WO1994014812A1 - Derives d'azole utilises comme antagonistes de l'adenosine - Google Patents

Derives d'azole utilises comme antagonistes de l'adenosine Download PDF

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Publication number
WO1994014812A1
WO1994014812A1 PCT/GB1993/002525 GB9302525W WO9414812A1 WO 1994014812 A1 WO1994014812 A1 WO 1994014812A1 GB 9302525 W GB9302525 W GB 9302525W WO 9414812 A1 WO9414812 A1 WO 9414812A1
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Prior art keywords
compound
furyl
formula
triazolo
pharmaceutically acceptable
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PCT/GB1993/002525
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English (en)
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Geraint Jones
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Zeneca Limited
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Publication date
Application filed by Zeneca Limited filed Critical Zeneca Limited
Priority to AU56564/94A priority Critical patent/AU5656494A/en
Publication of WO1994014812A1 publication Critical patent/WO1994014812A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention concerns novel azole derivatives, more particularly a novel 2-heteroaryl-triazolo[1,5-a][1,3,5]triazine and the pharmaceutically acceptable salts thereof, which have useful pharmacological properties (and in particular antagonise the actions of adenosine, such as vasodilation).
  • the invention also includes pharmaceutical compositions containing the novel azole derivatives for use in treating certain diseases and disorders affecting mammalian cardiac, peripheral and/or cerebral vascular systems. Also included are processes for the manufacture and formulation of the novel azole derivatives.
  • the compound theophylline (1,3-dimethylxanthine) has been used clinically (usually as its ethylene diamine salt, which is also known as aminophylline) as a respiratory stimulant, a centrally acting stimulant, a bronchodilator, a cardiac stimulant and as a diuretic.
  • This diversity of clinical uses is an indication of the range of pharmacological actions which have been attributed to theophylline. These include phosphodiesterase inhibition, adenosine receptor antagonism, mobilisation of intracellular calcium and the release of catecholamines.
  • the "vascular steal” phenomenon can occur when the major artery supplying a particular vascular bed is partially or totally occluded resulting in ischaemia.
  • the compromised vascular bed dilates and blood flow is maintained by either an increase in flow across the narrowed vessel or by an increase in flow through the collateral vessels.
  • increased metabolic activity in adjacent vascular beds results in release of mediators such as adenosine, causing them to dilate, resulting in the limited blood flow to the compromised vascular bed being "stolen” by these adjacent areas.
  • the loss of blood from compromised to normally perfused vascular beds by the phenomenon of "vascular steal” further diminishes the blood flow in the compromised vascular bed.
  • the diversity of pharmacological properties possessed by theophylline make it difficult to use in the regular treatment or prevention of occlusive diseases and conditions of the vasculature.
  • its associated action as a phosphodiesterase inhibitor results in cardiac stimulation which is deleterious for patients with myocardial ischaemia.
  • the relatively low potency of theophylline means that dose-levels which are therapeutically useful are close to those which can cause serious central side-effects.
  • EP-A1-459702 discloses certain 2-heteroaryl-triazolo[1,2,4]triazolo[1,5-a][1,3,5]- triazines and pyrazolo[2,3-a][1,3,5[triazines that are effective antagonists of the actions of adenosine, particularly of its vasodilatory actions.
  • the compound according to the invention may be represented by the formula I, which is set out hereinafter together with the other formulae referred to herein by Roman numerals. It will be referred to hereinafter as the compound of formula I.
  • the compound of formula I has been found to be a selective antagonist of adenosine at the adenosine A2a receptor, the receptor which mediates the vasodilatory action of adenosine. It has also been found to possess particularly good aqueous solubility and to be surprisingly effective in vivo on oral and parenteral administration. This combination of properties is unexpected and particularly desirable .
  • Particular pharmaceutically acceptable salts of the compound of formula I include, for example, salts with acids affording physiologically acceptable anions, for example, salts with acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, trifluoracetic, oxalic, citric and maleic acid.
  • acids such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, trifluoracetic, oxalic, citric and maleic acid.
  • the invention provides a process for the preparation of the compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises
  • a compound of the formula II in which Z is a suitable leaving group for example hydrocarbylsulphonyl such as (1-6C)alkylsulphonyl (such as raethylsulphonyl or ethylsulphonyl), aryloxy such as phenoxy, or halogeno (such as chloro or bromo), with N-(2-aminoethyl)morpholine or a salt thereof.
