Compounds effective in inducing cell differentiation and process for preparing same
First Claim
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1. A process for the preparation of vitamin D compounds having the general structure:
- ##STR8## where X and Y, which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, hydroxy and fluoro-substituted alkyl, hydroxy-protected hydroxy-substituted alkyl and hydroxy-protected hydroxy- and fluoro-substituted alkyl, which comprises treating a vitamin D-22-tosylate derivative, of the general structure;
##STR9## where X and Y are selected from the group consisting of hydrogen and hydroxy-protecting groups, with an alkylphenylsulfone derivative of the general structure;
space="preserve" listing-type="equation">Ph--SO.sub.2 --CH.sub.2 --Rwherein R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, and hydroxy- and fluoro-substituted alkyl, any hydroxy group present being preferably derivatized by hydroxy-protecting groups, thereby obtaining a side chain sulfone adduct, having the following general structure;
##STR10## wherein X, Y and R represent the groupings defined above, and reductively desulfonating said side chain sulfone adduct so as to obtain the corresponding vitamin D compound, and, optionally removing the hydroxy-protecting groups present.
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Abstract
This invention provides novel side chain homologs of 1α,25-dihydroxyvitamin D3 which exhibit enhanced and highly selective activity in inducing differentiation of malignant cells. It also provides a general method of synthesis applicable to the preparation of a variety of vitamin D side chain analogs, and a method of treatment of neoplastic diseases which takes advantage of the selective differentiation activity of the new vitamin D homologs.
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Citations
26 Claims
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1. A process for the preparation of vitamin D compounds having the general structure:
- ##STR8## where X and Y, which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, hydroxy and fluoro-substituted alkyl, hydroxy-protected hydroxy-substituted alkyl and hydroxy-protected hydroxy- and fluoro-substituted alkyl, which comprises treating a vitamin D-22-tosylate derivative, of the general structure;
##STR9## where X and Y are selected from the group consisting of hydrogen and hydroxy-protecting groups, with an alkylphenylsulfone derivative of the general structure;
space="preserve" listing-type="equation">Ph--SO.sub.2 --CH.sub.2 --Rwherein R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, and hydroxy- and fluoro-substituted alkyl, any hydroxy group present being preferably derivatized by hydroxy-protecting groups, thereby obtaining a side chain sulfone adduct, having the following general structure;
##STR10## wherein X, Y and R represent the groupings defined above, and reductively desulfonating said side chain sulfone adduct so as to obtain the corresponding vitamin D compound, and, optionally removing the hydroxy-protecting groups present. - View Dependent Claims (2, 3, 4)
- ##STR8## where X and Y, which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, hydroxy and fluoro-substituted alkyl, hydroxy-protected hydroxy-substituted alkyl and hydroxy-protected hydroxy- and fluoro-substituted alkyl, which comprises treating a vitamin D-22-tosylate derivative, of the general structure;
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5. Compounds having the structure:
- ##STR11## wherein X and Y, which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R is selected from the group consisting of 4-methyl-4-hydroxy-pentyl, 5-methyl-5-hydroxy-hexyl, and their corresponding hydroxy-protected forms.
- View Dependent Claims (6, 7, 8, 9, 10, 11)
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12. Compounds having the structure:
- ##STR12## where X, Y and Z, which may be the same or different, selected from the group consisting of hydrogen and a hydroxy-protecting group, and where n is 3 or 4.
- View Dependent Claims (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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25. 24-dihomo-1α
- ,25-dihydroxyvitamin D3.
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26. 24-trihomo-1α
- ,25-dihydroxyvitamin D3.
Specification