WO2005018532A2 - Composes de liaison aux recepteurs de purine - Google Patents

Composes de liaison aux recepteurs de purine Download PDF

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Publication number
WO2005018532A2
WO2005018532A2 PCT/SE2004/001224 SE2004001224W WO2005018532A2 WO 2005018532 A2 WO2005018532 A2 WO 2005018532A2 SE 2004001224 W SE2004001224 W SE 2004001224W WO 2005018532 A2 WO2005018532 A2 WO 2005018532A2
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groups
optionally substituted
cio
aryl
heteroatoms
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WO2005018532A3 (fr
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Jacob Westman
Gunnar Norstedt
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ACTAR AB
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ACTAR AB
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/20—Nitrogen atoms

Definitions

  • the present invention relates to compounds of formula (I), (II) or (III)
  • Compounds of formulae I-LU have good affinity and selectivity towards purine receptors, in particular towards the A 2 a-G olf complex or the A 2 a-G s complex and they act either as agonist or antagonist and can therefore be used for the treatment or prevention of diseases mediated by these receptors.
  • Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors.
  • the potential of adenosine receptors as drug targets have been known for more than 20 years.
  • There are presently four known receptors for adenosine which are classified as Ai, A 2A , A 2B and A 3 . All these different receptors show different biological response upon activation or inhibition.
  • the adenosine A 2A receptor belongs to the 7-TM G protein coupled receptor (GPCR) family. When ligands bind and activate theses receptors, this induces a change in the conformation of the associated G-protein that in turn influences different second messengers such as cAMP. In this sequence of events the G-protein is essential and it is known that different forms of G- proteins activate numerous biochemical response pathways.
  • a 2A receptors are present on numerous tissues including platelets, lymphocytes, neutrophils, monocytes, macrophages and mast cells but then coupled to G s protein.
  • a truly efficient drug molecule in addition to having affinity towards A 2A , must also be specific towards the different G proteins of interest associated to A 2A -
  • the object of the present invention is to provide new compounds represented by scaffolds with the formula (I) or pharmaceutically acceptable salts or prodrugs thereof.
  • the present invention provides a method of preparing said compounds. According to a further aspect the present invention provides the use of compounds of the formulae I-III as pharmaceutical compositions.
  • the invention provides new pharmaceutical compositions comprising said compounds of formulae I-III, or salts or prodrugs thereof.
  • the invention provides a method of medical treatment by use of said compounds of formulae I-III.
  • the invention provides the use of the inventive compounds, or salts or prodrugs thereof in the manufacture of a medicament for the treatment or prevention of a disorder by blocking of purine receptors, particularly adenosine receptors and more particularly A 2A receptors.
  • A is a 5- or 6-membered aryl or heteroaryl, optionally substituted with one or more groups selected from unbranched or branched, CI to CIO, more preferably CI to C6, most preferably CI to C5 acyclic saturated or unsaturated hydrocarbyl, or C3 to C12, more preferably C5 to CIO, most preferably C5 to C7 cyclic saturated or unsaturated hydrocarbyl, optionally substituted with one or more groups Y; halogen; protected or unprotected hydroxy; thiolo, amino, or carboxyl groups; C6-C14 aryl, optionally substituted with one or more groups Y; 5- to 14- membered heteroaryl with one or more heteroatoms, optionally substituted with one or more groups Y; 5- to 14-membered non-aromatic heterocycles having one or more heteroatoms, optionally substituted with one or more groups Y;
  • R 1 represents H; halogen; CI to CIO, more preferably CI to C6, most preferably CI to C5 acyclic, or C3 to C12, more preferably C5 to CIO, most preferably C5 to C7 cyclic, saturated or unsaturated hydrocarbyl; C6-C14 aryl, optionally substituted with one or more groups Y; 5- to 14-membered heteroaryl having one or more heteroatoms, unsubstituted or substituted with one or more groups Y, C6-C14 aryl; ; 5- to 14-membered non-aromatic heterocycles having one or more heteroatoms, optionally substituted with one or more groups Y;
  • R 2 represents NR 3 R 4 , NR 3 COR 4 , NR 3 CONR 3 R 4 or NR 3 COOR 4 ;
  • R 3 is H or R 4 ;
  • R 4 represents CI to CIO, more preferably CI to C6, most preferably CI to C5 acyclic, or C3 to C12, more preferably C5 to CIO, most preferably C5 to C7 cyclic, saturated or unsaturated hydrocarbyl, optionally substituted with one or more groups Y; C6-C14 aryl, optionally substituted with one or more groups Y; 5- to 14-membered heteroaryl having one or more heteroatoms, optionally substituted with one or more groups Y; 5- to 14-membered non-aromatic heterocycles having one or more heteroatoms, optionally substituted with one or more groups Y; and
