AU2003250232A1 - 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors - Google Patents

1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors Download PDF

Info

Publication number
AU2003250232A1
AU2003250232A1 AU2003250232A AU2003250232A AU2003250232A1 AU 2003250232 A1 AU2003250232 A1 AU 2003250232A1 AU 2003250232 A AU2003250232 A AU 2003250232A AU 2003250232 A AU2003250232 A AU 2003250232A AU 2003250232 A1 AU2003250232 A1 AU 2003250232A1
Authority
AU
Australia
Prior art keywords
alkyl
general formula
compounds
group
disorders
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
AU2003250232A
Other versions
AU2003250232B2 (en
Inventor
Jacobus A. J. Den Hartog
Gary R. Gustafson
Maria L. Pras-Raves
Jan H. Reinders
Guustaaf J. M. Van Scharrenburg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Arqule Inc
Original Assignee
Hartog Jacobus A J
Solvay Pharmaceuticals BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hartog Jacobus A J, Solvay Pharmaceuticals BV filed Critical Hartog Jacobus A J
Publication of AU2003250232A1 publication Critical patent/AU2003250232A1/en
Assigned to ARQULE, INC, SOLVAY PHARMACEUTICALS B.V. reassignment ARQULE, INC Alteration of Name(s) of Applicant(s) under S113 Assignors: ARQULE, INC, DEN HARTOG, JACOBUS A.J., GUSTAFSON, GARY R., PRAS-RAVES, MARIA L., REINDERS, JAN H., SOLVAY PHARMACEUTICALS B.V., VAN SCHARRENBURG, GUUSTAAF J.M.
Application granted granted Critical
Publication of AU2003250232B2 publication Critical patent/AU2003250232B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/50—Two nitrogen atoms with a halogen atom attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Description

