Europäisches Patentamt

(19) European Patent Office Office européen des brevets (11) EP 1 002 535 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int. Cl.7: A61K 31/435, A61K 31/55, 24.05.2000 Bulletin 2000/21 A61K 31/495 (21) Application number: 98250380.7

(22) Date of filing: 28.10.1998

(84) Designated Contracting States: (71) Applicant: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Ikonomidou, Hrissanthi MC NL PT SE 13505 Berlin (DE) Designated Extension States: AL LT LV MK RO SI (72) Inventor: Ikonomidou, Hrissanthi 13505 Berlin (DE)

(54) New use of glutamate antagonists for the treatment of cancer

(57) New therapies can be devised based upon a are likely to be useful in treating cancer and can be for- demonstration of the role of glutamate in the pathogen- mulated as pharmaceutical compositions. They can be esis of cancer. Inhibitors of the interaction of glutamate identified by appropriate screens. with the AMPA, kainate, or NMDA receptor complexes EP 1 002 535 A1 Printed by Xerox (UK) Business Services 2.16.7 (HRS)/3.6 12EP 1 002 535 A1

Description system, seizures and hypoglycemia. In addition, gluta- mate is thought to be involved in the pathogenesis of [0001] Glutamate is a major neurotransmitter but chronic neurodegenerative disorders, such as amyo- possesses also a wide metabolic function in the body. It trophic lateral sclerosis, Huntington's, Alzheimer's and is released from approximately 40% of synaptic termi- 5Parkinson's disease. Functional glutamate receptors nals and mediates many physiological functions by acti- have been also identified in lung, muscle, pancreas and vation of different receptor types (Watkins and Evans bone (Mason DJ, Suva LJ, Genever PG, Patton AJ, (1981) Excitatory amino acid transmitters, Annu. Rev. Steuckle S, Hillam RA, Skerry TM (1997) Mechanically Pharmacol., 21: 165-189; Gasic and Hollmann (1992) regulated expression of a neural glutamate transporter Molecular neurobiology of glutamate receptors, Annu. 10 in bone: a role for excitatory amino acids as osteotropic Rev. Physiol., 54: 507-536). Two main categories of agents? Bone 20: 199-205; Patton AJ, Genever PG. glutamate receptors have been identified, ionotropic Birch MA, Suva LJ, Skerry TM (1998) Expression of an and metabotropic (Bettler and Mulle, (1995) Neuro- N-methyl-D-aspartate-type receptor by human and rat transmitter Receptors II, AMPA and Kainate Receptors, osteoblasts and osteoclasts suggests a novel glutamate Neuropharmacology, 34: 123-139; Pin and Duvoisin 15 signaling pathway in bone, Bone 22; 645-649). How- (1995) Neurotransmitter receptors I, The Metabotropic ever, no link has been established so far between gluta- Glutamate Receptors: Structure and Functions, Neu- mate receptor stimulation and tumor growth. ropharmacology, 34: 1-26; Mori and Mishina (1995) [0003] Many forms of cancer have been described Neurotransmitter Receptors VIII, Structure and Func- affecting every form of tissue known in man. Of the tion of the NMDA Receptor Channel, Neuropharmacol- 20 described forms of human cancer, none is curable in ogy, 34: 1219-1237). Ionotropic glutamate receptors 100% of the affected patients. Treatment modes include can be subdivided into N-methyl-D-aspartate (NMDA), surgical removal, chemotherapy with cytostatic agents α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate alone or in combination with hormone receptor modula- (AMPA), and kainate receptors. Metabotropic glutamate tors and/or steroids and/or interferons, and radiation receptors can be subdivided into three classes, mGluRI, 25 (Hill R (1992): Cellular basis for radiotherapy, in The mGluRII and mGluRIII (Pin and Duvoisin (1995) Neuro- Basic Science of Oncology, McGraw-Hill, pp. 259-275). transmitter receptors I, The Metabotropic Glutamate [0004] The present inventor has provided evidence Receptors: Structure and Functions, Neuropharmacol- that glutamate antagonists supress tumor growth. This ogy, 34: 1-26). Five receptor subunits form the func- invention represents a major advance in the treatment tional NMDA receptor which is modulated by 30 of cancer. and polyamines and blocked by Mg2+ Activation of [0005] According to the present invention, gluta- NMDA receptors leads to influx of Na+ and K+- ions into mate antagonists which block glutamate function at the cell as well as Ca2+-ions, either through the receptor NMDA, AMPA or complexes, when channel itself or through voltage dependent Ca2+-chan- used in combination with cytostatic agents or physical nels (Bettler and Mulle, (1995) Neurotransmitter Recep- 35 measures, such as irradiation, will result in anticancer tors II, AMPA and Kainate Receptors, Neuro- activity superior to that achieved with cytostatic agents pharmacology, 34: 123-139; Mori and Mishina (1995) or physical measures alone. Neurotransmitter Receptors VIII, Structure and Func- tion of the NMDA Receptor Channel, Neuropharmacol- I. The term inhibitor of the interaction of glutamate ogy, 34: 1219-1237). Four different subunits, named 40 with the AMPA receptor complex applies to: GluR1-GluR4, form the AMPA receptor channel. AMPA receptors are highly permeable to Na+- and K+-ions. [0006] AMPA receptor assemblies lacking the GluR2 subunit are also permeable to Ca2+-ions (Hollmann M, Heine- 1. all agents that bind to the AMPA receptor and mann S (1994): Cloned glutamate receptors, Annu. 45 prevent or reduce the binding of glutamate to the Rev. Neurosci., 17: 31-108). AMPA binding site in a competitive- or non-compet- [0002] Kainate receptors are built from five subu- itive manner. These are antagonists of the binding nits, GluR5-7 as well as KA1 and KA2. Kainate receptor of glutamate to the AMPA receptor; associated ion channels are permeable to Na+- and K+- ions as well as Ca2+. Ca2+-permeability of kainate 50 2. all agents that do not bind to the AMPA receptor receptor associated ion channels is dependent on the binding site but bind or interact with AMPA receptor presence of the GluR6 subunit within the receptor com- modulatory sites and thus prevent glutamate from plex (Hollmann M, Heinemann S (1994): Cloned gluta- triggering the signal that would occur when gluta- mate receptors, Annu. Rev. Neurosci., 17: 31-108). mate binds to the AMPA binding site; There is considerable experimental and clinical evi- 55 dence indicating that glutamate is involved in the patho- 3. all agents that interact directly with the AMPA-ion genesis of neuronal degeneration in the context of channel, i.e. AMPA receptor channel blockers. hypoxia/ischemia and trauma of the central nervous These agents reduce permeability of the ion chan-

