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WO1999043678A1 - Medicaments et prophylaxie contre la maladie de parkinson - Google Patents

Medicaments et prophylaxie contre la maladie de parkinson Download PDF

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Publication number
WO1999043678A1
WO1999043678A1 PCT/JP1999/000828 JP9900828W WO9943678A1 WO 1999043678 A1 WO1999043678 A1 WO 1999043678A1 JP 9900828 W JP9900828 W JP 9900828W WO 9943678 A1 WO9943678 A1 WO 9943678A1
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WIPO (PCT)
Prior art keywords
group
compound
substituted
triazolo
pyrimidine
Prior art date
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PCT/JP1999/000828
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English (en)
Japanese (ja)
Inventor
Hiroshi Tsumuki
Akiko Nakamura
Shizuo Shiozaki
Michio Ichimura
Yoshihisa Kuwana
Junichi Shimada
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU26392/99A priority Critical patent/AU2639299A/en
Publication of WO1999043678A1 publication Critical patent/WO1999043678A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention relates to a medicament having an antagonistic action on adenosine A2A receptor and useful for, for example, treating and / or preventing Parkinson's disease.
  • the present invention also relates to a novel [1,2,4] triazolo [1,5-a] pyrimidine derivative or salt useful as an active ingredient of the above-mentioned medicament.
  • Adenosine, adenosine A 2A receptor via known to attenuate the effects of the neurotransmitter [® sip Bien 'journal O Bed & Famako port G. (Eur. J. Pharmacol.), 168, 285 (1989)].
  • substances having an antagonistic action against the adenosine A 2A receptor each species diseases resulting from hyperactivity of adenosine A 2A receptors, such as Parkinson's disease, dementia, or as therapeutic and Z or pre Bozai for such depression Is expected to be useful.
  • [1,2,4] triazolo [l, 5-a] pyrimidine derivatives compounds having an inhibitory effect on atherosclerotic vascular hypertrophy (JP-A-4-99775 and JP-A-3-118383) Gazette), a compound having a vasodilatory effect, a hypotensive effect, a platelet aggregation inhibitory effect, and a cholesterol lowering effect (JP-A-57-35592), and a compound having an antitumor effect (JP-A-55-51089) ) And compounds useful as therapeutic agents for cardiovascular diseases, especially cerebral cardiovascular diseases (JP-A-2-212488).
  • An object of the present invention is to have a strong adenosine A 2A receptor antagonistic effect, and to be effective in treating and / or preventing Z- or prophylaxis of a disease derived from hyperactivity of adenosine A 2A receptor, preferably Parkinson's disease [1, 2, [4] It is an object of the present invention to provide a medicament comprising a triazolo [1,5-a] pyrimidine derivative or a physiologically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide a novel [1,2,4] triazolo [l, 5-a] pyrimidine derivative or a salt thereof having the above characteristics.
  • [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the following general formula is a powerful adenosine derivative. It has an A2A receptor antagonistic activity and has been found to be useful as an active ingredient of a medicament for treating and / or preventing Parkinson's disease.
  • the present invention has been completed based on the above findings.
  • Upsilon represents an oxygen atom, (wherein, R 'represents a hydrogen atom or a lower alkyl group) a sulfur atom, NR 1, or a single bond; eta represents an integer of 0 to 5; X 1 , X 2 , and X 3 Each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a substituted or unsubstituted arylo group, substituted or unsubstituted Which represents a substituted or unsubstituted heterocyclic group, a hydroxyl group or a nitro group, or a group represented by the following formula:
  • Z is an oxygen atom or a sulfur atom
  • Y is an oxygen atom, a sulfur atom, one NR 1 — (wherein, R 1 is a hydrogen atom or Represents a lower alkyl group) or a single bond
  • n is an integer of 0 to 5
  • X 1 , X 2 and X 3 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group Group, lower alkylthio group, amino group, mono- or di-lower alkylamino group, lower alkanoyl group, substituted or unsubstituted arylo group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic group, hydroxyl group, or A nitro group (except when X 1 , X 2 , and X 3 are both hydrogen atoms); 111 is an integer from 1 to 5
  • a lower alkyl group or a substituent containing a lower alkyl moiety for example, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoyl group, a hydroxy lower alkyl group, or an amino lower alkyl group; And the like.
  • the lower alkyl moiety in, for example, may be straight-chain or branched, and includes, for example, an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Can be used.
  • lower alkyl group use methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, or tert-butyl group, pentyl group, neopentyl group, hexyl group, etc.
  • substituent having a lower alkyl moiety it is preferable that these lower alkyl groups constitute the alkyl moiety.
  • Examples of the “lower alkoxy group” include, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, and a tert-butoxy group.
  • Examples of the "alkylthio group” include a methylthio group, an ethylthio group, and a propylthio group.
  • Examples of the "mono-lower alkylamino group” include a methylamino group, an ethylamino group, a propylamino group, and an n-amino group.
  • Examples of the “di-lower alkylamino group” include a dimethylamino group, a getylamino group, and an ethylmethylamino group.
  • Examples of the "lower alkanoyl group” include, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, bivaloyl group, hexanoyl group, and the like.
  • Examples of the "aroyl group” Examples thereof include a benzoyl group and a naphthoyl group. However, these substituents are not limited to the above specific examples.
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the two alkyl groups in the di-lower alkylamino group may be the same or different.
  • the substitution position of the hydroxyl group or amino group present in each group is not particularly limited.
  • the number of hydroxyl groups or amino groups is not particularly limited, but is preferably one.
  • an aryl group in an aryl group or a substituent containing an aryl group for example, an aryl group
  • an aryl group for example, a 5- to 14-membered monocyclic, bicyclic, or tricyclic aryl group is used.
  • a phenyl group, a naphthyl group, an indenyl group, an anthryl group, and the like can be used.
  • substituent containing an aryl group it is preferable that these aryl groups constitute the aryl group.
