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WO2014168211A1 - Procédé de production de 2-(4-tétrahydropyranyl)imidazole et/ou d'un sel acide de celui-ci - Google Patents

Procédé de production de 2-(4-tétrahydropyranyl)imidazole et/ou d'un sel acide de celui-ci Download PDF

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Publication number
WO2014168211A1
WO2014168211A1 PCT/JP2014/060416 JP2014060416W WO2014168211A1 WO 2014168211 A1 WO2014168211 A1 WO 2014168211A1 JP 2014060416 W JP2014060416 W JP 2014060416W WO 2014168211 A1 WO2014168211 A1 WO 2014168211A1
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Prior art keywords
compound
acid salt
tetrahydropyran
imidazole
tetrahydropyranyl
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PCT/JP2014/060416
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English (en)
Japanese (ja)
Inventor
尊洋 本山
康明 福原
健二 有光
智親 岩田
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Ube Corp
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Ube Industries Ltd
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Publication of WO2014168211A1 publication Critical patent/WO2014168211A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a method for producing 2- (4-tetrahydropyranyl) imidazole and / or an acid salt thereof, and an intermediate thereof.
  • pyranylimidazole is a compound useful as a synthetic intermediate for therapeutic agents for dysuria and neurodegenerative diseases (see, for example, Patent Documents 1 and 2).
  • the imidazole skeleton is also included in liquid crystal compounds, and has attracted attention in recent years (see, for example, Patent Document 3).
  • the imidazole skeleton is also included in materials for organic electroluminescence elements or metal surface treatment agents, and material development utilizing the high coordination property, rigidity, aromaticity, etc. of imidazole has been actively conducted. (For example, refer to Patent Documents 4 and 5).
  • a tetrahydropyranyl group has an effect of improving the water solubility of an organic compound, and is well known to be incorporated into a pharmaceutical intermediate (for example, see Patent Document 1).
  • Patent Document 1 does not describe the yield.
  • paragraph 0475 of Patent Document 2 describes a method of treating the reaction solution with hydrochloric acid following the reaction of tetrahydro-2H-pyran-4-carbimidate hydrochloride and aminoacetaldehyde dimethylacetal (2,2-dimethoxyethylamine).
  • the raw material aldehyde compound is unstable, a method of manufacturing from a raw material that is easier to handle is required.
  • An object of the present invention is to provide a production method that makes it possible to obtain 2- (4-tetrahydropyranyl) imidazole and / or its acid salt with high yield and high purity.
  • the subject of the present invention is, for example, the general formula (3): (Wherein R 2 represents an alkyl group having 1 to 8 carbon atoms, and two R 2 s may be the same or different, and may be bonded to each other to form a ring.) From the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt represented by the general formula (4): It is solved by a process for producing 2- (4-tetrahydropyranyl) imidazole and / or its acid salt, which comprises the step of producing 2- (4-tetrahydropyranyl) imidazole and / or its acid salt represented by the formula: In addition, in the said process, when a solvent or an acid is provided with water, it is not necessary to add water separately.
  • the production method according to the present invention has the general formula (1): (Wherein R 1 represents an alkyl group having 1 to 8 carbon atoms.) And a tetrahydropyran-4-imidate compound represented by the general formula (2): (Wherein R 2 represents an alkyl group having 1 to 8 carbon atoms, and two R 2 s may be the same or different, and may be bonded to each other to form a ring.) And a step of reacting a 2,2-dialkoxyethylamine compound represented by the above in a reaction liquid containing the compound to produce a tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or an acid salt thereof. May be.
  • reaction process formula (1) The two steps shown in FIG.
  • R 1 represents an alkyl group having 1 to 8 carbon atoms
  • R 2 represents an alkyl group having 1 to 8 carbon atoms.
  • Two R 2 s may be the same or different, and may be bonded to each other to form a ring.
  • the tetrahydropyran-4-imidate compound represented by the general formula (1) and / or its acid salt is reacted with 2,2-dialkoxyethylamine represented by the general formula (2) to give a general formula
  • the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound represented by (3) and / or its acid salt is produced. This process may be referred to as an amidine process.
  • the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt is reacted with an acid, in other words, the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound is present in the presence of acid and water.
  • the reaction is conducted to produce 2- (4-tetrahydropyranyl) imidazole and / or its acid salt represented by the general formula (4). This process may be referred to as an imidazolation process.
  • R 1 and R 2 in the reaction process formula (1) are alkyl groups having 1 to 8 carbon atoms, and may be alkyl groups having 1 to 4 carbon atoms.
