 ol, 45 mix)

Compound 44 mix (531 mg, 1.63 mmol) was dissolved in methylene chloride (16.3 mL), and tosyl chloride (341 mg, 1.79 mmol) and 4- (N, N-dimethylamino) pyridine (20 mg, 0.16 mmol) and triethylamine (895 2.44 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was separated with ethyl acetate (150 mL) -¾0 (60 mL). The organic layer was washed successively with ¾0 (60 mL) and then with saturated saline (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel gel chromatography (silica gel 10 g, 20% ethyl acetate / hexane) gave 45 mi of a colorless oily compound containing two diastereomers with R-configuration and S-configuration at the 2-position. (604 mg, 77% yield).

EIMS m / z: 480 (Μ) ⁺ ·

_{_{HREIMS calcd for [C 27 H 28}} 0 6 S] 480.1607, found for 480.1616.

(3) (3R, 4R, 5RS) -3- Benzoyloxy-4-benzyl-5,6-epoxyhex-1-ene ((3R, 4R, 5RS)-3-Benzoyloxy- 4-benzyl 5, 6 -epoxyhex-1-ene, synthesis of 46 mix)

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%).

¾ negation _{R (600 MHz, CDC1 3)} δ 7.96-7.86 (2.6Η, m), 7.47-7.42 (1.3H, m), 7.32-7.30 (2.6H, m), 7.13-7.10 (2.6H, m) , 7.07-6.96 (3.9H, m), 5.91 (0.3H, ddd, J = 6.6, 10.7, 17.3 Hz), 5.74 (1H, ddd, J = 6.0, 10.7, 17.0 Hz), 5.54 (0.3H, t , J = 5.5 Hz), 5.35 (1H, dd, J = 4.6, 5.7 Hz), 5.19-5.10 (2.6H, m), 3.59 (1H, t, J = 6.4 Hz), 2.97-2.95 (1H, m ), 2.92-2.89 (0.3H, m), 2.84 (1H, dd, J = 5.2, 13.7 Hz), 2.79 (0.3H, dd, J = 4.9, 9.0 Hz), 2.75 (1H, dd, J = 5.2 , 13.7 Hz), 2.62 (0.3H, dd, J = 4.9, 9.0 Hz), 2.50 (1H, dd, J = 2.7, 4.9 Hz), 2.45 (0.3H, t, J = 4.5 Hz).

EIMS m / z: 308 (M) +.

(4) (4RS, 5R, 6R) -6 Benzoyloxy-5-benzyl-1- (trimethylsilyl) otato-7-ene-1-in-4-ol ((4RS, 5R, 6R) -6_Benzoyloxy_5- benzyl Synthesis of (trimethylsilyl) oct-7-en-l-yn-4-ol (compound 47 mix)) Dissolve ethynyltrimethylsilane (66 μm, 0.47 mmol) in THF (4 mL) under an anoregone atmosphere. After cooling to 78 ° C, a 1.6 M hexane solution of n-butyllithium (0.23 mL, 0.37 ranol) was added, and the mixture was stirred for 10 minutes. A solution of the epoxide compound 46 mix (57.5 mg, 0.186 mmol) in THF (5 mL) was added thereto, and boron trifluoride getyl ether complex (26 μm, 0.20 mmol) was further added, followed by stirring for 5 hours. . The reaction solution was separated with ethyl acetate (50 mL) -saturated aqueous sodium chloride solution (20 mL). The organic layer was washed with saturated bicarbonate Natoriumu solution _{(20 mL), H 2 0} ( to 20 m), was washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (silica gel 50 g, 4% ethyl acetate Z hexane) to obtain 4 mi of a colorless oily compound containing two diastereomers of R configuration and S configuration at the 4-position. 52.8 mg was obtained (yield 70%). 14 rags of 46 mixes as raw materials were recovered (recovery rate 25%).

EIMS m / z: 406 (M) ⁺ .

(5) (3R, 4R, 5R) -4-benzyloct-1-ene-7-in-3,5-diol ((3R, 4R, 5R) -4-benzyloct- 1-en-7- Synthesis of yn_3, 5-diol, compound 48 epi)

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 ° /.).