  • heterocyclic group a 5- to 14-membered heterocyclic group containing one or more hetero atoms (for example, an oxygen atom, a nitrogen atom, a sulfur atom, etc.) as a ring-constituting atom can be used.
  • heterocyclic group for example, a monocyclic, bicyclic, or tricyclic heterocyclic group can be used, and in addition to an aromatic heterocyclic group, a partially saturated heterocyclic group can also be used. .
  • a substituent when referred to as “substituted or unsubstituted”, the substituent is further substituted with one or more, preferably one to three functional groups. It means that it may be substituted. When the substituent has two or more functional groups, those functional groups may be the same or different. Examples of such a functional group include a lower alkyl group, a halogenated lower alkyl group (such as a chloromethyl group and a trifluoromethyl group), a hydroxy lower alkyl group (such as a hydroxymethyl group), a lower alkoxy group, and a lower alkoxy group.
  • a functional group include a lower alkyl group, a halogenated lower alkyl group (such as a chloromethyl group and a trifluoromethyl group), a hydroxy lower alkyl group (such as a hydroxymethyl group), a lower alkoxy group, and a lower alkoxy group.
  • these functional groups are
  • Z represents an oxygen atom or a sulfur atom
  • Y represents an oxygen atom, a sulfur atom, —NR 1 — (wherein R 1 represents a hydrogen atom or a lower alkyl group), or a single bond Is shown.
  • R 1 represents a hydrogen atom or a lower alkyl group
  • Y represents a single bond, it means that [1,2,4] triazolo [l, 5-a] pyrimidine and a group represented by one (CH 2 ) listen— are directly bonded.
  • N is 0 or an integer from 5 to 5, but when n is 0, it means that the benzene ring substituted by X 1 , X 2 , and X 3 is directly bonded to Y.
  • the benzene ring substituted by X 1 , X 2 , and X 3 is [1,2,4] triazolo [l, 5-a] It means that it is directly bonded to pyrimidine
  • the substitution positions of X 1 , X 2 , and X 3 are not particularly limited, and each can be substituted at an arbitrary position.
  • m represents an integer of 0 to 5
  • Q represents an oxygen atom, a sulfur atom, -NH-, or a methylene group. It means that the ring is a five-membered ring.
  • the group represented by 1 (CH 2 ) k — R 2 is directly bonded to any of the ring-constituting atoms of the ring containing Q (however, [1, 2, 4] triazolo [1, 5-a] pyrimidine skeleton
  • k represents an integer of 0 to 5.
  • k it means that a ring-constituting atom of the ring containing Q (excluding the above-mentioned nitrogen atom) is directly bonded to R 2 .
  • it is preferable that a group represented by one (CH 2 ) k — is bonded to Q.
  • physiologically acceptable salt of the compound represented by the formula (I) examples include a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, an acid addition salt and the like.
  • the metal salt examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and the like.
  • the ammonium salt examples include ammonium and tetra Salts such as methylammonium can be mentioned.
  • Physiologically acceptable organic amine addition salts include, for example, the addition of bases such as morpholine and piperidine.
  • physiologically acceptable amino acid addition salts include, for example, addition salts of amino acids such as lysine, glycine, and phenylalanine.
  • Physiologically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate and phosphate, and organic acids such as acetate, maleate, fumarate, tartrate, citrate and the like. Salts may be mentioned.
  • the compound represented by the above formula (I) can be produced, for example, according to the method disclosed in the scheme shown below.
  • the compound (I-II) shown in the above scheme 1 can be produced according to the above steps 1 and 2.
  • the compound (IV) can be obtained by reacting the compound (II) with 2 to 10 equivalents of the compound (III) in an inert solvent in the presence of 1 to 10 equivalents of the base (Step 1).
  • the reaction is completed, for example, at a temperature of 0 ° C to 200 ° C, preferably at room temperature for about 10 minutes to 50 hours.
  • the type of the solvent inert to the reaction is not particularly limited, but examples thereof include dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methizoletetrahydrofuran, and dioxane.
  • the base may be sodium carbonate, carbon dioxide, hydrogen hydride, hydrogen hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropyl pyrethylamine, or 1, 8- Diazabicyclo [4,5,0] pande-7-ene (DBU) or the like can be used, and preferably, sodium hydride, potassium carbonate, or DBU can be used.
  • DBU 1, 8- Diazabicyclo [4,5,0] pande-7-ene
  • the compound (IV) is reacted with 1 equivalent to a large excess, preferably a large excess of ammonia saturated with a suitable solvent to obtain the compound (IB) (Step 2).
  • a suitable solvent water, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethyl acetate, or any mixture thereof can be used.
  • ethanol or acetonitrile can be used. This reaction is completed in about 10 minutes to 50 hours at a temperature of, for example, 0 ° C to 100 ° C.
  • the compound (IC) can be obtained by reacting with (V) (Step 3). This reaction is carried out without solvent or in the presence of 1 to 10 equivalents of a base as necessary.
  • the reaction can be performed in an active solvent, for example, at a temperature of 0 ° C. to 200 ° C. in about 10 minutes to 50 hours.
  • the type of the inert solvent is not particularly limited, but includes, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetyl ether, benzene, tonolene, Xylene, ethyl acetate, acetonitrinole, pyridine, dichloromethane, dichloroethane, ethanolanol, methanolol, and phenol.
  • phenol, butanol, or any mixture thereof can be used.
  • dimethylformamide, tetrahydrofuran, or the like can be used.
  • sodium carbonate, carbonated lime, sodium hydride, hydrogenated hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, or DBU can be used.
  • hydrogenated sodium or DBU can be used.
  • Ar represents a phenyl group substituted with X ′, X 2 , and X 3 , and n and Z, and ⁇ ′, ⁇ , and X 3 have the same meanings as defined above.
  • Compound (VI) and a substantially equivalent amount of compound (VII) are mixed in an acidic solvent such as formic acid, acetic acid, or propionic acid, preferably in acetic acid, for example, at a temperature from room temperature to reflux, preferably under reflux.