  • R 1 and R 2 include a straight chain alkyl group such as a methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group and n-octyl group, isopropyl group, isobutyl group, sec Examples thereof include branched alkyl groups such as -butyl group and tert-butyl group, and cyclic alkyl groups such as cyclopropyl group, cyclopentyl group and cyclohexyl group.
  • the tetrahydropyran-4-imidate compound represented by the general formula (1) and / or its acid salt is produced, for example, using 4-cyanotetrahydropyran as a starting material as represented by the following reaction process formula (2) Can do.
  • the acid salt of the tetrahydropyran-4-imidate compound can be obtained, for example, by a method in which the reaction represented by the following reaction process formula (2) is carried out in the presence of an acid.
  • Examples of the acid constituting the acid salt of the tetrahydropyran-4-imidate compound include hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, and the like.
  • R 1 has the same meaning as described above.
  • the amount of the 2,2-dialkoxyethylamine compound used in the amidination step is 1 to 2 mol or 1 to 1.5 mol with respect to 1 mol of the tetrahydropyran-4-imidate compound and / or its acid salt. It may be.
  • the amount of 2,2-dialkoxyethylamine compound used in this range it is easy to remove unreacted raw materials and / or by-products from the reaction solution after the reaction while maintaining a high reaction rate. be able to.
  • the tetrahydropyran-4-imidate compound and / or its acid salt used in the amidation step is produced without any purification after the production of 4-cyanotetrahydropyran as a starting material as shown in the reaction process formula (2). It may be introduced into the liquid.
  • the reaction in this step can be performed in the presence of a solvent.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
  • alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol; ketones such as acetone and methyl ethyl ketone; N, N-dimethylformamide, N Amides such as N, N-dimethylacetamide and N-methylpyrrolidone; esters such as ethyl acetate and butyl acetate; urea compounds such as N, N′-dimethylurea; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile and propionitrile; Aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane; Halogenated aliphatic hydrocarbons such as methylene chloride and dichloroethane; Aromatic hydro
  • the amount of the solvent used is appropriately adjusted depending on the homogeneity or stirring ability of the reaction, but may be 1 to 20 mL or 1 to 10 mL with respect to 1 g of the tetrahydropyran-4-imidate compound and / or its acid salt. Good. By making the usage-amount of a solvent into this range, solidification of a reaction liquid can be prevented, maintaining favorable stirring property.
  • the reaction in this step is performed by, for example, mixing a tetrahydropyran-4-imidate compound, a 2,2-dialkoxyethylamine compound, and a solvent to prepare a reaction solution containing them, and advancing the reaction while stirring the reaction solution. Etc. are performed.
  • the reaction temperature at that time may be 10 to 50 ° C. or 10 to 40 ° C., and the reaction pressure is not particularly limited. By making reaction temperature into this range, generation
  • the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt is formed in the reaction solution by the reaction in this step.
  • the produced tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt is one or more selected from, for example, neutralization, extraction, filtration, concentration, distillation, crystallization and column chromatography after completion of the reaction. It can be isolated and / or purified by this method.
  • a solid product containing a tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or an acid salt thereof may be obtained from the reaction solution by the above method.
  • the target tetrahydropyranyl imidazole can be produced with higher yield and higher purity by once obtaining a solid product containing an amidine compound and then subjecting it to the next imidazolation step.
  • the solid product obtained from the reaction solution usually contains a tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt with high purity.
  • the purity of the solid product can be evaluated, for example, by high performance liquid chromatography (HPLC) using an ODS column and based on the area ratio in a chromatogram obtained at a detection wavelength of 220 nm.
  • HPLC high performance liquid chromatography
  • the purity of the product in this specification shall be the same as the area% value of each peak in the chromatogram measured on the above-mentioned conditions.
  • the areas of peaks derived from the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt are 90 area% or more, 92 area% or more, 94 based on the total peak area. Area% or more, 96 area% or more, or 98 area% or more may be sufficient.
  • the step of obtaining the solid product may include separating the amidine compound by crystallization. According to the crystallization, a solid product containing an amidine compound with high purity can be easily obtained. In this case, for example, the crystals of the amidine compound can be precipitated by concentrating the reaction solution and adding a poor solvent for the amidine compound to the resulting concentrate.
  • the solvent used in the crystallization is not limited as long as the target product can be sufficiently recovered while maintaining good stirring properties and filterability, and examples thereof include methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol.
