16-ENE-vitamin D derivatives

Details 16-ENE-vitamin D derivatives 16-ENE-vitamin D derivatives

2000-08-18

2001-12-04

Qazi, Sabiha (Department: 1616)

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

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S523000, C552S623000, C552S632000

Reexamination Certificate

active

06326503

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel vitamin D derivatives with high binding ability to vitamin D receptors and weak hypercalcemic activity, useful compounds as pharmaceutical agents such as antitumor agents, antirheumatic agents, etc., and novel synthetic intermediates which are useful for synthesis of said compounds.
BACKGROUND ART
Activated vitamins D
3
including 1&agr;, 25-dihydroxy-vitamin D
3
are known to have many physiological activities such as calcium catabolism regulation, growth inhibition and differentiation induction of tumor cells, immunoregulation. However, some activated vitamins D
3
disadvantageously cause hypercalcemia during long-term and continuous administration so that they are not suitable for use as antitumor agents, antirheumatic agents or the like. Thus, a number of vitamin D derivatives have been synthesized and examined for the purpose of separating activities of these vitamins D.
For example, JPA No. 267550/86 discloses 1&agr;,3&bgr;-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy)-9,10-secopregna-5,7,10(19)-triene and JPA No. 330714/95 discloses a vitamin D derivative substituted by a sulfur atom at the 22-position.
Various vitamin D derivatives having a double bond at the 16-position are described in JPA No. 9861/90, JPA No. 17019/91, JPA No. 188159/95, JPA No. 40975/94, JPA No. 179418/95, U.S. Pat. No. 5,087,619 and U.S. Pat. No. 5,145,846, etc. However, none of these compounds are said to have weak hypercalcemic activity.
Many of these known vitamin D compounds have high binding ability to vitamin D receptors but strong hypercalcemic activity, or weak hypercalcemic activity but unsatisfactory binding ability to vitamin D receptors. Therefore, it would be desirable to develop promising compounds with high binding ability to vitamin D receptors and weak hypercalcemic activity.
DISCLOSURE OF INVENTION
As a result of careful studies of compounds with high binding ability to vitamin D receptors and weak hypercalcemic activity in view of the above problems, we found that compounds of general formula (1):
wherein X represents an oxygen or sulfur atom, R
11
represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a —COR
12
group where R
12
represents an alkyl, aryl or alkoxy group, R
2
represents —OR
9
or a hydrogen atom, and R
9
and R
10
may be the same or different and each represent a hydrogen atom or a protecting group, have high binding ability to vitamin D receptors and weak hypercalcemic activity, and thus accomplished the present invention.
According to one aspect of the present invention, vitamin D derivatives of general formula (1):
wherein X represents an oxygen or sulfur atom, R
11
represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a —COR
12
group where R
12
represents an alkyl, aryl or alkoxy group, R
2
represents —OR
9
or a hydrogen atom, and R
9
and R
10
may be the same or different and each represent a hydrogen atom or a protecting group are provided.
In general formula (1), R
2
is preferably —OR
9
.
In general formula (1), R
11
is preferably a saturated C1-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (1), R
11
is preferably an unsaturated C2-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (1), R
11
is preferably a group (2):
wherein R
3
and R
4
may be the same or different and each represent a hydrogen atom or a hydroxyl group, or are combined to represent ═O, provided that R
3
and R
4
can not be a hydroxyl groups simultaneously, R
5
and R
6
each represent a hydrogen atom or a hydroxyl group, but R
6
can not be a hydroxyl group simultaneously with R
3
or R
4
, m represents an integer of 1 to 4, and n represents an integer of 0 to 2; or a group (3):
wherein R
5
and R
6
may be the same or different and each represent a hydrogen atom or a hydroxyl group, R
7
and R
8
each represent a hydrogen atom or are combined to represent a covalent bond, p represents an integer of 1 to 3, and q represents an integer of 0 to 2.
In general formula (1), R
11
is especially preferably a 3-hyroxy-3-methylbutyl group.
In an embodiment of compounds represented by general formula (1), the 20-position is in S-configuration.
In another embodiment of compounds represented by general formula (1), the 20-position is in R-configuration.
Specific examples of compounds represented by general formula (1) include 1,3-dihydroxy-20-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene. Sterically defined examples of this compound include 1&agr;,3&bgr;-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene and 1&agr;,3&bgr;-dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.
Other specific examples of compounds represented by general formula (1) include 1&agr;,3&bgr;-dihydroxy-20(R)-((E)-4-hydroxy-4-methyl-2-pentenylthio)-9,10-secopregna-5,7,10 (19),16-tetraene and 1&agr;,3&bgr;-dihydroxy-20(R)-((E)-4-ethyl-4-hydroxy-2-hexenylthio)-9,10-secopregna-5,7,10(19),16-tetraene.
Other specific examples of compounds represented by general formula (1) include 1&agr;,3&bgr;-dihydroxy-20(S)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene; 1&agr;,3&bgr;-dihydroxy-20(R)-(2-hydroxy-2-methylpropyl-thio)-9,10-secopregna-5,7,10(19),16-tetraene; 1&agr;,3&bgr;-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene; 1&agr;,3&bgr;-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene; 1&agr;,3&bgr;-dihydroxy-20(S)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene; and 1&agr;,3&bgr;-dihydroxy-20(R)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.
According to another aspect of the present invention, compounds of general formula (4):
wherein X represents an oxygen or sulfur atom, R
11
represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a —COR
12
group where R
12
represents an alkyl, aryl or alkoxy group, and R
9
and R
10
may be the same or different and each represent a hydrogen atom or a protecting group are provided.
In general formula (4), R
11
is preferably a saturated C1-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (4), R
11
is preferably an unsaturated C2-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (4), R
11
is preferably a group (2):
wherein R
3
and R
4
may be the same or different and each represent a hydrogen atom or a hydroxyl group, or are combined to represent ═O, provided that R
3
and R
4
can not be a hydroxyl group simultaneously, R
5
and R
6
each represent a hydrogen atom or a hydroxyl group, but R
6
can not be a hydroxyl group simultaneously with R
3
or R
4
, m represents an integer of 1 to 4, and n represents an integer of 0 to 2; or a group (3):
wherein R
5
and R
6
may be the same or different and each represent a hydrogen atom or a hydroxyl group, R
7
and R
8
each represent a hydrogen atom or are combined to represent a covalent bond, p represents an integer of 1 to 3, and q represents an integer of 0 to 2.
In general formula (4), R
11
is especially preferably a 3-hyroxy-3-methylbutyl group.
According to another aspect of the present invention, compounds of general formula (24):
wherein R
9
and R
10
may be the same or different and each represent a hydrogen atom or a protecting group are provided.
According to still another aspect of the present invention, compounds of general formula (5):
wherein R
9
and R
10
may be the same or different and each represent a hydrogen atom or a protecting group, and the conjugated double bond in the formula may be protected by a protecting group are provided.
A

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