606080-73-3

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.

The invention provides an environment-friendly preparation method of istradefylline. 2-methyl aminocyanoacetate is taken as an initial raw material and is firstly subjected to an amidation reaction and then cyclized or firstly cyclized and then subjected to the amidation reaction, 1,3-diethyl-5-(N-methyl-N-(E)-3,4-dimethoxy phenylpropylene acryl)amino-6-aminouracil is prepared and then cyclized inthe presence of alkali, and istradefylline is prepared. According to the method, raw materials are cheap and easy to obtain, the step is simple and safe, and the method is green, environmentally friendly and low in cost; the prepared product has a shallow color and luster and is high in purity and yield.

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%.

The invention discloses a method for treating Parkinson's drug Iraq curved tea preparation method of alkali crystalline form II, Iraq and curved theophylline with the mixed solvent after mixing, heating to 70 - 90 °C dissolved, then rapidly cooling to 0 - 5 °C, crystallization, to obtain the treatment of Parkinson's drug Iraq curved tea alkali crystalline form II; the invention for the treatment of Parkinson's drug Iraq curved tea alkali crystalline form II, its stability and the prior of the Iraqi curved tea alkali crystalline form II considerable, but yield and purity higher, greatly improves the quality of the product, and can improve its bioavailability, conducive to its pharmaceutical processing and in the use of the drug combination in, at the same time can provide qualitative and quantitative information, to further study the solid curative effect of the medicament has important significance. (by machine translation)

The invention discloses a method of preparing an istradefylline crystal form III by means of a ball-milling method. The method comprises the following steps: putting istradefylline in a ball-milling tank; adding 100mg of istradefylline into 15-20 mu L tetrahydrofuran; and grinding the mixture at a grinding frequency of 5-10HZ for 60-100min to obtain the tetrahydrofuran crystal form III. The preparation method is novel in process, the reaction yield is improved, and the purity of the finally prepared istradefylline product reaches 99.6% through detection. The istradefylline prepared by the method is matched with a special solvent, and the grinding frequency and the grinding time as a raw material, so that the optical purity of the prepared istradefylline crystal form III is 99.9% or above,and the product quality is improved greatly.

The invention provides an improved synthesis technology of istradefylline. According to the technology, istradefylline is prepared from 1,3-diethyl-6-amino-5-nitrosouracil (SM-III) as a starting material through four steps.

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.

The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method and use of istradefylline; specifically, with 1,3-diethyl formamide and cyanoacetic acid as raw materials, istradefylline is prepared through cyclization, nitration, reduction, condensation, cyclization, methylation reaction and other steps; the preparation method provided by the invention is simple, high in production efficiency and wide in application prospect.

The invention discloses a method for the synthesis of the Iraqi curved theophylline new method, the present invention provides a compound (E)- 8 - [(3, 4 - dimethoxyphenyl) vinyl] - 1, 3 - diethyl - 7 - methyl - 3, 7 - dihydro - 1H - purine - 2, 6 - dione (also known as the Iraqi curved theophylline) new methods of synthesis, has been good purity and high yield of iraqi tune theophylline, improves the Iraq curved theophylline drug production and safety in the use of, at the same time reducing the cost of industrial production. (by machine translation)

The invention relates to a preparation method for Istradefylline represented by a formula (I) shown in the description. The method comprises the following steps: subjecting 6-amino-1,3-diethyl-5-nitroso-1H-pyrimid-2,4-dione represented by a formula (II) shown in the description, which serves as a raw material, to catalytic reduction and salt forming, so as to obtain 5,6-diamino-1,3-diethyl-1H-pyrimid-2,4-dione hydrochloride represented by a formula (III) shown in the description; then, carrying out acetylation on the compound (III), so as to obtain N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimid-5-yl)acetamide represented by a formula (IV) shown in the description; carrying out further ring closing, so as to obtain 1,3-diethyl-8-methyl-1H-purin-2,6(3H,7H)-dione represented by a formula (V) shown in the description; and carrying out methylation on the compound (V) firstly, and then, subjecting the methylation product to a condensation reaction with veratraldehyde represented by a formula (VII) shown in the description, thereby obtaining the end product Istradefylline. According to the novel preparation method for the Istradefylline, provided by the invention, raw materials, which are readily available industrially and are low in price, are used, the production process is more environmentally friendly, and the obtained product Istradefylline is high in yield and purity, thereby having a relatively high practical value.

