Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Patent
1996-10-01
1998-10-20
Robinson, Allen J.
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
552533, 552560, 552582, 574167, C07C40100, C07J 1300, C07J 500
Patent
active
058248110
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00699 filed Apr. 10, 1995.
1. Field of the Invention
This invention relates to novel vitamin D.sub.3 derivatives. More specifically, this invention relates to vitamin D.sub.3 derivatives substituted by sulfur atoms at the 22-position and processes for preparing said derivatives. This invention also relates to intermediates which are useful for preparing said compounds and processes for preparing said intermediates.
2. Description of the Prior Art
Active-type vitamin D.sub.3 is known to have many physiological activities including calcium metabolism regulation, differentiation induction, immunoregulation, etc.
In recent years, physiological activities of D vitamins have been gradually illuminated. D vitamins, such as 1.alpha.,25-dihydroxyvitamin D.sub.3, are known to exhibit a wide range of physiological activities including calcium metabolism regulation, proliferation inhibition or differentiation induction of oncocytes or the like, immunoregulation, etc. However, 1.alpha.,25-dihydroxyvitamin D.sub.3 is not suitable for use as, for example, antineoplastic, antirheumatic, etc., because it disadvantageously causes hypercalcemia after long-term and continuous administration. Thus, a number of vitamin D derivatives have recently been synthetized in order to divide these activities of D vitamins, and their physiological activities have been investigated.
One example of such derivatives is 1.alpha.,3.beta.-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy-9,10-secopreg na-5,7,10(19)-triene which is a derivative of vitamin D.sub.3 substituted by an oxygen atom at the 22-position, disclosed in JPA (Unexamined Japanese Patent Application) 61-267550 (1986).
DISCLOSURE OF THE INVENTION
After profound study on vitamin D derivatives, the inventors of this invention found that vitamin D derivatives substituted by sulfur atoms at the 22-position have a strong inhibitory effect against proliferation of keratinocytes.
This invention relates to 22-thiavitamin D derivatives of the following general formula (I): ##STR2## wherein R.sub.1 represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups, R.sub.2 represents a hydrogen atom or a hydroxyl group, and R.sub.3 represents a hydrogen atom or a hydroxyl group; and processes for preparing said derivatives.
This invention also relates to synthetic intermediates which are useful for preparing the compounds of the general formula (I) and processes for preparing said intermediates.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing an inhibitory effect against proliferation of human keratinocytes at each concentration of 1.alpha.,25-dihydroxyvitamin D.sub.3 ;
FIG. 2 is a graph showing an inhibitory effect against proliferation of human keratinocytes at each concentration of the compound of Example 88;
FIG. 3 is a graph showing an inhibitory effect against proliferation of human keratinocytes at each concentration of 1.alpha.,25-dihydroxyvitamin D.sub.3 ;
FIG. 4 is a graph showing an inhibitory effect against proliferation of human keratinocytes at each concentration of the compound of Example 33; and
FIG. 5 is a graph showing an inhibitory effect against proliferation of human keratinocytes at each concentration of the compound of Example 35.
THE BEST EMBODIMENTS OF THE INVENTION
As described above, this invention provides 22-thiavitamin D derivatives of the following general formula (I): ##STR3## wherein R.sub.1 represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups, R.sub.2 represents a hydrogen atom or a hydroxyl group, and R.sub.3 represents a hydrogen atom or a hydroxyl group.
In the compounds of the general formula (I), R.sub.3 is preferably a hydroxyl group. R.sub.1 is preferably a C1-10 alkyl group substituted by one or more hydroxyl groups, and more preferably a group of the following general formula (III): ##STR4## wherein R.sub.4 and R.sub.5, which may be the same or different, each represents a hydrogen atom or a hydroxyl group provided that the both are not hyd
REFERENCES:
patent: 5554599 (1996-09-01), Gue-Sorensen et al.
E. Murayama, K. Miyamoto, N. Kubodera, T. Mori, and I. Matsunaga, "Synthesis of 22-Oxavitamin D.sub.3 Analogues" Chemical Pharm. Bull., 34 (10) 4410-4413 (1986).
N. Kobodera, K. Miyamoto, M. Akiyama, M. Matsumoto, and T. Mori Synthetic Studies of Vitamin D Analogues. IX.sup.1.) 1a,25-Dihydroxy-23-ox-, thia-, and azavitamin D.sub.3.sup.2) Chemical. Pharm. Bull., 39 (12) 3221-3224 (1991).
N. Kobodera, H. Watanabe, T. Kawanishi, and M. Matsumoto, Synthetic Studies of Vitamin D Analogues. XI..sup.1) 1a,25-Dihydroxy-22-oxavitamin D.sub.3 Analogues Chemical Pharm. Bull., 40 (6) 1494-1499 (1992).
Kawase, et al. Bioorg & Med Chem Lett, 5(3), pp. 279-280, 2 Feb. 1995.
Kawase Akira
Kubodera Noboru
Badio Barbara
Chugai Seiyaku Kabushiki Kaisha
Robinson Allen J.
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