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

• US 20180118669A1
• Filed: 12/22/2017
• Published: 05/03/2018
• Est. Priority Date: 04/08/2011
• 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, BOI, Valeria, CAVALIERI, Livio, GALIMBERTI, Laura, GAZZETTO, Sonia, LATTUADA, Luciano, MAISANO, Federico, RIVOLTA, Giovanni, VELLA, Fulvia
• Granted Patent: US 10,457,635 B2
• Time in Patent Office: Days
• 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 chlorosulfonic 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

1-28. -28. (canceled)

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

30. The process according to claim 29, wherein T3S after steps a)-c) has a purity of at least 95%.

31. The process according to claim 30, wherein T₃S has a purity of at least 99%.

32. The process according to claim 29, further comprising the steps of

i—

micronizing the pure T₃S to reduce the particle size and

ii—

formulating the micronized T₃S with the following ingredients in powder mixtures;

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

33. The process according to claim 32, wherein T₃S is micronized under nitrogen pressure.

34. The process according to claim 33, wherein at least 90% of the micronized T₃S particles has a size lower than 25 μ

m.

35. The process according to claim 34, wherein at least 95% of the micronized T₃S particles has a size lower than 25 μ

m.

36. The process according to claim 32, wherein all the ingredients are solid and formulated under granular or microgranular form.

37. The process according to claim 36, wherein the ingredients are formulated as tablets or pills through direct compression of the powder mixture.

38. The process according to claim 32, wherein the active principle T₃S is firstly mixed with at least 30% of the microcrystalline cellulose and/or calcium carbonate, and then mixed with the other components.

39. The process according to claim 32, wherein the micronized T₃S is formulated for oral administration.

40. 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.

41. The composition of claim 40 wherein T₃S is in a quantity of from 2.5 to 500 μ

g.

42. The composition of claim 41, wherein T₃S is in a quantity of from 5-250 μ

g.

43. The composition of claim 40, 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 of from 10-200 μ

g.

44. The composition of claim 40, wherein T₃S is in solid form and with a purity of at least 95%.

45. The composition according to claim 44, wherein T₃S has a purity of at least 99%.