JPH07258207A - 1alpha-lower alkyl vitamin d derivative - Google Patents

Abstract

PURPOSE:To provide a new 1 alpha-lower alkyl vitamin D derivative useful as an agent for the treatment of calcium hypometabolism, dermatic diseases and diseases accompanying cell differentiation function disorder. CONSTITUTION:This compound is expressed by formula I [R is a lower alkyl; R<1> and R<2> each is H or an OH-protecting group; R<3> is an alkyl which may be substituted with (protected)OH] e.g. 1beta, 25-dihydroxy-1alpha-butylvitamin D3. The compound can be produced by reacting a l-oxoprevitamin derivative of formula III (R<6> is H or an OH-protecting group) with an alkyllithium of formula, RLi in an inert solvent, optionally carrying out the protection and deprotection of the hydroxyl groups, thermally isomerizing the resultant la-lower alkyl previtamin D derivative of formula II (R<4> and R<5> each is H or an OH-protecting group) by conventional method and optionally protecting or deprotecting the hydroxyl groups. Examples of diseases on which the compound of formula I is effective are osteoporosis, psoriasis and myelocytic leukemia.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 1α-lower alkyl vitamin D derivative and a synthetic intermediate thereof. The 1α-lower alkylvitamin D derivative of the present invention is used as a therapeutic agent for calcium metabolism deficiency diseases such as osteoporosis, osteomalacia, hypoparathyroidism, and chronic renal failure, as well as skin diseases such as psoriasis and myeloid leukemia. , It is useful as a therapeutic drug for diseases in which cell differentiation functions such as malignant tumors represented by breast cancer are abnormal.

[0002]

2. Description of the Related Art In recent years, with the progress of research on vitamin D, various 1α-hydroxyvitamin D derivatives have been developed as pharmaceuticals. For example, 1α-hydroxyvitamin D ₃ and 1α, 25-dihydroxyvitamin D ₃ are available. It is already clinically used as a therapeutic drug for osteoporosis.
However, since these compounds have side effects such as an action of increasing blood calcium, a vitamin D derivative with less side effects has been actively developed recently. For example, 24,25-dihydroxyvitamin D ₃ , 24 -epivitamin D _{2 and the} like have been attempted to be developed as therapeutic agents for osteoporosis, and 22-oxa-
1,25-Dihydroxyvitamin D _{3 and the} like are being investigated as therapeutic agents for hyperparathyroidism.

[0003]

[Problems to be Solved by the Invention] Vitamin D
Although some derivatives have been studied, the fact is that from the standpoint of treating diseases, the development of vitamin D derivatives with higher activity and higher safety is desired. Therefore, it is an object of the present invention to provide novel vitamin D derivatives having such action properties and novel compounds useful as synthetic intermediates thereof.

[0004]

According to the present invention, the above object is achieved by the following general formula (I):

[0005]

[Chemical 3]

(In the formula, R represents a lower alkyl group, and R ¹
And R ² each represent a hydrogen atom or a hydroxyl-protecting group, and R ³ represents an alkyl group which may be substituted with an optionally protected hydroxyl group. ) 1α-lower alkyl vitamin D derivative (hereinafter, this is abbreviated as 1α-lower alkyl vitamin D derivative (I)), and the following general formula (II)

[0007]

[Chemical 4]

(In the formula, R and R ³ are as defined above, and R ⁴ and R ⁵ are each a hydrogen atom or a hydroxyl-protecting group.) 1α-lower alkylprevitamin D derivative (hereinafter , Which is abbreviated as 1α-lower alkyl previtamin D derivative (II)).

In the above general formulas (I) and (II), R
Examples of the lower alkyl group represented by include an alkyl group having 1 to 6 carbon atoms. Such an alkyl group may be linear or branched, and specifically, a methyl group,
Examples thereof include ethyl group, propyl group, butyl group, isobutyl group, pentyl group and hexyl group.

