191732-72-6

Basic information

• Product Name: Lenalidomide
• Synonyms: lenalidomide;3-(7-amino-3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione;LenalidomideLenalidomide; 1-Oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione;CC-5013;Revlimi;Lenalidomide(other anti-cancers)
• CAS NO: 191732-72-6
• Molecular Formula: C₁₃H₁₃N₃O₃
• Molecular Weight: 259.26062
• EINECS: 1308068-626-2
• Product Categories: Molecular Targeted Antineoplastic;Intermediates & Fine Chemicals;Pharmaceuticals;Amines;Heterocycles;Inhibitor;CC-5013;Inhibitors;pharmaceutical intermediate
• Mol File: 191732-72-6.mol

Chemical Properties

• Melting Point: 269-271°C
• Boiling Point: 614 °C at 760 mmHg
• Flash Point: 325.1 °C
• Appearance: yellow solid
• Density: 1.46 g/cm³
• Vapor Pressure: 5.2E-15mmHg at 25°C
• Refractive Index: 1.672
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (up to 30 mg/ml)
• PKA: 10.75±0.40(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Lenalidomide(CAS DataBase Reference)
• NIST Chemistry Reference: Lenalidomide(191732-72-6)
• EPA Substance Registry System: Lenalidomide(191732-72-6)

Safety Data

• Statements: 20/21/22
• Safety Statements: 36/37
• HazardClass: IRRITANT
• Hazardous Substances Data: 191732-72-6(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Lenalidomide is used as an antitumor agent for the therapy of multiple myeloma. It inhibits TNF-alpha production, stimulates T cells, reduces serum levels of cytokines VEGF and bFGF, and inhibits angiogenesis. Additionally, it promotes G1 cell cycle arrest and apoptosis of malignant cells. Lenalidomide has shown curative effects on myelodysplastic syndromes (MDS), myeloma, leukemia, metastatic renal cell carcinoma, solid tumors, idiopathic generalized amyloidosis, and systemic bone marrow fibrosis disease with marrow unripe.
Used in Immunomodulation:
Lenalidomide is used as an immunomodulator to regulate the immune system and enhance its response against cancer cells. It can inhibit the hyperplasia of certain cell lines, such as the Namalwa cell line, and has demonstrated synergistic anticancer effects when combined with conventional chemotherapeutic drugs, enhancing chemo-sensitivity and efficacy in resistant cases.
Used in Angiogenesis Inhibition:
Lenalidomide is used as an angiogenesis inhibitor to prevent the formation of new blood vessels that supply nutrients to tumors, thereby inhibiting their growth and progression.
Used in Inflammatory Cytokine Regulation:
Lenalidomide is used to regulate the secretion of inflammatory cytokines, such as TNF-alpha, and increase the secretion of peripheral blood mononuclear anti-inflammatory cytokines, which can help in controlling the inflammatory response associated with certain diseases and conditions.
Used in Drug Delivery Systems:
Lenalidomide can be incorporated into drug delivery systems to improve its bioavailability, delivery, and therapeutic outcomes. Various organic and metallic nanoparticles can be employed as carriers for lenalidomide delivery, aiming to enhance its efficacy against cancer cells.
Chemical Properties:
Lenalidomide is a yellow solid with the brand name Revlimid, developed by Celgene. It is a member of isoindoles, a dicarboximide, a member of piperidones, and an aromatic amine.

Originator

Celgene (US)

History

In December 2005, the US Food and Drug Administration (FDA) approved lenalidomide to be used in the treatment of myelodysplastic syndrome (MDS).In March 2006, the FDA approved lenalidomide that was produced by American Celgene Biological Pharmaceutical Companies to be used in the treatment of multiple myeloma (MM).On September 23, 2011, the European Medicines Agency (EMA) released information that they have confirmed that the benefits of lenalidomide(trade name: Revlimid) to be used in the treatment of patients group that was approved outweighed the risks. Meanwhile they warned the doctor the risk of the drug to cause new cancer cases. Lenalidomide has been used with dexamethasone to treat adult patients with multiple myeloma that has received at least one treatment. Three new studies show that the incidence of new cancer will be increased in the patients with newly diagnosed multiple myeloma treated by lenalidomide and other combined treatment increased incidence of cancer.