_{¾ NMR (400 MHz, CDC1 3} ) δ 7.33-7.29 (2Η, m), 7.26-7.22 (3H, m), 6.04 (1H, ddd, J = 5.5, 10.5, 17.0 Hz), 5.32 (1H, d, J = 17.0 Hz), 5.21 (1H, d, J = 11.0 Hz), 4.33 (1H, m), 3.95 (1H, m), 2.89 (1H, dd, J = 7.7, 13.7 Hz), 2.77 (1H, dd, J = 7.1, 13.7 Hz), 2.57-2.56 (2H, m), 2.18-2.14 (1H, m), 2.07 (1H, m), 1.65 (1H, brS).

EIMS m / z: 230 (M) ⁺ .

HREIMS calcd for [C ₁₅ H ₁₈ 0 ₂ ] 230.1307, found for 230.1308. (6) (3R, 4R, 5R) -4-benzyl-3,5_bis [(tert-butyldimethylsilyl) oxy] otato-1-ene-7-yne ((3R, 4R, 5R ) synthesis of -4-Benzyl-3,5-bis [ (tert- butyldimethylsilyl) oxyj oct-l-en-7-yne% I匕合was 4 9 epi)

Compound 48 epi (66.6 mg, 0.289 mmol) was dissolved in methylene chloride (5 mL), and trifluoromethanesulfonic acid tert-butyl dimethylsilyl ester (116, 0. 723 mmol) and 2,6-lutidine (135 μ, 1.16 mmol) were added, and the mixture was stirred at 0 ° C. for 80 minutes. Furthermore, trifluoromethanesulfonate tert-butyldimethylsilyl ester (83 μl, 0.506 mmol) and 2,6-lutidine (68 zL, 0.578 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was separated with ethyl acetate (50 mL) -saturated aqueous sodium hydrogen carbonate solution (20 mL). The organic layer H ₂ 0 (20 mL), Tsugire, in dried with anhydrous sodium sulfate and saturated brine (20 raL). After filtration and concentration, 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)

EIMS m / z: 458 (M) +.

HREIMS calcd for [C ₂₇ H ₄₆ 0 ₂ Si ₂ ] 458.3036, found for 458.3028.

(7) 3-Epi-1,3-bis (0-tert-butyldimethylsilyl) _2a-benzyl-1,25-dihydroxyvitamin D ₃ (3-epi-1,3-Bis (O- tert-butyldimetylsilyl)-Synthesis of -2-benzyl-1 α, 25-dihydroxyvitamin D ₃ , 5 o epi)

Under an atmosphere of anoregon, 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. After cooling, the 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.

(8) 3-Epi-2a-benzinole-1α, 25-dihydroxyvitamin D ₃ (3-epi-2a- Synthesis of Benzyl—1H, 25—Dihydroxy vitamin D ₃ , 51 epi)

Compound 5 Oepi (32.3 mg, 0.044 mmol), a bissilyl ether compound, was dissolved in THF (3 mL), and a 1.0 M THF solution (0.220 mL, 0.220 mraol) of tetrabutylammonium fluoride was dissolved in an argon atmosphere. The mixture was stirred at room temperature for 2 days. The reaction solution was separated and purified by preparative TLC (25% ethyl acetate hexane) to obtain 8.0 mg of a colorless oily compound 5 lepi (36% yield). This compound was repurified by reversed-phase HP LC (YMC-Pack 0DS column 20 × 150 mm, 9.9 ml / min, CH ₃ CN: H ₂₀ = 95: 5) to obtain a white powder. Using this product, ¾ NMR was performed binding experiments to the vitamin D receptor _{(600 MHz, CDC1 3) δ} 7.33-7.21 (9H, m), 6.50 (1Η, d, J = 11.5

Hz), 6.03 (1H, d, J = 11.5 Hz), 5.16 (1H, d, J = 2.2 Hz), 4.95 (1H, d, J

= 2.2 Hz), 4.18 (1H, BrS), 3.95 (1H, BrS), 3.06-2.98 (2H, m), 2.87-2.85

(1H, m), 2.58 (1H, dd, J = 3.3, 14.3 Hz), 2. 8-2.45 (1H, m), 2,10-0.55 (m).

