2-(2,6-Dioxo-3-piperidinyl)-1H-isoindol-1,3(2H)-dion

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H301：Giftig bei Verschlucken.

  H312：Gesundheitsschädlich bei Hautkontakt.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P301+P310：BEI VERSCHLUCKEN: Sofort GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

Thalidomide Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R46:Kann vererbbare Schäden verursachen.
  R61:Kann das Kind im Mutterleib schädigen.
  R21:Gesundheitsschädlich bei Berührung mit der Haut.
  R25:Giftig beim Verschlucken.
  R62:Kann möglicherweise die Fortpflanzungsfähigkeit beeinträchtigen.

• S-Sätze Betriebsanweisung:

  S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
  S22:Staub nicht einatmen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).

• Beschreibung

  Thalidomide is a glutamic acid derivative first synthesized in 1953 by Swiss Pharmaceuticals; however, due to lack of pharmacological effects, the development was discontinued. In 1954, Chemie Grünenthal, a German company, undertook the development of thalidomide and, in 1957, thalidomide was marketed as an anticonvulsant for the treatment of epilepsy. Since the drug caused drowsiness, it was also marketed as a sedative. Thalidomide was considered a safe and effective drug that caused deep sleep with no hangover, and by the end of the 1950s, 14 pharmaceutical firms were marketing the drug in countries of Europe, Asia, Australia, the Americas, and Africa. However, the drug was never approved for use in the United States due to concerns about the safety of the drug raised by Frances Kelsey, MD, a drug reviewer at Food and Drug Administration (FDA). The approval process was delayed due to her repeated requests for additional safety information from William S. Merrell Company, the licensee of Chemie Grünenthal that applied to market thalidomide in the United States. Dr Kelsey’s concerns were mostly related to thalidomideinduced neuropathy. Previous research had shown that drugs that irritated nerves in adult rabbits could have adverse effects on growth and cause deformities in fetal rabbits. During this time, the use of the drug became widespread and, because it was effective in alleviating morning sickness, it became popular among pregnant women. In 1961, two physicians, William G. McBride, MD of Australia and Widulind Lenz, MD of Germany, associated the increase in malformation of the limbs (phocomelia) and other congenital abnormalities with the use of thalidomide by pregnant women. By late 1961, birth defects in more than 12 000 children were associated with thalidomide use, which forced companies to withdraw the drug worldwide.
  The birth defects were due to thalidomide teratogenecity: mainly phocomelia and malformation of ears, often accompanied by malformation of the internal organ. In 1965, an experimental use of thalidomide in patients with lepromatous leprosy proved to be effective in treating painful skin lesions that resulted from the inflammatory complications of leprosy. In fact, experimental use of thalidomide had been extended to a variety of diseases with various degrees of success, including refractory rheumatoid arthritis, Crohn’s disease, human immunodeficiency virus (HIV)-1 associated Kaposi’s sarcoma, cutaneous lupus, prostate cancer, and colorectal cancer. In 1998, the FDA approved Thalomid as a therapy for erythema nodosum leprosum (ENL), or leprosy. Subsequently in 2006, Thalomid in combination with dexamethasone was approved for treatment of multiple myeloma.

• Beschreibung

  (±)-Thalidomide is an immunomodulatory compound with diverse biological activities, including anticancer, anti-inflammatory, and teratogenic properties. It prevents polymorphonuclear leukocyte (PMN) chemotaxis when used at concentrations of 1, 10, and 100 μg/ml. (±)-Thalidomide increases IL-2-induced proliferation and IFN-γ production in primary human T cells in vitro. It enhances natural killer (NK) cell-mediated cytotoxicity in MM.1S multiple myeloma cells. Thalidomide (4 mg/animal) reduces lung IL-6, TGF-β, VEGF, angiopoietin-1, angiopoietin-2, and collagen type Iα1 expression, inhibits pulmonary angiogenesis, and attenuates fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis. It induces apoptosis in primary human embryonic fibroblasts (EC₅₀ = 8.9 μM) and induces limb and eye defects in chicken embryos (EC₅₀ = 50 μg/kg egg weight). Formulations containing thalidomide have been used in the treatment of multiple myeloma and erythema nodosum leprosum (ENL) in non-pregnant individuals.

• Chemische Eigenschaften

  White Powder

• Originator

  Contergan,Grunenthal,Germany

• Verwenden

  antiinfective (topical)

• Verwenden

  Thalidomide was formerly used as a sedative-hypnotic drug. It is used in the treatmentof leprosy. Recent studies indicate that thecompound may be effective against cancer.