2 34EP 1 002 535 A1

nels associated with the AMPA receptor to ions associated with the KA receptor to ions (preferably (preferably Na+, K+ and/or Ca2+); Na+, K+ and/or Ca2+).

4. all agents that decrease the release of glutamate 4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus pre- 5from nerve endings or other tissues and thus pre- vent glutamate from binding to the AMPA binding vent glutamate from binding to the KA binding sites sites and from triggering the signal that would occur and from triggering the signal that would occur as a as a result of binding of glutamate to AMPA binding result of binding of glutamate to KA binding site; site; 10 5. all agents that decrease synthesis of glutamate 5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to its bind- and thus prevent glutamate from binding to its bind- ing sites; ing sites; 6. all agents that increase the metabolism of gluta- 6. all agents that increase the metabolism of gluta- 15 mate and therefore prevent glutamate from trigger- mate and therefore prevent glutamate from trigger- ing the signal that would occur as a result of binding ing the signal that would occur as a result of binding of glutamate to its binding sites; of glutamate to its binding sites; 7. all agents that increase the uptake of glutamate 7. all agents that increase the uptake of glutamate 20 and thus decrease the binding of glutamate to KA and thus decrease the binding of glutamate to binding site; AMPA binding site; 8. all agents that interfere with glutamate trans- 8. all agents that interfere with glutamate trans- porter systems and decrease the concentration of porter systems and decrease the concentration of 25 glutamate in synaptic cleft and thus prevent gluta- glutamate in synaptic cleft and thus prevent gluta- mate from triggering the signal that would occur as mate from triggering the signal that would occur as a result of binding of glutamate to its binding sites; a result of binding of glutamate to its binding sites; 9. all agents that interact with glutamate and pre- 9. all agents that interact with glutamate and pre- 30 vent its binding to the KA receptor. Such com- vent its binding to the AMPA receptor. Such com- pounds include e.g. glutamate partial agonists or pounds include i.e. glutamate partial agonists or molecules binding to glutamate; molecules binding to glutamate; 10. antibodies to KA receptor subunits, or to the KA 10. antibodies to AMPA receptor subunits, or to the 35 receptor, or to glutamate decreasing the binding of AMPA receptor, or to glutamate decreasing the glutamate to KA binding site. binding of glutamate to AMPA binding site. III. The term inhibitor of the interaction of glutamate II. The term inhibitor of the interaction of glutamate with the NMDA/glycine/polyamine receptor complex with the KA receptor complex applies to: 40 applies to:

[0007] [0008]

1. all agents that bind to the KA receptor and pre- 1. all agents that bind to the NMDA receptor or vent or reduce the binding of glutamate to the KA 45 NMDA associated glycine or polyamine binding site in a competitive- or non-competitive binding site and prevent or reduce the binding of manner. These are antagonists of the binding of glutamate to the NMDA binding site in a competi- glutamate to the KA receptor; tive- or non-competitive manner. These are antago- nists of the interaction of glutamate with the NMDA 2. all agents that do not bind to the KA receptor 50 receptor; binding site but bind or interact with KA receptor modulatory sites and thus prevent glutamate from 2. all agents that do not bind to the NMDA receptor triggering the signal that would occur when gluta- binding site but bind or interact with NMDA receptor mate binds to the KA binding site; modulatory sites and thus prevent glutamate from 55 triggering the signal that would occur when gluta- 3. all agents that interact directly with the KA-ion mate binds to the NMDA binding site; channel, i.e. KA receptor channel blockers. These agents reduce permeability of the ion channels 3. all agents that interact directly with the NMDA-ion