In the above general formulas (I) and (II), R
^The hydroxyl-protecting group represented by ¹ , R ² , R ⁴ and R ⁵ may be any group that plays a role of protecting the hydroxyl group, and examples thereof include a formyl group, an acetyl group, a propionyl group, a butyryl group,
Isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, caproyl group, benzoyl group, optionally substituted acyl group such as trifluoroacetyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, Alkoxycarbonyl groups such as allyloxycarbonyl group and benzyloxycarbonyl group; Trisubstituted silyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group; methoxymethyl group , A 1-alkoxyalkyl group such as a methoxyethoxymethyl group, a 1-ethoxyethyl group, a 1-methyl-1-methoxyethyl group; a 2-o, such as a tetrahydrofuranyl group and a tetrahydropyranyl group. , And the like Sa cycloalkyl group.

In the above general formulas (I) and (II), R
The alkyl group moiety in the alkyl group which may be substituted with an optionally protected hydroxyl group represented by ³ may be linear or branched, and specifically, a methyl group or an ethyl group. Group, propyl group, 4-methylpentyl group,
3,4-dimethylpentyl group, 3,3,4-trimethylpentyl group, 5-methylhexyl group, 4-ethylhexyl group, 6-methylheptyl group, 3-cyclopropyl-4
-Methylpentyl group, 3-cyclopropylpropyl group,
A 3-cyclopentyl propyl group etc. can be mentioned.

The alkyl group represented by R ³ may be substituted with an optionally protected hydroxyl group, and as the hydroxyl-protecting group in the protected hydroxyl group which the alkyl group may have as a substituent, , R ¹ , R ² , R ⁴ and R
The same protecting groups as those defined for the hydroxyl protecting group represented by ⁵ can be mentioned. Examples of the alkyl group which is substituted with an optionally protected hydroxyl group represented by R ³ include 4-hydroxy-4-methylpentyl group, 3-hydroxy-4-methylpentyl group and 5-hydroxy-5-methylhexyl group. Is mentioned.

The 1α-lower alkyl vitamin D derivative (I) and the 1α-lower alkyl previtamin D derivative (II) of the present invention can be produced according to the following reaction steps.

[0014]

[Chemical 5]

(During the above reaction step, R, R ¹ , R ² ,
R ³ , R ⁴ and R ⁵ are as defined above and R ⁶
Represents a hydrogen atom or a hydroxyl-protecting group. ) Examples of the protective group for the hydroxyl group represented by R ⁶ include R ¹ , R ² and R ⁴
And the protecting groups similar to those defined for the hydroxyl protecting group represented by R ⁵ .

The above reaction step will be described in detail below. The 1-oxoprevitamin D derivative represented by the general formula (III) can be obtained, for example, from Journal of Organic
Chemistry (Journal of Organic)
Chemistry, 42, 3597 (197).
7) or 58: 1895 (1993). Also, tetrahedron (Tetra)
Hedron), 40, 1179 (1984), and can also be produced from a previtamin D derivative.

1-oxoprevitamin D derivative (III)
And an alkyllithium represented by the general formula R-Li (R is as defined above) in an inert solvent,
The 1α-lower alkyl previtamin D derivative (II) can be obtained by protecting or deprotecting the hydroxyl group as necessary. Examples of the alkyl lithium used here include methyl lithium, ethyl lithium, and butyl lithium. The amount of alkyllithium used is usually in the range of 1.0 to 10 times by mole with respect to the 1-oxoprevitamin D derivative (III). In addition, examples of the inert solvent used in this reaction include tetrahydrofuran, diethyl ether, dimethoxyethane and the like. These solvents can be used alone or in combination of two or more.

The 1α-lower alkyl previtamin D derivative (II) thus obtained is subjected to thermal isomerization in accordance with a conventional method adopted for ordinary previtamin D derivatives, and if necessary, hydroxyl group protection or deprotection. By carrying out, 1α-lower alkyl vitamin D derivative (I) can be obtained.

Isolation and purification of the 1α-lower alkyl previtamin D derivative (II) and 1α-lower alkyl vitamin D derivative (I) thus obtained from the reaction mixture are generally carried out by separating the organic compound from the reaction mixture. The separation and purification are performed by the same method as that used. For example, if necessary, the reaction mixture is contacted with water, followed by extraction with an organic solvent such as diethyl ether or ethyl acetate, and the extract is washed with cold dilute hydrochloric acid, aqueous sodium hydrogen carbonate, brine, or the like, if necessary, After drying, the product is concentrated to obtain a crude product, and the crude product is purified by recrystallization, chromatography or the like, if necessary, and the 1α-lower alkylprevitamin D derivative (II) and 1α-lower alkylvitamin D are obtained.
Each of the derivatives (I) can be obtained.