  • the compound (VIII) can be obtained by allowing the reaction to proceed for 10 minutes to 50 hours (step 4). Then, compound (VIII) is converted to an oxysalt Compound (IX) can be obtained by treating with a chlorinating agent such as phosphorus chloride or thionyl chloride, preferably phosphorus oxychloride (Step 5).
  • This reaction can be carried out without solvent or in an inert solvent, and is completed using 15 equivalents of phosphorus oxychloride, for example, at a temperature from room temperature to 100 ° C in about 10 minutes to 24 hours.
  • the inert solvent include tetrahydrofuran, dioxane, dichloromethane, chloroform, benzene, tonolen, xylene, ethynole acetate, triethynoleamine, pyridine, NN-dimethylaniline, and any mixture thereof. Etc. can be used.
  • the compound (IX) is reacted with 1 equivalent to a large excess, preferably a large excess of ammonia saturated with an appropriate solvent to obtain a compound (ID) (Step 6).
  • This reaction is completed in about 10 minutes to 50 hours at a temperature of, for example, 0 ° C to 100 ° C.
  • the reaction solvent include water, methanol, ethanol, propanol, isoprono, and the like. Nore, butanol, acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethyl acetate, etc., preferably ethanol, acetonitrile, or any mixture thereof can be used. .
  • Hal represents a halogen atom
  • k, and Z are as defined above.
  • the compound (I-E) can be obtained by reacting the compound (IF) with 1 to 20 equivalents of the compound (X) in a solvent-free or inert solvent (Step 7).
  • the reaction can be carried out in the presence of 15 equivalents of a base depending on the case. For example, the reaction is completed in about 10 minutes to 50 hours at 0 ° C and 150 ° C.
  • the type of the inert solvent is not particularly limited.
  • Examples of the base include cesium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium hydride, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, disopropylethylamine, and DBU.
  • triethylamine or the like can be used.
  • the compound (I-G) can be obtained by reacting the compound (I-B1) with 1 equivalent to a large excess of the compound (XI). This reaction can be performed, for example, in a solvent-free or inert solvent in the presence of 1 to 5 equivalents of a base, if necessary, at a temperature from room temperature to 200 ° C, for about 10 minutes to 50 hours.
  • the type of the inert solvent is not particularly limited, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dixan, getinole Athenole, benzene, tonole, xylene, Examples include ethyl sulphate, acetate nitrinole, pyridine, ethanol, methanol, propanol, and butanol.
  • dimethylformamide, dimethyl sulfoxide, or any mixture thereof can be used.
  • Examples of the base include sodium methoxide, sodium methoxide, carbon dioxide lime, sodium hydride, hydrogen hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, and DBU. And preferably hydrogenated sodium.
  • the compound represented by the formula (I) can also be produced, for example, by the method disclosed in the scheme shown below.
  • Compound (I) can be produced according to Step 9, Step 10 and Step 11 described above. That is, the compound (II) and 1 to 5 equivalents of 3,4-dimethoxybenzylamine (XII) are usually used without solvent or in a solvent inert to the reaction, usually Ot: to 100 ° C, preferably 0 ° C.
  • Compound (XIII) can be obtained by reacting at room temperature for 10 minutes to 24 hours (step 9). In this reaction, in some cases, 0.1 to 5 equivalents, preferably 1 equivalent, of a base may be added. Examples of the base to be added include triethylamine, diisopropylethyl / reamine, DBU, N, N-dimethyl.
  • the type of solvent inert to the reaction is not particularly limited.Examples include ethanol, methanol, propanol, butanol, water, dimethyl honolem amide, dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.
  • Tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, getyl ether, benzene, tonolen, xylene, ethynole acetate, acetonitrile, pyridine, dichloromethane, dichloroethane, etc., and any mixture thereof can be used.
  • ethanol or dimethylformamide can be used.
  • the compound (XIII) and 1 equivalent to a large excess, preferably 2 to 4 equivalents of a compound (XIV) represented by RH (wherein R is as defined above) are mixed with a solvent-free or
  • the compound (XV) can be obtained by reacting in a solvent inert to the reaction, usually at room temperature to 150 ° C. for 10 minutes to 24 hours (Step 10). In some cases, this reaction is carried out by adding 0.5 to 10 equivalents, preferably 2 to 4 equivalents of a base.
  • Examples of the base to be added include triethylamine, diisopropylethylamine, DBU, N, N-dimethylaniline, pyridine, quinoline, potassium carbonate, sodium carbonate, sodium bicarbonate, hydroxylated sodium, sodium hydroxide, potassium tert-butoxide, butyllithium, sodium hydride, potassium hydride, etc. And preferably DBU, potassium carbonate and sodium hydride.
  • the type of the solvent inert to the reaction is not particularly limited.
  • examples include ethanol, methanol, propanol, butanol, water, dimethyl honolemamide, dimethyl acetate, N-methylpyrrolidone, dimethyl sulfoxide, and tetrahydrofura.
  • 2-methinolete trahydrofuran dioxane, ethynoleatenole, benzene, toluene, xylene, ethynole acetate, acetonitrile, pyridine, dichloromethane, dichloroethane, etc., and any mixture thereof can be used, preferably Is ethanol, dimethyl sulfoxide or dimethylformamide, etc. Can be used.
  • the compound (I) is treated by treating the compound (XV) with 1 equivalent to a large excess of a strong acid in a solvent or in a suitable solvent, or treating with 1 equivalent to a large excess of a suitable oxidizing agent.
  • a strong acid examples include trifluoromethanesulfonic acid, naphion (Nafion®), trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and preferably trifluoromethanesulfonic acid, nafion, etc. 6 equivalents can be used.
  • the reaction is usually carried out at room temperature to 100 ° C, preferably at room temperature to 60 ° C, and is completed in about 10 minutes to 24 hours. At this time, it is advisable to add 1 equivalent to a large excess of anisol, dimethoxybenzene or trimethoxybenzene.