  • Y represents hydroxyl, amine, sulfide, silyl, carboxyl, halogen and C6-C14 aryl. of formula (II)
  • R 5 , R 6 , R 7 , R 8 and R 9 represent the same or different groups selected from H, unbranched or branched CI to CIO, more preferably CI to C6, most preferably CI to C5 acyclic saturated or unsaturated hydrocarbyl, or C3 to C12, more preferably C5 to CIO, most preferably C5 to C7 cyclic saturated or unsaturated hydrocarbyl, halogen, C6 to C14 aryl, optionally substituted with one or more groups Y; 5- to 14-membered heteroaryl having one or more heteroatoms, optionally substituted with one or more groups Y; 5- to 14-membered non-aromatic heterocycles; i ⁇
  • R represents H, unbranched or branched CI to CIO, more preferably CI to C6, alkyl; C3 to C12 cycloalkyl, benzyl, halogen, C6 to C14 aryl optionally substituted with one or more groups Y; 5- to 14-membered heteroaryl having one or more heteroatoms, optionally substituted with one or more groups Y; 5- to 14-membered non-aromatic heterocycles; COR 4 ; CONR 4 ; COOR 4 ;
  • R 4 represents CI to CIO, more preferably CI to C6, most preferably CI to C5 acyclic, or C3 to C12, more preferably C5 to CIO, most preferably C5 to C7 cyclic, saturated or unsaturated hydrocarbyl, optionally substituted with one or more groups Y; C6-C14 aryl, optionally substituted with one or more groups Y; 5- to 14-membered heteroaryl with one or more heteroatoms, optionally substituted with one or more groups Y; 5- to 14-membered non-aromatic heterocycles having one or more heteroatoms, optionally substituted with one or more groups Y; and
  • Y represents hydroxyl, amine, sulfide, silyl, carboxyl, halogen and C6-C14 aryl;
  • the present invention provides a compound of formula (III) "
  • R 11 , R 12 , R 13 and R 14 represent the same or different groups selected from H, unbranched or branched, CI to CIO, more preferably CI to C6, most preferably CI to C5 acyclic saturated or unsaturated hydrocarbyl, or C3 to C12, more preferably C5 to CIO, most preferably C5 to C7 cyclic saturated or unsaturated hydrocarbyl, benzyl; halogen, C6 to C14 aryl, optionally substituted with one or more groups Y; 5- to 14-membered heteroaryl having one or more heteroatoms, optionally substituted with one or more groups Y; 5- to 14-membered non- aromatic heterocycles; and
  • Y represents hydroxyl, arnine, sulfide, silyl, carboxyl, halogen and C6-C14 aryl;
  • the compounds of formulae I-i ⁇ that have a selectivity towards the A 2a -G 0 i f complex will be useful for treating or preventing various diseases such as Parkinson's, Alzheimer's, Hunting- ton's diseases, senile dementia and depression, schizophrenia or other related CNS conditions while compounds of formulae I-i ⁇ that have a selectivity towards the A 2a -G s complex will be useful as immunomodulators of inflammation and therefore of use in the treatment of conditions involving pathological inflammation.
  • the invention provides a method of preparing a compound of formula I comprising the steps of :
  • alkyl unless otherwise stated, means an unbranched or branched, acyclic or cyclic, saturated or unsaturated (alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C3 to C12, more preferably C5 to CIO, most preferably C5-C7.
  • the alkyl group is preferably CI to CIO, more preferably CI to C6, more preferably methyl, ethyl, propyl (n-propyl, isopropyl), butyl (branched or unbranched) or pentyl, most preferably methyl.
  • aryl means an aromatic group, such as phenyl or naphthyl.
  • heteroaryl means an aromatic group containing one or more het- eroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.
  • the term "functional groups” means in the case of unprotected: an hydroxy- thiolo- or amino-function, or a carboxyl group, and in the case of protected: lower alkoxy, N-, O- or S-acetyl, or a carboxyl ester group.
  • non-aromatic heterocycle means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group such as pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or a cyclic ether group such as tetrahydrofuranyl or monosaccharide.
  • halogen means fluorine, chlorine, bromine or iodine.
  • substituted means that the concerned groups are substituted with one or more functional group(s) such as hydroxyl, amine, sulfide, silyl, carboxylic acid, halogen, aryl, etc.
  • the compounds of the present invention may be used or administered in combination with one or more additional drugs useful, for example, in the treatment of movement disorder, such as L-DOPA, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • Examples of pharmaceutically acceptable addition salts for use in the present inventive pharmaceutical compositions include those derived from mineral acids, such as hydrochloric, hy- drobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsul- phonic acids.