  • ketones such as acetone and methyl ethyl ketone
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone
  • esters such as ethyl acetate and butyl acetate
  • ureas such as N, N′-dimethylurea Compounds
  • Sulfoxides such as dimethyl sulfoxide
  • Nitriles such as acetonitrile and propionitrile
  • Aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane
  • Halogenated aliphatic hydrocarbons such as methylene chloride and dichloroethane
  • aromatic hydrocarbons such as emissions and mesitylene diethyl ether, diisopropy
  • a bisacetal compound represented by the general formula (5) may be generated as a by-product of the amidine formation step.
  • R 2 is the same meaning as R 2 in formula (2).
  • the amidine compound may be obtained as a solid from the reaction solution, and may include the separation of the amidine compound by crystallization during the obtaining step.
  • the ratio of the bisacetal compound in the solid product may be 8% area or less, 6 area% or less, 4 area% or less, 2 area% or less, or 1 area% or less.
  • the content of the bisacetal compound can be easily lowered.
  • the content of the bisacetal compound can be determined by HPLC analysis similar to the purity of the solid product containing the amidine compound. The purity of the product is the same as the area% value of each peak in the chromatogram measured under the above conditions.
  • the acid used in the reaction of this step can be selected from inorganic acids and organic acids.
  • inorganic acids include aqueous solutions of hydrogen halides such as hydrogen chloride and hydrogen bromide; halogen oxo acids such as perchloric acid and chloric acid; sulfuric acids such as sulfuric acid and fluorosulfonic acid; phosphoric acid and hexafluorophosphoric acid Phosphoric acids such as boric acid; boric acids such as boric acid and tetrafluoroboric acid; and nitric acid, chromic acid, hexafluoroantimonic acid, and the like.
  • organic acids examples include sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid, citric acid, and benzoic acid; cresol, catechol, and the like Phenols.
  • sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid
  • carboxylic acids such as acetic acid, formic acid, citric acid, and benzoic acid
  • cresol, catechol, and the like Phenols Among them, hydrochloric acid, sulfuric acid, carboxylic acid or carbonate, or hydrochloric acid can be used. These acids may be used alone or in admixture of two or more.
  • the amount of acid used in the reaction in this step is 0.01 to 1 mol, or 0.01 to 0.1 mol, relative to 1 mol of the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt. It may be 5 moles.
  • the amount of water used in the reaction of this step is 0.01 to 2 mL, or 0.01 to 1 mL with respect to 1 g of the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt. Also good. By making the usage-amount of water into this range, removal of the unreacted raw material and / or by-product from the reaction liquid after the reaction can be further facilitated while maintaining a high reaction rate.
  • the reaction in this step can be performed in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not significantly inhibit the reaction.
  • alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol; ketones such as acetone and methyl ethyl ketone; N, N-dimethylformamide Amides such as N, N-dimethylacetamide and N-methylpyrrolidone; esters such as ethyl acetate and butyl acetate; urea compounds such as N, N′-dimethylurea; sulfoxides such as dimethyl sulfoxide; acetonitrile and propionitrile Nitriles; aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane; halogenated aliphatic hydrocarbons such as methylene chloride and dichloroethane; aromatic hydrocarbons such as benz
  • the amount of the solvent used is appropriately adjusted in consideration of the uniformity of the reaction and the stirring ability.
  • the amount of the solvent used may be, for example, 1 to 30 mL, or 1 to 25 mL with respect to 1 g of the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt.
  • the reaction in this step is, for example, preparing a reaction liquid by mixing a tetrahydropyran-4-dialkoxyethylcarboxyamidine compound and / or its acid salt, acid, water and solvent, and proceeding while stirring the reaction liquid. It is done by the method. When a solvent or an acid is supplied to the reaction solution together with water, it is not necessary to mix water separately.
  • the reaction temperature at that time may be 50 to 90 ° C. or 60 to 80 ° C., and the reaction pressure is not particularly limited. By setting the reaction temperature within this range, generation of by-products due to the reaction can be more effectively suppressed while maintaining a high reaction rate.
  • 2- (4-Tetrahydropyranyl) imidazole and / or its acid salt are formed by the reaction in this step.
  • the produced 2- (4-tetrahydropyranyl) imidazole and / or its acid salt is selected from, for example, neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization and column chromatography after completion of the reaction. It can be isolated and purified by more than one method.
  • 2- (4-tetrahydropyranyl) imidazole and its acid salt obtained by the production method of the present embodiment are useful as intermediates for pharmaceutical synthesis and the like, it is possible to achieve higher purity and simple post-treatment. From this point, it can be purified by crystallization.
  • 2- (4-tetrahydropyranyl) imidazole and / or its acid salt can be obtained as a high-purity white solid.