  • hydrocarbylsulphonyl such as (1-6C)alkylsulphonyl (such as raethylsulphonyl or ethylsulphonyl), aryloxy such as phenoxy, or halogeno (such as chloro or bromo), with N-(2-aminoethyl)morpholine or a salt thereof.
  • the reaction may conveniently be carried out at a temperature in the range of from 0 to 120°C, for example from 10 to 80°.
  • Suitable solvents for the reaction include nitriles, such as acetonitrile; alcohols, such as ethanol or propanol; ethers, such as tetrahydrofuran, 1,2-dimethoxyethane or t-butyl methyl ether; and amides such as N,N-dimethylformamide.
  • salts of N-(2-aminoethyl)morpholine include alkali metal salts, such as the lithium, sodium and potassium salts.
  • those compounds of formula II in which Z is alkylsulphonyl may be made by oxidation of the corresponding alkylthio derivative of formula III in which R 1 is (1-6C)alkylthio, using a conventional oxidant such as a peracid, for example, peracetic, perbenzoic or chloroperbenzoic acid, conveniently at a temperature in the range, for example, 0 to 40 °C, and in a suitable solvent or diluent such as dichloromethane or chloroform.
  • a peracid for example, peracetic, perbenzoic or chloroperbenzoic acid
  • those compounds of the formula II in which Z is chloro or bromo may be obtained, for example, by reacting an alkylthio derivative of formula III (especially in which R 1 is methylthio or ethylthio) with chlorine or bromine in the presence of hydrogen chloride or hydrogen bromide, respectively, at a temperature in the general range, for example, -20 to 15 °C and in a generally inert polar solvent such as ethanol or 2-propanol.
  • the starting alkylthio starting materials of formula III may themselves be obtained, for example, by reaction of a compound of the formula IV with the appropriate dialkyl N-cyanodithioiminocarbonate of formula V, at elevated temperature in the range, for example, 60 to 200 °C, conveniently as a melt in the absence of solvent or diluent.
  • a suitable base such as pyridine or 2,6-lutidine, which may also be used as the reaction solvent, at a temperature in the range, for example, 60-120 °C.
  • the compounds of formula II in which Z is a phenoxy group may conveniently be prepared by reacting a 5,7-diphenoxy-[1,2,4]- triazolo[1,5-a][1,3,5]triazine with ammonia. The process is
  • Suitable solvents for the process include alcohols such as ethanol and ethers such as tetrahydrofuran. It is
  • the 5,7-diphenoxy-[1,2,4]triazolo[1,5-a][1,3,5]triazine starting materials may be obtained by dehydrating a compound of formula VI in which each Z is a phenoxy group.
  • Suitable dehydration agents include, for example, polyphosphoric acid silyl esters, such as polyphosphoric acid trimethylsilyl ester; phosphorus pentoxide and sulphonyl chlorides such as p-toluenesulphonylchloride.
  • dehydration is conveniently effected at a temperature in the range of from 60-180°C.
  • convenient solvents include the aromatic
  • hydrocarbons such as xylene or toluene.
  • convenient solvents include tertiary amines such as pyridine.
  • the compounds of formula VI may be obtained by reacting a compound of formula VII in which each Z is a phenoxy group with a compound of formula QCOHal in which Hal is a halogen atom such as a chlorine atom. The reaction is conveniently effected at a temperature in the range of from -10 to 40°C. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloromethane.
  • the compounds of formula VII may be obtained by reacting a compound of formula VIII in which each Z is a phenoxy group with hydrazine.
  • the compounds of formula VI may be obtained by reacting a compound of formula VIII in which each Z is a phenoxy group with a compound of formula QCONHNH 2 .
  • the invention provides another process for the preparation of the compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises
  • Suitable solvents for the reaction include, for example alcohols such as ethanol, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and ethers such as tetrahydrofuran,
  • the starting materials of formula IX may be obtained by standard procedures well known in the art from the corresponding compound of formula IX in which Z is a hydroxy group.
  • This compound may itself be prepared by reacting a compound of formula II with 2-aminoethanol according to the method of process (a) described hereinabove.