3 56EP 1 002 535 A1

channel, i.e. NMDA receptor channel blockers. azepine, amino- or desamino-2,3-benzodiazepine, ben- These agents reduce permeability of the ion chan- zothiadiazine, β-carboline-3-carboxylic acid, fused nels associated with the NMDA receptor to ions cycloalkylquinoxalinediones, decahydroisoquinoline, 4- (preferably Na+, K+ and Ca2+). hydroxypyrrolone, 4-hydroxy-pyrrolo-pyridazinone, imi- 5dazo-pyrazinone, imidazolo-quinoxalinone, indeno- 4. all agents that decrease the release of glutamate pyrazine-carboxylic acid, indeno-pyrazinone, indolone- from nerve endings or other tissues and thus pre- oxime, indolo-pyrazinone, isatine, isatinoxime, oxadia- vent glutamate from binding to the NMDA binding zole, phenyl-azolophthalazine, phenylpyridazino-indole- sites and from triggering the signal that would occur 1,4-dione, quinoline, quinolinone, , quinoxa- as a result of binding of glutamate to NMDA binding 10 linedione, quinazolinone, quinolone, nitroquinolone, and site; sulphamate derivatives.

5. all agents that decrease synthesis of glutamate B. AMPA receptor channel blockers - and thus prevent glutamate from binding to NMDA and NMDA channel associated binding sites; 15 [0012] AMPA receptor channel blockers refer to compounds that reduce the permeability of channels 6. all agents that increase the metabolism of gluta- associated with the AMPA receptor to cations (prefera- mate and therefore prevent glutamate from trigger- bly to Na+, K+ and/or Ca2+ ions). AMPA receptor chan- ing the signal that would occur as a result of binding nel blockers can therefore be used to prevent a signal of glutamate to NMDA and NMDA channel sites; 20 being transmitted due to ionic flux that would otherwise occur when glutamate binds to the AMPA receptor. 7. all agents that increase the uptake of glutamate [0013] AMPA receptor channel blockers include e.g. and thus decrease the binding of glutamate to fluorowillardiine, Joro spider toxin, NSTX spider toxin, NMDA binding site; argiotoxin. 25 8. all agents that interfere with glutamate trans- C. KA receptor antagonists - porter systems and decrease the concentration of glutamate in synaptic cleft and thus prevent gluta- [0014] KA receptor antagonists refer to compounds mate from triggering the signal that would occur as that bind to KA receptors in a competitive manner or a result of binding of glutamate to NMDA binding 30 interact with KA receptor associated sites and block KA sites; mediated signal in a non-competitive manner. [0015] Such antagonists include L-glutamate deriv- 9. all agents that interact with glutamate and pre- atives, derivatives, acid amide derivatives, vent its binding to the NMDA receptor. Such com- aminoalkanoic acid derivatives, aminophenyl(alkyl)ace- pounds include e.g. glutamate partial agonists or 35 tic acid derivatives, fused cycloalkylquinoxalinediones, molecules binding to glutamate; , imidazolo-quinoxalinone, isatine, phenylazolophthalazine, pyridothiazines, 4-phospho- 10. antibodies to NMDA receptor subunits, or to the noalkyl-quinolinone, quinolinone, quinazoline, quinazo- NMDA receptor, or to glutamate decreasing the linedione, quinoxalinedione and sulphamate deriv- binding of glutamate to NMDA binding site. 40 atives.

[0009] Various glutamate antagonists and receptor D. KA receptor channel blockers - channel blockers that are within the scope of the present invention will now be described in greater detail: [0016] KA receptor channel blockers refer to com- 45 pounds that reduce the permeability of channels associ- A. AMPA receptor antagonists - ated with the KA receptor to cations (preferably to Na+, K+ and/or Ca2+ ions). KA receptor channel blockers can [0010] AMPA receptor antagonists refer to com- therefore be used to prevent a signal being transmitted pounds that bind to AMPA receptors in a competitive due to ionic flux that would otherwise occur when gluta- manner or interact with AMPA receptor associated sites 50 mate binds to the KA receptor. and block AMPA mediated signal in a non-competitive [0017] KA receptor channel blockers include i.e. manner. Joro spider toxin, NSTX spider toxin and argiotoxin 636. [0011] Such antagonists include L-glutamate deriv- atives, amino alkanoic acid derivatives, α-amino-3- E. NMDA/glycine/polyamine receptor antagonists - hydroxy-5-methyl-4-isoxazolepropionate derivatives, 55 acetyl-aminophenyl-dihydro-methyl-dioxolobenzodi- [0018] NMDA/glycine receptor antagonists refer to azepine, acid amide derivatives, amino-phenyl-acetic compounds that bind to NMDA receptors in a competi- acid, 2,3-benzodiazepin-4-one, alkoxy-phenyl-benzodi- tive manner or interact with NMDA receptor associated