WO 03/101980 PCT/EP03/50203 1 1,3,5-TRIAZINE DERIVATIVES AS LIGANDS FOR HUMAN ADENOSINE-A3 RECEPTORS The present invention relates to a group of novel triazine derivatives which are ligands for human adenosine-A 3 receptors. The invention also relates to 5 pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel triazine derivatives as an active ingredient. Caffeine and theophylline, two well known natural compounds, exert their pharmacological activities by interacting with adenosine receptors. This discovery 10 had a major impact on adenosine receptes search. At present, four types of adenosine receptors have been identified and designated A,, A2A, A2B and A 3 respectively. All four belong to the super-family of seven transmembrane G-protein coupled receptors. Adenosine receptors are ubiquitous and involved in a great variety of biological processes. Thus, during the past decades the therapeutic 15 potential of adenosine receptor ligands has resulted in a substantial research interest. Recent reviews are: S. Hess, Recent advances in adenosine receptor antagonist research, Expert Opin. Ther. Patents, 11, 1547-1562, 2001, and M.A. Jacobson, Adenosine receptor agonists, Expert Opin. Ther. Patents, 12(4), 489-501, 2002. 20 Ligands for the various adenosine receptors are the subject of a large number of patent applications and patents. In only two of those triazines are described. WO 991163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A 1 receptors. 25 The second patent application describing triazines, JP 11158073, is the closest prior art. It describes a series of substituted 1,3,5-triazines which are ligands for human adenosine-A 3 receptors, the most potent of which having affinities around 15 nM. 30 Surprisingly, it has now been found that in a series of triazine derivatives with novel combinations of substituents, a group of compounds was shown to have an affinity for human adenosine-A 3 receptors in the low nanomolar range.
WO 03/101980 PCT/EP03/50203 2 The invention relates to compounds of the general formula (1)
R
2 R
R
3 N N I (1) R4 X N Y wherein: 5
R
1 represents halogen, alkyl(1-3C), 0-alkyl(1-3C), CF 3 , NH 2 , N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C)alkynyl(1 -3C), N-alkenyl(1-3C)alkynyl(1 -3C) or an optionally substituted C2-C8 cycloalkylamino group, 10
R
2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1 3C), phenoxy, hydroxyalkyl(1 -3C), alkoxy(1 -2C)-alkyl(1 -2C), phenyl, N-(di)-alkyl(1 3C), 15 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2
CH
3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system, 20 X represents NH, N-alkyl(1-3C), CH 2 , 0, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C): R, R RRy R7 R9 N 1 R9 N N
R
5 RR Z
K
1 0 OH R 10 Z (A) (B) (C) 25 in which:
R
5 is either OH or CH 2
OH
WO 03/101980 PCT/EP03/50203 3
R
6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, 0-alkyl(1-3C) or hydroxyalkyl(1-2C); n has the value of 0, 1 or 2; 5
R
7 represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),
R
8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, 0-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, I-piperazinyl, OCF 3 , SCH 3 , 10 SOCH 3 , or S0 2
CH
3 ,
R
1 o represents H or alkyl(1-3C),
R
11 represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), 15 Z represents NOH, NOalkyl(1-3C), 0 or S, and pharmacologically acceptable salts thereof. 20 In the description of the substituents the abbreviation 'alkyl(1-3C)' means 'methyl, ethyl, n-propyl or isopropyl'. In this specification 'C 2 -CB cycloalkylamino' means any cyclic amine containing from 25 2 to 8 carbons in the ring. The cycloalkylamino ring may contain other atoms and may be optionally substituted. Examples of 02-CS cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like. In this specification 'optionally substituted' means that a group may or may not be 30 further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic 35 or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen WO 03/101980 PCT/EP03/50203 4 or sulphur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include C1-3 alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C 1
..
3 alkyloxy such as for example methoxy, ethoxy and 5 trifluoromethoxy, and amino. All compounds having formula (1) in which the substituents on asymmetrical carbon atoms are in either the R-configuration or the S-configuration belong to the invention. 10 Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolized to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino groups or hydroxy groups, a typical example being the compound with formula (9) and its enantiomers (see below). Such compounds can be reacted with organic acids to 15 yield compounds which can be metabolized to compounds having formula (1). The invention particularly relates to compounds having formula (1) wherein R, represents halogen, alkyl(1-3C), 0-alkyl(1-3C), CF 3 , NH 2 or N-(di)-alkyl(1-3C), and all other symbols have the meanings as given above. 20 More particular the invention relates to compounds having formula (1) wherein R1 = Cl,
