24-hydroxy vitamin D derivatives

Details 24-hydroxy vitamin D derivatives 24-hydroxy vitamin D derivatives

2002-03-19

2003-03-25

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C514S167000, C514S182000, C552S653000

Reexamination Certificate

active

06538145

ABSTRACT:

TECHNICAL FIELD
The present invention relates to vitamin D derivatives having a hydroxy group at 24-position thereof, and particularly relates to vitamin D derivatives having a substituent at 2&bgr; position and a hydroxy group at 24-position.
BACKGROUND OF THE INVENTION
Recently, some of the physiological activities of vitamins D have been revealed. It is known that a certain vitamin D, for example, 1&agr;, 25-dihydroxyvitamin D
3
, exhibits a variety of physiological activities such as a calcium metabolism-controlling activity, a proliferation-inhibiting activity and a differentiation-inducing activity on cells such as tumor cells, and an immune-controlling activity.
However, 1&agr;, 25-dihydroxyvitamin D
3
disadvantageously causes hypercalcemia depending on the dose and/or the administration route and thus is not suitable for use as an antitumor agent, a therapeutic agent for rheumatic diseases, etc. In order to isolate such activities of the vitamin D derivatives, numerous vitamin D derivatives have been synthesized these days and their physiological activities were evaluated.
Among numerous vitamin D
3
derivatives, some of those which have a substituent at the 2&bgr;-position possess physiological activities such as calcium metabolism-controlling activity and differentiation-inducing activity on cells such as tumor cells and are known to be useful as a medicine, such as a therapeutic agent for diseases associated with abnormal calcium metabolism, such as osteoporosis, osteomalacia, etc. and an antitumor agent (Japanese Patent Publication (Kokoku) No. 3-14303, Japanese Patent Publication (Kokai) No. 61-267549 and Japanese Patent Publication (Kokai) No. 6-41059). Among them, 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25 -dihydroxyvitamin D
3
is expected to be of practical use in treating osteoporosis, with a high blood level being able to be maintained for a long duration.
Vitamin D
3
derivatives may be synthesized, for example, by epoxidation and then opening the A ring structure of a steroid compound (used as a starting material) so as to introduce the substituent to 2-position (Japanese Patent Publication (Kokai) No. 61-267549) or by coupling the A ring part and the CD ring part of the vitamin D derivative, which parts have been synthesized separately. Japanese Patent Publication (Kokai) No. 6-25039 and Japanese Patent Application No. 9-53316 (published as Japanese Patent Publication (Kokai) No. 10-251183) disclose processes for synthesizing the A ring part of vitamin D derivatives.
As described above, the 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25 -dihydroxyvitamin D
3
has been developed as a useful medicine; at the same time, its metabolites are also under study. With recent progress in the study of 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25 -dihydroxyvitamin D
3
metabolites, it has been suggested that some of the metabolites have their side chain hydroxylated. However, no report has been made concerning the synthesis of a 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25-dihydroxyvitamin D
3
derivative of which the 24-position is hydroxylated.
DISCLOSURE OF THE INVENTION
One object of the present invention is to provide a novel vitamin D derivative of which 24-position is hydroxylated.
Another object of the present invention is to provide novel intermediates which are useful for synthesizing the above-mentioned novel vitamin D derivative of which 24 -position is hydroxylated, more specifically, intermediates corresponding to the A ring part and intermediates corresponding to the C ring part of the vitamin D derivative skeleton.
Still another object of the present invention is to provide a process by which the novel vitamin D derivative of the present invention of which 24-position is hydroxylated is synthesized by using the intermediates of the present invention.
Still another object of the present invention is to provide a process for synthesizing 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25-dihydroxyvitamin D
3
by using the novel intermediates of the present invention.
With a view to attaining the above-mentioned objects, the inventors of the present invention investigated the various reactions involved in the synthesis of the CD ring part and A ring part of vitamin D skeleton and in the coupling of the CD ring part and the A ring part and, as a result, achieved the synthesis of the desired vitamin D
3
derivative having a hydroxy group at 24-position by first synthesizing 1-[4,5-bis(t-butyldimethylsilyloxy)-1,5 -dimethylhexyl]-4-bromomethylene-7a-methyl-octahydro-1H-indene and 3,5-bis(t-butyldimethylsilyloxy)-4-(3 -t-butyldimethylsilyloxypropoxy)-1-octen-7-ine,separately as the CD ring part and the A ring part, respectively and coupling them together, thereby completing the present invention.
According to a first aspect of the present invention, there are provided vitamin D derivatives having the general formula (1):
[wherein R
1
, R
2
, R
3
and R
4
, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR
5
, provided Y is OR
5
when X is H and Y is H when X is OR
5
(wherein R
5
is a hydrogen atom or a protecting group and R
1
and R
5
may together form a vicinal-diol protecting group)].
Preferably, the 1-position of the general formula (1) is in R-configuration.
According to a second aspect of the present invention, there are provided compounds having the general formula (2):
[wherein R
1
and R
6
, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR
5
, provided Y is OR
5
when X is H and Y is H when X is OR
5
(wherein R
5
represents a hydrogen atom or a protecting group and R
1
and R
5
may together form a vicinal-diol protecting group)];
compounds having the general formula (3):
[wherein R
1
represents a hydrogen atom or a protecting group; X and Y represent H or OR
5
, provided Y is OR
5
when X is H and Y is H when X is OR
5
(wherein R
5
represents a hydrogen atom or a protecting group and R
1
and R
5
may together form a vicinal-diol protecting group)]; and
compounds having the formula (4):
[wherein R
1
represents a hydrogen atom or a protecting group; X and Y represent H or OR
5
, provided Y is OR
5
when X is H and Y is H when X is OR
5
(wherein R
5
represents a hydrogen atom or a protecting group and R
1
and R
5
may together form a vicinal-diol protecting group)]. These compounds are useful as intermediates for the synthesis of compounds of the general formula (1).
According to a third aspect of the present invention, there are provided compounds having the general formula (5):
(wherein R
7
represents a trimethylsilyl group or a hydrogen atom; and R
2
, R
3
and R
4
, which are the same or different, represent a hydrogen atom or a protecting group). These compounds are useful as intermediates for the synthesis of compounds of the general formula (1).
According to a fourth aspect of the present invention, there is provided a process for preparing vitamin D derivatives having the general formula (1):
[wherein R
1
, R
2
, R
3
and R
4
, which may be the same or different, represent a hydrogen atom or a protecting group; X and Y represent H or OR
5
, provided Y is OR
5
when X is H and Y is H when X is OR
5
(wherein R
5
is a hydrogen atom or a protecting group and R
1
and R
5
may together form a vicinal-diol protecting group)] comprising:
reacting a compound having the general formula (4):
[wherein R
1
represents a hydrogen atom or a protecting group; X and Y represent H or OR
5
, provided Y is OR
5
when X is H and Y is H when X is OR
5
(wherein R
5
represents a hydrogen atom or a protecting group and R
1
and R
5
may together form a vicinal-diol protecting group)]
with a compound of the general formula (5):
(wherein R
7
represents a hydrogen atom; and R
2
, R
3
and R
4
, which are the same or different, represent a hydrogen atom or a protecting group).
In the above process, the OR
2
group at the 3-position of the compound having the general formula (5) is in R-configurati

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