  • Suitable solvents to be used include acetic acid, trifluoroacetic acid, trifluoroacetic acid, dichloroacetic acid, methanesnolephonic acid, ethanol, methanol, propanol, butanol, benzene, tonolene, xylene, chlorophonolem, dichloromethane, dichloroethane, carbon tetrachloride, and tetrachloromethane. Examples thereof include drofuran, getyl ether, dioxane, ethyl acetate, ethyl methyl ketone, and dimethylformamide. An arbitrary mixture thereof can be used, and trifluoroacetic acid can be preferably used.
  • examples of the oxidizing agent to be used include 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Kuguchi Rael and the like.
  • the reaction can be usually performed at 0 ° C to 100 ° C, preferably at room temperature, and is completed in about 10 minutes to 24 hours.
  • Suitable solvents used are benzene, toluene, xylene, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, tetrahydrofuran, getyl ether, dioxane, ethyl acetate, ethynole methyl ketone, and dimethylform.
  • Amide, acetate nitrile and the like can be mentioned, and an arbitrary mixture thereof can be used.
  • Step 9 The compound (XIII) obtained in Step 9 is subjected to the same treatment as in Step 11 to lead to the compound (I-H) (Step 12), and the compound (I-H) is used in Step 10
  • Compound (I) can be obtained by performing the same operation as in (Step 13).
  • the intermediates and target compounds in each of the above production methods are separated and purified by methods commonly used in the field of synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of mouth chromatography, etc. Can be isolated and purified. Further, the production intermediate can be subjected to the next reaction without purification.
  • a salt of the compound represented by the formula (I) is produced, if the final product is obtained in the form of a salt in the above reaction step, it may be purified as it is, and the final product may be converted into a free form.
  • the compound When the compound is obtained as a compound, the compound may be dissolved or suspended in an appropriate solvent, an acid or a base may be added to form a salt, and then the desired product may be isolated and purified. Further, the final product obtained in the form of a salt may be converted into a compound in a free form and then further converted into a target salt.
  • Z is an oxygen atom or a sulfur atom
  • Y is an oxygen atom, a sulfur atom, NR 1 (wherein, R 1 is a hydrogen atom or a lower alkyl group.
  • N) is an integer of 0 to 5;
  • X 1 , X 2 , and X 3 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, An amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a substituted or unsubstituted arylo group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group ( Provided that m is an integer of 1 to 5 except that X 1 , X 2 , and X 3 are simultaneously hydrogen atoms.
  • Ri is located at 5 integer from 0; Q is an oxygen atom, a sulfur atom, - NH -, or is methylene group; R 2 Gahi Dorokishi lower alkyl group, Amino lower alkyl group, a lower alkoxy group, a lower An alkylthio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or —CO—R 3 (wherein R 3 is a lower alkyl group, a lower alkoxy group, A lower alkylthio group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group (however, when k is 0, R 2 is not an unsubstituted aryl group) Is a new compound.
  • novel compounds provided by the present invention is not limited to the use as an active ingredient of the medicament of the present invention, but may be used as an active ingredient of another medicament or an intermediate for producing another compound. Can be used. It goes without saying that the scope of the present invention relating to the novel compound includes such other uses.
  • any hydrates or solvates as well as any salts such as the above-mentioned physiologically acceptable salts are also included in the scope of the present invention.
  • the type of the solvent that forms the solvate is not particularly limited, and examples thereof include ethanol, tetrahydrofuran, and dioxane.
  • the present invention also includes pure optical isomers, pure isomers such as diastereoisomers, arbitrary mixtures of isomers, and racemic isomers. Is included in the range.
  • the medicament of the present invention comprises a [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the formula (I) and a physiologically acceptable salt thereof, and a hydrate and a hydrate thereof.
  • a substance selected from the group consisting of a solvate is characterized by containing as an active ingredient, various diseases resulting from hyperactivity of adenosine emissions a 2A receptor, for example, Parkinson's disease, senile dementia, such as depression It can be used for treatment and / or prevention.
  • a particularly preferred subject of the medicament of the present invention is Parkinson's disease.
  • the above-mentioned substance which is an active ingredient may be administered as it is, but generally, a pharmaceutical composition comprising the above-mentioned substance which is an active ingredient and one or more pharmaceutical additives It is desirable to administer in the form of Such a pharmaceutical composition is known or commonly used in the field of pharmaceuticals. It can be manufactured according to the method.
  • the medicament of the present invention in the form of a pharmaceutical composition may contain one or more active ingredients of another medicament.
  • the medicament of the present invention is applicable to mammals including human.
  • the administration route of the medicament of the present invention is not particularly limited, and the most effective administration route for treatment and / or prevention can be appropriately selected from oral or parenteral administration.
  • Oral or parenteral such as oral, respiratory, rectal, subcutaneous, intramuscular and intravenous.
  • preparations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, and suspensions.
  • Preparations suitable for parenteral administration examples thereof include injections, drops, inhalants, sprays, suppositories, transdermal absorbers, transmucosal absorbers, and the like.
  • liquid preparations suitable for oral administration for example, sugars such as water, sucrose, sorbitol, fructose; glycols such as polyethylene glycol and propylene d'alicol; Preservatives such as p-hydroxybenzoic acid esters; and additives for pharmaceutical preparations such as flavors such as strobe leaf flavor and peppermint.
  • sugars such as water, sucrose, sorbitol, fructose
  • glycols such as polyethylene glycol and propylene d'alicol
  • Preservatives such as p-hydroxybenzoic acid esters
  • additives for pharmaceutical preparations such as flavors such as strobe leaf flavor and peppermint.
  • excipients such as lactose, glucose, sucrose, and mannite
  • disintegrants such as starch and sodium alginate
  • magnesium stearate
  • binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin
  • surfactants such as fatty acid esters
  • plasticizers such as glycerin.
  • preparations suitable for parenteral administration can be prepared preferably using an aqueous medium isotonic with human blood.
  • the propellant is prepared as a solution, suspension, or dispersion using an aqueous medium selected from a salt solution, a glucose solution, or a mixture of a salt water and a glucose solution with an appropriate auxiliary according to a conventional method. can do.