  • the invention provides another process for the preparation of the compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises (c) reacting a compound of formula X in which Z is a suitable leaving group, for example aryloxy (such as phenoxy), alkylthio (such as methylthio) or halogeno (such as chloro or bromo) with ammonia.
  • Z is a suitable leaving group, for example aryloxy (such as phenoxy), alkylthio (such as methylthio) or halogeno (such as chloro or bromo) with ammonia.
  • the reaction is conveniently effected at a temperature in the range of, for example, from 0 to 100°C.
  • Suitable solvents for the process include water, alcohols such as ethanol and ethers such as tetrahydrofuran.
  • the starting materials of formula X may be obtained by dehydrating a compound of formula XI.
  • Suitable dehydration agents include, for example, phosphorus pentoxide, a polyphosphoric acid silyl ester such as polyphosphoric acid trimethylsilyl ester or a sulphonyl chloride such as p-toluenesulphonylchloride.
  • dehydration is conveniently effected at a temperature in the range of from 60-180°C.
  • convenient solvents include the aromatic hydrocarbons such as xylene or toluene.
  • convenient solvents include tertiary amines such as pyridine.
  • the compounds of formula XI may be obtained by reacting a compound of formula VI with N-(2-aminoethyl)morpholine.
  • the invention provides another process for the preparation of the compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises
  • Suitable dehydration agents include, for example, polyphosphoric acid silyl esters, such as polyphosphoric acid trimethylsilyl ester; phosphorus pentoxide and sulphonyl chlorides such as p-toluenesulphonylchloride.
  • the dehydration is conveniently effected at a temperature in the range of from 60-180°C.
  • convenient solvents include the aromatic hydrocarbons such as xylene or toluene.
  • convenient solvents include tertiary amines such as pyridine.
  • the starting materials of formula XII may be prepared from a compound of formula VIII by reaction, in any convenient order, with ammonia, N-(2-aminoethyl)morpholine and 2-furoic acid hydrazide. Whereafter, when a pharmaceutically acceptable salt is required, it may be obtained, for example, by reacting a compound of formula I with the appropriate acid or base affording a
  • the compounds of the invention possess the property of antagonising one or more of the physiological actions of adenosine and are valuable in the treatment of diseases and medical conditions affecting the mammalian cardiac, peripheral and/or cerebral vascular systems, such as ischaemic heart disease (angina), peripheral vascular disease (claudication) and cerebral ischaemia.
  • the compounds may also be useful in the treatment of migraine.
  • This test involves the ability of a test adenosine antagonist to displace the known adenosine mimetic agent
  • the membrane preparation is obtained as follows:
  • Frozen pellets of PC12 cells are washed twice with ice cold, buffered, physiological saline and the cells recovered by centrifugation (1500G) at 3°C. The separated cells are then suspended in hypotonic solution
  • the mixture is then incubated at 37°C. After 20 minutes, the reaction is terminated by dilution with ice-cold buffer and transfer onto ice.
  • the material obtained containing the cell membranes is recovered by centrifugation and washed by resuspension in buffer and recentrifugation.
  • the pellet produced is then resuspended in ice-cold buffer using a hand-driven homogenizer.
  • the resultant membrane suspension is frozen and stored under liquid nitrogen until required.
  • Binding studies are carried out in microtitre plates, the assay mixtures being buffered in 50 mH tris-HCl, pH 7.4 at room temperature.
  • the test compound is dissolved in dimethyl sulphoxide (DMSO) and then diluted with assay buffer to give the test solutions.
  • DMSO dimethyl sulphoxide
  • the final concentration of DMSO is not allowed to exceed 1% by volume, at which level it does not affect radioligand binding to the membrane receptor.
  • Incubations are performed at 30°C for 90 minutes in a total volume of 150 ⁇ l comprising the test solution or buffer (50 ⁇ l), tritiated NECA (50 ⁇ l) and membrane suspension (50 ⁇ l).
  • the samples are rapidly filtered over glass-fibre mats and the filter mats are washed to remove non-receptor-bound radioligand.
  • Receptor-bound radioligand entrapped on the filter mats is then determined by liquid scintillation counting. Filtration and washing are carried out using a conventional vacuum filtration cell harvester.