The 1α-lower alkyl vitamin D derivative (I) of the present invention is 1α, 25-dihydroxyvitamin D ₃
It shows a binding activity with the receptor, has a weak effect of increasing blood calcium even when administered to rats fed a low calcium and low vitamin D diet, and has low toxicity in an acute toxicity test. , Is useful as a therapeutic drug for calcium metabolism deficiency diseases such as osteomalacia, hyperparathyroidism, and chronic renal failure. In addition, since it has an action of inducing differentiation of myeloid leukemia cells, it is used as a therapeutic drug for skin diseases such as psoriasis and diseases with abnormal cell differentiation functions such as myeloid leukemia and malignant tumors represented by breast cancer. It is useful.

[0021]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 25-Hydroxy-1-oxoprevitamin D ₃ (20
hexamethylphosphoric triamide (39 mg) in a tetrahydrofuran solution (5 ml) of mg, 4.8 × 10 ⁻⁵ mol).
μl, 2.2 × 10 ⁻⁴ mol) was added, and while stirring at −78 ° C., a tetrahydrofuran solution of butyllithium (139 μl, butyllithium 2.2 × 10 ⁻⁴ mol).
Was added little by little. After 10 minutes, a solution of butyllithium in tetrahydrofuran (139 μl, butyllithium 2.2
× 10 ⁻⁴ mol) was added, and the mixture was stirred at −78 ° C. for 30 minutes. Ammonium chloride aqueous solution was added to the obtained reaction solution,
After extraction with ethyl acetate, the organic layer was washed with water and dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography (silica gel 6 g, 25% benzene-ethyl acetate) to give the following physical properties. 1β, 25-dihydroxy-1α-butylprevitamin D ₃ 5 mg (yield 22%), raw material 25-hydroxy-1-oxoprevitamin D ₃ 2 mg, and 1α, 25-dihydroxy-1β-butylprevitamin D ₃ 8 mg (35% yield)
Were sequentially obtained.

1β, 25-dihydroxy-1α-butyl previtamin D ₃ : UV spectrum (95% ethanol) 255 nm mass spectrum m / z 454 (M ⁺ -18); 4
36,415,397,379,361 1α, 25-dihydroxy-1β-butylprevitamin D ₃ : UV spectrum (95% ethanol) 261
nm mass spectrum m / z 472 (M ⁺ ); 454, 4
36,415,397 ¹ H-NMR spectrum (CD ₃ OD) δ 0.73 (3H, s, H-18), 0.92 (3H,
t, J = 7.2 Hz, Bu), 0.98 (3H, d, J
= 6.6 Hz, H-21), 1.16 (6H, s, H-
26 & -27), 1.64 (3H, s, H-19),
3.90 (1H, m, H-3), 5.51 (1H, m,
H-9), 5.76 (1H, d, J = 11.9 Hz, H
-7), 5.87 (1H, d, J = 11.9 Hz, H-
6)

Example 2 1β, 25-dihydroxy-1 obtained according to Example 1
α-Butylprevitamin D ₃ was allowed to stand at room temperature for 16 days for thermal isomerization to obtain 1β, 25-dihydroxy-1α-butylvitamin D ₃ (2.2 mg, yield 44%).

UV spectrum (95% ethanol) 2
63 nm ¹ H-NMR spectrum (CD ₃ OD) δ 0.52 (3H, s, H-18), 0.87 (3H,
t, J = 7.09 Hz, Bu), 0.96 (3H, d,
J = 5.9 Hz, H-21), 1.16 (6H, s, H
-26 & -27), 3.74 (1H, m, H-3),
4.88 (1H, m, H-19), 5.34 (1H,
m, H-19), 6.02 (1H, d, J = 11.2H
z, H-7), 6.32 (1H, d, J = 11.2H
z, H-6)

Example 3 1β, 25- having the following physical properties was obtained by carrying out the reaction and separation and purification in the same manner as in Example 1 except that methyllithium was used in place of butyllithium in Example 1.
Dihydroxy-1α-methylprevitamin D ₃ and 1
α, 25-dihydroxy-1β-methylprevitamin D
Got _three .

