Granted Patent B2

US 7,067,505 · App. 11/009,618 · Granted Jun 27, 2006

Abstract

Claims (57)

1. A di-steroidal prodrug of 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(CH 2 ) f —

wherein f is 0 to 5, and B is —O—(CH 2 CH 2 O) 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.

2. The prodrug of claim 1 , wherein R is

3. The prodrug of claim 1 , wherein R is selected from the group consisting of:

4. The prodrug of claim 1 , wherein R is:

5. The prodrug of claim 1 , wherein said prodrug is selected from the group consisting of di-(3-estradiol)carbonate, di-(3-estradiol)succinate, di-(3-estradiol) glutarate and di-(3-estradiol)aspartate.

6. A pharmaceutical composition comprising:

(a) a di-steroidal prodrug of 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(CH 2 ) f —

wherein f is 0 to 5, and B is O—(CH 2 CH 2 O) 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.

7. A method of synthesizing a di-steroidal prodrug of 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(CH 2 ) f wherein f is 0 to 5, and B is —O—(CH 2 CH 2 O) 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 estradiol or a derivative thereof;

(B) admixing said 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 estradiol or pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein said linking agent is a carbonate,

H—Y-Z-X—H, or

G-CO-Z-X-G

wherein G is a halogen.

9. The method of claim 7 , wherein said coupling agent is selected from the group consisting of: bis(4-nitrophenyl)carbonate, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, and mixtures thereof.

10. The method of claim 7 , wherein said at least one base is selected from the group consisting of: 4-dimethylamino pyridine, triethylamine, and mixtures thereof.

11. The method of claim 7 , wherein said prodrug is di-(3-estradiol)carbonate or a pharmaceutically acceptable salt thereof.

12. The method of claim 7 , wherein said prodrug is selected from the group consisting of: di-(3-estradiol) succinate, di-(3-estradiol)glutarate, di-(3-estradiol)aspartate, and a pharmaceutically acceptable salts thereof.

13. A method of providing contraception comprising the step of:

administering to a patient in need thereof, an effective amount of said di-steroidal prodrug of estradiol of claim 1 , for an effective period of time.

14. A method of providing hormone treatment therapy to a patient in need thereof, comprising the step of:

administering to said patient in need thereof, an effective amount of said di-steroidal prodrug of estradiol of claim 1 , for an effective period of time.

Assignments (8)