2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione

• ChemBase ID: 913
• Molecular Formular: C13H10N2O4
• Molecular Mass: 258.2295
• Monoisotopic Mass: 258.06405681
• SMILES: O=C1NC(=O)CCC1N1C(=O)c2c(C1=O)cccc2
• Canonical SMILES: O=C1CCC(C(=O)N1)N1C(=O)c2c(C1=O)cccc2
• InChI: InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)
• InChIKey: UEJJHQNACJXSKW-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
• IUPAC Traditional name: thalidomide
• Brand Name: Algosediv; Asidon 3; Asmadion; Asmaval; Bonbrain; Bonbrrin; Calmore; Calmorex; Contergan; Corronarobetin; Distaval; Distaxal; Distoval; Ectiluran; Enterosediv; Gastrinide; Glupan; Glutanon; Grippex; Hippuzon; Imida-Lab; Imidan; Imidene; Isomin; Kedavon; Kevadon; Lulamin; Neaufatin; Neo; Neosedyn; Neosydyn; Nerosedyn; Neufatin; Neurodyn; Neurosedin; Neurosedym; Neurosedyn; Nevrodyn; Nibrol; Noctosediv; Noxodyn; Pangul; Pantosediv; Poly-Giron; Polygripan; Predni-Sediv; Pro-ban M; Profarmil; Psycholiquid; Psychotablets; Quetimid; Quietoplex; Sandormin; Sedalis; Sedalis sedi-lab; Sedimide; Sedin; Sedisperil; Sedoval; Shin-naito S; Shinnibrol; Sleepan; Slipro; Softenil; Softenon; Thalomid; Talargan; Talimol; Talismol; Telagan; Telargan; Telargean; Tensival; Thalin; Thalinette; Theophilcholine; Valgis; Valgraine; Yodomin
• Synonyms: 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione; (±)-2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione; (±)-Thalidomide; Thalidomine USP26; thalidomide; Thalidomide; alpha-phthalimidoglutarimide; N-Phthalimidoglutamic acid imide; N-Phthaloylglutamimide; N-Phthalylglutamic acid imide; Thalomid; (±)-N-(2,6-Dioxo-3-piperidinyl)phthalimide; 2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-Dioxo-3-piperidinyl)-1H-iso-indole-1,3(2H)-dione; α-Phthalimidoglutarimide; 3-Phthalimidoglutarimide; Celgene; Contergan; Distaval; K 17; Kevadon; Myrin; N-(2,6-Dioxo-3-piperidyl)phthalimide; NSC 527179; NSC 66847

Database IDs

• CAS Number: 50-35-1
• EC Number: 200-031-1
• MDL Number: MFCD00153873
• PubChem SID: 24278765; 160964376; 46505665
• PubChem CID: 5426
• CHEBI ID: 9513
• ATC CODE: L04AX02
• CHEMBL: 468
• Chemspider ID: 5233
• DrugBank ID: DB01041
• KEGG ID: D00754
• Unique Ingredient Identifier: 4Z8R6ORS6L
• Wikipedia Title: Thalidomide
• Medline Plus: a699032

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.593279
• H Acceptors: 4
• H Donor: 1
• LogD (pH = 5.5): 0.01570701
• LogD (pH = 7.4): 0.015679834
• Log P: 0.015707357
• Molar Refractivity: 64.3248 cm^3
• Polarizability: 24.014824 Å^3
• Polar Surface Area: 83.55 Å^2
• Rotatable Bonds: 1
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 0.42
• LOG S: -2.0
• Solubility (Water): 2.55e+00 g/l

PROPERTIES

Physical Property

• Solubility: 45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: soluble0.6 mg/mL; 545 mg/L; Acetone; Butyl Acetate; DMSO; DMSO: >20 mg/mL; Ethanol; ethanol: insoluble; Ethyl Acetate; H2O: insoluble; Methanol; Sparingly Soluble In Water
• Apperance: white solid; White Solid
• Melting Point: 266-270°C; 269-271 °C
• Hydrophobicity(logP): 0.3; 0.528