1β, 25-dihydroxy-1α-methylprevitamin D ₃ : UV spectrum (95% ethanol) 256 nm mass spectrum m / z 412 (M ⁺ -18); 3
94,379,361 1α, 25-dihydroxy-1β-methylprevitamin D ₃ : UV spectrum (95% ethanol) 262
nm mass spectrum m / z 430 (M ⁺ ); 412, 3
94,379,361

Example 4 1β, 25-dihydroxy-1 obtained according to Example 3
α-Methylprevitamin D ₃ was allowed to stand at room temperature for 16 days for thermal isomerization to obtain 1β, 25-dihydroxy-1α-methylvitamin D ₃ . UV spectrum (95% ethanol) 262nm

[0029] By carrying out the reaction and separation and purification in the same manner as in Example 3 except for using 1-oxo-previtamin D ₃ in place of Example 5 in Example 3 25-hydroxy-1-oxo previtamin D ₃ , 1β-hydroxy-1 having the following physical properties
α-methylprevitamin D ₃ and 1α-hydroxy-
1β-methylprevitamin D ₃ was obtained.

1β-hydroxy-1α-methylprevitamin D ₃ : mass spectrum m / z 414 (M ⁺ ); 396, 3
78,363 ¹ H-NMR spectrum (CDCl ₃ ) δ 0.70 (3H, s, H-18), 0.87 (6H,
d, J = 6.4 Hz, H-26 & -27), 0.94
(3H, d, J = 6.4 Hz, H-21), 1.23
(3H, s, CH3-1), 1.75 (3H, s, H-
19), 4.21 (1H, m, H-3), 5.55 (1
H, m, H-9), 5.78 (1H, d, J = 11.9).
Hz, H-7), 5.90 (1H, d, J = 11.9H)
z, H-6) 1α-hydroxy-1β-methylprevitamin D ₃ : mass spectrum m / z 414 (M ⁺ ); 396, 3
78,363 ¹ H-NMR spectrum (CDCl ₃ ) δ 0.69 (3H, s, H-18), 0.87 (6H,
d, J = 6.4 Hz, H-26 & -27), 0.94
(3H, d, J = 6.4 Hz, H-21), 1.33
(3H, s, CH3-1), 1.59 (3H, s, H-
19), 3.98 (1H, m, H-3), 5.32 (1)
H, m, H-9), 5.76 (1H, d, J = 11.9).
Hz, H-7), 5.87 (1H, d, J = 11.9H
z, H-6)

Example 6 The 1β-hydroxy-1α-methylprevitamin D ₃ obtained in Example 5 was left to stand at room temperature for 16 days for thermal isomerization to obtain 1β-hydroxy-1α-methylvitamin D ₃ .

¹ H-NMR spectrum (CDCl ₃ ) δ 0.54 (3H, s, H-18), 0.87 (6H,
d, J = 6.4 Hz, H-26 & -27), 0.92
(3H, d, J = 6.4 Hz, H-21), 1.40
(3H, s, CH3-1), 4.09 (1H, m, H-
3), 4.95 & 5.32 (each 1H, m, H-
19), 5.98 (1H, d, J = 10.4Hz, H-
7), 6.42 (1H, d, J = 10.4Hz, H-
6)

[0033]

INDUSTRIAL APPLICABILITY The 1α-lower alkyl vitamin D derivative (I) provided by the present invention is used for osteoporosis, osteomalacia,
It is useful as a therapeutic drug for calcium metabolism deficiency such as hypoparathyroidism and chronic renal failure, and abnormal cell differentiation function such as skin diseases such as psoriasis and myeloid leukemia and malignant tumors represented by breast cancer. It is useful as a remedy for the diseases that caused the disease.

Claims (2)

[Claims] 1. The following general formula (I): (In the formula, R represents a lower alkyl group, R ¹ and R ² each represent a hydrogen atom or a hydroxyl-protecting group, and R ³ represents an alkyl group which may be substituted with an optionally protected hydroxyl group. .) 1α-lower alkyl vitamin D derivative. 2. The following general formula (II): (In the formula, R represents a lower alkyl group, R ³ represents an alkyl group which may be substituted with an optionally protected hydroxyl group, and R ⁴ and R ⁵ each represent a hydrogen atom or a hydroxyl group-protecting group. .) 1α-lower alkyl previtamin D derivative.