  • the specific binding (defined as the difference between the total binding and the non-specific binding) in the presence of the particular test compound is determined and compared with the control value. Results are conveniently expressed as the negative logarithm of the concentration required to cause a 50% displacement of control specific binding (pIC 50 ).
  • the compound of Example 1 herein shows a pIC 50 of 7.6.
  • the known compound 1,3-dimethylxanthine typically shows a pIC 50 of about 5.
  • the atrial pair preparation may be obtained as follows:- Atrial pairs are obtained from guinea-pigs (Dunkin Hartley strain, 250-400g males) and mounted in organ baths containing oxygenated Krebs buffer solution (952 O 2 ; 5% CO 2 ) at 37°C. The spontaneously beating atria are then placed under a resting tension of 1 g and allowed to equilibrate for 50 minutes with continuous overflow. Overflow is then stopped and adenosine deaminase (1 Unit ⁇ ml) added to prevent the accumulation of endogenously produced adenosine.
  • a cumulative dose response curve to the adenosine mimetic, 2-chloroadenosine (10 -8 M to 10 -4 M) is administered to produce a maximal slowing of atrial rate.
  • adenosine deaminase is readministered to the bath which is allowed to equilibrate for 15 minutes.
  • Test compounds are assessed by comparing dose response curves to 2-chloroadenosine alone with those obtained in the presence of the compound.
  • Competitive adenosine antagonists produce a parallel shift in the 2-chloroadenosine dose response curve.
  • the dose ratio is assessed by comparing dose response curves to 2-chloroadenosine alone with those obtained in the presence of the compound.
  • the pA2 is then calculated using a standard computational technique.
  • the compound of Example 1 herein has a pA2 of 5.5.
  • the compound is over one hundred fold selective for the A 2a receptor over the A 1 receptor. This is particularly desirable, because antagonism of adenosine at the A 1 receptor is associated with effects on the kidney, adipocytes, heart and central nervous system.
  • This test involves the assessment of the effects of a test compound on antagonising the actions of adenosine in lowering heart rate and increasing vasodilation (as measured by a fall in hind-limb perfusion pressure).
  • Beagles (12 - 18 kg) are anaesthetised with sodium pentobarbitone (50 mg/kg, iv).
  • the following blood vessels are catheterised: right jugular vein (for infusion of the anaesthetic at approximately 112 mg per hour as a 3 mg/ml solution in isotonic saline), right brachial vein (for administration of drugs and test agents), right brachial artery (for measurement of systemic blood pressure and pulse rate) and the left carotid artery (for
  • adenosine into the left ventricle. Both vagi, the right femoral and sciatic nerves are ligated and severed. A bolus injection of 1250 U heparin is administered before perfusing the right hindlimb at constant blood flow with blood from the iliac artery. The right leg is tied just below the ankle. Xamoterol (1 mg/kg) is then administered to the animal to stabilise heart rate at a high level and nitrobenzylthioinosine (NBTI, 0.5 mg/kg) to inhibit the uptake of adenosine. The animal is sensitised to adenosine during the
  • DRC dose response curve
  • the amount of adenosine required to cause a 50% fall in measured parameter (ED 50 ) i.e. heart rate and hindlimb perfusion pressure is calculated for each does of test compound and a Schild plot constructed. From this plot a K B value is determined for antagonism of heart rate response and vasodilator response to adenosine.
  • the compound of Example 1 has been found to give a K B in the range of from 0.01 - 0.24 mg/kg for antagonism of vasodilator response to adenosine with no indication of toxic or other untoward properties at doses several times greater than the minimum effective dose.
  • the right carotid artery (for measurement of systemic arterial blood pressure) and the right jugular vein (for administration of adenosine or test substance) are catheterised and exteriorised. Both catheters are sutured in and the incision closed using suture. The cats are allowed to regain consciousness before being transported to the animals rooms where they are housed
  • the cats are placed individually, unrestrained into open fronted boxes. After a short period of acclimatisation a siting dose of 0.6mg/kg adenosine is administered to assess the sensitivity of the cat towards adenosine. Three consecutive bolus injections of either 0.6, 1.0 or 1mg/kg adenosine are administered and the fall in diastolic blood pressure is measured. Cats are then dosed with the test compound either as a solid or as a solution in polyethylene glycol (PEG) 400, p.o. or in solution for intravenous administration.