• Verwenden

  Thalidomide was prescribed as an anti-nausea agent to help pregnant women with morning sickness in the late 1950s. It was found to be a potent teratogen, causing many different forms of birth defects and was withdrawn from the market. Thalidomide and synthetic analogs have recently been proven effective in treating inflammation associated with diseases such as leprosy, arthritis and Crohn’s disease, and in cancers such as multiple myeloma. The direct target for the teratogenicity of thalidomide was not discovered until 2010, when it was found that it interacts directly with the protein cereblon (CRBN; IC50 = 8.5 nM), a ubiquitously-expressed E3 ligase. Binding of thalidomide analogs to CRBN-DNA damage binding protein-1 complexes account for the immunomodulatory and antiproliferative effects of these compounds.[Cayman Chemical]

• Verwenden

  Inhibits FGF-induced angiogenesis. Inhibits replication of human immunodeficiency virus type 1. Teratogenic sedative. There is now a growing clinical interest in Thalidomide, and it is introduced as an immunomodulatory agent used primarily in combination with dexamethasone to treat multiple myeloma.

• Indications

  Thalidomide (Thalomid) is a derivative of glutamic acid that is chemically related to glutethimide. It exerts a number of biological effects as an immunosuppressive, antiinflammatory, and antiangiogenic agent, yet its mechanisms of action have not been fully elucidated. Thalidomide potently inhibits production of tumor necrosis factor (TNF) and interleukin (IL) 12, and its effect on these and other cytokines may account for some of its clinical effects.

• Definition

  ChEBI: A dicarboximide that is isoindole-1,3(2H)-dione in which the hydrogen attached to the nitrogen is substituted by a 2,6-dioxopiperidin-3-yl group.

• Manufacturing Process

  26 g of N-phthalyl glutaminic acid anhydride are melted with 12 g of urea in an oil bath at 170-180°C until the reaction is completed, which takes about 20 min. The reaction takes place with violent evolution of carbon dioxide and ammonia. After cooling, the reaction product is recrystallised by fractionation from 95% alcohol, and the first fraction may contain phthalic acid derivatives. The required product N-(2,6-dioxo-3-piperidyl)-phthalimide melts at 269- 271°C. The yield is about 65-70% of the theoretical.

• Trademarks

  Algosediv;Asidon;Bonbrain;Contergan;Distaval;Funed;Glutanon;Hippuzon;Imidan;Isomin;Kevadone;Nerufatin;Neurosedyn;Pantosedive;Pro-ban;Quetimid;Sanodormin;Sedalis;Sedoval;Shinaito;Shinnibrol;Sleepan;Softenil;Softenon;Talimol;Tlargan;Yodomin.

• Therapeutic Function

  Sedative, Hypnotic, Antiarthritic

• Weltgesundheitsorganisation (WHO)

  Notwithstanding the highly potent teratogenic action of thalidomide, this drug retains a place in the treatment of reactional lepromatous leprosy and several serious dermatological conditions refractory to other treatment. In many countries, the competent authorities have granted exemption from licensing requirements to enable doctors to obtain limited supplies of thalidomide under strictly controlled circumstances for use in named patients. Arrangements have also been made by some national drug regulatory authorities for thalidomide to be used in institutions concerned with the treatment of leprosy.

• Synthesis Reference(s)

  Synthetic Communications, 33, p. 1375, 2003 DOI: 10.1081/SCC-120018698

• Allgemeine Beschreibung

  Needles or white powder.

• Air & Water Reaktionen

  Insoluble in water.

• Reaktivität anzeigen

  Organic amides/imides, such as Thalidomide, react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

• Health Hazard

  Thalidomide is a strong teratogen. Exposureto this compound during the first trimesterof pregnancy resulted in deformities inbabies. Infants born suffered from ameliaor phocomelia, the absence or severe shortening of limbs. Administration of thalidomide in experimental animals caused fetaldeaths, postimplantation mortality, and specific developmental abnormalities in theeyes, ear, central nervous system, musculoskeletal system, and cardiovascular system. Several thousand children were affected.The drug has been withdrawn from themarket.
  Thalidomide is usually administeredorally. Its toxicity is dose dependent. Someother effects are drowsiness, constipation andrash and nerve damage in the arms and legs.
  Interest in thalidomide resurged in recentyears because of its antitumor activity in thetreatment of multiple myeloma (Oxberry andJohnson 2006). The compound is an inhibitorof angiogenesis, that is, it prevents formationof new blood vessels in tumors. Also, it hasbeen found to be effective in treating AIDS-related Kaposis sarcoma.

• Brandgefahr

  Flash point data for Thalidomide are not available; however, Thalidomide is probably combustible.

• Biologische Aktivität

  Teratogen, sedative-hypnotic with inherent anti-inflammatory properties. A selective inhibitor of tumor necrosis factor α (TNF- α ) synthesis.