  • mineral acids such as hydrochloric, hy- drobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsul- phonic acids.
  • the pharmaceutically acceptable carrier may be anyone which is chemically inert to the active compounds and which have no detrimental side effects or toxicity under the conditions of use.
  • Pharmaceutical formulations are found e.g. Remington: "The Science and Practice of Pharmacy,” 20th Edn., A.R. Gennaro, Editor, Mack Publishing Co., Easton, PA (2003) (ISBN 0- 7817-5025-3). A brief review of methods of drug delivery is also found in e.g. Langer, Science 249:1527-1533 (1990).
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease.
  • the dose will also be determined by the route (administration form) timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I), (IT), (III) or the corresponding amount of a pharmaceutically acceptable salt thereof.
  • inventive compounds of formula I are provided.
  • the preparation of a compound according to formula I wherein A is phenyl is described:
  • the first reaction step is the formation of 4H-3,l-benzoxazin-4-one (X) which is a central compound.
  • X 4H-3,l-benzoxazin-4-one
  • a number of synthetic methods for the preparation of 2-substituted 4H-3,1- benzoxazin-4-ones have been described: (i) cyclodehydration of N-acylanthranilic acids by acetic anhydrides 2a"c , (ii) reaction of anthranilic acid with acid chlorides in pyridine 3a"b ; (iii) condensation of anthranilic acid with orthoesters 4 .
  • the compound X was synthesized in a number of different routes as described below. Several methods were developed and it was found that some methods are more preferable than others depending on the 2- substituent of interest. It was found, for example, that the use of orthoesters are most suitable for the synthesis of 2-H- and 2-Me- 4H-3,l-benzoxazin-4-ones. Trifluoroacetic acid anhydride was used for the synthesis of 2-trifluoromethyl-4H-3,l-benzoxazin-4-one and for the synthesis of 2-aryl/heteroararyl-4H-3,l-benzoxazin-4-one acid chlorides and pyridine was used.
  • Naphtho[2,3-d][l,3]oxazin- 4-ones could be formed from the corresponding 3-amino-naphthalene-2-carboxylic acid 6 .
  • the following steps in the reaction sequence are practicable independently of the identity of A, possibly with adaptive measures within the knowledge of the skilled person, such as pro- tection/deprotection of functional groups.
  • the second step is the formation of 2-amino-5-aryl/alkyl triazolo[l,5-c]pyrimidines.
  • the reaction mixture is refluxed for about 10 hours. It was found that when applying microwave heating the reaction time could be reduced dramatically.
  • the benzoxazines were treated with 1.2-1.5 eq. aminoguanidine hy- drogencarbonate in pyridine for 15 min at 180 °C.
  • the product is slowly precipitated in pure form (based on GC-MS) from the reaction mixture.
  • the product is filtered and washed with cold hexane or DCM.
  • MeOH MeOH
  • the amino function on the 2-amino-5-aryl/alkyl-triazolo[l,5-c]pyrimidine derivatives could finally be coupled with a number of derivatives to form secondary amines, amides, car- bamates, ureas etc.
  • Methods for the formation of secondary amines, tertiary amines, amides, carbamates, and ureas from primary amines are well established and well known for the person skilled in the art. Below the JV-acylation is described.
  • the 2-amino-5-aryl/alkyl-triazolo[l,5-c]pyrimidine derivatives were dissolved in MeCN/Pyridine 3:1 and 1.5 equiv. of the acid chloride was added. The reaction mixture was heated at 170 °C for 5 min. Half of the produced products precipitated from the reaction mixture in a pure form. The rest of the compound was purified with preparative HPLC. 90% of the produced compound was found in a purity>95%. The rest of the compounds was found in >90% purity.
  • the examples. describe the structure of different compounds and how they bind A 2 a receptors coupled to G s (Ki leukocytes) and A 2 a receptors coupled to G 0 i f (Ki striatum).
  • the ratio indicates selectivity of binding where a low ratio indicate selectivity towards A 2 a-G 0 i f coupled receptors and a high ratio a selectivity towards A 2 a-G s coupled receptors.
  • the pigs (20-25 kg) were from Swedish Meat, Uppsala, Sweden.
  • the brain striatum was dissected out and the tissue was homogenized using an Ultra-Turrax, 3x15s at full speed in 50 mM Tris-HCl buffer, pH 7.4. The homogenate was centrifuged at 30,000 g for 50 min at 4°C and resuspended in the 50 mM Tris-HCl buffer. Finally the striatal membrane preparation was frozen in aliquots at - 20°C until used.
  • Ficoll-PaquePLUS Heparin-treated blood (0.2 ml/10 ml whole blood) was mixed with an equal volume of PBS and 4 ml of the diluted blood was carefully layered over 3 ml of Ficoll- Paque PLUS in a 15 ml centrifuge tube. After a centrifugation at 400g for 30 min at room temperature in a swing-out rotor, the white leukocyte rich layer in the middle of the tube was transferred to other tubes with 3 volumes of PBS and pelleted by centrifugation at 400g for 15 min at room temperature. The supernatant was removed and the pellet was resuspended in 6 ml of PBS and centrifuged at 400g for 15 min at room temperature. Finally, the pellet was resuspended in 0.4 ml of 50 mM Tris-HCl buffer containing 5 mM MgCl 2 , pH 7.4, and frozen at-20°C.
