JPS61254558A - Fluorine derivative of 1alpha 24-dihydroxy-vitamin d3 - Google Patents

Abstract

NEW MATERIAL:The fluorine derivative of 1alpha, 24-dyhydroxy-vitamin D3 of formula I. USE:A vitamin D3 derivative stimulating the absorption of calcium through the small intestine, increasing the calcium concentration in blood, having extremely excellent osteolytic activity and remedying effect for rickets, osteoporosis, etc., and expected to have a long-acting pharmaceutical effect. PREPARATION:The compound of formula I can be produced by (1) treating the compound of formula II (R1 and R2 are H or acyl; R3 is acyl) preferably with NH3, etc., in a solvent such as methanol, (2) heating the obtained compound of formula III together with a dehydration agent to obtain the compound of formula IV, (3) dissolving the compound THF, etc., and adding hydrogen peroxide and a catalytic amount of an alkali to the solution to obtain the compound of formula Vab, (4) reducing the product with a reducing agent, and (5) thermally isomerizing the resultant compound after irradiation with ultraviolet radiation, etc.

Description

[Detailed description of the invention] The present invention relates to novel vitamin D3 derivatives.

More specifically, the present invention relates to 1α,24-dihydroxy-26゜26.2 represented by the formula [I) EI
6.27.27.27-Relating to hexafluorovitamin D3.

1α,25-dihydroxyvitamin D3, which is an in vivo metabolite of vitamin D3 and is known as active vitamin D3, or 1α-hydroxyvitamin C, 1α, which is an artificial homolog thereof.

24R-dihydroxyvitamin D3 has the effect of promoting calcium absorption from the small intestine and increasing blood calcium, and is effective in various disorders caused by abnormal calcium metabolism, such as rickets, osteomalacia, and bone lesions in patients with renal failure. It is known that it is effective in
In the publication, la, 25-dihydroxy-26°26,2
6,27,27.27-hexafluorovitamin D3 is the active form in vivo.

Vitamin D is stronger than 25-dihydroxyvitamin D3
Based on this background technology, the inventors of the present invention have conducted extensive research on a compound that has a more useful biological activity similar to vitamin D, and have found a compound represented by the formula CI]. Due to the previously unknown combination of hydroxyl groups at the 1α and 24th positions and fluorine atoms at the 26th and 27th positions, the compound stimulates the absorption of calcium from the small intestine and has the effect of increasing blood calcium concentration. At the same time, they discovered that it has extremely excellent bone mineral dissolving action and therapeutic effects on rickets, osteoporosis, etc., has a long duration of action, and can be expected to have special effects as a medicine, resulting in the present invention.

The compound represented by formula [I] according to the present invention can be produced by various methods, for example, easily and advantageously by the method shown in the following scheme.

(IV) OH()H In the above scheme, Rs and R2 are the same or different and represent a hydrogen atom or an acyl group, and R3 represents an acyl group. The acyl groups mentioned here include C1-04 lower alkanoyl groups, such as acetyl, propionyl, piparoyl, etc., and aromatic acyl groups, such as benzoyl, p-chlorobenzoyl, p-nide 1. , lobenzoyl, etc., with acetyl groups being particularly advantageously used.

In addition, in the process of producing compound [v] in the scheme, 24
Two types of optical isomers derived from the asymmetric carbon atom are generated, and these isomers can be separated, if desired, by common means such as chromatography or recrystallization in an appropriate step after compound [v]. The symbols a and b attached to each compound represent the difference in the steric configuration at the 24th position. That is, a represents a low polar isomer of compound (V), and b represents a high polar isomer. The relative polarity of these isomers may be reversed in the compound obtained in subsequent steps, but the optical properties of each isomer, that is, the conformation at position 24, will change until the desired product is obtained. It will be retained as is. Therefore, from the isomer [Va], the compound (Ia) is obtained, and from the isomer [Vb], the compound [from]
is generated.

Next, the best mode for carrying out the method shown in the above diagram will be described in more detail.

First, the step of obtaining the compound represented by the general formula [m] is to dissolve the compound [II] disclosed in Japanese Patent Publication No. 58-501176 etc. in a suitable inert solvent, such as methanol, ethanol, tetrahydrofuran, acetone, acetic acid. Amines in a solvent such as ethyl at about 0 to 50°C, preferably at room temperature,
This is preferably carried out by treatment with ammonium or tetrabutylammonium fluoride, and by this method compound CI[[] can be easily obtained in almost quantitative yield.

