540737-29-9

Basic information

• Product Name: Tofacitinib citrate
• Synonyms: 1-PIPERIDINEPROPANENITRILE, 4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YLAMINO)-BETA-OXO-, (3R,4R)-, 2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE (1:1);1-Piperidinepropanenitrile, 4-Methyl-3-(Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMino)-β-oxo-, (3R,4R)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1);Tofacitinib citrate (CP-690550);Tofacitinib citrate;Tasocitinib citrate;Tasocitinib citric acid s...;Xeljanz;CP-690550 (Tofacitinib citrate)
• CAS NO: 540737-29-9
• Molecular Formula: C16H20N6O.C6H8O7
• Molecular Weight: 504.497
• EINECS: 1592732-453-0
• Product Categories: Inhibitor;Inhibitors;JAK;STAT;API
• Mol File: 540737-29-9.mol
• Article Data: 37

Chemical Properties

• Melting Point: 201 °C (decomp)
• Boiling Point: 585.8 °C at 760 mmHg
• Flash Point: 308.1 °C
• Appearance: white to beige/
• Storage Temp.: room temp
• Solubility: DMSO: soluble5mg/mL (clear solution; warmed)
• CAS DataBase Reference: Tofacitinib citrate(CAS DataBase Reference)
• NIST Chemistry Reference: Tofacitinib citrate(540737-29-9)
• EPA Substance Registry System: Tofacitinib citrate(540737-29-9)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 540737-29-9(Hazardous Substances Data)

Usage

Description

Tofacitinib citrate is a king of drugs developed by the US pharmaceutical company Pfizer for treating rheumatoid arthritis, trade name Xeljanz, for the treatment of methotrexate inadequate response or intolerance to severe active rheumatoid arthritis (RA) in adult patients. This product is a Janus kinase inhibitor, administered twice daily. November 6, 2012, the US Food and Drug Administration (FDA) and Pfizer jointly announced Tofacitinib citrate is approved for the treatment of methotrexate inadequate response or intolerance to severe active rheumatoid joints arthritis (RA) in adult patients. Xeljanz can be used as monotherapy or in combination with methotrexate or other non-biological disease-modifying antirheumatic drugs (the DMARD) in combination. This medicine should not be in combination with biological DMARD or strong immunosuppressants (such as cyclosporine and azathioprine). Xeljanz is approved by the daily dose of 2 times, each time 5mg. Seven clinical trials evaluated the safety and efficacy of Tofacitinib citrate in moderate to severe active RA in adult patients. In all tests, compared with patients receiving placebo, patients receiving Xeljanz treatment showed significant improvement in clinical response and physical function. In Clinical trials, the most common adverse events were upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat, and nasopharyngitis. Using Xeljanz was associated with an increased risk of serious infections, including opportunistic infections, tuberculosis, cancer and lymphoma. Xeljanz product label attaches boxed warning on these security risks. Xeljanz treatment is also associated with reducing blood cell counts and increasing cholesterol and liver enzyme values. In order to study Xeljanz long-term impact on heart disease, cancer and severe infections, FDA requires for a post-marketing study, which will evaluate two doses of Xeljanz (Tofacitinib citrate) therapy, and accept a integration of another group of patients approved by the treatment as a control.

In vitro

CP-690550 is a specific, orally inhibitor of JAK3, it is 20-to 100-fold less potent for JAK2 and JAK1 with IC50 of 20 nM and 112 nM, respectively. CP-690550 doesn't have potent activity against 30 other kinases (all median IC50 > 3000 nM). CP-690,550 inhibits IL-2–induced proliferation with 30-fold greater potency than its effects on GM-CSF–induced proliferation. CP-690550 effectively inhibits a murine mixed lymphocyte reaction (MLR) (IC50 = 91 nM).? CP-690550 potently inhibits IL-4 induced upregulation of CD23 (IC50=57 nM) and class II major histocompatibility complex (MHCII) expression (IC50=71 nM) on murine B cells. A recent research indicates low dose of CP-690550 accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation.

In vivo

In a murine model of heterotopic heart transplantation (DBA2 donor heart into C57/BL6 host), CP-690550 results in a dose-dependent increase in survival of transplanted hearts.The EC50 (drug concentration in blood at which 50% of mice will maintain their graft for >28 days) to be ～60 ng/mL.CP-690550 prevents rejection of allogeneic kidneys in nonhuman primate (NHPs, macaca fascicularis) (MST of 62 and 83 days for the 50 to 100 ng/ml groups and 200 to 400 ng/ml groups, respectively). Mice chronically dosed with CP-690550 (1.5-15 mg/kg/day) demonstrate dose and time-dependent alterations in lymphocyte subsets when examined by flow cytometry. The most dramatic change observed is a 96% reduction in splenic NK1.1+TCRb-cell numbers following 21 days of treatment. Delayed-type hypersensitivity (DTH) responses in sensitized mice are reduced in a dose-dependent manner following treatment with CP-690550 (1.87–30 mg/kg, s.c.).

References

http://www.medicinenet.com/tofacitinib_citrate_xeljanz/article.htm

Uses

Tofacitinib citrate has been used:as a ligand for human serum albumin in fluorescence quenching, dynamic light scattering (DLS) measurements, differential scanning calorimetry and molecular docking studiesas a medium supplement for full depth articular cartilage (FDC) explants to monitor cytokine-induced proteoglycan lossas a Janus kinase inhibitor in MCF7 breast cancer cells

Definition

ChEBI: A citrate salt obtained by combining equimolar amounts of tofacitinib and citric acid. Used to treat moderately to severely active Rheumatoid Arthritis.