  • PEG polyethylene glycol
  • the adenosine challenges are repeated at between 15 min and 24 hours post administration of the test compound.
  • Activity of the test compound is expressed as a percentage inhibition of the diastolic blood pressure response.
  • the compound of Example 1 has been found to have significant adenosine antagonist acitivity at a dose of 0.3 - lmg/kg without any sign of overt toxicity at several times the minimum effective dose.
  • the compounds of the invention are generally best administered to warm-blooded animals for therapeutic or prophylactic purposes in the treatment or prevention of cardiovascular diseases and adverse conditions in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising said compound of formula I or a pharmaceutically acceptable salt thereof, in admixture or together with a pharmaceutically acceptable diluent or carrier.
  • Such compositions are provided as a further feature of the invention.
  • a compound of formula I will be administered orally, intravenously or by some other medically acceptable route (such as by inhalation, insufflation, sub-lingual or transdermal means) so that a dose in the general range, for example, 0.001 mg to 10 (and more particularly in the range, for example, 0.05 to 5 mg/kg) mg/kg body weight is received.
  • a dose in the general range for example, 0.001 mg to 10 (and more particularly in the range, for example, 0.05 to 5 mg/kg) mg/kg body weight is received.
  • the precise dose administered will necessarily vary according to the nature and severity of the disease or condition being treated and on the age and sex of the patient.
  • a composition according to the invention may be in a variety of dosage forms.
  • it may be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of a suppository for rectal administration; in the form of a sterile solution or suspension for administration by intravenous or intramuscular injection; in the form of an aerosol or a nebuliser solution or suspension, for administration by inhalation; in the form of a powder, together with pharmaceutically acceptable inert solid diluents such as lactose, for administration by insufflation; or in the form of a skin patch for transdermal administration.
  • the compositions may conveniently be in unit dose from containing, for example, 5 - 200 mg of the compound of formula I or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • composition may comprise from 0.1 to 99.5% by weight of the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • compositions may be obtained by conventional procedures using pharmaceutically acceptable diluents and carriers well known in the art.
  • Tablets and capsules for oral administration may be obtained by conventional procedures using pharmaceutically acceptable diluents and carriers well known in the art.
  • enteric coating such as one based on cellulose acetate phthalate
  • compositions of the invention may also contain one or more agents known to be of value in the diseases or conditions of the cardiovasculature intended to be treated.
  • agents known to be of value in the diseases or conditions of the cardiovasculature intended to be treated may contain, in addition to the compound of formula I, for example: a known platelet aggregation inhibitor, prostanoid constrictor antagonist or synthase inhibitor (thromboxane A 2 antagonist or synthase inhibitor),
  • cyclooxygenase inhibitor cyclooxygenase inhibitor, hypolipidemic agent, inotropic agent or thrombolytic agent.
  • the compounds of formula I are also. useful as pharmacological tools in the development and standardisation of test systems for the evaluation of new cardiovascular agents in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice.
  • N-(2-Aminoethyl)morpholine (2.60g) was added to a stirred suspension of 7-amino-2-(2-furyl)-5-methylsulphonyl- -[1,2,4]triazolo[1,5-a][1,3,5]triazine (3.36g) in acetonitrile 200ml and stirring was continued for 2 hours.
  • the solvent was evaporated and the residue was purified by chromatography on silica (200g) eluting with dichloromethane containing methanol (10% v/v).
  • the solid (4.0g) obtained was crystallised from ethanol to give
  • the necessary starting material was prepared as follows:- (1) Hydrogen chloride gas (20.0g) was bubbled into an ice-cooled mixture of 2-furonitrile (46.5 g) and absolute ethanol (23.0 g).
  • the necessary starting material may be prepared as follows:-
  • Hexamethyldisiloxane (3.0 mole) is charged to a slurry of phosphorus pentoxide (1.5 mole, measured as P 4 O 10 ) in xylene. The mixture is then heated to 90°C over 1.5 hours and then stirred for 1 hour at 90°C during which time all of the solid dissolves.
  • N-2-(4,6-diphenoxy)-[1,3,5]triazinyl]-N'-(2-furoyl)hydrazine (1.0 mole) is then charged to the solution and the temperature is increased to reflux.
  • the solid dissolves, but during the course of the cyclisation a second solid is precipitated.