The above compound (IM) was then mixed with a dehydrating agent, preferably triphenylphosphine and carbon tetrachloride, from room temperature to 120°C.
By heating to ℃, preferably 40 to 100℃,
Compound (IV) is obtained in high yield. At this time, a reaction solvent is not necessarily required, but for example, 1,2-dichloroethane gives good results. The amounts of triphenylphosphine and carbon tetrachloride to be used are equal moles or more, preferably 1 to 5 moles, respectively, relative to compound [1] to give good results.

The process for compound [v] is Cholesta-5,7°24-1! j
This is carried out by dissolving the engineering substance El in a suitable inert solvent, such as methanol, ethanol, tetrahydrofuran, dioxane, etc., and adding hydrogen peroxide and a catalytic amount of alkali. Here, the amount of hydrogen peroxide is compound (IV)
Good results are obtained when the amount is equal to or more than 5 moles, preferably 5 moles or more. As the alkali, a caustic alkali such as sodium hydroxide or potassium hydroxide is used, and a catalytic amount of about 0.01 to 0.5 mol based on the compound (ff) is sufficient. The reaction temperature is -10 to 50°C, preferably around room temperature, which gives good results1. As a result of the reaction conducted in this way, two isomers (Va
.

vb) in a ratio of approximately 1:l. These two isomers can be separated by easy means such as silica gel column chromatography if desired, but the two compounds (Vl) can also be branched after compound [■] by subjecting them to the reduction reaction in the next step without separation. This step is easily carried out by treating compound [v] with a reducing agent such as triphenylphosphine or an alkali metal iodide in an inert solvent using a method generally used for reducing hydroperoxides. In this case, the reducing agent is sodium iodide,
Alkali metal iodides such as potassium iodide are most conveniently used. For example, the reaction proceeds simply by dissolving the compound [Vl] in an inert solvent such as ethyl acetate, acetone, dimethylformamide, or tetrahydrofuran, adding the alkali metal iodide described above, and stirring at room temperature. When the raw material [v] used in this reaction is a mixture of the above-mentioned 2m isomers, a mixture of compounds CVI&) and (■b') 1 is produced, but both isomers can be mixed with silica gel if desired. It can be separated by easy means such as column chromatography, recrystallization, etc.

The step for compound [■] is carried out by a method known per se, that is, by irradiating compound [VI] with ultraviolet light.

In this ultraviolet irradiation step, the compound represented by the general formula [VI] is mixed with a suitable inert solvent, such as evabenzene, toluene,
In an organic solvent such as methanol, ethanol, diethyl ether, acetonitrile, or a mixed solvent thereof, irradiate with ultraviolet rays using a knife. It is done by

As the ultraviolet light source, commonly used sources can be used.
For example, a mercury lamp is an easily available source, and a filter may be used if necessary. An irradiation temperature of -10 to 40°C, preferably -10 to 20°C gives good results.

The irradiation time depends on the type of ultraviolet radiation source and the raw material compound CVI)
Although it varies depending on the concentration of the solvent, the type of solvent, etc., it usually takes several minutes to several tens of minutes. The compound [■] produced by this ultraviolet irradiation can be isolated by easy means such as chromatography, but usually it is not isolated and is thermally isomerized by heating the reaction solution after ultraviolet irradiation. Compound [■]
In many cases, the process is carried out continuously.

The step for compound [■] is also a method known per se, in which compound [■] is heated at 20 to 120°C, preferably at 50 to 100°C, in a suitable inert solvent, preferably the solvent used in the above ultraviolet irradiation step. This is done by heating at ℃ for about 2 to 5 hours ~ this Hi! + - It is preferable to carry out the process in a small T Bodhi carp zesu. Isolation of the compound [■] from the reaction mixture is carried out by a simple method such as chromatography after distilling off the solvent. When R1 or R2 of the compound [■] obtained here is the above-mentioned acyl group, it can be hydrolyzed by a method known per se, for example, by hydration using a caustic alkali such as IJum or potassium hydroxide. Alternatively, in the case of the compounds of the present invention, which can easily yield the compound (Il), this deacylation reaction is generally carried out using a method such as reduction with a metal hydride complex such as lithium aluminum hydride. The method using metal complexes gives good results.

The compound [Il of the present invention is produced as described above.

The compound [I) thus obtained is administered parenterally, for example, by intramuscular or intravenous injection, or orally or as a suppository.