  • the protocol for the Ficoll-PaquePLUS method was scaled up, since a large amount of leukocytes was needed in later assays.
  • 1200 ml of heparin-treated blood was diluted with an equal volume of PBS.
  • 10 ml of Ficoll-PaquePLUS was added to 50 ml centrifuge tubes and 15 ml of the diluted blood was carefully layered over.
  • a white leukocyte-rich layer in the middle of the tubes was created after a centrifugation at 400g for 30 min at room temperature in a swing-out rotor. Then the same isolation procedure as for the small volume of blood, as described above, was followed.
  • the leukocytes were thawed on ice, sonicated (3 times 5 sec), diluted in 50 mM Tris-HCl buffer containing 5 mM MgCl 2 , pH 7.4, and then centrifuged at 50,000 g for 30 min at 4°C. The supernatant was decanted, the pellet was resuspended in 5 ml of the 50 mM Tris-HCl buffer and centrifuged at 50,000 g for 20 min at 4°C. The resulting pellet was resuspended in 5 ml of the 50 mM Tris-HCl buffer. Aliquots of the leukocyte membrane preparation were then rapidly frozen and stored at -20°C.
  • the protein concentrations were determined according to the method of Lowry et al. s with bovine serum albumin as reference standard.
  • Adenosine deaminase (2 units/ml) was added to the membrane preparation for 1 h at 37°C to remove the endogenous adenosine before the binding assays.
  • the assays were carried out in triplicate and in a final volume of 300 ⁇ l.
  • the membranes 25 ⁇ g/well for striatum) (lOO ⁇ g/well for leukocytes) were incubated with 10 different concentrations of [ 3 H]-ZM241385 ranging from 0.10 nM to 7.5 nM.
  • the membrane suspension was incubated with radioligand in Tris-HCl buffer, pH 7.4, containing 5 mM MgCl 2 for 1 h at 4°C.
  • the non-specific binding was determined in the presence of lOO ⁇ l 50 ⁇ M 5 '-N-ethylcarboxamidoadenosine (NECA).
  • the samples were harvested by filtration through Whatman GF/B filters with a semi-automatic cell harvester (Skatron A/S, Norway). Each filter was rinsed with 6 ml of cold 50 mM Tris- HCl buffer, pH 7.4. Then the filters were punched out into scintillations vials and the radioactivity was determined in an LKB 1209 RackBeta Liquid Scintillation Counter with 3 ml Ready Safe scintillation liquid. The binding data were analysed with the GraphPad Prism pro- gramme (GraphPAD, San Diego, CA, USA) for the determination of dissociation constants (Kd) and the number of receptors expressed as a B max value.
  • Kd dissociation constants
  • the competition assays at least seven different concentrations of the substances were used.
  • the assays were carried out in triplicate in a final volume of 300 ⁇ l.
  • the concentration of [ 3 H]-ZM241385 was l,5nM - 2,5nM and the concentration of the striatal and leukocytes membranes were 25 ⁇ g/assay and 100 ⁇ g/assay respectively.
  • the samples were filtered through Whatman GF/B filters with the same semi-automatic cell harvester system that were used in the saturation binding assays.
  • Ki The inhibitory binding constant, Ki was calculated from the IC 50 values according to the Cheng and Prusoff equation 9 /((1+[C*])/Kd*)) where [C*] is the concentration of the radioligand and K * its dissociations constant.
  • the product is formed by the use of trimethylorthoacetate in the same way as described above.
  • the product was precipitated from the reaction mixture and filtered and dried in a desiccator.
  • the product is formed in quantitatively yield and purity and is confirmed by GC-MS.
  • Anthranilic acid (MW:137, 3.65 mmol) and 2.0 mL trimethylorthobenzoate (2.122 g, MW:182, d: 1.061, 11.65 mmol, 3.2 eq.) is heated under microwave conditions for 5 min at 160 °C.
  • the reaction mixture is after irradiation evaporated in order to withdraw the formed MeOH.
  • Hexane is then added to the reaction mixture and the product is precipitated over night. The product is formed but a noncyclic bi-product is also formed (+MeOH).
  • anthranilic acid MW: 137, 3.65 mmol
  • 2.0 mL acetic acid anhydride excess
  • the excess of reagent is after irradiation evaporated to dryness. Based on GC analysis the use of orthoester gives a purer reaction.
  • the benzoxazine (1 mmol) is treated with 1.2 mmol ammoguamdine hydrogencarbonate in 2.5 ml pyridine for 15 min at 180 °C under microwave conditions.
  • the reaction mixture is cooled to room temperature.
  • the product is slowly precipitated in pure form (based on GC- MS) from the reaction mixture.
  • the product is filtered and washed with cold hexane or DCM. For some derivatives we had to concentrate the reaction mixture and add MeOH in order to make the product to precipitate.