4 78EP 1 002 535 A1 sites and block NMDA mediated signal in a non-compet- derivative or its salts, a 2-amino-3,4-dioxo-1- itive manner. cyclobutene derivative, a 2-acyl-amido derivative of [0019] Such antagonists include L-glutamate deriv- 3,4-dihydro-3-oxo-quinoxaline, a benzimidazole phos- atives, tetrahydroquinoline, imidazoloquinoxalinone, phono-aminoacid derivative, a quinoxaline phosphono- isatine, fused cycloalkylquinoxalinediones, quinoxaline, 5aminoacid derivative, a piperazine, piperidine or pyrro- , a 4-hydroxy-3-nitro-1,2-dihydroquinolon-2- lidone derivative, ist salts and isomeric forms including one derivative, an indole derivative , a benzo-thiadi- stereoisomers, a 4-hydroxy-2(1H)-quinolinone deriva- azine dioxide derivative, an indeno(1,2-b)pyrazin-3-one tive, ist salts and prodrugs, a fused pyrazine derivative, or corresponding 2,3-dione, a quinoline derivative, an a 2-phenyl or 2-thienyl-(2)-piperidine derivative, a 3- ethyl(phenylcarbamoyl)-ethenyl)dichloroindole carboxy- 10 amido or 3-sulphamido-indolyl derivative, a 3-aryl-4- late, a thienopyrazine 2,3-dione derivative, a 2-(2,3- hydroxy-2-(1H)-quinolone derivative, a 2-heterocyclyl-2- dicarboxycyclopropyl) glycine, a 2-amino-3-substituted hydoxy-ethylamine derivative, a 1-aryl-2-aminomethyl phenyl propionic acid derivative, 1-carboxyalkylquinoxa- pyrrolidine, its optical isomers and acid-addn. salts, a line-2.3(1H,4H)dione derivative, a thienyl-glycine deriv- 4,6-dihalo indole-2-carboxylic acid derivative, a cyclic ative, a benzo-fused azacyclic compounds, an 15 aminohydroxamate derivative, a tetracyclic amine deriv- indole derivatives, a tricyclic quinoxaline-diene deriva- ative, a 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivative, tive, a 3-hydroxy anthranilic acid and salts, a decahydr- a 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivative, a 3- oisoquinoline compound, a tri- or terta-substituted phosphonopiperidine and p-pyrrolidine derivative, a guanidine derivatives, a D- or L-tryptophan derivative, a benzothieno (2,3-B)-pyrazine-2,3-(1H,4H)-dione, a tetrazolyl(alkyl)-cyclohexyl-aminoacid derivative, an 20 spiro dibenzosuberane derivative, a benzomorphan octahydrophenanthrene derivative, a benzomorphan derivative, a preparation of 3,4-disubstituted 2-isoxazo- compound, a piperazinyl or piperidinyl-alkyl substi- line(s) and isoxazoles(s), a 3-indolyl thio-acetate deriv- tuted isoxazole derivative, a decahydroisoquinoline-3- ative, an arginine-derived biosynthesis carboxylic ester or amide preparation, a compounds inhibitor, a dicyclic amine derivative, a spiroisoindole based on -G peptide, a 3-heterocyclyl-alkyl- 25 derivative, an imidazo(1,2-A)-pyridinylalkyl compound, benzopyran-2-one derivative, a phosphono-alkyl imi- a 1,2,3,4-tetrahydro-9H-pyrido indole or benzothi- dazo-pyrimidine carboxylic acid derivative, amantidine, ophene derivative, an indole-2,3-dione-3-oxime deriva- , rimantidine, a histogranin peptide or ana- tive, a 1-aryl-2-(aminomethyl)cyclopropanecarbox- logue, a nitrobenzoic acid derivative, e.g 4-((2-methoxy- amide derivative, a 4-phosphono-2-amino-alkenoic acid carbonyl-4-nitrophenyl)methyl)piperazine carboxylic 30 derivative, a naphthopyran derivative, a beta-ketone, a acid, a diamine derivative with selective sigma receptor beta oxime or beta hydrazine phosphonate, a topa qui- affinity, (2-amino-N-(1,2-diphenyl-1-meth- none aminoacid, or a derivative, a quino- ylethyl)acetamide), a phosphono-alkylidene- or phos- line- or thienopyridine-carboxylic acid derivative, a 10,5- phono-alkoxy-imino-piperidine acid, a benzothiadiazine (imino-methano)-10,11-dihydro-5H- carboxylic acid derivative, a dihydro-benzothiadiazine 35 dibenzo(A,D)cycloheptene or a derivative, a bicyclic dioxide carboxylic acid derivative, a 4-hydroxy 2(H) pyr- amino-hydroxamate derivative, an indole-2-carboxylic rolone derivative, a quinoxaline derivative, a tetrahydro- acid derivative, a substituted adamantane derivative, a imidazo (1,2-a) pyrimidines or its salt, a alpha-amino benzobicycloalkane derivative, a 2,4-disubstituted- acid, a 4-hydroxy-pyrrolo(1,2-b)pyridazin-2(1H)-one 1,2,3,4-tetrahydro-quinoline derivative, a dihydro-alkyl- derivative, a nitroquinolone derivative, a 3-aryl-substd 40 substituted-(immunomethano)-5H-dibenzo-cyclohep- 2(1H)quinolone, a 2(1H)-quinolone, a phosphonic acid tene, an aryl cyclohexylamine, an N-substd. benzobicy- quinoline-2-carboxylic acid derivative, its per hydro qui- cloalkane amine, an isoquinoline phosphonate noline derivative or salt, a benzimidazole(s) carrying 2 derivative, an N,N'-disubstd.-guanidine compound, a acidic groups, an N,N'-disubstituted guanidine deriva- phosphonopropenyl piperidine carboxylic acid com- tive, a tricyclic quinoxaline dione, a 2-(2,3-dicarboxycy- 45 pound, (2R,3S,4S)-alpha-carboxycyclo-propyl-glycine, clopropyl) glycine stereoisomer, pregnenolone sulphate a pyrrolidine derivative, a dihydroxy-fused heterocyclyl or one of its derivative, an isatine derivative, a 3-amino- quinoxaline derivative, a hydrogenated derivative of MK indolyl-derivative, 2-phenyl-1,3-propanediol dicar- 801 and analogues, a 5-substd.10,11-dihydro 5H- bamate (), a benzomorphan derivative, a dibenzo (a,d) cycloheptene 5,10-imine, an 11-Exo- dihydrothienopyridine derivative, an enantiomer of (ami- 50 hydroxy MK 801 preparation including electrochemical nophenyl)-heteroaryl ethylamine, a pyridazine-dione cyclisation step to form 5,10-imine bridge in 5-methyl 5- derivative, a 2H-1-benzopyran-2-one compound, a 4- oxyamino 5H-dibenzo (A,D) cycloheptene, a tetra sulphonylamino-quinoline derivative, a R(plus)-3- hydro-isoquinoline or 2-benzazepine derivative, an N-3- amino-1-hydroxy-pyrrolidine-2-one, a 2-carboxy indole, phenylpropionyl-substd. spermine or related polyamine a substd. imino-methano dibenzo (A,D)cycloheptene 55 derivative, a 4a-amino-fluorene compound or a hetero- derivative, an indole-hydrazone, a piperazine derivative, cyclic analogue, a cyclooctane-imine derivative, a R-3- a 4,6-disubstituted tryptophan and deriva- amino-1-hydroxy pyrrolidin-2-one or methionine hydrox- tive, a fluorenamine compound, a diketo-pyrido pyrazine amate, a 10,11-dihydro-5H-dibenzo-cyclohepten-5,10-