It can be increased or decreased as appropriate depending on the strength of the pharmacological calcium balance response, which is a characteristic of vitamin D-like activity. This compound [
The formulations of [I] are prepared in combination with pharmacologically acceptable carriers well known in the art, and such carriers may be either solid or liquid. Specific examples of these carriers include corn starch, olive oil, sesame oil, and medium-chain fatty acid trigly-Ilide generally referred to as MCT. Examples of dosage forms used include tablets, capsules, liquids, powders, and granules.

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The display sj is [26°26.26°27.27.27
-hexafluoro".

Example (1) 1α,8β-diacetoxy-26,27-F6-
26.27-Fs-1α synthesized by the method described in Japanese Patent Publication No. 58-501176.

650 mf of 3β,25-triacetoxycholester-5゜7-dinine was dissolved in 10 tIt of tetrahydrofuran, and 1.0 mol of tetrabutylammonium fluoride was dissolved.
Tetrahydrofuran solution 5- was added. The reaction solution was stirred at room temperature under nitrogen atmosphere for 80 minutes, and then extracted with toluene and brine. The toluene layer was washed with INEIc/water and concentrated under reduced pressure to give 1α,8β-diacetoxy-26,27-Fa-25-hydroxycholester-5,
605 mt of 7-ginine was obtained as a white amorphous powder of 1·°. Ice crystals are IR (CHOja) Te 8850 cm
and 1720!1.Next, 600 mF of the 25-hydroxy compound obtained above, triphenylphosphine 11, nn-5e le β-'I-
It was dissolved in J t-I Q After the reaction solution was cooled to room temperature and concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-n-hexane (1:10) were collected, recrystallized from methanol, and purified to obtain the desired product. A 5.7°24-triene compound 560ynP was obtained.

Melting point 116-118℃ IR (Nujol, cm): 1785.167ON
MR (cDcg, δ): (162 (8■, S), 0.98 (8EI, d
, J=6.6EIz), 1.01 (8L S)
, 2.08 (8EI, 8), 2.09 (8EI,
S), 5.00 (2H, m), 5.40 (11
, m) , 5.68 (IEI, m) , 6.78 (
I.E.I.

t, J=8.0 Hz) UV (EtOH, nm): λm&X 271.5,
281,298(2) 1α,8β-diacetoxy-26
, 27-F6-Cholesta-5,7-renine-24-hydroperoxide 295 m9 of the triene obtained in (1) above was dissolved in methanol (10 m) and tetrahydrofuran (5 m), and 2 NNa0EI O, 1 mO and 85% hydrogen peroxide solution were added to the two reaction mixtures and stirred at room temperature for 20 hours. Benzene and saturated brine were added and extracted. The benzene layer was washed with water and then concentrated under reduced pressure at below 40°C. The residue was subjected to silica gel column chromatography, and ethyl acetate-n-
Eluted with hexane 1:1B, starting triene form 81 m
P was recovered. Then ethyl acetate-n-hexane 1:
5, the hydroperoxide compound of f1 title 246 m
P was obtained as a white powder. The crystal is produced using high performance liquid chromatography (hereinafter abbreviated as EIPLC) (column: Zor
bax 8ILo4.511X 15cm, Kiya'J
7-Ethyl diacetate-n-hexane solution, flow rate: 2
．． 5 d/min) showed two peaks with the same area ratio at 4.5 minutes and 4.9 minutes.

IR (Nujol, 5”-”): aa5o, 1740
,171ONMR(CDCI!3.δ): 0.61 and 0.62 (each 1.5H,s), 0.9
4 (8EI', d, J=5.3Hz)
, 1.0 1 (8H, 3) , 2.04 (8EL,
s), 2.09 (8F1.8), 8.77 (I
H,m), 4.81 (IEI.

m), 5.00 (2Et, m), 5.40 (1
■, m), 5.68 (1■, m), 8.12 and 8.
15 (each Q, 5El, s, depleted by heavy water substitution (3) lα, 8β-diacetoxy-26,27-Fs
Production of -24-hydroxycholester-5,7-diene and separation of stereoisomer Camb at position 24 Hydroperoxide obtained in (2) above 220 m
Dissolve lF in ethyl acetate, add sodium iodide l
? was added and stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and water, dried over magnesium sulfate, and concentrated under slightly reduced pressure to obtain two isomers of the title compound [a
, b](+) 210 mt of 1:1 mixture were obtained.

