8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione

Iupac Name：8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methylpurine-2,
6-dione

Molecular Weight：384.42896

Modify Date.: 2022-11-22 20:15

Introduction: In March 2013, istradefylline (also known as KW-6002) was approved in Japan for adjunctive treatment of Parkinson’s disease (PD). Istradefylline acts by antagonism of the adenosine A2A receptor, which is colocalized with dopamine D2 receptors in the striatum, to enhance dopamine D2-dependent signaling. 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. Istradefylline has a Ki of 2.2 nM for the rat adenosine A2A receptor and an ED50 of 0.03 mg/kg, po, in reversal of haloperidol-induced catalepsy in mice. Further characterization showed istradefylline to have a Ki of 12 nM for the human adenosine A2A receptor, to be highly selective, and to be a functional competitive antagonist. Istradefylline has activity alone and in combination with levo-dopa in preclinical animal models of PD. The synthesis of istradefylline was accomplished by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-mediated coupling of 5,6-diamino-1,3-diethyluracil with 3,4-dimethoxycinnamic acid, followed by cyclization upon treatment with aqueous NaOH, and selective methylation (MeI, K2CO3, and DMF). View more+

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1. Names and Identifiers

1.1 Name: 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione
1.2 Synonyms: (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methylxanthine 10mg 50mg 100mg 1g 5g 1H-Purine-2,6-dione, 3,7-dihydro-1,3-diethyl-8-(2-(3,4-dimethoxyphenyl)ethenyl)-7-methyl-, (E)- 1H-Purine-2,6-dione, 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-7-methyl- 8-[(1E)-2-(2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-7-methyl-1H-purine-2,6-dione 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6-dione 8-[(E)-2-(3,4-Dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione CS-285 istradefylline Istradefylline-13C-d3 Itraphylline KW 6002 KW-6002 UNII:2GZ0LIK7T4 UNII-2GZ0LIK7T4

1.3 CAS No.: 155270-99-8

1.4 CID: 5311037

1.5 Molecular Formula: C20H24N4O4 (isomer)

1.6 Inchi: InChI=1S/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+

1.7 InChIkey: IQVRBWUUXZMOPW-PKNBQFBNSA-N

1.8 Canonical Smiles: CCN1C2=C(C(=O)N(C1=O)CC)N(C(=N2)C=CC3=CC(=C(C=C3)OC)OC)C

1.9 Isomers Smiles: CCN1C2=C(C(=O)N(C1=O)CC)N(C(=N2)/C=C/C3=CC(=C(C=C3)OC)OC)C

2. Properties

2.1 Density: 1.24

2.1 Melting point: 189-193

2.1 Boiling point: 601°Cat760mmHg

2.1 Refractive index: 1.598

2.1 Flash Point: 317.3°C

2.1 Precise Quality: 384.18000

2.1 PSA: 80.28000

2.1 logP: 2.12410

2.1 Solubility: DMSO: soluble5mg/mL (clear solution)

2.2 Λmax: 362(CH2Cl2)nm

2.3 Appearance: white to beige

2.4 Storage: 2-8°C

2.5 Color/Form: white to beige

2.6 pKa: 0.47±0.70(Predicted)

2.7 Water Solubility: DMSO: soluble5mg/mL (clear solution)

2.8 StorageTemp: 2-8°C

3. Safety and Handling

3.1 Symbol: GHS06

3.1 Hazard Codes: T

3.1 Signal Word: Danger

3.1 Risk Statements: 25

3.1 Safety Statements: 45

3.1 Hazard Declaration: H301

3.1 RIDADR: UN 2811 6.1 / PGIII

3.1 Caution Statement: P301 + P310

3.1 WGK Germany: 3

4. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 3

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H301 Toxic if swallowed
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product.
Response	P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/\u2026 P321 Specific treatment (see ... on this label). P330 Rinse mouth.
Storage	P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

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5. Other Information

5.0 Description: In March 2013, istradefylline (also known as KW-6002) was approved in Japan for adjunctive treatment of Parkinson’s disease (PD). Istradefylline acts by antagonism of the adenosine A_2A receptor, which is colocalized with dopamine D₂ receptors in the striatum, to enhance dopamine D₂-dependent signaling. 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. Istradefylline has a Ki of 2.2 nM for the rat adenosine A_2A receptor and an ED₅₀ of 0.03 mg/kg, po, in reversal of haloperidol-induced catalepsy in mice. Further characterization showed istradefylline to have a Ki of 12 nM for the human adenosine A_2A receptor, to be highly selective, and to be a functional competitive antagonist. Istradefylline has activity alone and in combination with levo-dopa in preclinical animal models of PD. The synthesis of istradefylline was accomplished by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-mediated coupling of 5,6-diamino-1,3-diethyluracil with 3,4-dimethoxycinnamic acid, followed by cyclization upon treatment with aqueous NaOH, and selective methylation (MeI, K₂CO₃, and DMF).

5.1 Description: Istradefylline is an adenosine receptor 2A (A_2A) antagonist (K_i = 2.2 nM in a radioligand binding assay). In vivo, istradefylline inhibits catalepsy induced by haloperidol (Item No. 12014) with an ED₅₀ value of 0.23 mg/kg in rats. Oral administration of istradefylline alleviates postural defects in a dose-dependent manner without inducing dyskinesias or hyperactivity in an MPTP-induced marmoset model of Parkinson''s disease. It also decreases bradykinesias induced by L-DOPA (Item No. 13248) and improves attentional and working memory deficits in an MPTP-induced macaque model of Parkinson''s disease. Formulations containing istradefylline are used to extend on-time in Parkinson''s disease patients experiencing motor fluctuations.

5.2 Originator: Kyowa Hakko Kirin (Japan)

5.3 Brand name: Nouriast

5.4 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.

5.5 Chemical 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.

6. Computational chemical data

Molecular Weight: 384.42896g/mol
Molecular Formula: C₂₀H₂₄N₄O₄
Compound Is Canonicalized: True
XLogP3-AA: 2.5
Exact Mass: 384.17975526
Monoisotopic Mass: 384.17975526
Complexity: 613
Rotatable Bond Count: 6
Hydrogen Bond Donor Count: 0
Hydrogen Bond Acceptor Count: 5
Topological Polar Surface Area: 76.9
Heavy Atom Count: 28
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 1
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADceB7uAAAAAAAAAAAAAAAAAAAAWAAAAA8QAAAAAAAAFgBwAAAHgAAAAAADAzBnwYztpcMFACoAydydACCiC0nMKAJ2AG+3NiNbirEeTqUMKosxzPKqGeAwBAOIAABAAAAQABAAAIAAACAAAAAAAAAAA==