R
2 =H, X = NH, Y is either group (A), (B) or (C), R 6 = H, n=1, Z=0, R 1 o=H and R 3 , R 4 , R5, R 7 , R 8 , Reand R 1 1 have the meanings as described above, and including all 25 possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas (2), (3) and (4): C1 CI 3 IN NN R 3 N N R 7 RR N
R
9 Ra N ),N No N '1,N'_ H 4 H H OH (2) R 5 (3) WO 03/101980 PCT/EP03/50203 5 CI R 3 N ' N
R
1 1 R 8 R R N N R N 4HH 0 (4) Yet more particular the invention relates to compounds of either formula (2), (3) or (4) in which R 5 = 3-CH 2 OH; R 7 = CH 3 ; R8 = H; R 9 = H; R 11 = CH 3 and R 3 and R 4 have the meanings as described above, and including all possible stereo-isomers and 5 prodrugs as outlined above, thus as represented by the general formulas (5), (6) and (7): C1
R
3 NL CNR1~ ' HN N N OH NI I R N NN NOH 4H H (5) OH (6) CI N NN 4 H HJY 0 10 (7) Even more preferred is the compound having formula (8) and its enantiomers. Cl O 1 N(8) o0 N, N H H OH 15 The best mode of the invention is the compound represented by formula (9): WO 03/101980 PCT/EP03/50203 6 CI K * )"N"N" (9) oN N NR H H E OH This compound has an affinity for human adenosine-A 3 receptors of pKi 9.0 + 0.3. 5 The compounds of the invention and their salts can be obtained according to the general routes outlined below. Those with R 1 = Cl are synthesized according to scheme 1: CI R 2 CI
R
2 CI NRN N N R3 N N N 9) I'N C N CI R4 X N Cl R 4 X N Y scheme 1 10 Experimental details for the first step in this general route are given in: * J. Amer. Chem. Soc. 116, 1994, 4326 for X = NH; " Chem. Pharm. Bull. 45, 1997, 291 for X = N-alkyl; " Tetrahedron 56, 2000, 9705 for X = CH 2 ; 15 0 Pol. J. Chem. 74, 2000, 837 for X = 0; " J Chem. Soc. C 1967, 466 for X = S, and in * Tetrahedron 56, 2000, 9705 for X = carbon-carbon bond. The compounds of the invention with R 1 = F or Br can be obtained fully analogously 20 from the corresponding tri-halo derivatives. Experimental details are given in: * J. Med Chem. 36 (26), 4195-4200, 1993 for R 1 is F, and in " J. Prakt. Chem. 82, 536, 1910 for R 1 = Br. The compounds of the invention with R 1 = 0-alkyl(1-3C) or any of the amine 25 substituents: NH 2 , N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C) alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted C2-C8 cycloalkylamino group, can be obtained by further substitution of the chloro-derivatives as outlined below in scheme 2: WO 03/101980 PCT/EP03/50203 7
R
2 CI R2 R, 4RR X N Yi X N Y scheme 2 Experimental details are given in: e Heterocycles 31 (5), 895-909, 1990 for R 1 = alkoxy, and in 5 0 Tetrahedron, 54 (1998) 4051-4065 for R 1 = (substituted) amine. Compounds of the invention with R 1 = alkyl(1-3C), CF 3 or iodine can be obtained by following the sequence of synthetic steps outlined below in Scheme 3. c R, 2 R R 2 R N NN N' N R, NkN R3 - N N cl N cI CI N Cl R X N cI R N Y 10 Scheme 3 Experimental details are given in: 15 e J. Med Chem 42 (5), 805-818, 1999 for R, = alkyl, * J. Chem Soc., Chem Comm 1988, (10) 638-639 for R, = CF 3 , and in " Eur. J. Org. Chem., 2002, 4181-4184 for R, = iodine Pharmaceutically acceptable salts may be obtained using standard procedures well 20 known in the art, for example by mixing a compound of the present invention with a suitable acid. Suitable acid addition salts can be formed with inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid and nitric acid, or with organic acids such as 25 citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, trifluoro acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid. The compounds of the invention of the general formula (1), as well as the salts 30 thereof, have adenosine-A 3 (ant)agonistic activity. They are useful in the treatment of WO 03/101980 PCT/EP03/50203 8 disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation of those receptors. For instance in: acute and chronic pain, inflammatory diseases including, arthritis, multiple sclerosis, asthma and psoriasis; gastro-intestinal disorders such as ulcers, inflammatory bowel disease (Crohn's 5 disease) and ulcerative colitis; allergic responses such as eczema, atopic dermatitis and rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including chronic obstructive 10 pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; 15 diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. The adenosine-A 3 receptor (ant)agonistic properties of the compounds of the invention were determined using the method outlined below. 