DL-Thyroxin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H225：Flüssigkeit und Dampf leicht entzündbar.

  H370：Schädigt die Organe.

• Sicherheit

  P210：Von Hitze, heißen Oberflächen, Funken, offenen Flammen und anderen Zündquellenarten fernhalten. Nicht rauchen.

  P260：Dampf/Aerosol/Nebel nicht einatmen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P370+P378：Bei Brand: zum Löschen verwenden.

Levothyroxine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R40:Verdacht auf krebserzeugende Wirkung.

• S-Sätze Betriebsanweisung:

  S22:Staub nicht einatmen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Beschreibung

  L-Thyroxine is a synthetic form of the thyroid hormone thyroxine. In vivo, L-thyroxine (0.9 and 2.7 μg) inhibits synthesis and release of thyrotropin induced by thyrotropin-releasing hormone from the anterior pituitary in mice. It also reverses decreases in levels of circulating thymic serum factor (FTS) and the number of T rosette-forming cells in an old age-induced mouse model of hypothyroidism. Formulations containing L-thyroxine have been used in the treatment of hypothyroidism.

• Chemische Eigenschaften

  Crystalline Solid

• Originator

  Synthroid,Flint,US,1953

• Verwenden

  Thyroxine is one of the thyroid hormones involved in the maintenance of metabolic homeostasis. Synthesized and stored as amino acid residues of thyroglobulin, the major protein component of the thyroid follicular colloid. Synthesis and secretion are regulated by the pituitary hormone (TSH). Deiodinated in peripheral tissues to the active metabolite, liothyronine. The D-form has very little activity as a thyroid hormone, but has been used to treat hyperlipidemia.

• Verwenden

  antihypercholesterimic, thyromimetic

• Verwenden

  One of the thyroid hormones involved in the maintenance of metabolic homeostasis. Synthesized and stored as amino acid residues of thyroglobulin, the major protein component of the thyroid follicular colloid. Synthesis and secretion are regulated by the pituitary hormone (TSH). Deiodinated in peripheral tissues to the active metabolite, liothyronine. The D-form has very little activity as a thyroi d hormone, but has been used to treat hyperlipidemia.

• Definition

  ChEBI: The L-enantiomer of thyroxine.

• Indications

  Effects of this drug depend heavily on dosage. In small doses, levothyroxine exhibits anabolic action. In medium doses, it stimulates growth and development of tissue, metabolism of protein, fats, and carbohydrates, increases functional activity of central nervous and cardiovascular systems, as well as kidneys and liver. In large doses, it slows the thyrotropic activity of the hypophysis and suppresses thyroid gland production. Levothyroxine is used for hypothyroidism, myxedema, thyrotoxicosis, erythyroid conditions, and cretinism.

• Manufacturing Process

  A 9.30 g portion of N-acetyl-L-diiodotyrosinamide was suspended in 100 ml of 0.05M boric acid (H3BO3) and 100 ml of 95% ethanol, and the solid was dissolved by adjusting the pH to 10.5 with 2N sodium hydroxide (NaOH). A 15% (by weight) portion of manganese sulfate monohydrate was added and the solution heated at 44°C under conditions of oxygenation while being agitated mechanically. After approximately 24 hours of incubation, the precipitated product was collected and separated from the catalyst, providing the amide of N-acetyl-L-thyroxine in 30.6% yield. On hydrolysis (removal of both amide functions), achieved by refluxing in glacial acetic acid-hydrochloric acid (approximately 2:1), L-thyroxine is obtained. It was isolated as the sodium salt, containing approximately 5 molecules of water of hydration.

• Trademarks

  Levo-T (Alara); Levolet (Vintage); Levothroid (Lloyd); Levoxyl (Jones); Novothyrox (Genpharm); Synthroid (Abbott); Unithroid (Stevens J).