  • the cyclisation is normally complete in 2.5 hours at which point the mixture is cooled to 25°C, and can for convenience be held overnight.
  • Acetonitrile is then added and the temperature reduced to 15°C. Water is then added. The mixture is then cooled back to 15°C and 0.91 ammonia solution is added, keeping the temperature below 25°C. Once the addition is complete the temperature is increased to 40°C for 1 hour.
  • compound X pharmaceutically acceptable salt thereof, for therapeutic or prophylactic use in humans:-
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne la 2-(2-Furyl)-5-[2-(morpholino)ethylamino][1,2,4]triazolo[1,5-a][1,3,5]triazine-7-amine et ses sels pharmaceutiquement acceptables constituant des antagonistes sélectifs de l'adénosine A2a. L'invention concerne également les compositions pharmaceutiques comprenant ces composés et leurs procédés de préparation.
PCT/GB1993/002525 1992-12-22 1993-12-10 Derives d'azole utilises comme antagonistes de l'adenosine WO1994014812A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56564/94A AU5656494A (en) 1992-12-22 1993-12-10 Azole derivatives as adenosine antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929226735A GB9226735D0 (en) 1992-12-22 1992-12-22 Azole derivatives
GB9226735.0 1992-12-22

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WO1994014812A1 true WO1994014812A1 (fr) 1994-07-07

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CN (1) CN1093708A (fr)
AP (1) AP9300596A0 (fr)
AU (1) AU5656494A (fr)
GB (2) GB9226735D0 (fr)
HR (1) HRP931512A2 (fr)
IL (1) IL107876A0 (fr)
SI (1) SI9300674A (fr)
WO (1) WO1994014812A1 (fr)
ZA (1) ZA939045B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999043678A1 (fr) * 1998-02-24 1999-09-02 Kyowa Hakko Kogyo Co., Ltd. Medicaments et prophylaxie contre la maladie de parkinson
WO2001017999A2 (fr) * 1999-09-06 2001-03-15 F. Hoffmann-La Roche Ag 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
US6514989B1 (en) 2001-07-20 2003-02-04 Hoffmann-La Roche Inc. Aromatic and heteroaromatic substituted 1,2,4-triazolo pyridine derivatives

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA04011948A (es) * 2002-05-30 2005-03-31 Arqule Inc Derivados de 1,3,5-triazina como ligandos para receptores humanos de adenosina-a3.
CN112479956A (zh) * 2019-07-30 2021-03-12 杭州阿诺生物医药科技有限公司 一种用于制备腺苷受体抑制剂中间体的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459702A1 (fr) * 1990-05-29 1991-12-04 Zeneca Limited Dérivés d'azoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459702A1 (fr) * 1990-05-29 1991-12-04 Zeneca Limited Dérivés d'azoles

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999043678A1 (fr) * 1998-02-24 1999-09-02 Kyowa Hakko Kogyo Co., Ltd. Medicaments et prophylaxie contre la maladie de parkinson
WO2001017999A2 (fr) * 1999-09-06 2001-03-15 F. Hoffmann-La Roche Ag Derives amino-triazolopyridine
WO2001017999A3 (fr) * 1999-09-06 2001-12-06 Hoffmann La Roche Derives amino-triazolopyridine
US6355653B1 (en) 1999-09-06 2002-03-12 Hoffmann-La Roche Inc. Amino-triazolopyridine derivatives
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
US6514989B1 (en) 2001-07-20 2003-02-04 Hoffmann-La Roche Inc. Aromatic and heteroaromatic substituted 1,2,4-triazolo pyridine derivatives
WO2003010167A1 (fr) * 2001-07-20 2003-02-06 F. Hoffmann-La Roche Ag Derives de 8-methoxy-(1,2,4)triazolo(1,5-a)pyridine et utilisations de ceux-ci sous la forme de ligands de recepteur d'adenosine

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CN1093708A (zh) 1994-10-19
AU5656494A (en) 1994-07-19
GB9324349D0 (en) 1994-01-12
GB9226735D0 (en) 1993-02-17
IL107876A0 (en) 1994-04-12
AP9300596A0 (en) 1994-01-31
SI9300674A (en) 1994-06-30
ZA939045B (en) 1994-06-22
HRP931512A2 (en) 1994-12-31

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