Biochem/physiol Actions

Lenalidomide, a derivative of thalidomide, is an immunomodulatory agent that is approved drug for treatment of multiple myeloma. Apparently Lenalidomide is a ligand of ubiquitin E3 ligase cereblon that induces the enzyme to degrade the Ikaros transcription factors IKAROS family zinc finger 1 (IKZF1) and IKZF3. Lenalidomide possess pleiotropic antitumor effects. It is used in the treatment of 5q-deletion associated myelodysplastic syndrome (del(5q)-MDS).

Drug interactions

Lenalidomide is poorly metabolised as 82% of the dose is excreted unchanged in urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent. Approximately 4% of lenalidomide is eliminated in faeces.

Metabolism

Lenalidomide is poorly metabolised as 82% of the dose is excreted unchanged in urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent. Approximately 4% of lenalidomide is eliminated in faeces.

Clinical claims and research

Lenalidomide is a new derivative of thalidomide. But its teratogenic toxicity has not found. Its effectiveness is 100 times stronger than thalidomide. According to the result of three clinical trials, lenalidomide is the most effective drug in the treatment of multiple myeloma. More than half of patients can prolong survival time to more than 3 years after taking the drug. In addition, it is also the only effective drugs to treat myelodysplastic syndrome (MDS). Clinical results find that 64% of the patients with MDS need not use blood transfusion after treated by lenalidomide.

References

1) Ito et al. (2010), Identification of a primary target of thalidomide teratogenicity; Science, 327 13452) Gandhi et al. (2014), Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T-cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN); Br.J. Haematol., 164 8113) Kronke et al. (2014), Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells; Science, 343 3014) Lu et al. (2014), The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins; Science., 343 305

InChI:InChI=1/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)

Upstream product

• 827026-45-9 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 
• 59382-59-1 2-methyl-3-nitro-benzoic acid methyl ester 
• 2650-64-8 Cbz-L-Gln 
• 24666-56-6 rac-α-aminoglutarimide hydrochloride 
• 98475-07-1 2-bromomethyl-3-nitro-benzoic acid methyl ester 
• 24666-55-5 3-(benzyloxycarbonyl)-amino-2,6-dioxopiperidine 
• 19171-18-7 4-NT 
• 1187443-54-4 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)piperidine-2,6-dione methylsufonate 
• 295357-66-3 2-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)glutaric acid 
• 1198299-50-1 dimethyl 2-(4-amino-2,3-dihydro-1-oxo-1H-isoindol-2-yl)glutarate 
• 1198299-53-4 C₁₄H₁₇N₃O₄ 
• 1198299-48-7 3-(4-chloro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione 
• 1198299-57-8 2-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]glutaramide 
• 1198299-71-6 4-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]isoglutamine 

Downstream Products

• 444288-89-5 3-[4-(3-Chloro-benzylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione 
• 1061604-41-8 3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione 
• 847871-99-2 3-(4-amino-1-oxo-1,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione hemihydrate 
• 1265684-18-1 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)piperidine-2,6-dione p-toluenesulfonate 
• 1265684-17-0 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)piperidine-2,6-dione benzenesulfonate 
• 1243329-97-6 (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione hydrochloride 
• 1334496-42-2 C₃₀H₂₉N₅O₁₂S 
• 1334496-39-7 C₃₀H₃₄N₄O₇ 
• 1334496-41-1 C₂₆H₂₆N₄O₇ 
• 1421593-80-7 N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide 

Relevant articles and documents

Compound for targeted degradation of BTK protein

The invention provides a compound with the capability of degrading Bruton's tyrosine protein kinase (Btk) protein in a targeted manner, and particularly provides a compound as shown in the following formula I0, wherein the definition of each group is described in the specification. The compound provided by the invention can well degrade Btk protein in a targeted manner, so that the compound can be used for treating diseases related to Btk activity or expression quantity, such as tumors.

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.

Method for synthesizing lenalidomide

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing lenalidomide. The method adopts three-step polymerization, and specifically comprises: (1) carrying out a bromination reaction on 2-methyl-3-nitromethyl benzoate as a starting raw material and a bromination reagent to generate a compound 1 2-bromomethyl-3-nitromethyl benzoate; (2) performing cyclization on the compound 1 and 3-aminopiperidine-2,6-dione hydrochloride under a solvent-free condition to generate a compound 2 3-(4-nitro-1-oxo-1,3-dihydroisoindole-2-yl)piperidine-2,6-dione; and (3) reducing the compound 2 with a reducing agent to obtain lenalidomide. According to the invention, the method is a novel preparation process method of lenalidomide, and has advantages of easily available process raw materials, short steps, simple and convenient operation, environmental friendliness, implementation value of industrial production, and social and economic benefits.