The invention discloses a new crystal form of istradefylline and a preparation method thereof. The powder X-ray diffraction of the new crystal form of istradefylline has characteristic peaks where 2theta is equal to 10.4 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.8 +/-0.2 degrees, 24.6 +/-0.2 degrees, and 25.2 +/-0.2 degrees. The new crystal form of istradefylline is thermodynamically stable and has obviously improved solubility in water; the new crystal form of istradefylline, which is crystalline solid powder having a small particle size, is good in fluidity, so that the problem of non-uniform crystal condensation and dispersion in process operation of a preparation can be solved; the new crystal form of istradefylline is more suitable for storage and for use as a bulk pharmaceutical chemical; and a new way is provided for the preparation of istradefylline drugs.

The invention provides a novel synthesis method for a compound 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (also called Istradefylline). According to the novel synthesis method, environment-friendly dimethyl carbonate is adopted to substitute iodomethane, dimethyl sulfate and the like and serves as a methylation reagent, and a phase transfer catalyst-acid binding agent catalysis system is used, so that Istradefylline with good purity and high yield is obtained, the safety of Istradefylline drugs during production and use is improved, and meanwhile, the cost of industrial production is reduced.

The invention discloses a crystal form I, a crystal form II and a crystal form III of 8-[(E)-2-(3, 4-dimethoxy phenyl) vinyl]-1, 3-diethyl-7-methylpurine-2, 6-dione (istradefylline) and a preparation method thereof. The preparation method of the crystal forms is simple, and the crystal forms have good stability and meet the medicinal requirement.

Growing evidence has suggested a role in targeting the adenosine A 2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position.

A Pd/Cu-catalyzed dehydrogenative Heck coupling is established that allows direct alkenylation of various biologically relevant N-heteroarenes with alkenes. The resulting π-extended alkenylated N-heteroarenes exhibit interesting fluorescent properties and have proven to be potentially useful fluorescent probes for bioimaging. The Royal Society of Chemistry 2012.

A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A2A adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

The improved multigram-scale syntheses of the important 8-styrylxanthine A2A adenosine receptor antagonist MSX-2 (8), its water-soluble prodrug MXS-3 (9), and KW-6002 (16) are described. N-Alkylation reactions at different positions of uracil derivatives were optimized. Two different methods for xanthine formation from 6-amino-5-cinnainoylaminouracil precursors were investigated, (a) the elimination of water by alkaline catalysis and (b) hexamethyldisilazane as a condensing agent; the latter was found to be superior. The photosensitivity of 8-styrylxanthines was studied. The (E)-configurated stryrylxanthine MSX-2 (8) isomerized in diluted solution, and the resulting (Z)-isomer (10a) was isolated and characterized. Furthermore, we describe for the first time that solid 8-styrylxanthines can dimerize upon exposition to daylight or irradiation with UV light. The resulting cyclobutane derivatives with head-to-tail (syn) configuration exhibited a considerably lower A 2A adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A 1 and A2A antagonist (Ki(Ai) = 273 nM, Ki(A2A) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A1 and only weakly active at A 2A adenosine receptors (Ki = 1.57 μM). The light sensitivity of 8-styrylxanthine derivatives, not only in solution, but also in the solid state, has to be considered when using those compounds as pharmacological tools or drugs.

Adenosine receptor antagonists that are selective for the A2A receptor subtype (A2A antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A2A antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A2A antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A2A antagonists examined display significant MAO-B inhibitory properties in vitro with Ki values in the low μM to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A2A antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A2A receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD.

Structure-activity relationships of 8-styrylxanthines for in vivo adenosine A(2A) antagonism were explored. Diethyl substitution both at the 1- and S-position was found to dramatically potentiate the anti-cataleptic activity.

The present invention relates to an antidepressant containing as an active ingredient a xanthine derivative or a pharmaceutically acceptable salt thereof, the xanthine derivative being represented by Formula (I) : STR1 in which R1, R2, and R3 represent independently hydrogen, lower alkyl, lower alkenyl; R4 represents cycloalkyl, --(CH2)n --R5 (in which R5 represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or STR2 (in which Y1 and Y2 represent independently hydrogen, halogen or lower alkyl; and Z represents substituted or unsubstituted aryl, STR3 (in which R6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 3), or a substituted or unsubstituted heterocyclic group); and X1 and X2 represent independently O or S.

Agents for the treatment of Parkinson''s disease contain, as an active ingredient, a xanthine derivative or a pharmaceutically acceptable salt thereof. The xanthine derivative is represented by the formula: STR1 in which R 1, R 2 are R 3 are independently hydrogen, lower alkyl, lower alkenyl, or lower alkynyl; and R 4 represents cycloalkyl, --(CH 2) n --R 5 (in which R 5 represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4), or STR2 in which Y 1 and Y 2 represent independently hydrogen, halogen, or lower alkyl; and Z represents substituted or unsubstituted aryl, STR3 in which R 6 represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, or amino; and m represents an integer of 1 to 4, or a substituted or unsubstituted heterocyclic group; and X 1 and X 2 represent independently O or S.