| Identification | More | [Name]
Tofacitinib (CP-690550,Tasocitinib) | [CAS]
477600-75-2 | [Synonyms]
CP 690550
Tasocitinib
Tofacitinib
Tropsch iMatinib
Tofacitinib,CP-690550
CP 690550(Tasocitinib)
Tasocitinib (CP 690550)
3-((3R,4R)-4-Methyl-3-(Me...
CP-690550(Tasocitinib,CP690550)
Tofacitinib (CP-690550,Tasocitinib)
477600-75-2
3-Piperidinamine, 1-(cyanoacetyl)-4-methyl-N-methyl-N-1H-pyrrolo(2,3-D)pyrimidin-4-yl-, (3R,4R)-
(3R,4R)-4-methyl-3-(methyl-1H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-2-piperidinepropanenitrile
(3R,4R)-4-methyl-3-(methyl-1H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropanenitrile
1-Piperidinepropanenitrile, 4-Methyl-3-(Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMino)-β-oxo-, (3R,4R)-
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
3-((3R,4R)-4-Methyl-3-(Methyl(7H-pyrrolo[2,3-d]pyriMidin-4-yl)aMino)-2-oxopiperidin-1-yl)propanenitrile
1-Piperidinepropanenitrile, 4-Methyl-3-(Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMino)-beta-oxo-, (3R,4R)-
CP 690550
3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile | [EINECS(EC#)]
689-145-4 | [Molecular Formula]
C16H20N6O | [MDL Number]
MFCD11035919 | [MOL File]
477600-75-2.mol | [Molecular Weight]
312.37 |
| Chemical Properties | Back Directory | [density ]
1.3 | [storage temp. ]
-20°C | [solubility ]
Soluble in DMSO (up to 100 mg/ml) or in Ethanol (up to 100 mg/ml). | [form ]
Pale powder. | [pka]
6.04±0.60(Predicted) | [color ]
Off-white | [Stability:]
Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months. | [InChI]
InChI=1/C16H20N6O/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/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/s3 | [InChIKey]
UJLAWZDWDVHWOW-BCFRMRSDNA-N | [SMILES]
N([C@@H]1[C@@H](CCN(C(=O)CC#N)C1)C)(C1N=CN=C2NC=CC=12)C |&1:1,2,r| | [CAS DataBase Reference]
477600-75-2 |
| Hazard Information | Back Directory | [Chemical Properties]
Light Pink to Pale Orange Solid | [Usage]
CP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis | [Description]
In November 2012, the US FDA approved tofacitinib (also referred to as
CP-690550) for the treatment of adult patients with moderate to severely
active rheumatoid arthritis (RA) who have had an inadequate response or
intolerance to methotrexate. Tofacitinib is the first small molecule kinase inhibitor approved for the treatment of RA. Tofacitinib is an inhibitor of the four subtypes of Janus kinase (JAK): JAK1, JAK2, JAK3, and Tyk2. The JAKs are intracellular, nonreceptor tyrosine kinases that play important roles in the signal transduction pathway of many cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) and are involved in the propagation of inflammation in RA. Tofacitinib acts by inhibiting the phosphorylation and activation of signal transducers and activators of transcription (STATs), thereby suppressing the production of inflammatory mediators in joint tissue. At the enzyme level, tofacitinib inhibits JAKs 1, 2, 3, and Tyk2 with IC50s of 3.2, 4.1, 1.6, and 34 nM, respectively. At the cellular level, tofacitinib inhibits the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50s of 406, 56, and 1377 nM, respectively. | [Originator]
Pfizer (United States) | [Uses]
CP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis | [Definition]
ChEBI: A pyrrolopyrimidine that is pyrrolo[2,3-d]pyrimidine substituted at position 4 by an N-methyl,N-(1-cyanoacetyl-4-methylpiperidin-3-yl)amino moiety. Used as its citrate salt to treat moderately to severely
ctive rheumatoid arthritis. | [Indications]
The JAK family includes four isoforms, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). Ruxolitinib (Jakafi(R), Incyte Corp.) was the first approved JAK inhibitor, which inhibits both JAK1 and JAK2, used for the treatment of different types of myelofibrosis. Tofacitinib (Xeljanz(R), Pfizer) was approved by FDA as a JAK3-selective inhibitor for the treatment of rheumatoid arthritis and is one of the only two FDA-approved kinase inhibitors for non-oncological indications. | [Brand name]
Xeljanz | [Synthesis]
Commercially available aminopyridine 171 was reacted with dimethyl dicarbonate in the presence of
potassium t-butoxide to give the methyl carbamate 172 in 87% yield. Hydrogenation of this carbamate
172 in the presence of 20 wt% of 5% Rh/C (JM type C101023-5) in acetic acid followed by reductive
amination with benzaldehyde and sodium triacetoxy borohydride furnished the cis-benzyl protected
piperidine 173 in 73% yield. Reduction of the methyl carbamate within 173 with lithium aluminum
hydride (LAH) in THF gave the corresponding methyl amino piperidine which was isolated as the
dihydrochloride salt 174 in 87% yield. Enantiomeric resolution of the methyl amino piperidine was
achieved by freebasing the di-hydrochloride salt 174 with sodium hydroxide and then conversion to the
di-toluol-L-tartaric acid salt followed by crystallization to give 175 in 42% yield and 98.6% ee. The
enantioenriched tartrate salt 175 was then directly reacted with dichloride 176 (obtained from reaction
of commercial 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (178) with phosphorous oxychloride) in the
presence of potassium carbonate in water to give the coupled product 177 in essentially quantitative
yield. Hydrogenation of intermediate 177 with DeGussa?ˉs catalyst triggered concomitant debenzylation
and chloride removal, and this was followed by installation of the cyanoacetate group and subsequent
treatment with citric acid to provide tofacitinib citrate (XXVII) in 90% yield.
| [storage]
Store at -20°C | [References]
1) Jiang et al. (2008), Examining the chirality, confirmation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitril (CP-690,550); J. Mol. Chem., 51 8012
2) Cutolo and Meroni (2013), Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis; J. Inflamm. Res., 6 129
3) Martina et al. (2016), Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro; Transplant. Proc., 48 3046
4) Moisan et al. (2015), White-to-brown metabolic conversion of human adipocytes by JAK inhibition; Nat. Cell Biol., 17 57
5) Dowty et al. (2014), Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis; J. Pharmacol. Exp. Ther., 348 165 |
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