  • Suppositories for enteral administration can be prepared using carriers such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids.
  • the propellant is It can be prepared using a carrier that does not irritate the oral cavity and respiratory tract mucosa of humans and that can promote absorption by dispersing the above-mentioned substance as an active ingredient as fine particles.
  • a carrier for example, lactose or glycerin can be used.
  • it can be prepared as a preparation in the form of an aerosol or a dry powder.
  • parenteral preparations for example, one or more selected from diluents, fragrances, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Pharmaceutical additives can be used.
  • the dose and frequency of administration of the medicament of the present invention are not particularly limited, and the kind of the substance as the active ingredient, the administration route, the purpose of treatment and prevention or prevention, the age and weight of the patient, the nature and severity of symptoms It can be appropriately selected according to various conditions such as. For example, it is preferable to administer 1 to 50 mgZkg per adult daily in 3 to 4 divided doses.
  • Example 13 7-Amino-2- (2-furyl) -5- (4-fuyruphenoxy) [1,2,4] triazolo [1,5-a] Pyrimidine [Compound (13)]
  • Example 6 800 mg (2.21 mmol) of the compound (6) obtained in Example 6 was dissolved in 5 ml of dimethyl sulfoxide (DMS0), and 1.07 ml (6.65 mmol) of N-phenylbiperazine and 0.3 ml (2.21 bandol) of DBU were added. And stirred at 140 ° C for 6 hours. The reaction mixture was returned to room temperature, and extracted by adding chloroform and 1N aqueous sodium hydroxide solution.
  • DMS0 dimethyl sulfoxide
  • the title compound (20) was obtained as a brown solid (yield: 73%) in the same manner as in Example 19 using N-piperonylbiperazine.
  • Example 24 7-Amino-2- (2-furyl) -5- [4- (2-methoxethyl) piperazinyl] [1,2,4] triazolo [1, 5-a] pyrimidine [compound (24)]
  • Example 26 (Example): 7-amino-2- (2-furyl) -5- [4- (tert-butoxycarbonyl) piperazinyl] [1,2,4] triazolo [1 , 5-a] Pyrimidine [Compound (26)]
  • Example 30 The same operation as in Example 30 using 800 mg (2.08 mmol) of the compound (29) obtained in Example 29, 23 g (5.29 mmol) of 1- (3-chlorophenyl) piperazine 'hydrochloride, and 1.15 ml (8.32 mmol) of DBU By this, 673 mg (yield: 59%) of the title compound (31) was obtained as a cream-colored powder.
  • Example 30 Perform the same operation as in Example 30 using 800 mg (2.08 ol) of compound (29) obtained in Example 29, 1.23 g (6.24 mmol) of tri (2-chlorophenyl) piperazine, and 1.0 ml (7.30 mmol) of DBU. Thereby, 732 mg (yield: 64%) of the title compound (32) was obtained.
  • Example 40 (Reference example): 7- (3,4-Dimethoxybenzylamino) -2- (2-furinole) -5- (1-hexamethyleneimino) [1,2,4] triazolo [1,5-a] pyrimidine [compound (40)] hexamethyleneimine 0.54 ml (4.83 mmol) and the compound obtained in Example 29 (29) 620 mg (1.61 mmol) The title compound was obtained by performing the same operation as in Example 33 using
  • Example 33 The same procedure as in Example 33 was carried out using 800 mg (2.07 ol) of the compound (29) obtained in Example 29 and 1.09 ml (6.47 mmol) of 3,4-dimethoxyphenethylamine to give the title compound (45). 529 mg (yield: 48%) were obtained as a yellow powder.
  • Example 46 Example 47 (Example): 7-amino-5- [4- (4-chlorophenyl) piperazinyl] -2- (2-furyl) [1,2,4] Triazolo [1,5-a] pyrimidine [Compound (46)] 620 mg (1.14 mmol) of the compound (30) obtained in Example 30 was dissolved in 10 ml of trifluoroacetic acid, 0.5 ml of anisol and 1.2 g of naphion were added, and the mixture was heated under reflux for 1.5 hours.
  • Example 46 The same operation as in Example 46 was carried out using 650 mg (1.20 ol) of the compound (31) obtained in Example 31 to obtain 118 mg (yield: 25%) of the title compound (47) as a white powder. .
  • Example 46 The same operation as in Example 46 was carried out using 700 mg (1.28 mmol) of the compound (32) obtained in Example 32 to obtain 271 mg (yield: 53%) of the title compound (48) as a yellow powder.
  • Example 46 The same operation as in Example 46 was carried out using 574 mg (1.06 mmol) of the compound (33) obtained in Example 33 to obtain 188 mg (yield: 45%) of the title compound (49) as a white powder.
  • Example 46 The same operation as in Example 46 was carried out using 620 mg (1.17 mmol) of the compound (34) obtained in Example 34 to obtain 193 mg (yield: 44%) of the title compound (50) as a yellow powder.
  • Example 46 The same operation as in Example 46 was carried out using 710 mg (1.91 mmol) of the compound (35) obtained in Example 35. This gave 180 mg (yield: 25%) of the title compound (51) as a white powder.
  • Example 46 The same operation as in Example 46 was carried out using 600 mg (1.19 mmol) of the compound (36) obtained in Example 36 to obtain 196 mg (yield: 47%) of the title compound (52) as a white powder.
  • Example 46 The same operation as in Example 46 was carried out using 377 mg (0.73 ol) of the compound (37) obtained in Example 37 to obtain 300 mg (yield: 56%) of the title compound (53) as a pale brown powder. .
  • Example 46 The same operation as in Example 46 was carried out using 450 mg (0.84 ol) of the compound (38) obtained in Example 38 to obtain 157 mg (yield: 49%) of the title compound (54) as a yellow powder.
  • Example 46 The same operation as in Example 46 was carried out using 700 mg (1.61 mmol) of the compound (39) obtained in Example 39 to obtain 399 mg (yield: 87%) of the title compound (55) as a pale yellow powder. .
