18-substituted-19-nor-vitamin D compounds
First Claim
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1. A method of making a ketone of the formula where R is represented by the structure:
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where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5 -alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3 and R4, independently is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group, ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —
CH(CH3)—
, —
CH(R3)—
, —
CH(R2)—
at positions 20, 22 and 23, respectively, may be replaced by an oxygen or sulfur atom, and further wherein R5 is a protected-hydroxy group, which comprises the steps of selectively tosylating a diol of the formulato obtain a mono-tosolyate of the formula
thereafter converting the mono-tosylate to an acetylenic compound having the formula
catalytically hydrogenating the acetylenic bond to obtain a hydroxylated derivative of the formula
and oxidizing the hydroxylated derivative to said ketone.
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Abstract
This invention provides a novel class of vitamin D compounds, namely, 13-ethyl and 13-vinyl-18,19-dinor-vitamin D derivatives, as well as a general method for their chemical synthesis. The compounds have the formula:
where Y1 and Y2, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R6 is selected from the group consisting of an ethyl or vinyl radical, and where the group R represents any of the typical side chains known for vitamin D type compounds. These 18-substituted compounds are characterized by minimal intestinal calcium transport activity and minimal bone calcium mobilization activity resulting in novel therapeutic agents for the treatment of secondary hyperparathyroidism. These compounds also exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as anti-cancer agents and for the treatment of diseases such as psoriasis.
13 Citations
6 Claims
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1. A method of making a ketone of the formula
where R is represented by the structure: -
where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5 -alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3 and R4, independently is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group, ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —
CH(CH3)—
, —
CH(R3)—
, —
CH(R2)—
at positions 20, 22 and 23, respectively, may be replaced by an oxygen or sulfur atom, and further wherein R5 is a protected-hydroxy group, which comprises the steps of selectively tosylating a diol of the formulato obtain a mono-tosolyate of the formula thereafter converting the mono-tosylate to an acetylenic compound having the formula catalytically hydrogenating the acetylenic bond to obtain a hydroxylated derivative of the formula and oxidizing the hydroxylated derivative to said ketone. - View Dependent Claims (2, 3, 4, 5)
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6. A compound having the formula:
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where the group R is represented by the structure;
where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3 and R4, independently is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and a straight-chain C1-5 alkyl, which may optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group, ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R5 represents a protected hydroxy group and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —
CH(CH3)—
, —
CH(R3)—
, or —
CH(R2)—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom, with the proviso that R cannot bewhere R6 is hydrogen, a hydroxy group, or a protected hydroxy group.
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Specification
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Current AssigneeWisconsin Alumni Research Foundation (University of Wisconsin System)
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Original AssigneeWisconsin Alumni Research Foundation (University of Wisconsin System)
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InventorsDeLuca, Hector F., Cai, Zu Y.
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Primary Examiner(s)QAZI, SABIHA NAIM
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Application NumberUS09/353,866Time in Patent Office775 DaysField of Search568/309, 514/675US Class Current514/675CPC Class CodesC07C 401/00 Irradiation products of cho...Y02P 20/55 Design of synthesis routes,...