Safety Information

• Storage Condition: -20°C; -20°C Freezer; Room Temperature (15-30°C), Protect from light
• RTECS: TI4375000
• European Hazard Symbols: Toxic (T)
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3; III
• Australian Hazchem: 2X
• Risk Statements: 46-61-21-25-62; R:25
• Safety Statements: 53-22-26-36/37/39-45; S:28-29-36/37/39-45
• EU Classification: T2
• EU Hazard Identification Number: 6.1B
• Emergency Response Guidebook(ERG) Number: 154
• GHS Pictograms: GHS06; GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H301-H312-H361
• GHS Precautionary statements: P280-P301 + P310
• Personal Protective Equipment: Eyeshields, Faceshields, full-face particle respirator type N100 (US), Gloves, respirator cartridge type N100 (US), type P1 (EN143) respirator filter, type P3 (EN 143) respirator cartridges
• RID/ADR: UN 2811 6.1/PG 3

Pharmacology Properties

• Admin Routes: oral
• Half Life: mean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
• Metabolism: Hepatic (CYP2C19)
• Protein Bound: 55% and 66% for the (+)-R and (–)-S enantiomers, respectively
• Legal Status: Rx-only
• Pregnancy Category: X (Australia); X (US)
• Gene Information: human ... LITAF(9516), TNF(7124)mouse ... Nos2(18126)rat ... Nos1(24598)

Product Information

• Purity: ≥98%; 95%; 98%; 99%
• Salt Data: Free Base

DETAILS

MP Biomedicals - 02158753

Purity: 99% Inhibits HIV-I replication, FGF-induced angiogenesis, and α-TNF biosynthesis.

DrugBank - DB01041

• Drug Groups: approved; withdrawn; investigational
• Description: A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. [PubChem]
• Indication: For the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
• Pharmacology: Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: one enantiomer is effective against morning sickness, and the other is teratogenic. The enantiomers are converted to each other in vivo. That is, if a human is given D-thalidomide or L-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer will not prevent the teratogenic effect in humans.
• Toxicity: The R-configuration and the S-configuration are more toxic individually than the racemic mixture. The LD₅₀ could not be established in mice for racemic thalidomide, whereas LD₅₀ values for the R and S configurations are reported to be 0.4 to 0.7 g/kg and 0.5 to 1.5 g/kg, respectively.
• Affected Organisms: Humans and other mammals
• Biotransformation: Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate.
• Absorption: The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract.
• Half Life: The mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing.
• Protein Binding: 55% and 66% for the (+)R and (−)S enantiomers, respectively.
• Elimination: Thalidomide itself has less than 0.7% of the dose excreted in the urine as unchanged drug.
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1193

Research Area: Immunology, Neurological Disease
Biological Activity:
Thalidomide was introduced as a sedative drug in the late 1950s. However, it was withdrawn due to a teratogenic effect on fetal development. Thalidomide binds to inactivate the protein cereblon, which is important to limb formation. [1]There is now a growing clinical interest in thalidomide since it is introduced as an immunomodulatory agent used primarily, combined with dexamethasone, to treat multiple myeloma. The combination of thalidomide and dexamethasone, often in combination with melphalan, is now one of the most common regimens for patients with newly diagnosed multiple myeloma, with an improved response rate of up to 60-70%. [1]

Sigma Aldrich - T144

Biochem/physiol Actions
(±)-Thalidomide selectively inhibits biosynthesis of tumor necrosis factor α (TNF-α); inhibitor of angiogenesis; immunosuppressive; sedative; teratogen.
Other Notes
Tandem Mass Spectrometry data independently generated by Scripps Center for Metabolomics is available to view or download in PDF. T144.pdf Tested metabolites are featured on Scripps Center for Metabolomics METLIN Metabolite Database. To learn more, visit sigma.com/metlin.

Toronto Research Chemicals - T338850

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 combinatio

REFERENCES

• Makonkawkeyoon, S., et al., J. Pharmacol. Exp. Therap., 160: 189, (1968).
• D' Amato, R.J., et al., Proc. Natl. Acad. Sci. USA, 91: 4082, (1994).
• Weglicki, W.B., et al., Mol. Cell. Biochem., 129: 195, (1993).
• http://en.wikipedia.org/wiki/Thalidomide
• D’Amato, r.J., et al.: Proc. Natl. Acad. Sci. USA, 91, 4082 (1994)
• Makonkawkeyoon, S., et al.: Proc. Natl. Acad. Sci. USA, 90, 5974 (1994)
• Schumacher, H., et al.: J. Pharmacol. Exp. Therap., 160, 189 (1968)