5 91EP 1 002 535 A1 0 imine compound, a polyhydro-10,11-dihydro-5H- substd. 2-carboxy-indole derivative or intermediate, a benzo(a,d)cyclohepten-5,10 imine derivative, a 4-oxo- (2R)-N-trityl-4-oxo-5-(dimethyl phosphono)-nor-vali- 1,4-dihydroquinoline compound with 2-acidic groups, a nate ester, a kynurenic acid derivative, an indole car- heterocyclyl-alkene-phosphonic acid compound, a boxylic acid derivative, a 6-(tetrazolyl or isoxazolyl)- phosphono gp-containing pyridine 2-carboxylic acid, an 5decahydroisoquinoline-3-carboxylic acid derivative, a alpha-amino-alpha-(3-alkylphenyl)alkyl ethanoic acid, phenyl- or pyridinyl-thieno-pyridinone derivative, a fused its esters or amides, a 10,11-dihydro-5H-dibenzo-A,D- cycloalkyl-quinoxaline-dione derivative, a pyridazino- cyclohepten-5,10-imine compound, a phosphorus con- quinoline derivative, a 1-Alpha-amino-3-biphenyl-propa- taining unsatturated amino acid or its salts, a 5 Substd.- noic acid derivative, a 3-(Indol-3-yl)propenoic acid 1-,11-dihydro-5H-dibenzo-cyclohepten-5,10-imine or 10 derivative, a spiro-heterocycle-imidazo-indeno-pyra- analogue, a heterocyclic phosphonic acid derivative or zine-4-one derivative, a 2-heterocyclyl-3-indolylprope- its salt, a substituted 4-(amino-carbonyl-amino)quino- noic acid derivative, a piperidinoalkyl heterocyclic line derivative, a tricyclic quinoxaline derivative, a ketone or compound, a pyrrolyl-tetrahydro-ben- butyryl-tyrosine spermine or one of its analogue, a tri- or zoquinoxaline-dione derivative, a 7-imidazolyl or tetra-substituted guanidine, a quinoxalinylalkyl-aminoal- 15 dialkylamino,tetrahydroquinoxaline dione compound, a kane phosphonic acid derivative, a 2-(aminophenyl)-3- dibenzocycloheptene, a quinoxaline derivative, an aryl- (2-carboxy-indol-3-yl)-propenoic acid derivative, a 6- thio-quinoxaline derivative, a heterocyclic substd. imida- piperidinylpropionyl-2(3H)-benzoxazolone derivative, 6- zolo-quinoxaline derivative, a 1,4-dihydro-quinoxaline- (3-[4-(4-fluorobenzyl)piperidin-1-yl]propionyl)-3H-ben- 2,3-dione derivative, an oxa- or thia-aliphatically bridged zoxazol-2-one or one of its salts, an imidazo(1,2-a)pyri- 20 quinoxaline derivative, an aza-aliphatically bridged qui- dine compound, a tetrahydroquinoline derivative or one noxaline-2,3-dione compound, a 3-amido- or 3-sulpha- of ist salts, a 2-methyl-5,8-substituted 2,3,4,5-tetra- or mido-indole compound, a 3,5-disubstd. phenyl- 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, a 3- naphthalene derivative, an imidazo (1,2-a)indeno (1,2- aminoindolyl compound, a 6-pyrrolyl-quinoxaline-2.3- e) pyrazine-2-carboxylic acid derivative, a 3-phenyl- dione derivative, an imidazolyl-(mercaptoalkyl)-qui- 25 fused ring pyridine-dione derivative, a 2-phenyl-pyri- noxaline-dione compound, a 3-amidoindolyl derivative, dazino-indole-dione derivative, a 4,6-disubstd. kynure- a heterocyclyl-imidazolo-quinoxalinone compound, a nine compound, a phosphono derivative of imidazo(1,2- naphthyl-substituted alpha-amino acid derivative, a 5- a)pyrimidine-2-carboxamide, a tetrahydro-quinoxaline- heteroaryl-2,3-quinoxaline-dione derivative, a quinoxa- dione derivative with N-(alkyl)carbonyl-amino- or