20 Receptor Binding to human adenosine-A 3 receptors Affinity of the compounds for human adenosine-A 3 receptors was determined using the receptor binding assay described by C.A. Salvatore et al.: Molecular cloning and 25 characterization of the human A 3 adenosine receptor, Proc. Natl. Acad. Sci. USA, 90, 10365-10369, 1993. Briefly, membrane preparations were obtained from human recombinant (HEK 293) cells in which the human adenosine-A 3 receptor was stably expressed. Membranes were incubated at 22 0 C for 90 minutes with [125l]-AB-MECA in the absence or presence of testcompounds in a concentration range from 10 pM 30 down to 0.1 nM, diluted in a suitable buffer. Separation of bound radioactivity from free was done by filtration through Packard GF/B glass fiber filters with several washings with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured with a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). Measured radioactivity was plotted against the 35 concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in ICsa values, i.e. that WO 03/101980 PCT/EP03/50203 9 concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pKI values were calculated by correcting the IC50 values for radioligand concentration and its affinity for the human adenosine-A 3 receptor according to the Cheng-Prusoff equation: 5 pKI = -log (IC5 / (1 + S/Kd)) in which the IC50 is as described above, S is the concentration [ 1 25 i]-AB-MECA used in the assay expressed in mol/l (typically 0.1 nM), and Kd is the equilibrium 10 dissociation constant of [ 125 ]-AB-MECA for human adenosine-A 3 receptors (0.22 nM). The compounds of the invention have a high affinity for adenosine-A 3 receptors in the binding assay described above. This property makes them useful in the 15 treatment of disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation of these receptors. EXAMPLES 20 (1 S,2R)-2-{[4-chloro-6-(3,4-methylenedioxy-phenylamino)-[1,3,5]triazin-2 yl]-amino}-1 -phenyl-propan-1 -ol To a solution of cyanuric chloride (1.84 gr) in acetonitrile (20 ml), kept at a temperature of - 200C under stirring, dropwise were subsequently added solutions of 25 3,4-methylenedioxy-aniline (1.37 gr) in acetonitrile (20 ml) and diisopropylethylamine (DIPEA) (1.29 gr) in acetonitrile (20 ml). After stirring at - 20 0 C for 1 hour, again dropwise were subsequently added solutions of DIPEA (1.29 gr) in acetonitrile (20 ml) and (1S,2R)-(+)-norephedrine (1.51 gr) in acetonitrile (20 ml). The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The 30 resulting reaction mixture was concentrated in vacuo. After addition of ethylacetate (250 ml) the organic layer was subsequently washed with a solution of HCI in water (IM, 100ml) , a solution of NaOH in water (1M, 100 ml) and brine (50 ml). The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography using silicagel and a 35 mixture of heptane: ethylacetate (3:1) as the eluent. The resulting pure product (formula (9), see above, example B-44, see table) was obtained as a white solid in 80 % yield.
WO 03/101980 PCT/EP03/50203 10 The invention is further illustrated by means of the following specific examples listed in the tables below and represented by the general formula: R2 Ri
R
3
-
N I N N (1) 5 R4 d N;Y wherein Y represents a group of the general formula (A), (B) or (C): R, Re R7 Ri N R 9R9
R
5
R
6 OH
R
1 o Z (A) (B) (C) 10 These examples are only intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way.
WO 03/101980 PCT/EPO3/50203 11 0000000000c0111J OOOOOOOOOOOOOOOO0I 0000t=='= 0- 0 3: I u s- U L)O 0 C E -1r000 000000 0 000 0 0 I,- comNIqC Lo" WO 03/101980 PCT/EP03/50203 12 V- T- -- -- T. V- V- T- -- T-T -T = C a0 3 0 r 6 0 000~ 0 0 E -6 E 6666666666666 K 14 4 N NN IN IN IN N N 00 xZZZZzz z z z z z z z o ( ZZZZZ Z Z Z Z Z ~ Cl
I
~>
L.S
WO 03/101980 PCT/EP03/50203 13 000000999 " 00 E z~ 00Z'L~J 0 xzzzzzzzzzz M O o r- m w owwtot r WO 03/101980 PCT/EP03/50203 14 X:3 E:r 3 = MIZI ZI m 3: x : : 3 : - = - - - = M 3: X 3- M: 3 -M o~t =ZZZ~ ==Z =ZZZ ZZZZ ZZZ= =Z= L)I =='.m~ 0000'-0 0 E m c 3:= - 5 C C 0003: L) 0 00 0 0~ 3:M: CM a :M0u- )00u 3 I ~ ~ ~ L 0 0 J~C' ~ mmmmmmmuu WO 03/101980 PCT/EP03/50203 U) ' - I- V"T T- T V. T-Il I - T. - T - T - - - r. V- V- T- V- T- T Lo co M~Z X :ma : 00 66 OOOO000000000 ~ 00000000 >, C, - I I I N lc 1 I zz WO 03/101980 PCT/EP03/50203 16 0 0 =1=111 00000 3:1= = ED co mmca 3: 000000 0 0 0 0 666666666 NN cm N NN 000o000 66666666 zzzzzz 0 0 75 ;5cu Mzzzzzzzzzzz E- .. T.. L~ 0 z 0 z rz~o
C?
WO 03/101980 PCT/EP03/50203 17 EXAMPLES OF PRODRUGS To illustrate the concept 'prodrugs' the following compounds with the general formula (10) have been prepared: 5 CI N N N H H OR example R-group Pro-I propionyl Pro-2 pivaloyl Pro-3 nicotinoyl Pro-4 N-acetyl-isonipecotyl Pro-5 methoxyacetyl Pro-6 acethoxyacetyl Pro-7 nonaoyl Prodrugs having formula (10) have no affinity for human adenosine-A3 receptors, 10 but after hydrolysis they generate the compound with formula (9) (see above) which is highly active.

