Vitamin D derivatives: therapeutic applications and applications to assays of metabolities of vitamin D

• US 5,093,519 A
• Filed: 05/01/1989
• Issued: 03/03/1992
• Est. Priority Date: 05/04/1988
• Status: Expired due to Fees

• Current Assignee: K.U. Leuven Research, Prof Bouillon
• Original Assignee: Ire-Medgenix SA
• Inventors: Eliard, Pierre, De Clercq, Pierre J., Bouillon, Roger, Vandewalle, Maurits
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US07/345,623
• Time in Patent Office: 1,037 Days
• Field of Search: 558/155, 558/156, 558/194, 558/428, 556/449, 560/194, 560/231, 562/498, 564/188, 564/310, 564/454, 564/456, 564/458, 568/33, 568/37, 568/62, 568/441, 568/591, 568/665, 568/704, 568/712, 568/713, 568/819
• US Class Current: 560/194
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: C07C 49/733 having two rings
• CPC Class Codes: C07C 49/753 containing ether groups, groups, groups, or groups
• CPC Class Codes: G01N 33/82 involving vitamins or their receptors

Abstract

Vitamin D derivatives corresponding to the following formula I ##STR1## in which R₁ denotes a substituted alkyl group having 1 to 15 carbon atoms, in particular the side chains of vitamin D₂ (C²⁰ to C²⁸) or D₃ (C²⁰ to C²⁷), or these same chains partially modified,

Y denotes H or OH or groups derived from the latter such as ester and ether;

X denotes

an alkyl chain, in particlar of 1 to 6 carbon atoms, optionally substituted at different points by one or more functional group (s)

an unsaturated alkyl chain having one or more carbon-carbon double or triple bond(s), it being possible for these chains, in addition, to bear functional groups, or

an aromatic or heteroaromatic ring, optionally substituted with halogens, one (or more) hydroxyl, amine, formyl carboxyl, thiol, cyano or nitro group(s), or alternatively groups derived from these latter, such as ether, ester, acetal or amide, or

a halogen, a cyano, sulfoxide, sulfone, hydroxyl, thiol or amine group, or alternatively derivatives of these latter, such as ether, ester, amine and hydrazine;

R₂ denotes a methyl group and R₃ an H, or R₂ is H and R₃ is methyl, or R₂ and R₃ are H, or alternatively R₂ and R₃ together denote a methylene group=CH₂.

The present invention relates to the therapeutic application of these derivatives.

The present invention also relates to a method for preparing these derivatives; and to an antigen prepared by the covalent binding of these derivatives with an immunogenic carrier protein and antibodies prepared using this antigen. Finally, the present invention also relates to tracers consisting of the conjugation of a derivative according to the invention with a labeling component such as an enzyme or an iodinated molecule, as well as to an assay method for metabolites of vitamin D comprising the use of these tracers as a reagent.

Claims

1. Vitamin D derivatives corresponding to the following formula I ##STR16## in which R₁ denotes a substituted alkyl group having 1 to 15 carbon atoms wherein the substituent is

an hydroxyl, ester or ether at one or more positions;

a methyl or ethyl group at one or more positions;

a halogen or a plurality of halogens at one or more positions;

one or more carbon atoms added;

a substituent formed by replacing one or more carbon atoms of said alkyl group by oxygen, nitrogen or sulfur atoms;

a ring formed by directly linking carbons C²⁶ and C²⁷ or by linking said carbons via a chain of 1 to 3 carbon atoms;

it being possible for each carbon atom in said chain of carbon atoms to optionally bear any of the groups or modifications described above, and/or

a saturated, unsaturated, aromatic or heteroaromatic ring, capable of optionally bearing any of the groups and modifications described above, and wherein said alkyl group is

saturated or unsaturated, and

Y denotes H, OH, ester or ether; and

X denotes

an alkyl or substituted alkyl chain, saturated or unsaturated, optionally substituted by one or more functional group Z, wherein Z is halogen, hydroxyl, formyl, carboxyl, amine, thiol, cyano, nitro, sulfoxide, sulfone, phosphono, ether, ester, acetal, amide, hydrazine, phosphate or bis(phosphate), or

an aromatic or heteroaromatic ring, optionally substituted with halogen, hydroxyl, amine, formyl, carboxyl, thiol, cyano, nitro, ether, ester, ester, acetal or amide, or

halogen, cyano, sulfoxide, sulfone, hydroxyl, thiol, amine, ether, ester, or hydrazine; and

R₂ denotes a methyl group and R₃ an H, or R₂ is H and R₃ is methyl, or R₂ and R₃ are H, or alternatively R₂ and R₃ together denote a methylene group=CH₂.

2. The derivatives as claimed in claim 1, in which R₁ denotes one of the following chains ##STR17##

8. A vitamin D derivative according to claim 1, wherein R₂ denotes the side chains of vitamin D₂ (C²⁰ to C²⁸) or D₃ (C²⁰ to C²⁷);

said hydroxyl, ester or ether is at positions 24-, 25- and/or 26-;

said methylation or ethylation is at positions 24-, 26- and/or 27-;

said halogenated or polyhalogenated is perfluoro at the 26- and/or 27-positions or difluoro at the 24-position;

said added carbon atom(s) is between positions 24- and 25-;

said substitution of one or more carbon atoms by an oxygen, sulfur or nitrogen atom is at positions 22-, 23- or 24-;

or

said ring formation is a bond between C²⁶ and C²⁷ or a chain of from 1 to 3 carbon atoms.

3. Vitamin D₃ derivatives corresponding to the formula I'"'"' ##STR18## which Y, R₄ and R₅ denote H or OH, and

X denotes an alkyl chain of 1 to 6 carbon atoms, optionally substituted, with a functional group Z, wherein Z is an hydroxyl, formyl, carboxyl, amine, amide ester, ether or acetal group, X being in the α

or β

isomeric form.

4. The derivatives as claimed in claim 3, in which (Y, R₄, R₅) is chosen from (H, OH, H), (OH, OH, H), (H, H, OH), (H, OH, OH), (OH, H, OH), (OH, H, H).

5. A Vitamin D₃ derivative according to claim 3, wherein Z is at the terminus of X.

6. The derivatives as claimed in claim 5, in which X denotes (2-Z-ethyl), a methyl or a phenyl.

7. The derivatives as claimed in claim 5, in which Z denotes a ##STR19## group with n between 2 and 10, or an OH group.