ureido line derivative, a 5H,10H-imidazo indeno 4-pyrazinone 30 group, a tryptophan derivative, a hetero-aliphatic or het- derivative, a hydroxy-(aryl-substituted phenyl)-qui- ero-araliphatic substd. quinolone derivative, an imidazo- nolone compound, an imidazo indolo pyrazinone deriv- pyridine dicarboxylic acid derivative, a composition con- ative, a ((phenyl-amino)-(m)ethyl)-pyridine derivative, a taining pyrazolo-quinoline derivatives, an ethanodihyd- tetrahydro-isoquinoline derivative, a 4-substituted pipe- robenzoquinolizinium salt, an oxopyridinylquinoxaline ridine analogue, a 2-substituted piperidine derivative, a 35 derivative, an indeno-triazolo-pyrazin-4-one derivative, tri- or tetra-substituted guanidine derivative, a 3- an imidazo-indeno-pyrazinone derivative, an imidazo- Hydroxy-4-imidazolidinone, a 3-aminoquinoxalin-2-one indeno-pyrazin-4-one derivative, an imidazo(1,2-a)pyra- derivative, rapamycin or a derivative e.g. 1,3-Diels Alder zine-4-one derivative, a 5H-indeno-pyrazine-2,3-dione adduct with phenyl-triazoline-dione, 1-amino-1-cyclobu- derivative, a phenyl-aminoalkyl- N,N-die- tanecarboxylic acid, a thiamorphinan derivative, a 40 thyl carboxamide compound, a derivative, pyrido[4,3-b]indole derivative, 4-phenyl carbamoyl a substituted chroman derivative, a sulphonamide methylene tetrahydro quinoline-2-carboxylic acid or a quinazoline-2-4-dione compound, a 6-and 8-aza-, and derivative thereof, (3R,4S)-3-(4-(4-fluorophenyl)-4- 6,8-diaza-1,4-dihydro-quinoxaline-2,3-dione derivative, hydroxy-piperidin-1-yl)-chroman-4,7-diol, a phenol a substituted quinoline derivative, a tetrazolylalkyl derivative, an indeno-pyrazin-4-one, a 2,3-dioxo- 45 cyclohexyl aminoalkanoic acid, a tricyclic indole 2-car- 1,2,4,5-tetrahydro-quinoxalinyl derivative, a 4,5-bridged boxylic acid derivative, a 6-substd-7H-imidazo-8-pyrazi- quinoxalinedione or quinolone, (1S,2S)-1-(4-hydroxy- none derivative, a quinoxaline dione derivative or one of phenyl)2-(4-hydroxy 4-phenyl piperidin-1-yl) 1-propanol its radiolabelled compounds, a tricyclic pyridazinopyrid- methane sulphonate trihydrate, a 4-sulphanimide-quin- ine derivative, an N-substituted heterocyclylideneme- oline derivative, a methanobenzocyclodecen-13-amine 50 thyl-indole carboxylic acid derivative, a 3-aza-8- compound, a derivatives of pregnenolone sulphate, a substituted-bicyclo(3.3.0)octane-2-carboxylic acid quinoxalinyl-(alkane,alkene,or alkyne)-phosphonic acid derivative, an ethano-heterocyclo-isoquinolinium salt, a or one of ist esters, a diarylalkylamine related to spider phenyl alkanolamine derivative, a dihydrobenzothiadi- and wasp venom toxins, a piperazine R-alpha-carboxy- azinedioxide carboxylic acid derivative, a methyl-bute- lic acid derivative, an imidazo-indeno-pyrazin-4-one 55 nylmethyl(hydroxy-propyl)carbazoledione, an imidazo derivative, a pyridazino-quinoline derivative, a 1-substi- pyrazinone derivative, an imidazo-(1,2-a)pyrazine-4- tuted. or 1,3-di-substituted. 1,3-diaryl-guanidine com- one, a benzazepine-dione derivative, disulfiram, a 3- pound, an aza-cycloalkyl-fused quinoxaline-dione, a 3- (indol-3-yl)-propenoic acid derivative, a 1,2,3,4-tetrahy-