  • the purity of the resulting 2- (4-tetrahydropyranyl) imidazole and / or its acid salt may be 99.0 area% or more, or 99.9 area% or more.
  • the purity may be 99.99 area% or more. This purity can be determined by HPLC analysis similar to the purity of the solid product containing the amidine compound.
  • 2- (4-tetrahydropyranyl) imidazole and / or its acid salt are obtained in a high yield while undergoing a two-step reaction (amidination step and imidazolation step). Can be obtained. That is, according to the production method of the present embodiment, the yield of 2- (4-tetrahydropyranyl) imidazole and / or its acid salt relative to the imidate compound of the formula (1) can be increased.
  • the yield of 2- (4-tetrahydropyranyl) imidazole and / or its acid salt combined with the two-step process can be, for example, 70% or more, 75% or more, 80% or more, or 90% or more.
  • the tetrahydropyran-4-dialkoxyethylcarboxyamidine compound of the present embodiment has a general formula (3): It is a compound shown by these.
  • the compound may form an acid salt.
  • R 2 represents an alkyl group having 1 to 8 carbon atoms. Two R 2 s may be the same or different, and may be bonded to each other to form a ring.
  • This compound is a novel compound. Such a compound is useful as an intermediate in the production method according to the present embodiment.
  • Tetrahydropyran-4-imidate hydrochloride (20.09 g, 111.8 mmol) and methanol (155 g) were added to a 500 mL glass flask equipped with a stirrer and a thermometer.
  • reaction solution 14.00 g (133.2 mmol) of 2,2-dimethoxyethylamine and 4.6 g of methanol were slowly added, and the reaction solution was stirred at room temperature (20 ° C. to 30 ° C.). The reaction was allowed to proceed for 2 hours.
  • the reaction solution was allowed to stand at room temperature (10 to 20 ° C.) for 16 hours, and then concentrated under reduced pressure.
  • To the concentrate was added 41 g of tert-butyl methyl ether, and the mixture was stirred at room temperature (20-30 ° C.) for 30 minutes.
  • the solution containing the suspension precipitated by recrystallization was filtered under reduced pressure, and the residue was washed with 15 g of tert-butyl methyl ether.
  • the obtained residue was dried under reduced pressure to obtain 21.70 g of white crystals (isolated yield: 76.8%).
  • the obtained white crystals showed the following physical property values and were confirmed to be a novel compound tetrahydropyran-4-dimethoxyethylcarboxyamidine hydrochloride.
  • a glass flask having an internal volume of 3 L equipped with a stirrer, a thermometer and a reflux condenser was charged with 100.0 g (395.7 mmol) of tetrahydropyran-4-dimethoxyethylcarboxyamidine hydrochloride, 1791 g of tetrahydrofuran, and 1 mol / L hydrochloric acid. 100.2 g (100 mmol) was added to prepare a reaction solution, and the reaction was allowed to proceed for 1.5 hours under reflux (60 ° C. to 70 ° C.) while stirring the reaction solution.
  • the reaction solution was allowed to stand at room temperature (10 to 20 ° C.) for 13 hours, and then concentrated under reduced pressure.
  • To the concentrate was added 304 g of toluene, and concentrated under reduced pressure. Furthermore, the same operation was performed twice.
  • the concentrate was cooled and stirred for 1 hour at room temperature (20-30 ° C.).
  • the suspended solution was filtered under reduced pressure, and the residue was washed with 103 g of toluene.
  • the filtrate was dried under reduced pressure to obtain 74.06 g of white crystals (isolated yield: 99.2%).
  • the obtained white crystals showed the following physical properties and were confirmed to be 2- (4-tetrahydropyranyl) imidazole hydrochloride.
  • the yield of 2- (4-tetrahydropyranyl) imidazole hydrochloride relative to the starting material, tetrahydropyran-4-imidate hydrochloride, was 76.1%.
  • the yield of the production method described in paragraph 0475 of Patent Document 2 was 55%, it was confirmed that the yield of the production method of the present application greatly exceeds this.
  • the resulting solution was concentrated under reduced pressure, cooled to room temperature (10 to 20 ° C.), and 150 g of tert-butyl methyl ether was added. The resulting solution was stirred at room temperature (20-30 ° C.) for 30 minutes, and then the solution containing the precipitated suspension was filtered under reduced pressure, and the residue was washed with 100 g of tert-butyl methyl ether. The obtained filtrate was dried under reduced pressure to obtain 90.9 g of white crystals (recovery rate: 90.9%).