• Biochem/physiol Actions

  (±)-Thalidomide selectively inhibits biosynthesis of tumor necrosis factor α (TNF-α). It also functions as an inhibitor of angiogenesis, an immunosuppressive agent, a sedative and a teratogen. Furthermore, thalidomide is known to exhibit antitumor functions in refractory multiple myeloma.

• Mechanism of action

  Its absorption from the gastrointestinal tract is slow, with peak plasma levels being reached after 3 to 6 hours. It appears to undergo nonenzymatic hydrolysis in the plasma to a large number of metabolites.The elimination half-life is approximately 9 hours.

• Clinical Use

  Thalidomide is approved for use in the United States for the treatment of cutaneous manifestations of erythema nodosum leprosum, a potentially lifethreatening systemic vasculitis that occurs in some patients with leprosy.Although not approved for other indications, thalidomide has also been shown to be very effective in the management of Beh?et’s disease, HIVrelated mucosal ulceration (aphthosis), and select cases of lupus erythematosus.

• Nebenwirkungen

  Thalidomide is a highly teratogenic drug, characteristically causing phocomelia (aplasia of the midportions of the limbs). Even a single dose may cause fetal malformation. Thalidomide should be prescribed to women of childbearing potential only when no acceptable alternative exists. Because it is not known whether thalidomide is present in the ejaculate of males receiving the drug, male patients must use a latex condom when engaging in sexual activity with women of childbearing potential.
  Other side effects of thalidomide may include sedation (in fact, thalidomide was originally marketed in Europe as a sleeping aid), constipation, and peripheral neuropathy, which may be permanent.

• Sicherheitsprofil

  Poison by ingestion. Moderately toxic by skin contact and intraperitoneal routes. Human teratogenic effects by ingestion: developmental abnormalities of the musculoskeletal and cardiovascular systems. Experimental reproductive effects. Questionable carcinogen with experimental tumorigenic and teratogenic data. Human mutation data reported. It was commonly used as a prescription drug in Europe in the late 1950s and early 1960s. Its use was dscontinued because it was lscovered to cause serious congenital abnormalities in the fetus, notably amelia and phocomelia (absence or deformity of the limbs, including hands and feet) when taken by a woman during early pregnancy. When heated to decomposition it emits toxic fumes of NOx. Used as a sedative and hypnotic.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Thalidomide enhances the effects of barbiturates, alcohol, chlorpromazine and reserpine.
  Use with caution with other drugs that can cause peripheral neuropathy.

• Stoffwechsel

  Thalidomide is metabolised almost exclusively by nonenzymatic hydrolysis. In plasma, unchanged thalidomide represents 80
  % of the circulatory components. Unchanged thalidomide was a minor component (<3
  % of the dose) in urine. In addition to thalidomide, hydrolytic products N-(o-carboxybenzoyl) glutarimide and phthaloyl isoglutamine formed via non-enzymatic processes are also present in plasma and in urine.

• Lager

  Store at RT

• Toxicity evaluation

  The mechanism of teratogenecity of the thalidomide is not clearly understood; however, recent studies have shed some light on the potential mechanism. CRBN has been identified as a thalidomide-binding protein. The teratogenic effects start with binding of thalidomide to CRBN and inhibiting the associated ubiquitin ligase activity.Many E3 ubiquitin ligases are important for various physiological processes such as cell cycle regulation, carcinogenesis, immune response, and development. It has been shown that CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cullin-4A (Cul4A), which are important factors for expression of the fibroblast growth factor Fgf8 in zebra fish and chicks as well as the limb outgrowth. In thalidomide-treated zebra fish embryos, formation of proximal endoskeletal disc of the pectoral fin was severely inhibited and the otic vesicle size was significantly reduced. Pectoral fins and otic vesicles in fish share common molecular pathways with tetrapod limbs and ears development. Down-regulation of the CRBN complex causes similar developmental defects in zebra fish. Thalidomide does not cause limb malformations in rodents but does in rabbits, monkeys. In pregnant rats, thalidomide can cause other types of developmental defects such as vertebral column, rib, and eye malformation. There is very strong conservation of the amino acid sequence of CRBN between rat, rabbit, monkey, mouse and human and has been shown that they can bind to thalidomide. The role and importance of CRBN in different species have not been identified; therefore, the degree of teratogenecity could depend in part on the nature of the protein substrates that are modified by CRBN activity during embryonic development. There are some species differences in teratogenecity between thalidomide and its close analogs.

• Einzelnachweise

  1) Ito et al. (2010), Identification of a primary target of thalidomide teratogenicity; Science, 327 1345 2) Weglicki et al. (1993), Inhibition of tumor necrosis factor-alpha by thalidomide in magnesium deficiency; Mol. Cell. Biochem., 129 195 3) D’Amato et al. (1994), Thalidomide is an inhibitor of angiogenesis ; Proc. Natl. Acad. Sci. USA, 91 4082

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