Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-10-06
2002-06-25
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S167000, C552S653000
Reexamination Certificate
active
06410523
ABSTRACT:
TECHNICAL FIELD
This invention relates to a vitamin D derivative having a substituent at the 2&bgr;-position. More particularly, the invention relates to a vitamin D derivative having at the 2&bgr;-position an alkoxy group substituted at the terminal position by SO
3
R
1
wherein R
1
represents a hydrogen atom or a straight chain or branched chain alkyl group with 1 to 3 carbon atoms or by COOR
2
wherein R
2
represents a hydrogen atom or a straight chain or branched chain alkyl group with 1 to 3 carbon atoms.
BACKGROUND ART
In recent years, vitamin D derivatives have been shown to have various physiological activities. One of vitamin D derivatives, 1&agr;,25-dihydroxyvitamin D
3
(1,25(OH)
2
D
3
), is known to show wide varieties of physiological activities, such as calcium metabolism regulating activity, activity of suppressing proliferation, or inducing differentiation, of tumor cells, etc., and immunomodulating activity.
However, 1&agr;,25-dihydroxyvitamin D
3
is defective in that it may develop hypercalcemia, depending on its dose or its mode of administration. Using it, for example, as an antitumor agent or an antirheumatic agent poses difficulty. To separate these activities of vitamin D, numerous vitamin D derivatives, such as 1&agr;-hydroxyvitamin D
3
, 1&agr;, 24-dihydroxyvitamin D
3
, 22-oxa-1&agr;,25-dihydroxyvitamin D
3
, and various fluorinated vitamin D
3
products, have recently been synthesized, and their physiological activities are under investigation.
Of many vitamin D derivatives, known vitamin D
3
derivatives having substituents at the 2&bgr;-position include 1&agr;,25-dihydroxy-2&bgr;-fluorovitamin D
3
described in Japanese Patent Publication No. 1991-14303, vitamin D
3
derivatives having at the 2&bgr;-position an amino group or a C
1-7
lower alkoxy group optionally substituted with a hydroxyl group, a halogen atom, a cyano group or an acylamino group (the derivatives described in Japanese Patent Publication No. 1994-23185), and vitamin D
3
derivatives having at the 2&bgr;-position an optionally substituted lower alkyl, alkenyl or alkinyl group which are described in Japanese Unexamined Patent Publication No. 1994-41059. Some of these vitamin D
3
derivatives having substituents at the 2&bgr;-position are known to have physiological activities, such as in vivo calcium regulating activity, and activity of inducing differentiation of tumor cells, etc., and also known to be useful as drugs, such as therapeutic agents for diseases due to disorder of calcium metabolism, such as osteoporosis or osteomalacia, or antitumor agents. Of these derivatives, 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.
As noted above, 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25-dihydroxyvitamin D
3
is under vigorous development as a useful drug, and its metabolites are also under investigation. As studies of such metabolites of 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxyvitamin D
3
are under way, it has been suggested recently that these metabolites appear to include those in which the terminal position of the 3-hydroxypropoxy group at the 2&bgr;-position has been converted to a carboxylic acid or a sulfonic acid. However, no reports have been issued on the synthesis of compounds in which the terminal position of the 3-hydroxypropoxy group at the 2&bgr;-position of 2&bgr;-(3-hydroxypropoxy)-1&agr;, 25-dihydroxyvitamin D
3
has been converted to a carboxylic acid or a sulfonic acid.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel vitamin D derivative having at the 2&bgr;-position an alkoxy group substituted at the terminal position by a sulfonic acid or a carboxylic acid or an ester of any of these acids.
Another object of the invention is to provide a novel synthetic intermediate useful for synthesizing the novel vitamin D derivative having at the 2&bgr;-position an alkoxy group substituted at the terminal position by a sulfonic acid or a carboxylic acid or an ester of any of these acids; specifically, a steroid compound having at the 2&bgr;-position an alkoxy group substituted by a halogen atom at the terminal position.
Still another object of the invention is to provide a drug containing the above-mentioned vitamin D derivative according to the invention as an active ingredient.
In an attempt to attain these objects, the inventor of the present invention used as a starting material a cholestane compound having at the 2&bgr;-position an alkoxy group substituted by a hydroxyl group at the terminal position, protected the hydroxyl groups and the 5,7-diene portion that require protection, then converted the terminal hydroxyl group of the substituted alkoxy group at the 2&bgr;-(3-position into a nitrile and then into an ester, deprotected the conversion product, and then performed light irradiation and thermal isomerization. By this procedure, the inventor succeeded in synthesizing the desired vitamin D derivative having at the 2&bgr;-position an alkoxy group substituted by an ester of a carboxylic acid at the terminal position. The inventor also found this vitamin D derivative to have affinity for a vitamin D receptor and a vitamin D-binding protein, and also to be useful as a drug. These achievements led to accomplishment of the present invention.
According to a first aspect of the invention, here is provided a vitamin D derivative of the general formula (I):
wherein
A denotes a straight chain or branched chain alkylene group with 2 to 10 carbon atoms; and
R denotes
SO
3
R
1
in which R
1
represents a hydrogen atom or a straight chain or branched chain alkyl group with 1 to 3 carbon atoms or
COOR
2
in which R
2
represents a hydrogen atom or a straight chain or branched chain alkyl group with 1 to 3 carbon atoms.
In the general formula (I), A is preferably a straight chain alkylene group with 2 to 10 carbon atoms.
In the general formula (I), R is preferably COOR
2
wherein R
2
represents a hydrogen atom or a straight chain or branched chain alkyl group with 1 to 3 carbon atoms.
In the general formula (I), it is particularly preferred that A is an ethane-1,2-diyl group, and R is COOR
2
wherein R
2
represents a hydrogen atom or a straight chain or branched chain alkyl group with 1 to 3 carbon atoms.
Further preferred compounds as the vitamin D derivative of the general formula (I) are 2&bgr;-(2-carboxyethyloxy)-1&agr;, 3&bgr;,25-trihydroxycholesta-5,7-10(19)-triene and 2&bgr;-(2-methoxycarbonylethyloxy)-1&agr;, 3&bgr;,25-trihydroxycholesta-5,7-10(19)-triene.
According to a second aspect of the invention, there is provided a steroid compound of the general formula (II):
wherein
A denotes a straight chain or branched chain alkylene group with 2 to 10 carbon atoms;
X denotes a halogen atom;
R
a
, R
b
and R
c
denote, independently of each other, a hydrogen atom or a hydroxyl group protecting group; and
R
p
, R
q
, R
y
and R
z
are such that
R
p
and R
q
together form a double bond between the 5-position and the 6-position and R
y
and R
z
together form a double bond between the 7-position and the 8-position or
R
q
and R
y
together form a double bond between the 6-position and the 7-position and R and R
z
are bound to a dienophile capable of protecting conjugated double bonds.
This compound is an intermediate compound useful for the synthesis of the vitamin D derivative of the general formula (I).
In the general formula (II), it is preferred that A is a straight chain alkylene group with 2 to 10 carbon atoms, and X is an iodine atom.
According to a third aspect of the invention, there is provided a pharmaceutical composition containing the vitamin D derivative of the general formula (I) as an active ingredient (e.g., a therapeutic agent for a disease due to a disorder of calcium metabolism).
PREFERRED MODES FOR CARRYING OUT THE INVENTION
In defining the vitamin D derivative of the general formula (I), examples of the straight chain or branched chain alkylene group with 2 to 10 carbon atoms,
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
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