  • reaction solution was concentrated under reduced pressure to precipitate product crystals, and the solution was filtered under reduced pressure. The filtrate was dried under reduced pressure to obtain 13.0 g of white crystals (isolated yield: 89.8%).
  • reaction solution was concentrated under reduced pressure to precipitate product crystals, and the solution was filtered under reduced pressure. The filtrate was dried under reduced pressure to obtain 28.2 g of white crystals (isolated yield: 94.4%).
  • the tetrahydropyranyl imidazole hydrochloride obtained from the crude product or white crystals had high purity, but the tetrahydropyranyl imidazole hydrochloride obtained from the crude product containing the bisacetal compound was a trace amount.
  • it is more advantageous to synthesize tetrahydropyranylimidazole hydrochloride via a white crystalline amidine compound with a low content of bisacetal compound because it is recognized as containing impurities and is colored. it is conceivable that.
  • a glass flask having an internal volume of 1 L equipped with a stirrer, a thermometer, a gas introduction tube and a reflux condenser was charged with 100.06 g (900.3 mmol) of 4-cyanotetrahydropyran, 28.83 g (899.8 mmol) of methanol and chloride. 327 g of methylene was added, and the reaction was carried out at 0 to 7 ° C. for 7 hours with stirring while blowing hydrogen chloride gas.
  • the present invention relates to a process for producing 2- (4-tetrahydropyranyl) imidazole and / or its acid salt.
  • 2- (4-Tetrahydropyranyl) imidazole and its acid salt are useful compounds as synthetic raw materials and intermediates for pharmaceuticals.
  • 2- (4-tetrahydropyranyl) imidazole and its acid salt are compounds that can be expected to be useful, for example, as pharmaceuticals, liquid crystal compound intermediates, materials for organic electroluminescence devices, metal surface treatment agents, and the like. is there.
  • 2- (4-tetrahydropyranyl) imidazole is a new imidazole compound that has never been reported before. Can be expected to express the function.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention concerne un procédé de production de 2-(4-tétrahydropyranyl)imidazole et/ou d'un sel acide de celui-ci, qui comprend une étape de production de 2-(4-tétrahydropyranyl)imidazole représenté par la formule générale (4) et/ou d'un sel acide de celui-ci à partir d'un composé de tétrahydropyran-4-dialcoxyéthylcarboxyamidine représenté par la formule générale (3) (R2 représentant indépendamment un groupe alkyle ayant 1 à 8 atomes de carbone, les deux R2 pouvant être identiques ou différents l'un de l'autre et pouvant être liés l'un à l'autre pour former un cycle) ou d'un sel acide de celui-ci en la présence d'un acide et d'eau.
PCT/JP2014/060416 2013-04-11 2014-04-10 Procédé de production de 2-(4-tétrahydropyranyl)imidazole et/ou d'un sel acide de celui-ci Ceased WO2014168211A1 (fr)

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JP2015511300A JPWO2014168211A1 (ja) 2013-04-11 2014-04-10 ２−（４−テトラヒドロピラニル）イミダゾール及び／又はその酸塩の製造方法

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057114A1 (fr) * 1998-05-04 1999-11-11 Fujisawa Pharmaceutical Co., Ltd. Derives de carboxamide heterocycliques utilisees comme inhibiteurs de la production de monoxyde d'azote
WO2008021849A2 (fr) * 2006-08-09 2008-02-21 Smithkline Beecham Corporation Nouveaux composés comme antagonistes ou agonistes inverses à des récepteurs d'opioïdes
WO2008072779A1 (fr) * 2006-12-13 2008-06-19 Aska Pharmaceutical Co., Ltd. Dérivé de quinoxaline
WO2012178015A2 (fr) * 2011-06-24 2012-12-27 Zenobia Therapeutics, Inc. Inhibiteurs de lrrk2

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057114A1 (fr) * 1998-05-04 1999-11-11 Fujisawa Pharmaceutical Co., Ltd. Derives de carboxamide heterocycliques utilisees comme inhibiteurs de la production de monoxyde d'azote
WO2008021849A2 (fr) * 2006-08-09 2008-02-21 Smithkline Beecham Corporation Nouveaux composés comme antagonistes ou agonistes inverses à des récepteurs d'opioïdes
WO2008072779A1 (fr) * 2006-12-13 2008-06-19 Aska Pharmaceutical Co., Ltd. Dérivé de quinoxaline
WO2012178015A2 (fr) * 2011-06-24 2012-12-27 Zenobia Therapeutics, Inc. Inhibiteurs de lrrk2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WHITLOCK,G.A. ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, 2008, pages 2930 - 2934 *

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