Claims (14)

1. Compounds of the general formula (1) R2 RI R 3 N N (1) 5 RA X N Y wherein: R, represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 , N-(di)-alkyl(1-3C), N-(dI)-alkenyl(1-3C), N-(di)-alkyny(1-3C), N-alkyl(1-3C)alkenyl(1-3C), 10 N-alkyl(1-3C)alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted 2-C cycloalkylamino group, R 2 , R3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, 0-alkyl(1 3C), 15 phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1 3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, 20 benzodioxane, benzodioxolane or naphthalene ring system, X represents NH, N-alkyl(1-3C), CH 2 , 0, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C): 25 R8 R R RR 70 R 9 RN R 9 R 5 R 6 I OH I~N (A) (B) (C) 30 in which: WO 03/101980 PCT/EP03/50203 19 R 5 is either OH or CH 2 OH R 6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) 5 or hydroxyalkyl(1-2C); n has the value of 0, 1 or 2; R 7 represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), 10 R 8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, 0-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , or SO 2 CH 3 , 15 R 10 represents H or alkyl(1-3C), R 11 represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), Z represents NOH, NOalkyl(1-3C), 0 or S, 20 pharmacologically acceptable salts thereof, and all compounds having formula (1) in which the substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, as well as prodrugs thereof. 25
2. Compounds as claimed in claim 1 of the general formula (1) wherein R 1 represents halogen, alkyl(1 -3C), O-alkyl(1 -3C), CF 3 , NH 2 or N-(di)-alkyl(1 3C); R 2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), phenyl, 30 N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , S02CH 3 , or R 2 and R 3 together with the phenyl ring to which they are attached, represent a benzofuran, benzodioxane, or benzodioxolane ring system, X repre-sents NH, N-alkyl(1-3C), CH 2 , 0, S or a carbon-carbon bond, Y represents a group of the general formula (A) or (B), in which R 5 is either 35 OH or CH 2 OH; R 6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl WO 03/101980 PCT/EP03/50203 20 (1-2C); n has the value of 0, 1 or 2; R 7 represents alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R 8 and R 9 independently represent H, halogen, alkyl(1 3C), CF 3 , OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , or SO 2 CH 3 ; and R 10 =H 5
3. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (A) and R 1 , R 2 , R 3 , R 4 , R 5 , RG, X and n have the meanings as in claim 1. 10
4. Compounds as claimed in claim I of the general formula (1) wherein Y is a group of the general formula (A) and R 1 , R 2 , R 3 , R 4 , R
5 , R 6 , X and n have the meanings as in claim 2. 15 5. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (B) and R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , RIO and X have the meanings as in claim 1.
6. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a 20 group of the general formula (B) and R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , RIO and X have the meanings as in claim 2.
7. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (C) and R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R 10 , R 11 , X and Z 25 have the meanings as in claim 1.
8. Compounds as claimed in claim 1 having formula (1) wherein R 1 = Cl, R 2 =H, X=NH, Y is either group (A), (B) or (C), R 6 = H, n=1, Z=O, RIO=H and R 3 , R 4 , R 5 , R 7 , R 8 , R 9 and R 11 have the meanings as in claim 1 30
9. Compounds as claimed in claim 1 having formula (1) wherein R 1 = Cl, R 2 =H, X=NH, Y is either group (A), (B) or (C), R 5 = 3-CH 2 OH, R 6 = H, n=1, R 7 = CH 3 ; R8 = H; R 9 = H, Z=O, R 10 =H, R 11 = CH 3 and R 3 and R4, have the meanings 35 as in claim 1 WO 03/101980 PCT/EP03/50203 21
10. Compound as claimed in claim 1 having formula (8) and enantiomers thereof: CI K I I (8) o N N% N H HJY OH
11. Compound as claimed in claim 1 having formula (9) 5 CI K N 1 N R 0 9 H H E OH
12. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in one of the claims 1-11 as an 10 active ingredient,
13. Use of a compound as claimed in one of the claims 1-11 for the preparation of a pharmaceutical composition for the treatment of disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation 15 of those receptors,
14. Use as claimed in claim 13 characterized in that said disorders are acute and chronic pain, inflammatory diseases including, arthritis, multiple sclerosis, asthma and psoriasis; gastro-intestinal disorders such as ulcers, 20 inflammatory bowel disease (Crohn's disease) and ulcerative colitis; allergic responses such as eczema, atopic dermatitis and rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological 25 disorders like glaucoma; respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's WO 03/101980 PCT/EP03/50203 22 disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. 5
AU2003250232A 2002-05-30 2003-05-28 1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors Ceased AU2003250232B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP02077310 2002-05-30
EP02077310.7 2002-05-30
PCT/EP2003/050203 WO2003101980A1 (en) 2002-05-30 2003-05-28 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors