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Abstract

Cette invention concerne les composés représentés par la formule (I) ou un sel ou un promédicament pharmaceutiquement acceptable de ces composés ainsi que des méthodes de préparation correspondantes. Cette invention concerne également l'utilisation de ces composés ainsi que des composés représentés par les formules (II) ou (III) dans le traitement de troubles induits par des récepteurs de purine.
PCT/SE2004/001224 2003-08-25 2004-08-25 Composes de liaison aux recepteurs de purine Ceased WO2005018532A2 (fr)

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US49731203P 2003-08-25 2003-08-25
US60/497,312 2003-08-25

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WO2005018532A2 true WO2005018532A2 (fr) 2005-03-03
WO2005018532A3 WO2005018532A3 (fr) 2005-06-16

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7879846B2 (en) 2006-09-21 2011-02-01 Kyorin Pharmaceutical Co.., Ltd. Serine hydrolase inhibitors
WO2011029775A1 (fr) 2009-09-10 2011-03-17 Nerviano Medical Sciences S.R.L. Derives [1,2,4]triazolo [1,5-c]pyrimidine comme modulateurs de hsp90
US8431596B2 (en) 2007-10-10 2013-04-30 Cancer Research Technology Limited [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use
US11718622B2 (en) 2020-03-16 2023-08-08 Exelixis Inc. Heterocyclic adenosine receptor antagonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB873223A (en) * 1959-04-13 1961-07-19 Ici Ltd Heterocyclic compounds
US4075209A (en) * 1977-02-07 1978-02-21 Hoffmann-La Roche, Inc. Process for preparing substituted 2,4-diaminopyrimidines and isoxazole intermediate
JPS57175193A (en) * 1981-04-17 1982-10-28 Sankyo Co Ltd Preparation of triazolopyrimidine derivative
AU2003291608A1 (en) * 2002-12-27 2004-07-22 Actar Ab A method of drug screening to select agonists or antagonists of g protein coupled receptors (gpcr).

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7879846B2 (en) 2006-09-21 2011-02-01 Kyorin Pharmaceutical Co.., Ltd. Serine hydrolase inhibitors
US8431596B2 (en) 2007-10-10 2013-04-30 Cancer Research Technology Limited [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use
US9012633B2 (en) 2007-10-10 2015-04-21 Cancer Research Technology Limited [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use
US9394301B2 (en) 2007-10-10 2016-07-19 Cancer Research Technology Limited [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use
US9771362B2 (en) 2007-10-10 2017-09-26 Cancer Research Technology Limited [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use
WO2011029775A1 (fr) 2009-09-10 2011-03-17 Nerviano Medical Sciences S.R.L. Derives [1,2,4]triazolo [1,5-c]pyrimidine comme modulateurs de hsp90
US8580783B2 (en) 2009-09-10 2013-11-12 Nerviano Medical Sciences S.R.L. [1,2,4]triazolo [1,5-c]pyrimidine derivatives as Hsp90 modulators
US11718622B2 (en) 2020-03-16 2023-08-08 Exelixis Inc. Heterocyclic adenosine receptor antagonists
US12264161B2 (en) 2020-03-16 2025-04-01 Exelixis, Inc. Heterocyclic adenosine receptor antagonists

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