Process For The Preparation Of A Sulfated Derivative Of 3,5-Diiodo-O-[3-Iodophenyl]-L-Tyrosine

• US 20140024717A1
• Filed: 04/05/2012
• Published: 01/23/2014
• Est. Priority Date: 11/13/2002
• Status: Active Grant

• Current Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Original Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Inventors: Anelli, Pier Lucio, Argese, Maria, Lattuada, Luciano, Maisano, Federico, Gazzetto, Sonia, Galimberti, Laura, Rivolta, Giovanni, Vella, Fulvia, Boi, Valeria, Cavalieri, Livio
• Granted Patent: US 9,890,116 B2
• Time in Patent Office: Days
• US Class Current: 514/562
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: C07C 227/16 by reactions not involving the amino or carboxyl groups
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 303/24 of esters of sulfuric acids
• CPC Class Codes: C07C 305/24 of non-condensed six-membered aromatic rings
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07F 1/04 Sodium compounds

Abstract

The present invention relates to a process for the preparation of the mono sodium salt of the derivative 3,5-diiodo-O-[3-iodo-4-(sulphooxy)phenyl]-L-tyrosine (T3S) by starting from the corresponding phenolic compound, in the presence of chloro-sulfonic acid and dimethylacetamide as a solvent. The so obtained T3S compound may conveniently be isolated in a pure form as a solid in good yields. The present invention further relates to the process for T3S preparation, wherein the starting reagent is T2 and further comprising the formulation of such compound in tablets. Furthermore, the invention discloses non-radioactive immunoassays based on T3S derivatives.

Claims

1. A process for the preparation of a sulfated form of a thyroid hormone having formula II (T₃S) according to the following reaction:

2. The process according to claim 1, wherein said inorganic salt is a sodium salt.

3. The process according to claim 1, wherein the molar ratio between CSA and the compound of formula I is comprised from 4 to 10.

4. The process according to claim 1, wherein in step a) the concentration of the compound of formula I in DMAC is comprised from 0.060 to 0.090 mol/L of DMAC.

5. The process according to claim 1, wherein the sulfation reaction in step a) is carried out at a temperature below 10°

C.

6. The process according to claim 5, wherein the sulfation in step a) is left to occur for at least 2 hours.

7. The process according to claim 1, wherein the salification according to step b) is carried out in an aqueous solution of NaHCO₃.

8. The process according to claim 1, wherein step c) is preceded by a filtration step.

9. The process according to claim 1, wherein said decreasing polarity mixture is a mixture of water and a polar solvent in a ratio comprised from 1.0:

0 to 0.7;

0.3.

10. The process according to any one of claims 8-9, wherein after elution, the solution is concentrated to at least 10 g of Formula II compound/kg, and the solution is brought to pH values comprised from 5.5 to 6.5.

11. The process according to claim 1, wherein the compound of formula II is obtained as a solid after treatment with an organic polar solvent.

12. The process according to claim 11, wherein said polar organic solvent is selected from the group consisting of:

acetone, ethanol, isopropanol and acetonitrile.

13. The process according to claim 11, wherein the compound of formula II in the solid form is further micronized.

14. The process according to any one of claims 11-13, which comprises further admixing the solid and/or micronized form of the compound of formula II, optionally in combination with levo-thyroxine (T4), with at least one diluent selected from the group consisting of:

cellulose or a derivative thereof, kaolin, starch and inorganic alkaline salts selected from;

calcium and magnesium carbonate.

15. The process according to claim 14, wherein the mixture of the compound of formula II and the diluent which is microcrystalline cellulose, is further admixed with at least one glidant agent selected from the group consisting of:

glycerol dibehenate, tribasic calcium phosphate, talc, starch and derivatives thereof, at least one disintegrant selected from the group consisting of;

croscarmellose or derivatives thereof, crospovidone, polymethylacrylates, maltodextrin, sodium glycolate starch, pre-gelatinized starch, sodium alginate, and optionally, a lubricating agent selected from the group consisting of;

magnesium stearate, zinc stearate, colloidal hydrated silica and colloidal silicon dioxide, and then formulated in tablets by direct compression of the mixture.

16. The process according to claim 1, wherein the reagent of formula I is obtained by iodinating a 3′

,5 di-iodothyronine (T2) with an iodinating agent in an aqueous media and in the presence of an aliphatic amine.

28. The process according to claim 1, wherein M is Na.

29. The process according to claim 3 wherein the molar ratio is comprised from 7 to 9.

30. The process according to claim 5, wherein the sulfation reaction in step a) is carried out at a temperature comprised from −

10°

C. to 8°

C.

31. The process according to claim 16. wherein the iodinating agent is a mixture comprising I₂/NaI.

17. A pharmaceutical composition comprising T₃S as the active principle, in a quantity of from 1 to 1000 μ

g, optionally in combination with T4, together with the following ingredients;

calcium carbonate, glycerol dibehenate, croscarmellose sodium salt, hydrate colloidal silica, magnesium stearate, and microcrystalline cellulose.

18. The composition of claim 17 wherein T₃S is in a quantity of from 2.5 to 500 μ

g.

19. The composition of any one of claims 17-18, comprising T₃S and T₄ as active principles, in quantities selected from the group consisting of:

T3S of from 2.5-500 μ

g and T₄ of from 1 to 800 μ

g;

T₃S of from 5-250 μ

g and T₄ of from 5-400 μ

g; and

T₃S of from 10-100 μ

g and T₄ 10-200 μ

g.

32. The composition of claim 18, wherein T₃S is in a quantity of from 5-250 μ

g.

20. A non-radioactive immuno-assay for T₃S detection and quantitation comprising a non radioactive T₃S-conjugate.

21. The immunoassay of claim 20, wherein the non radioactive conjugate is a T₃S-biotin of Formula A′

or a T₃S-HRP

22. The immunoassay of claims 20-21 wherein the immunoassay is a competitive ELISA.

23. The immunoassay of claim 20 comprising a lanthanide fluorescence detection system.

24. The immunoassay of claim 23, wherein said non radioactive T₃S conjugate is a compound of Formula IV and is a Lanthanide chelating agent

25. The immunoassay according to claim 23, wherein the chelated Lanthanide metal is selected from the group consisting of:

Samarium, Terbium, Dysprosium and Europium.

26. The immunoassay according to claim 25 comprising an Europium chelate of Formula V

27. A kit comprising a container with a non radioactive T₃S-conjugate as defined in any one of claims 23-26 and a container with the reagents for the preparation of a T₃S calibration curve and optionally a reagent, or a combination thereof, selected from the group consisting of:

a diluent, a dye-molecule, a buffer, a preservative, an anti-T₃S antibody, and an instruction leaflet.