This mixture was subjected to silica gel (80P) column chromatography and eluted with ethyl acetate-n-hexane to separate the less polar isomer [a] and the more polar isomer (b). The isomer [a] was recrystallized from n-hexane to give 88 mF, and the isomer (b) was recrystallized from ethyl acetate-n-hexane 1:5 to give 41 mF. Both isomers were E [PLO (Column: Zorbax SI
L■4.6111φX15511 Carrier: Ethyl acetate-n-hexane 1nia, flow rate: 2.5 d/min)
[a)1. Single peaks were observed at t5.4 minutes and [b:l h]5.9 minutes, respectively.

Low polarity isomer [a]> Melting point 129-180°C IR (Nujol, m-'): 8B50, 1
785.171ONMR (CDCI!3, δ): 0, 62 (8t11.3), 0.97 (8H, d
, J=6.6 Hz), 1.01 (gJ s),
2.08 (8El, s), 2.09 (8El, s,
8.06 (IH, m), 4.10 (IH, m)
, 5.00 (2E[, m), 5.89 (LH, m
), 5.68 (ltl, m) U V (E to
H, nm): λma” 271 e 282 e
298 (Highly polar isomer [b]) Melting point: 176-177°C IR (Nujol, am-”): 8850
, 1785.171ONMR (ODC/3, δ): 0.62 (8El, S), 0.96 (J3H, d,
J=5-6H, 1.01 C8H, 3), 2.
08 (IEI, s), 2, OD (8I1.3),
3.06 (I El, m), 4.10 (l H,
m), 5.00 (2H, m), 5.89 (I E1
%m), 5.68 (I El, m)UV (Eto
El, nm): λmal 271, 282.298
(4) 1α,24-dihydroxy-26,27-F6-
Production of vitamin D3 (compound [■])■ Isomer [I
Preparation of diacetoxycholester-5,7-obtained in (3) above
Low polar diene isomer C8125m? benzene-
It was dissolved in a mixed solvent of 4:1 ethanol (300%), and argon gas was passed through it for 10 minutes. Cool the reaction solution to 0-5°C,
2 using a 160W low pressure mercury lamp in an argon atmosphere.
Ultraviolet rays were irradiated for 5 minutes. The resulting solution was refluxed for 3 hours, and the solvent was distilled off under reduced pressure to give 1α-acetoxy-26°27
A crude product of the corresponding isomer [8] of -F6-24-hydroxyvitamin D3 was obtained.

This crude product was dissolved in tetrahydrofuran 1-20
It was added to a mixture of 0.11 l of water-accumulated lithium aluminum and 2 - of tetrahydrofuran at ℃, and deesterified by stirring for 2 minutes at the same temperature.Water was added to the reaction mixture, extracted with ethyl acetate, and the ethyl acetate layer was extracted. It was washed with water, dried (My804), and then concentrated. The residue was subjected to silica gel column chromatography twice (solvent system: ethyl acetate-n-hexane 1:2,
and dichloromethane-methanol 50:1) to obtain 2mf of one stereoisomer [a] of the target compound [I]. Ice crystals are E [PLC (kara A HZorbax
SIL■8111X25+11. The retention time was 17.8 minutes using carrier dichloromethane-methanol 100:8, flow rate: 8wI4/min).

NMR (CDCI!3, δ): 0,55 (8H,S), 0.96 (8H,d,
J=6.6m), 1.26 (8H, 8), 8.05
(1a, m), 4.11 (IE[, m), 4.2
8 (IH, m), 4.48 (IH, m), 5.
00 (IH, ri, 5.84 (I L s), 6.0
2 (IH, d, J=lIHz), 6.88 (IH,
d, J=11Hz) UV (EtoH, nm): λm
a! 264.5.1m1n22BQ) isomer [IJ
Production of diacetoxycholester-5,7- obtained in (3) above
Using 25 mF of the highly polar diene isomer (b), 2.8 mP of the target compound [Ib] was obtained in the same manner as in the case of the above isomer [Ia:l]. The ice crystals were retained for a retention time of 17.0 minutes under the same tlPLC conditions as those for compound (Ia) above.

NM, R (ODCg, δ): 0.56 (8E1.S), 0.95 (8H, d
, J=6.6 Hz), 1.26 (8t1.8),
8.05 (I El, m), 4.18 (lJm)
, 4.28 (III, m), 4.48 (IH,
m, ), 5.00 (IH,8), 5.88 (I
H, ri, 6.02 (IH, d, J=11Hz), 6
．． 88 (IH, d, J=11EIz)UV (Eto
fl, nm): λmB! 264.5, λmin
22g liver liver applicant Sumitomo Pharmaceutical Co., Ltd.

Claims (1)

[Claims] Fluorine derivative of 1a,24-dihydroxyvitamin D_3 represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