155270-99-8 Usage
Description
8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6-dione, also known as istradefylline (KW-6002), is a compound that was approved in Japan in March 2013 for the adjunctive treatment of Parkinson's disease (PD). It acts as an adenosine A2A receptor antagonist, enhancing dopamine D2-dependent signaling by antagonizing the adenosine A2A receptor, which is colocalized with dopamine D2 receptors in the striatum. Istradefylline is a light-sensitive compound and has been evaluated in vitro under low-light conditions to prevent isomerization of the (E)-styryl group and decomposition. It is highly selective and functions as a competitive antagonist.
Uses
Used in Pharmaceutical Industry:
Istradefylline is used as an adenosine receptor 2A (A2A) antagonist for the treatment of Parkinson's disease. It inhibits catalepsy induced by haloperidol and alleviates postural defects in a dose-dependent manner without inducing dyskinesias or hyperactivity. It also decreases bradykinesias induced by L-DOPA and improves attentional and working memory deficits in PD models.
Used in Parkinson's Disease Treatment:
Istradefylline is used as an adjunctive treatment for Parkinson's disease to extend on-time in patients experiencing motor fluctuations. It has demonstrated activity alone and in combination with levo-dopa in preclinical animal models of PD.
Brand Name:
Nouriast
Originator
Kyowa Hakko Kirin (Japan)
Biochem/physiol Actions
Istradefylline (KW-6002) is a potent and selective adenosine A2A receptor selective antagonist which has been investigated for use in Parkinson′s Disease.
Synthesis
Numerous synthetic approaches to istradefylline have been
developed, with a large majority of these methods employing
5,6-amino-1,3-diethyluracil 97 as a key intermediate.
Despite the commercial availability of 96, most reported routes
to istradefylline rely on sourcing of this intermediate via a wellestablished
four-step synthesis from N,N-diethylurea (94) and cyanoacetic
acid (95). Specifically, 6-amino-1,3-diethyluracil
(96) can be formed by sequential treatment of 94 and 95 with Ac2O
and NaOH. Nitrosation of 96 with NaNO2/AcOH/H2O, followed by
Na2S2O4/NH3-mediated nitroso reduction provided 5,6-amino-
1,3-diethyluracil (97).
Even though other groups have recently reported modified scale
routes to istradefylline, the route described herein will focus on
the sequence outlined by Kyowa Hakko Kogyo research laboratories
during their initial development of istradefylline.
EDC-mediated amine coupling involving 97 and 3,4-dimethoxycinnamic
acid (98) led to the corresponding amide intermediate. After
aqueous workup, this crude amide intermediate underwent cyclization with aqueous sodium hydroxide to yield the desired
purine dione 99 in 47% yield over 2 steps. Methylation of 99 with
MeI/K2CO3 provided istradefylline (XII) in 68% yield.
in vitro
the affinity of kw-6002 for the a2ar is 70-fold greater than that for the a1 receptor. the binding affinities (ki) of kw-6002 for human a1 receptor and a2a receptor are >287 nm and 9.12 nm, respectively [1].
in vivo
in mptp neurotoxin model of pd in mice, kw-6002 significantly attenuated striatal dopamine depletion under various conditions. in addition, pretreatment with kw-6002 (3.3 mg/kg, i.p.) before a single dose of mptp attenuated the partial dopamine and dopac depletions 1 week later [2].
references
[1] park a, stacy m. istradefylline for the treatment of parkinson's disease. expert opin pharmacother. 2012 jan;13(1):111-4. [2] chen jf, xu k, petzer jp, staal r, xu yh, beilstein m, sonsalla pk, castagnoli k, castagnoli n jr, schwarzschild ma. neuroprotection by caffeine and a(2a) adenosine receptor inactivation in a model of parkinson's disease. j neurosci. 2001;21(10):rc143.
Check Digit Verification of cas no
The CAS Registry Mumber 155270-99-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,5,2,7 and 0 respectively; the second part has 2 digits, 9 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 155270-99:
(8*1)+(7*5)+(6*5)+(5*2)+(4*7)+(3*0)+(2*9)+(1*9)=138
138 % 10 = 8
So 155270-99-8 is a valid CAS Registry Number.
InChI:InChI=1/C20H24N4O4/c1-6-23-18-17(19(25)24(7-2)20(23)26)22(3)16(21-18)11-9-13-8-10-14(27-4)15(12-13)28-5/h8-12H,6-7H2,1-5H3/b11-9+
155270-99-8Relevant articles and documents
Synthetic method of istradefylline
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Paragraph 0016-0021; 0025-0028, (2020/08/26)
The invention discloses a synthetic method of istradefylline, and belongs to the technical field of medicines. The synthesis method of the istradefylline mainly comprises the steps of acylation, ringclosing, methylation and the like. The method is high in yield, simple in step and single in solvent, wherein reaction selectivity can be effectively promoted and side reactions are reduced; after ring closing is finished, dimethyl sulfate is dropwise added for a methylation reaction by means of the alkalinity of dimethyl sulfate. The method can be more thorough and cleaner than a dimethyl carbonate reaction in the prior art. The whole process can be carried out in one reaction kettle, wherein the solvent only relates to ethanol and subsequently refined methanol and can be recycled, so that the synthesis method has advantages of high reaction selectivity and yield.
Istradefylline preparation method
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Paragraph 0029-0030; 0031-0032; 0033-0034, (2019/07/04)
The invention provides an istradefylline preparation method. 1,3-diethyl-5,6-diaminouracil used as a starting material undergoes an acylation reaction, a ring formation reaction and a methylation reaction to prepare istradefylline. The ring formation reaction and the methylation reaction are carried out simultaneously, an istradefylline intermediate (E)-1,3-diethyl-6-amino-5-(3,4-dimethoxyphenylacryloyl)aminouracil is reacted by adding a methylating agent in an alkaline environment, and the obtained solution is filtered and crystallized to obtain the istradefylline. The ring formation and themethylation are simultaneously carried out, and the methylation is immediately carried out after the completion of the ring formation to promote the forward proceeding, so the yield of the product isincreased, large amounts of organic solvents are saved, and the generation amount of an organic waste liquid is reduced; and the method has the advantages of simplicity in operation, and high reactionconversion rate, and allows the purity of the product to be higher than 99%.
Istradefylline raw material drug and preparation method thereof
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, (2018/12/14)
The invention relates to an istradefylline raw material drug and a preparation method thereof. Specifically, the invention relates to an istradefylline raw material drug. A compound shown in formula III is not higher than 0.5% and is a medicine preparation consisting of the istradefylline raw material drug and a pharmacologically acceptable carrier and/ or diluent. The raw material drug and the preparation thereof have better safety, effectiveness and stability. The formula III is shown in the description.