Publications (2)

Publication Number Publication Date
AU2003250232A1 true AU2003250232A1 (en) 2003-12-19
AU2003250232B2 AU2003250232B2 (en) 2008-09-11

Family

ID=29595045

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2003250232A Ceased AU2003250232B2 (en) 2002-05-30 2003-05-28 1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors

Country Status (16)

Country Link
EP (1) EP1513827A1 (en)
JP (1) JP4590260B2 (en)
CN (1) CN1329388C (en)
AR (1) AR040231A1 (en)
AU (1) AU2003250232B2 (en)
BR (1) BR0304925A (en)
CA (1) CA2484981C (en)
HK (1) HK1075045A1 (en)
HR (1) HRP20040970A2 (en)
IL (1) IL164240A (en)
MX (1) MXPA04011948A (en)
PL (1) PL372418A1 (en)
RU (1) RU2312859C2 (en)
UA (1) UA77816C2 (en)
WO (1) WO2003101980A1 (en)
ZA (1) ZA200408029B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2533397A1 (en) * 2003-07-22 2005-02-03 Neurogen Corporation Substituted pyridin-2-ylamine analogues
WO2005028467A1 (en) 2003-09-15 2005-03-31 Anadys Pharmaceuticals, Inc. Antibacterial 3,5-diaminopiperidine-substitute aromatic and heteroaromatic compounds
GB2465405A (en) * 2008-11-10 2010-05-19 Univ Basel Triazine, pyrimidine and pyridine analogues and their use in therapy
ES2665561T3 (en) 2012-07-04 2018-04-26 Agro-Kanesho Co., Ltd. Ester derivative of 2-aminonicotinic acid and bactericide containing the same as active ingredient
GB201810668D0 (en) 2018-06-28 2018-08-15 Stiftelsen Alzecure New compounds