• Therapeutic Function

  Thyroid hormone

• Pharmakokinetik

  Because of its firmer binding to carrier proteins, synthetic crystalline L-T4 sodium salt (levothyroxine sodium, Synthtoid, Euthyrox) has a slower onset of action than crystalline T3 or a desiccated thyroid preparation. Its administration leads to a greater increase in serum T4 but a lesser increase in serum T3 than compared with Thyroid USP. The availability of 11 different tablet strengths, ranging from 25 to 300 μg, allows individual dosing

• Synthese

  Levothyroxine, L-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl] alanine (25.1.10), is synthesized in a multi-stage synthesis from 4-hydroxy-3-iodo- 5-nitrobenzaldehyde. Reacting this with benzenesulfochloride in pyridine gives the corresponding benzenesulfonate 25.1.1, the benzenesulfonyl group of which is easily replaced with a 4-methoxyphenyloxy- group upon reaction with 4-methoxyphenol. The resulting 3-iodo-4-(4-methoxyphenoxy)benzaldehyde (25.1.2) is reacted further with N-acetylglycine in the presence of sodium acetate in a Knoevenagel reaction, in which the resulting ylidene compound cyclizes to an oxazolone derivative 25.1.3. The oxazolone ring of this compound is opened upon reaction with sodium methoxide, forming the desired cinnamic acid derivative 25.1.4. The nitro group of this product is reduced to an amino group by hydrogen in the presence of a Raney nickel catalyst, forming the corresponding amine, and subsequent diazotation and replacement of the diazo group of which with iodine gives the methyl ester of |á-acetamido-3,5-diiodo-4-(4-methoxyphenoxy)crotonic acid (25.1.6). The resulting compound undergoes simultaneous reaction with hydrogen iodide and phosphorous in acetic acid, in which the double bond in the crotonic acid is reduced, and the methoxy protection is removed from the phenol ring. During this, a simultaneous hydrolysis of the acetyl group on the nitrogen atom also takes place, forming D,L-3,5-diiodothyronine (25.1.7). The amino group in this product is once again protected by the reaction with formic acid in the presence of acetic anhydride, which gives D,L-N-formyl-3,5-diiodothyronine. Separation of isomers in the resulting racemic mixture is accomplished using brucine, giving D-(+)-N-formyl-3, 5-diiodothyronine L-(+)-N-formyl-3,5-diiodothyronine (25.1.8). The protecting formyl group is hydrolyzed using hydrobromic acid, giving L-(+)-3,5-diiodothyronine (25.1.9), which undergoes direct iodination using iodine in the presence of potassium iodide in aqueous methylamine, to give the desired levothyroxine.

  

• läuterung methode

  Purification is the same as for the D-isomer above. Likely impurities are tyrosine, iodotyrosine, iodothyroxines and iodide. Dissolve it in dilute ammonia at room temperature, then crystallise it by adding di[] 546 +27.8o (c 5, EtOH). [Harrington et al. Biochem J 39 164 1945, Nahm & Siedel Chem Ber 96 1 1963, Reineke & Turner J Biol Chem 161 613 1945, Chalmers et al. J Chem Soc 3424 1949, Beilstein 14 II 378, 14 III 1566, 14 IV 2373.]

• Einzelnachweise

  [1] C Y BOWERS. Interactions of L-thyroxine or L-triiodothyronine and thyrotropin-releasing factor on the release and synthesis of thyrotropin from the anterior pituitary gland of mice.[J]. Endocrinology, 1967, 81 4: 741-747. DOI: 10.1210/endo-81-4-741
  [2] N. FABIRS  E. M  M Muzzioli. Recovery of age-dependent immunological deterioration in Balb/c mice by short-term treatment with L-thyroxine[J]. Mechanisms of Ageing and Development, 1982, 18 4: Pages 327-338. DOI: 10.1016/0047-6374(82)90036-7
  [3] N. FABRIS  E. M. Endocrine control of thymic serum factor production in young-adult and old mice[J]. Cellular immunology, 1985, 91 2: Pages 325-335. DOI: 10.1016/0008-8749(85)90230-8

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