  • Example 40 500 mg (1.12 mmol) of the compound (40) obtained in Example 40 was dissolved in 10 ml of trifluoroacetic acid, 0.5 ml of anisol and 1.5 g of naphion were added, and the mixture was heated under reflux for 1.5 hours. The reaction was returned to room temperature, the naphthion was filtered off, and the naphthion was thoroughly washed with a methylamine-methanol solution and then with methanol. After the filtrate and the washings were distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: 20% hexane-chloroform).
  • Example 46 The same operation as in Example 46 was carried out using 650 mg (1.24 ramol) of the compound (41) obtained in Example 41 to obtain 351 mg (yield: 75%) of the title compound (57) as a yellow powder.
  • Example 46 The same operation as in Example 46 was carried out using 600 mg (1.31 mmol) of the compound (42) obtained in Example 42 to obtain 210 mg (yield: 52%) of the title compound (58) as a white powder.
  • Example 56 The same operation as in Example 56 was carried out using 580 mg (1.23 mmol) of the compound (43) obtained in Example 43 to obtain 211 mg (yield: 46%) of the title compound (59) as a white powder.
  • Example 46 The same operation as in Example 46 was carried out using 520 rag (1.07 mmol) of the compound (44) obtained in Example 44 to obtain 280 mg (yield: 78%) of the title compound (60) as a brown powder.
  • Example 56 The same operation as in Example 56 was carried out using 500 mg (0.94 mmol) of the compound (45) obtained in Example 45 to obtain 193 mg (yield: 47%) of the title compound (61) as a brown powder.
  • Test Example 1 Adenosine receptor antagonism (Adenosine A 2A receptor binding test)
  • the final precipitate was added to a 50 mM Tris'HCl buffer [10 mM magnesium chloride, adenosine deaminase 0.02 unit tissue mg (Sigma) to a tissue concentration of 5 mM (wet weight) Zml. ) was added to the suspension.
  • CGS 21680 [Adenosine A 2A receptor agonist: 1--2- [P- (2-carboxyethyl) phenylamino]]-5 '-(N-ethylca Levoxamide) Adenosine: 40 Curie / mmol; manufactured by New England Nuclear; The Giannareo lab Pharmacol 'and J. Pharmacol. Exp. Ther., 251, 888 (1989)] 50 ml (final concentration 4.0 nM) and 50 ⁇ l of the test compound suspension were added.
  • the mixture was allowed to stand at 25 ° C for 120 minutes, filtered through a glass fiber filter (GF / C; manufactured by Whatman) with a rapid suction filter, and immediately cooled with 5 ml of ice-cold 50 mM Tris'HCl buffer. Washed three times.
  • the glass fiber filter paper was transferred to a vial, a scintillator (EX-II; manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the radioactivity was measured with a liquid scintillation counter (manufactured by Packard).
  • Inhibition rate [11 (the amount of binding in the presence of the test compound-the amount of non-specific binding) Z (total amount of binding-the amount of non-specific binding)] x ioo in the presence drug; 3 H-CGS 21680 is a bond amount of radioactivity in; non-specific binding is 100 mM cyclopentyladenosine; be 3 H-CGS 21680 binding radioactivity in the presence (CPA Sigma Co.) Is the amount of 3 ⁇ 4-CGS 21680 bound radioactivity in the presence of various concentrations of the test compound]. The results are shown in Table 2.
  • All of the compounds included in the formula (I) have potent adenosine A2A receptor antagonism, and the medicament of the present invention is useful for treating Parkinson's disease derived from hyperactivity of adenosine A2A receptor, Or it was shown to be effective for prevention.
  • Test Example 2 Effect on CGS 21680-induced catalepsy
  • Parkinson's disease is a motor dysfunction based on degenerative 'cell death of the nigrostriatal dopamine nerve.
  • Intraventricular administration of CGS 21680 an adenosine A 2A receptor agonist GABAergic inhibitory synaptic transmission in the striatum medium sized spiny neurons is directly inhibited via the adenosine A 2A receptor [Journal of Ob 'Neuroscience (J. Neurosci. ), 16, 605 (1996)].
  • This result indicates that adenosine A 2A receptor functions to promote GABAergic nerve output from the striatum to the globus pallidum, and that catalepsy is induced by administration of CGS 21680. It suggests.
  • the experiment was conducted using 10 5-week-old male ddY mice (body weight: 22 to 25 g, Japan Sic) per group.
  • the test compound was used by suspending it in distilled water (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.3% Tween80 [polyoxylene (20) sorbitan monooleate].
  • a suspension containing the test compound or a solution containing no test compound [distilled water containing 0.3% Tween80: control] was orally administered 30 minutes before the injection of CGS 21680 into the ventricle (10 mg / kg). , 0.1 ml per 10 g of mouse weight).
  • the mice were hung on both forelimbs only and hindlimbs in turn on a vertical acryl stand of 4.5 cm in height and 1.0 cm in width, one at a time. did.
  • the effect was determined by totaling the catalepsy score of 10 animals per group using the following criteria (a maximum of 50 points). When the total score was 40 points or less, it was judged to be effective. The number of catalepsy-remission animals showed the number of catalepsy scores of 4 or less out of 10 animals. The power remission rate was shown as a percentage of the total score of the test compound administration group relative to the total score of the control group. Table 3 shows the results. Kukatalepsy score>
  • the duration of the posture with the forelimb hung on the table is 5 seconds or more and less than 10 seconds, and the duration of the hindlimb is less than 5 seconds;
  • the duration of the posture is 5 seconds or more, 10 For less than 5 seconds, or (2) the duration of the posture with the forelimb hung on the table is less than 5 seconds, and the duration of the hindlimb is 5 seconds or more;
  • the duration of the posture is 10 seconds or more with the forelimbs hung on the platform, and the duration on the hindlimbs is 5 seconds or more, less than 10 seconds, or (2) The forelimbs hung on the platform The duration of the posture is more than 5 seconds and less than 10 seconds, the duration of hind limbs is more than 10 seconds;
  • haloperidol a dopamine D1 / D2 antagonist
  • This haloperidol-induced catalepsy is known as a classical model for reproducing Parkinson's disease by drug administration [Eur. J. Pharmacol., 182, 327 (1990). ) And U.S. Pat. No. 3,991,207]].