Method for preparing lenalidomide

The invention provides a method for preparing lenalidomide. Specifically, the invention provides a method for preparing lenalidomide, which comprises a nitro-reduction step. The nitro-reduction step comprises the following steps: in a first solvent, under acidic conditions, in the presence of a reducing agent and a catalyst, a nitro-reduction reaction is carried out on a compound shown as a formula II to obtain a compound shown as a formula I; wherein the catalyst is palladium on carbon; the reducing agent is hypophosphorous acid or hypophosphite. The process is high in reaction yield, low inproduction cost and environment-friendly, and has great implementation value and social and economic benefits.

Anhydrous preparation method of lenalidomide

The invention relates to an anhydrous preparation method of lenalidomide. The invention discloses a novel method for preparing a 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidine-2,6-diketoneanhydrous compound, and belongs to the technical field of chemical synthesis. The process route is short in steps, simple and convenient to operate and mild in reaction conditions, and the finally obtained product is excellent in quality and easy for industrial production.

Preparation method of lenalidomide B crystal form

The invention provides a preparation method of a lenalidomide B crystal form. Specifically the method comprises the following steps: (1) dissolving a raw material lenalidomide in alcohol to obtain a solution containing lenalidomide; and (2) adding water into the lenalidomide-containing solution obtained in the step (1), and crystallizing to obtain a lenalidomide B crystal form, wherein the alcoholis selected from 1,3-propylene glycol, 1,2-propylene glycol, and a combination of 1,3-propylene glycol and 1,2-propylene glycol. The method has high stability and high reliability.

Green production method of low-cost lenalidomide

The invention relates to a green production method of low-cost lenalidomide. According to the method, in presence of a solvent and an alkali, 3-aminopiperidine-2,6-dione and 1-halo-acetoacetate are subjected to dehydrogenation halogen acid condensation, dealcoholizing amidation, 2-halo-4-nitrobutanal dehydration and dehydrochlorination or dehydrobromination, 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione is obtained, the process is completed with a one-pot method, nitro is reduced into amino by catalytic hydrogenation of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, and lenalidomide is prepared. The method has the advantages of cheap and easily available raw materials, short technological process, simple operation and environmental protection and is a production method beneficial to industrialization.

Preparation method of lenalidomide

The invention provides a preparation method of lenalidomide. The preparation method of the lenalidomide comprises the steps of preparing an intermediate 2-halogen methyl-3 methyl nitrobenzoate and anintermediate 3-amino piperidine-2,6-diketone, and preparing the lenalidomide by using the two intermediates. The preparation method of the lenalidomide is simple in steps, high in yield, low in cost,and beneficial to industrial production.

Preparation method of substituted dioxopiperidine derivative

The invention discloses a preparation method of a substituted dioxopiperidine derivative. The preparation method comprises the following steps that a compound shown in the formula (II) and formamide react in the presence of C1-C4 alkanol alkali metal salt or alkaline earth metal salt, and a compound shown in the formula (I) is obtained; substituent groups in the compound shown in the formula (I) and the compound shown in the formula (II) are defined in the description. The product obtained through method is high in yield and purity, and the method is easy and convenient to operate. The formulas are shown in the description.

Preparation method of lenadomide

The invention discloses a preparation method of lenalidomide, and belongs to the field of organic synthesis. 2-methyl-3-methyl nitrobenzoate and 3-N-benzyloxy-carbonyl-L-glutamine serve as starting materials, and an important intermediate 2-brooethyl-3-methyl nitrobenzoate is obtained through a bromination reaction of 2-methyl-3-methyl nitrobenzoate. 3-N-benzyloxy-carbonyl-L-glutamine is cyclizedunder catalysis to produce 3-N-benzyloxy-carbonyl-2,6-dioxopiperidine, an amino group is subjected to deprotection to produce 3-amino-2,6-piperidone halide, 3-(4-nitro-1-oxo-1,3-o-xylylenimine-2-yl)piperidine-2,6-diketone is obtained through an aminolysis reaction of 3-N-benzyloxy-carbonyl-2,6-dioxopiperidine and 2-brooethyl-3-methyl nitrobenzoate, and then lenalidomide is prepared through reduction. The method has the advantages that the cost of raw materials are low, aftertreatment is simple, and the yield is high, and the production cost of the lenalidomide as a bulk drug is greatly reduced. The method is a convenient and efficient lenalidomide synthesis method suitable for industrial production.