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US 7,067,504 B2Granted
Di-steroidal prodrugs of ethinyl estradiol
AssigneeWarner Chilcott Company, LLC
InventorsJohn Alexander King, James Keown, James William McIlroy, William Paul Armstrong, Michael Anthony McKervey, Austin McMordie
Life of this patent
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Abstract
The present invention is a di-steroidal prodrug of ethinyl estradiol according to formula I:
Claims14
A di-steroidal prodrug of ethinyl estradiol having the following formula:
- wherein R is selected from the group consisting of
- wherein X and Y are independently selected from
- and Z is
- (i) an aliphatic straight chain having 1 to 10 carbon atoms which may be saturated or unsaturated and optionally may be substituted by one or more lower alkyl, hydroxy or amino groups,
- (ii)
- A—B—D
- wherein A and D are independently
- —CO(CH2)f—, wherein f is 0 to 5, and B is —O—(CH2CH2O)p—, wherein p is 1 to 700, or
- (iii) a peptide linkage having 2 to 15 amino acid units derived independently from amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or combinations thereof wherein the end groups of the peptide are amino acid units independently derived from aspartic acid and glutamic acid.
6 more elements
A pharmaceutical dosage unit comprising:
- (a) a di-steroidal prodrug of ethinyl estradiol having the following formula:
- wherein R is selected from the group consisting of
- wherein X and Y are independently selected from
- and Z is
- (i) an aliphatic straight chain having 1 to 10 carbon atoms which may be saturated or unsaturated and optionally may be substituted by one or more lower alkyl, hydroxy or amino groups,
- (ii)
- A—B—D
- wherein A and D are independently
- —CO(CH2)f—, wherein f is 0 to 5, and B is —O—(CH2CH2O)p—, wherein p is 1 to 700, or
- (iii) a peptide linkage having 2 to 15 amino acid units derived independently from amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or combinations thereof wherein the end groups of the peptide are amino acid units independently derived from aspartic acid and glutamic acid;
- and
- (b) one or more pharmaceutically acceptable excipients.
9 more elements
A method of synthesizing a di-steroidal prodrug of ethinyl estradiol having the formula
- wherein R is selected from the group consisting of
- wherein X and Y are independently selected from
- and Z is
- (i) an aliphatic straight chain having 1 to 10 carbon atoms which may be saturated or unsaturated and optionally may be substituted by one or more lower alkyl, hydroxy or amino groups,
- (ii)
- A—B—D
- wherein A and D are independently
- —CO(CH2)f—, wherein f is 0 to 5, and B is —O—(CH2CH2O)p—, wherein p is 1 to 700, or
- (iii) a peptide linkage having 2 to 15 amino acid units derived independently from amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or combinations thereof wherein the end groups of the peptide are amino acid units independently derived from aspartic acid and glutamic acid, comprising the steps of:
- (A) providing ethinyl estradiol or a derivative thereof;
- (B) admixing said ethinyl estradiol and a linking agent, wherein said linking agent is selected from the group consisting of:
- (a) a carbonate;
- (b) an aliphatic diacid having a backbone of 1 to 10 carbon atoms;
- (c) G—CO—Z—X—G
- wherein G is a halogen;
- (d) a peptide linkage having 2 to 15 amino acid units derived independently from amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or combinations thereof wherein the end groups of the peptide are amino acid units independently derived from aspartic acid and glutamic acid;
- (e) a tert-butoxycarbonyl protected cysteic acid;
- and
- (f) a polyethylene glycol and succinic anhydride,
- (C) optionally, admixing a coupling agent and/or a base, thereby forming said di-steroidal prodrug of ethinyl estradiol or pharmaceutically acceptable salt thereof.
17 more elements
Dependencies are inferred from the claim text.