EIMS m / z: 506 (M) ⁺ .

HREIMS calcd for [C ₃₄ H ₅₀ 0 ₃ ] 506.3760, found for 506.3746.

(Test example) 実験 A binding experiment to thymus vitamin D receptor

Above in Example 1, 2, 3 compounds were synthesized in 1 1 (2 a -Benzyl- 1 a , 25- dihydr oxyvitamin D 3), Compound 33 (2 β -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).

1 shed, for 25 (used as a standard substance) dihydroxyvitamin D ₃ and Compound 1 1, 33, 5 each Lepi, were prepared various concentrations of ethanol. That is, as the amount of the compound contained in 50 L, 50 nanogram, 5 nanogram, 500 picogram, 250 picogram, 125 picogram, 63 picogram, 32 picogram, 16 picogram, 8 picogram, 4 picogram, 2 picogram, 1 picogram, A dilution series of 0.5 picogram and 0.25 picogram was prepared.

胸 One thymus, 25-dihydroxyvitamin D ₃ receptor is from Yamasa Shoyu Co., Ltd. Compound 11 was purchased from sa Biochemcal (Choshi, Chiba, Japan) (lot. 1 1283), and 1 ampoule (about 25 mg) was dissolved in 55 mL of 0.05 M phosphate 0.5 M potassium buffer (pH 7.4). compound 33, compound 5 Lepi or 1 alpha, 25-put ethanol solution of dihydroxy vitamin D ₃ 50 mu L and the receptor solution 500 Mi into a test tube, after 1 hour pre-incubator adipate at room temperature, ^[3 Eta ] 1 shed, 25-dihydroxy Vita Mi emissions 13 ₃ solution 50 / zL was added to a final concentration of 0. InM, and one晚incubated at 4 ° C. After mixing by force [] with DCC (dextran-coated charcoal), the mixture was allowed to stand at 4 ° C for 30 minutes, and centrifuged at 3000 rpm for 10 minutes to obtain [ ³ H] 1H, 25-dihydroxyl bound to the receptor. Vitamin D ₃ and free [ ³ H] la, 25-dihydroxyvitamin D ₃ were separated. The supernatant (500 L) was mixed with ACS-II (9.5 mL) (Amersham, England) and the radioactivity was measured.

1 Binding of α, 25-dihydroxyvitamin D ₃ to VDR The relative binding of each compound to VDR, assuming that 1 ”raw is 100, is as follows. The compound was 51 epi ^ 0.014, and the calculation formula is as follows.

X = (y / x) X 100 'X: Relative binding of compound 11 to VDR

y: 1, 25-dihydroxyvitamin D ₃ ^{is, [3 H] 1 α,} 25 - coupling a 50% inhibition of the dihydroxy vitamin D ₃ and VDR concentration

X: Compound 1 1, 33 or 51epi ^{is, [3 H] 1 α,} 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.

Claims

The scope of the claims

1. General formula (1)

General formula (1)

A vitamin D derivative represented by

2. The vitamin D derivative according to claim 1, wherein A is a straight- or branched-chain alkyl group having 1 to 10 carbon atoms substituted with a hydroxy group, and m is 0 to 2. 3. The vitamin D derivative according to claim 1, wherein A is a straight-chain or branched-chain C5 to L0 alkyl group substituted with a hydroxy group, and m is 0 to 2.

The vitamin D derivative according to claim 1, wherein A is a 4-hydroxy-1-methylpentyl group or a 4-ethyl-4-hydroxyhexyl group, and m is 0 to 2.

5. The vitamin D derivative according to claim 1, wherein A is a 4-hydroxy-1-methylpentyl group, and m is 0 to 2.

6. The vitamin D derivative according to claim 1, wherein A is a 4-hydroxy-1-methylpentyl group, and m is 1.

7. The vitamin D derivative according to claim 1, wherein A is a 4-hydroxy-4-methylpentyl group, and m is 0.

8. A pharmaceutical composition comprising the vitamin D derivative according to any one of claims 1 to 7 as an active ingredient.