6 11 EP 1 002 535 A1 12 dro-quinoline-2,3,4-trione-3 or 4-oxime compound, a phate, vanadyl acetylacetonate, methionine sulphox- peptide antagonist at NMDA receptors, a 2-amino-2- imine, chloroquine, amodiaquine, quinacrine, chinidine, phenyl(alkyl)-acetic acid derivative, 6-halo-tryptophan chinine, α-monofluoromethylputrescine and (R,R)- or a 4-halo-kynurenine, a 6-tetrazolyl or isoxazolyl-dec- delta-methyl-α-acetylenic-. ahydro-isoquinoline-3-carboxylic acid derivative, or an 5 imidazolylbenzene or salts thereof. J. Compounds accelerating glutamate uptake -

F. NMDA receptor channel blockers - [0027] Such agents decrease synaptic concentra- tion of glutamate by activating uptake mechanisms for [0020] NMDA receptor channel blockers refer to 10 glutamate preventing activation of either AMPA, kainate compounds that reduce the permeability of channels or NMDA receptors. associated with the NMDA receptor to cations (prefera- [0028] Compounds accelerating glutamate uptake bly to Na+ K+ and Ca2+ ions). NMDA receptor channel mechanisms include e.g. γ-glutamyl-transpeptidase. blockers can therefore be used to prevent a signal being transmitted due to ionic flux that would otherwise occur 15 K. Agents that interact with glutamate and prevent when glutamate binds to the NMDA receptor. its binding to its receptors - [0021] NMDA receptor channel blockers include i.e. , , , , [0029] Such agents include i.e. glutamate partial memantine, , , flupirtine, 1-[1-(2- agonists which activate glutamate receptors by them- thienyl)cyclohexyl]piperidine (TCP), (+)-(3S,4S)-7- 20 selves but are less active than glutamate at these hydroxy-delta6-tetrahydrocannabinol-1,1-dimethylhep- receptors and therefore decrease activation of these tyl (HU211). receptors by glutamate at physiological and excessively high concentrations or molecules binding to glutamate G. Glutamate release inhibitors - which change conformational state of glutamate and 25 therefore decrease its binding capability to its receptors. [0022] Such agents decrease the release of gluta- [0030] Glutamate partial agonists are e.g. D-, mate from nerve endings and prevent glutamate from D-, γ-L-glutamylglutamate, N-phthalamoyl- binding to either AMPA, kainate, or NMDA binding sites L-glutaminic acid, (R,S)-2-amino-3-[5-tert-butyl-3- and from triggering the signal that would occur as a (phosphonomethoxy)-4-isoxazolyl]propionic acid, α-N- result of binding of glutamate to these binding sites. 30 acetylaspartylglutamate, 1-aminocyclopropanecarboxy- [0023] Glutamate release inhibitors include e.g. rilu- lic acid, aminocyclobutane cyrboxylic acid, (+,R)-3- zole, lamotrigine, diphenylhydantoin, tetrodotoxin, aga- amino-1-hydroxy-2-pyrrolidine (HA966) and D,L-threo- toxin-glutamate-release-inhibitor (AG-GI), [5-(2,3,5- 3-hydroxyasparate. trichlorophenyl)]-2,4-diamino-pyrimidine (BW1003C87), [0031] Furthermore such agents include soluble (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) and 35 forms of NMDA, kainate or AMPA receptors or parts 4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichloroph- thereof These soluble forms can be used to circulate enyl)pyrimidine (BW619C89). and to bind to glutamate and therefore decrease its binding capability to the receptors. Membrane bound H. Glycine release inhibitors - forms of the glutamate receptors may also be incorpo- 40 rated into liposomes, circulate and bind to glutamate so [0024] Such agents decrease the release of glycine as to prevent it binding to its receptors. from nerve endings and prevent glycine from binding to glycine B binding sites and from triggering the signal L. Agents that interact with glutamate transporter that would occur as a result of binding of glutamate to systems - NMDA binding site. 45 [0032] Such agents accelerate glutamate trans- I. Glutamate synthesis inhibitors and interfer- porter function and decrease glutamate concentration ing with glutamate metabolism - at its receptors preventing activation of either AMPA, kainate or NMDA receptors. [0025] Such compounds block synthesis of gluta- 50 [0033] Such agents include e.g. 12-O-tetrade- mate or increase metabolism of glutamate preventing canoylphorbol-13-acetate, phorbol-12-myristate 13- activation of either AMPA, kainate or NMDA binding acetate. sites. [0026] Compounds interacting with glutamate syn- M. Antibodies interacting with AMPA receptors or thesis or metabolism and preventing activation of either 55 with glutamate - AMPA, kainate or NMDA receptors include e.g. gabap- entin, L-canaline, phenylsuccinate, , [0034] The AMPA, kainate or NMDA receptors or a putrescine, gentamicin, orthovanadate, vanadyl sul- part or parts of them, or glutamate can be used for rais-