  • the effect of the medicament of the present invention on oral peridol-induced catalepsy was examined.
  • the experiment was performed using 10 5-week-old male ddY mice (body weight: 22 to 24 g, Japan SIX) per group.
  • Haloperidol manufactured by Janssen
  • CMC carboxymethylcellulose
  • the test compound was used by suspending in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) to which Tween80 was added.
  • L-Dopa L-D0PA; Kyowa Hakko Kogyo
  • benserazide hydrochloride benserazide HC1; Kyowa Hakko Kogyo
  • Haroperi Doll intraperitoneal free suspension is suspension or test compound comprising the administration 1 hour after the test compound [T wee n80 distilled water for injection was added (manufactured by Otsuka Pharmaceutical Co., Ltd.): control] were orally administered respectively ( 10 mg / kg, 0.1 ml per 10 g of mouse body weight), 1 hour after administration of the test compound, one mouse was placed on a table 4.5 cm high and 1.0 cm wide, with both forelimbs and only hind legs The force talpe was measured.
  • L-dopa 100 mg / kg and benserazide 25 mg / kg (combined use) were administered intraperitoneally as control drugs.
  • the medicament of the present invention has an adenosine A 2A antagonistic activity and is useful for treatment and / or prevention of various diseases derived from augmentation of adenosine ⁇ 2 ⁇ receptor function, such as Parkinson's disease.

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Abstract

L'invention concerne des médicaments permettant de traiter et/ou de prévenir des maladies induites par l'hyperénergie d'un récepteur d'adénosine A2a telles que la maladie de Parkinson, contenant des dérivés de [1,2,4]triazolo[1,5-a]pyrimidine comme ingrédient actif, représentés par la formule (I) ou des sels parmaceutiquement acceptables de ceux-ci. Dans cette formule, Z représente oxygène, ou soufre; et R représente la formule (a) où Y représente oxygène, soufre, etc; n est un nombre entier compris entre 0 et 5; et X?1, x2 et x3¿ représentent chacun hydrogène, halogéno, alkyle inférieur, etc.
PCT/JP1999/000828 1998-02-24 1999-02-24 Medicaments et prophylaxie contre la maladie de parkinson WO1999043678A1 (fr)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017999A3 (fr) * 1999-09-06 2001-12-06 Hoffmann La Roche Derives amino-triazolopyridine
WO2002048145A1 (fr) * 2000-12-15 2002-06-20 F. Hoffmann-La Roche Ag Derives d'aminotriazolopyridine en tant que ligands du recepteur d'adenosine
WO2002080957A1 (fr) * 2001-04-09 2002-10-17 Neurosearch A/S Traitement de la maladie de parkinson par l'utilisation combinee d'un compose a activite neurotrope et d'un antagoniste du recepteur de l'adenosine a2a
WO2003020723A1 (fr) * 2001-08-30 2003-03-13 Kyowa Hakko Kogyo Co., Ltd. Derive de [1,2,4]triazolo[1,5-a]pyrimidine
WO2003048163A1 (fr) * 2001-11-30 2003-06-12 Schering Corporation Antagonistes du recepteur a2a d'adenosine bicyclique de [1,2,4]-triazole
WO2004092173A2 (fr) 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Antagonistes de recepteur d'adenosine a2a
WO2004092177A1 (fr) * 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolopyrazines et procedes de preparation et d'utilisation ce celles-ci
WO2004092171A3 (fr) * 2003-04-09 2005-03-31 Biogen Idec Inc Triazolo[1,5-a]pyrimidines et pyrazolo[1,5-a]pyrimidines et procedes de preparation et d'utilisation de celles-ci
WO2006132275A1 (fr) * 2005-06-07 2006-12-14 Kyowa Hakko Kogyo Co., Ltd. Agent prophylactique et/ou thérapeutique pour troubles moteurs
WO2007045705A2 (fr) 2005-10-14 2007-04-26 Proyecto De Biomedicina Cima, S.L. Composes servant a traiter la fibrillation auriculaire
US7285550B2 (en) 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same
EP2044940A2 (fr) 2002-01-28 2009-04-08 Kyowa Hakko Kogyo Co., Ltd Procédé de traitement de patients ayant des troubles du mouvement
CN103360398A (zh) * 2013-07-22 2013-10-23 山东大学 一种三唑并嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用
AU2011289407B2 (en) * 2010-08-11 2015-06-18 Philadelphia Health & Education Corporation Novel D3 dopamine receptor agonists to treat dyskinesia in Parkinson's disease
US9861594B2 (en) 2013-10-28 2018-01-09 Drexel University Treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder
CN110662544A (zh) * 2017-03-24 2020-01-07 纳诺森公司 具有有用的药学应用的稠合三唑并嘧啶化合物
JP2021529804A (ja) * 2018-07-05 2021-11-04 インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ Ａ２ａ／ａ２ｂ阻害剤としての縮合ピラジン誘導体
JP2021535897A (ja) * 2018-06-26 2021-12-23 チョーチヤン ビムグリーン ファーマシューティカルズ、リミテッド Ａ２ａ受容体拮抗薬として用いられるトリアゾロトリアジン誘導体
JP2021535898A (ja) * 2018-06-26 2021-12-23 チョーチヤン ビムグリーン ファーマシューティカルズ、リミテッド Ａ２ａ受容体拮抗薬として用いられるトリアゾロトリアジン誘導体