General Description

Tofacitinib is a synthetic molecule corresponding to a molecular weight of 312.4 Da and is permeable by transcellular diffusion.

Biological Activity

tofacitinib citrate, also known as cp-690550 citrate, is a potent inhibitor of janus kinase 3 (jak3), a hematopoetic cell-restricted tyrosine kinase involved in signal transduction regulating lymphocyte survival, proliferation, differentiation, and apoptosis. the inhibition is jak3 specific with a selectivity 1000-fold more than other non-jak family kinases. besides inhibiting jaks (ic50 = 1 nm), tofacitinib citrate also inhibits janus kinase 2 (jak2) and janus kinase 1 (jak1) with 20- and 100-fold less in potency respectively. however, in a recent study, the binding affinities (ki) of tofacitinib citrate towards jak1, jak2, and jak3 were reported to be 1.6 nm, 21.7 nm, and 6.5 nm respectively.lalitha vijayakrishnan, r. venkataramanan and palak gulati. treating inflammation with the janus kinase inhibitor cp-690,550. trends in pharmacological sciences 2011: 32 (1); 25-34

Biochem/physiol Actions

Tofacitinib is a potent inhibitor of Janus kinase 3 (JAK3) with some JAK-1 inhibitory activity as well. It blocks downstream STAT signaling resulting in potent inhibition of inflammatory cytokines with resultant immunosuppressive and anti-inflammatory activity. Tofacitinib is being investigated for for several autoimmune disorders including, rheumatoid arthritis, psoriasis and dry eye.

Clinical Use

Potent, selective inhibitor of the Janus kinase family: Treatment of moderate to severe active rheumatoid arthritis

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration of tofacitinib reduced by rifampicin - avoid. Antifungals: concentration of tofacitinib increased by fluconazole and ketoconazole - adjust tofacitinib dose. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid. Ciclosporin: concentration of tofacitinib reduced - avoid. Tacrolimus: concentration of tofacitinib reduced - avoid. Vaccines: risk of generalised infections with live vaccines - avoid.ccccccc

Metabolism

70% metabolised in the liver by CYP3A4 (major) and CYP2C19 (minor). The 8 metabolites produced are inactive.

InChI:InChI=1S/C16H20N6O.C6H8O7/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16;7-3(8)1-6(13,5(11)12)2-4(9)10/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t11-,13+;/m1./s1

Upstream product

• 477600-74-1 tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate 
• 105-56-6 ethyl 2-cyanoacetate 
• 77-92-9 citric acid 
• 1204176-45-3 methyl-(4-methylpiperidin-3-yI)carbamate 
• 1443435-54-8 tofacitinib mono-oxalate 
• 3430-27-1 3-amino-4-methylpyridine 
• 1259404-17-5 tasocitinib 
• 694495-63-1 O-methyl-N-(4-methylpyridin-3-yl)carbamate 
• 1616760-97-4 N-((3R,4R)-4-methyl-piperidin-3-yl)-N-methyl-2-chloro-7H-pyrrolo[2,3-D]pyrimidine-4-amine 
• 1616760-96-3 C₃₂H₃₂ClN₅ 
• 1616760-95-2 C₂₀H₂₄ClN₅O₂S 
• 1616760-94-1 C₃₉H₃₈ClN₅O₂S 
• 90213-66-4 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 
• 934524-10-4 2,4-dichloro-7-p-methylbenzenesulfonyl-7H-pyrrole[2,3-d]pyrimidin-4-amine 

Relevant articles and documents

Preparation method of tofacitinib citrate

The invention discloses a preparation method of tofacitinib citrate. The method comprises the following steps: by taking 7-tert-butyloxycarbonyl-4-amino-7H-pyrrolo[2, 3-D]pyrimidine and 1-benzyl-4-methyl-piperidine-3-ketone as initial raw materials, carrying out condensation under a weak acidic condition, then carrying out N methylation, selective reduction, debenzylation and Boc removal, and carrying out ester exchange and citric acid salification at a high temperature to obtain the tofacitinib citrate. The method has the advantages of mild reaction conditions, simple post-treatment mode, reduction of the generation amount of hazardous wastes, environmental protection, cost saving, and facilitation of industrial production.

Process for the preparation of tofacitinib and intermediates thereof

Provided is a process for the preparation of high purity tofacitinib, which reduces formation of N-methyl impurity. The invention also provides novel intermediates used in the process to prepare tofacitinib. There is provided an improved process for the preparation of tofacitinib (I), comprising the steps of: adding cyanoacetic acid in molar equivalent 0.2-1.2 to compound of formula (II-S), followed by addition of carbodiimide coupling agent of formula (III), optionally reacting tofacitinib base with citric acid.

Synthesis method of tofacitinib citrate

The invention relates to the technical field of medicinal chemistry, and discloses a synthesis method of tofacitinib citrate. The method comprises 1) preparing 2,4-dihydroxy pyrrolopyrimidine: adding4-aminouracil and anhydrous sodium acetate into water (in a molar ratio of (1: 3)-(1: 5)), heating to 60-80 DEG C, slowly adding a 2-chloroacetaldehyde aqueous solution having a concentration of 40%,stirring to react for 4-6 hours, cooling to room temperature, filtering, washing a solid with water, and drying under reduced pressure to obtain 2,4-dihydroxy pyrrolopyrimidine. According to the synthesis method of tofacitinib citrate, through two times of impurity removal, the purity of the produced tofacitinib citrate finished product is higher, subsequent purification is not needed, the synthesis time is short, the process is simple, the method is suitable for factory production, the production time of the tofacitinib citrate finished product can be saved, the production efficiency of the tofacitinib citrate finished product is improved, and the tofacitinib citrate is more convenient to use.