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9226735D0 (en) * 1992-12-22 1993-02-17 Ici Plc Azole derivatives
DE19735800A1 (en) * 1997-08-18 1999-02-25 Boehringer Ingelheim Pharma Use of known and new triazine derivatives
JPH11158073A (en) * 1997-09-26 1999-06-15 Takeda Chem Ind Ltd Adenosine a3 antagonist

Also Published As

Publication number Publication date
AR040231A1 (en) 2005-03-23
JP2005531600A (en) 2005-10-20
IL164240A (en) 2010-12-30
AU2003250232B2 (en) 2008-09-11
CA2484981A1 (en) 2003-12-11
ZA200408029B (en) 2005-10-06
UA77816C2 (en) 2007-01-15
PL372418A1 (en) 2005-07-25
CA2484981C (en) 2011-07-26
WO2003101980A1 (en) 2003-12-11
RU2004138803A (en) 2005-06-10
RU2312859C2 (en) 2007-12-20
CN1646520A (en) 2005-07-27
EP1513827A1 (en) 2005-03-16
MXPA04011948A (en) 2005-03-31
CN1329388C (en) 2007-08-01
BR0304925A (en) 2004-09-28
JP4590260B2 (en) 2010-12-01
HRP20040970A2 (en) 2005-06-30
IL164240A0 (en) 2005-12-18
HK1075045A1 (en) 2005-12-02

Similar Documents

Publication Publication Date Title
EP2927231B1 (en) Imidazopyridine compounds
KR101086678B1 (en) Processes for the preparation of 4-[[4-[[4- (2-cyanoethenyl)-2, 6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
CA2832530C (en) Hsp90 inhibitors
Hubschwerlen et al. Pyrimido [1, 6-a] benzimidazoles: a new class of DNA gyrase inhibitors
KR20180005248A (en) Synthesis of heterocyclic compounds
CN116589459A (en) Apoptosis inducer
AU2009306733B2 (en) Sulfoximine-substituted anilinopyrimidine derivatives as CDK inhibitors, the production thereof, and use as medicine
CA2268051A1 (en) Neuropeptide-y ligands
HU225270B1 (en) 2,4-diamino-1,3,5-triazine derivatives, process for their preparation, their use for the preparation of pharmaceutical compositions and the pharmaceutical compositions containing them
AU5675399A (en) Potassium channel inhibitors and method
KR20150041650A (en) Processes for the preparation of (s)-3-4-((4-(morpholinomethyl) benzyl)oxy)-1-oxoisoindolin-2-yl) piperidine-2,6-dione and pharmaceutically acceptable forms thereof
PH12015500716B1 (en) N-prop-2-ynyl carboxamide derivatives and their use as trpa1 antagonists
WO2004054584A1 (en) Novel quinoxalinone derivatives as bradykinin b1 antagonists
WO2008147831A1 (en) Anthranilamides
EP0018151B1 (en) 6-substituted-arylpyrido(2,3-d)pyrimidin-7-amines, derivatives and salts thereof, pharmaceutical compositions containing any of the foregoing, and processes for producing any of the foregoing
KR20030086338A (en) Method for the production of 4,6-diaminopyrimido[5,4-d]pyrimidines
JP2010509233A (en) Novel sEH inhibitors and their use
AU2003250232A1 (en) 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors
KR20160023676A (en) ARYL SULTAM DERIVATIVES AS RORc MODULATORS
US20040038972A1 (en) 1,3,5-Triazine derivatives as ligands for human adenosine-A3 receptors
WO2004000321A1 (en) Thiazine and oxazine derivatives as mmp-13 inhibitors for treating arthritis
WO2022152315A1 (en) Synthesis method for aminopyrimidine fak inhibitor compound
FI82456C (en) Process for the preparation of novel therapeutically useful 1-phenyl-1,2,4-thiadiazine-1-oxide derivatives
FI111842B (en) A process for the preparation of 2-substituted 4,6-dialkoxypyrimidines
KR20050019724A (en) 1,3,5-Triazine derivatives as ligands for human adenosine-A3 receptors

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
MK14 Patent ceased section 143(a) (annual fees not paid) or expired