EP4229063A4 (fr) * 2020-10-19 2024-12-25 TME Therapeutics LLC Nouveaux inhibiteurs de la pikfyve et leurs méthodes d'utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0597885A (ja) * 1990-04-04 1993-04-20 Chemprosa Chem Prod Saischek Gmbh ２−デオキシ−ｄ−トレオ−ペントフラノシドの製造方法、それらの製造中間生成物及びそれらの使用
JPH05155887A (ja) * 1991-05-23 1993-06-22 Imperial Chem Ind Plc <Ici> アゾール誘導体
WO1994014812A1 (fr) * 1992-12-22 1994-07-07 Zeneca Limited Derives d'azole utilises comme antagonistes de l'adenosine
WO1995003806A1 (fr) * 1993-07-27 1995-02-09 Kyowa Hakko Kogyo Co., Ltd. Remede contre la maladie de parkinson
WO1995007282A1 (fr) * 1993-09-06 1995-03-16 Kyowa Hakko Kogyo Co., Ltd. Antidepresseur

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0597885A (ja) * 1990-04-04 1993-04-20 Chemprosa Chem Prod Saischek Gmbh ２−デオキシ−ｄ−トレオ−ペントフラノシドの製造方法、それらの製造中間生成物及びそれらの使用
JPH05155887A (ja) * 1991-05-23 1993-06-22 Imperial Chem Ind Plc <Ici> アゾール誘導体
WO1994014812A1 (fr) * 1992-12-22 1994-07-07 Zeneca Limited Derives d'azole utilises comme antagonistes de l'adenosine
WO1995003806A1 (fr) * 1993-07-27 1995-02-09 Kyowa Hakko Kogyo Co., Ltd. Remede contre la maladie de parkinson
WO1995007282A1 (fr) * 1993-09-06 1995-03-16 Kyowa Hakko Kogyo Co., Ltd. Antidepresseur

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6355653B1 (en) 1999-09-06 2002-03-12 Hoffmann-La Roche Inc. Amino-triazolopyridine derivatives
WO2001017999A3 (fr) * 1999-09-06 2001-12-06 Hoffmann La Roche Derives amino-triazolopyridine
WO2002048145A1 (fr) * 2000-12-15 2002-06-20 F. Hoffmann-La Roche Ag Derives d'aminotriazolopyridine en tant que ligands du recepteur d'adenosine
US6506772B1 (en) 2000-12-15 2003-01-14 Hoffmann-La Roche Inc. Substituted [1,2,4]triazolo[1,5a]pyridine derivatives with activity as adenosine receptor ligands
WO2002080957A1 (fr) * 2001-04-09 2002-10-17 Neurosearch A/S Traitement de la maladie de parkinson par l'utilisation combinee d'un compose a activite neurotrope et d'un antagoniste du recepteur de l'adenosine a2a
US7160899B2 (en) 2001-04-09 2007-01-09 Neurosearch A/S Adenosine A2A receptor antangonists combined with neurotrophic activity compounds in the treatment of Parkinson's disease
WO2003020723A1 (fr) * 2001-08-30 2003-03-13 Kyowa Hakko Kogyo Co., Ltd. Derive de [1,2,4]triazolo[1,5-a]pyrimidine
US6875772B2 (en) 2001-11-30 2005-04-05 Schering Corporation [1,2,4]-Triazole bicyclic adeonsine A2a receptor antagonists
WO2003048163A1 (fr) * 2001-11-30 2003-06-12 Schering Corporation Antagonistes du recepteur a2a d'adenosine bicyclique de [1,2,4]-triazole
US7078408B2 (en) 2001-11-30 2006-07-18 Schering Corporation [1,2,4]-Triazole bicyclic adenosine A2a receptor antagonists
EP2260850A2 (fr) 2002-01-28 2010-12-15 Kyowa Hakko Kogyo Co., Ltd Antagonistes des récepteurs A2A pour utilisation dans le traitement des troubles du mouvement
EP2942082A2 (fr) 2002-01-28 2015-11-11 Kyowa Hakko Kogyo Co., Ltd Antagonistes des récepteurs A2A pour utilisation dans le traitement des troubles du mouvement
EP2044940A2 (fr) 2002-01-28 2009-04-08 Kyowa Hakko Kogyo Co., Ltd Procédé de traitement de patients ayant des troubles du mouvement
WO2004092177A1 (fr) * 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolopyrazines et procedes de preparation et d'utilisation ce celles-ci
US7285550B2 (en) 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same
WO2004092173A3 (fr) * 2003-04-09 2004-12-09 Biogen Idec Inc Antagonistes de recepteur d'adenosine a2a
US7674791B2 (en) 2003-04-09 2010-03-09 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
US7834014B2 (en) 2003-04-09 2010-11-16 Biogen Idec Ma Inc. A2a adenosine receptor antagonists
WO2004092173A2 (fr) 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Antagonistes de recepteur d'adenosine a2a
WO2004092171A3 (fr) * 2003-04-09 2005-03-31 Biogen Idec Inc Triazolo[1,5-a]pyrimidines et pyrazolo[1,5-a]pyrimidines et procedes de preparation et d'utilisation de celles-ci
WO2006132275A1 (fr) * 2005-06-07 2006-12-14 Kyowa Hakko Kogyo Co., Ltd. Agent prophylactique et/ou thérapeutique pour troubles moteurs
EP2258372A1 (fr) 2005-06-07 2010-12-08 Kyowa Hakko Kirin Co., Ltd. L'utilisation des antagonistes des récepteurs A2A pour le treaitment de troubles de motricité
US7851478B2 (en) 2005-06-07 2010-12-14 Kyowa Hakko Kirin Co., Ltd. Agent for preventing and/or treating movement disorder
WO2007045705A2 (fr) 2005-10-14 2007-04-26 Proyecto De Biomedicina Cima, S.L. Composes servant a traiter la fibrillation auriculaire
US9289400B2 (en) 2010-08-11 2016-03-22 Drexel University D3 dopamine receptor agonists to treat dyskinesia in parkinson's disease
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US9675565B2 (en) 2010-08-11 2017-06-13 Drexel University D3 dopamine receptor agonists to treat dyskinesia in parkinson's disease
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