Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-08-28
2002-01-01
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S001000, C560S008000, C560S045000
Reexamination Certificate
active
06335458
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the A ring part of vitamin D derivatives, intermediates for synthesizing them and a process for preparing them.
More particularly, the present invention relates to the A ring part of vitamin D derivatives having a 3-hydroxypropyloxy group at the 2&bgr;-position, intermediates for synthesizing them and a process for preparing them.
BACKGROUND ART
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-dihydroxy vitamin D
3
, exhibits a variety of physiological activities such as a calcium metabolism-controlling activity, proliferation-inhibiting and differentiation-inducing activities on cells such as tumor cells and an immune-controlling activity. However, 1&agr;,25-dihydroxy vitamin 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, an anti-rheumatic agent, etc.
In order to isolate such activities of the vitamin D derivatives, numerous vitamin D derivatives have been synthesized recently and their physiological activities evaluated. For example, the synthesis of vitamin D
3
derivatives which have a substituent at the 2&bgr;-position is described in, for example, Japanese Patent Publication (Kokoku) No. 3-14303, Japanese Patent Publication (Kokai) No. 61-267549 and Japanese Patent Publication (Kokai) No. 6-41059. Some of those vitamin D
3
derivatives which have a substituent at the 2&bgr;-position exhibit calcium metabolism-controlling activity in vivo 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 (e.g., osteoporosis, osteomalacia, etc.) and an antitumor agent. Among them, 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxy vitamin 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.
In synthesizing such vitamin D derivatives having a specific substituent at the 2-position, a process is known in which the A ring structure of a steroid compound, a starting material, is epoxylated and then cleaved so as to introduce the substituent to the 2-position (Japanese Patent Publication (Kokai) No. 61-267549; Chem. Pharm. Bull. 41(6), 1111-1113 (1993)). This process, however, has some disadvantages, such as difficulty in obtaining the raw material and low yield of the last step, i.e., light irradiation/thermal isomerization.
According to another known process for synthesizing the vitamin D
3
derivatives, the A ring part and the CD ring part of the vitamin D derivatives are synthesized separately and then coupled. Japanese Patent Publication (Kokai) No. 6-25039 discloses an A ring part of vitamin D derivatives and a process for synthesizing the A ring part. However, this process requires a considerably large number of reaction steps to synthesize the desired A ring part from a starting material. In addition, it is not suitable for synthesizing, for example, 2-(3-hydroxypropoxy)-1&agr;,25-dihydroxy vitamin D
3
, because a specific group cannot be introduced to the 2&bgr;-position by this process.
DISCLOSURE OF THE INVENTION
One object of the present invention is to provide compounds corresponding to the A ring part of vitamin D derivatives which have a substituent at the 2-position.
Another object of the present invention is to provide intermediates useful for the synthesis of the compounds of the present invention corresponding to the A ring part.
Still another object of the present invention is to provide a process for preparing the compounds of the present invention corresponding to the A ring part.
As a result of careful studies as to whether such vitamin derivatives that have a substituent at the 1-, 2- or 3-position stereochemically selectively can be synthesized by utilizing optically pure sugars, the inventors of the present invention have found that an A ring part having a substituent at a desired stereochemical conformation can be obtained by using D-mannitol as the starting material and thereby completed the present invention. Since D-mannitol is a low price sugar and readily available, the process of the present invention is expected to be applicable to the production of vitamin D derivatives on an industrial scale.
According to a first aspect of the present invention, there are provided compounds of the general formula (1):
(wherein R
1
, R
2
and R
3
, which may be the same or different, represent a hydrogen atom or a protecting group and R
4
represents a lower alkyl group).
Preferably, R
4
in the general formula (1) is methyl.
According to a second aspect of the present invention, there are provided compounds of the general formula (2):
(wherein R
1
, R
2
and R
3
, which may be the same or different, represent a hydrogen atom or a protecting group; and R
5
represents a hydrogen atom or a lower alkoxycarbonyl group).
Preferably, R
5
in the general formula (2) is a methoxycarbonyl group.
According to a third aspect of the present invention, there are provided compounds of the general formula (3):
(wherein R
1
and R
2
, which may be the same or different, represent a hydrogen atom or a protecting group).
The compounds of the general formulae (2) and (3) are intermediates for synthesizing the compounds of the general formula (1) of the present invention.
Japanese Patent Application No. 9-53316 (published as Japanese Patent Publication (Kokai) No. 10-251183 on Sep. 22, 1998 after the priority date of the present application) filed by the applicant of the present application discloses an epimer mixture of a compound having the same structure as the general formula (3) except for the stereochemical conformation. As is mentioned in the above, the present invention is aimed at synthesizing compounds corresponding to the A ring part of vitamin D derivatives, which are optically pure from the viewpoint of the positional and the stereochemical selectivity, without producing epimers by using an optically pure sugar, i.e. D-mannitol. However, the compounds of the general formulae (1) to (3) are novel and processes for synthesizing those compounds are not limited to a certain process. For example, the compounds of the general formula (3) of the present invention having a specific stereochemical conformation is theoretically obtainable by means of column chromatography, etc. from an epimer mixture of the compound disclosed in Japanese Patent Application No. 9-53316, that has the same structure as the compounds of the general formula (3) except for the stereochemical conformation. Compounds obtainable from such procedures are also included in the scope of the present invention. In addition, it is also possible to synthesize such vitamin D derivatives by coupling a compound corresponding to the CD ring part to a compound of the general formula (2) (wherein R
5
is H).
According to a fourth aspect of the present invention, there is provided a process for producing a compound of the general formula (1):
(wherein R
1
, R
2
and R
3
, which may be the same or different, represent a hydrogen atom or a protecting group and R
4
represents a lower alkyl group) comprising:
(a) reacting a compound of the general formula (3):
(wherein R
1
and R
2
, which may be the same or different, represent a hydrogen atom or a protecting group) with a metal acetylide to obtain a compound of the general formula (2):
(wherein R
1
, R
2
and R
3
, which may be the same or different, represent a hydrogen atom or a protecting group; and R
5
represents a hydrogen atom);
(b) reacting the compound of the general formula (2) with a lower alkyl halogenated carbonate to obtain a compound of the general formula (2) (wherein R
1
, R
2
and R
3
, which may be the same or different, represent a hydrogen atom or a protecting group; and R
5
represents a lower alkoxycarbonyl group); and
(c) subjecting the compound of the general formula (2) obtained in the
Ogasawara Kunio
Takahashi Michiyasu
Browdy and Neimark , P.L.L.C.
Chugai Seiyaku Kabushiki Kaisha
Qazi Sabiha
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