7 13EP 1 002 535 A1 14 ing antibodies that bind thereto. Preferred antibodies rectal, nasal, topical (including buccal, sublingual or bind specifically to either AMPA, kainate or NMDA transdermal), vaginal or parenteral (including subcuta- receptor or a part thereof, or to glutamate. The antibod- neous, intramuscular, intravenous or intradermal) ies may be monoclonal or polyclonal. Polyclonal anti- routes. Such a composition may be prepared by any bodies can be raised by stimulating their production in a 5 method known in the art of pharmacy, for example by suitable animal host (e.g. a mouse, rat, guinea pig, rab- admixing one or more active ingredients with a suitable bit, sheep, goat or monkey) when either AMPA, kainate carrier. Preferably it will be provided in unit dosage form. or NMDA receptor, or a part thereof, or glutamate is It will normally be provided in a sealed, sterile container injected into the animal. If necessary an adjuvant may - e.g. in an ampoule, a vial, a bottle, a blister pack, or be administered together with the AMPA, kainate or 10 etc. Different delivery systems can be used to NMDA receptor, or a part thereof, or with glutamate. In administer pharmaceutical compositions of the present addition to whole antibodies, antagonists of the present invention, depending upon the desired route of adminis- invention include derivatives thereof. tration. Such systems include aerosols, tablets, cap- sules, lozengers, pastilles, powders, solutions, Therapeutic use 15 suspensions, syrups, ointments, pastes, oils, supposito- ries, enemas, pessaries, tampons, sprays, nebulizers, [0035] Glutamate inhibitors of the present invention injectable compositions, etc. may be used in human and veterinary medicine. Treat- [0039] Dosages of the inhibitors of the present ments may be prophylactic or may be in respect of exist- invention can vary between wide limits, depending upon ing conditions. 20 the nature of the treatment and the age and condition of [0036] The glutamate antagonists may be used in the individual to be treated. However, a daily dosage of the manufacture of a medicament for treating cancer. from 0.01 mg to 1000 mg, preferably of from 0.5-200 mg The term cancer is used herein to include any disorder may be suitable. The dosage may be repeated as often that results from abnormal and uncontrolled cell growth as appropriate. If side-effects develop, the amount with resulting invasion and destruction of neighbouring 25 and/or frequency of the dosage can be reduced, in tissue which can but must not set metastases to distant accordance with good clinical practice. tissues. The present invention includes within its scope pharmaceutically acceptable compositions useful in Diagnostic Use treating cancer which comprise a glutamate antagonist of the present invention. The antagonist will usually be 30 [0040] Diagnostic use is possible for testing provided in combination with a pharmaceutically whether a form of cancer is susceptible to treatment acceptable carrier. It may be used in any suitable form, with glutamate antagonists. This testing would involve provided that it can act in inhibiting the interaction of isolation and culturing of tumor cells and subsequently glutamate with the AMPA, KA or NMDA/gly- testing tumoricidal effect of glutamate antagonists alone cine/polyamine receptor complex. Pharmaceutically 35 or in combination with cytostatic agents, or immu- acceptable salts may also be used. nomodulating agents, or physical measures such as [0037] Pharmaceutical compositions within the irradiation, photomodulation, or hyperthermia. scope of the present invention may include one or more [0041] The present invention will now be described of the following: preserving agents, solubilising agents, by way of example only, with reference to the accompa- stabilising agents, wetting agents, emulsifiers, sweeten- 40 nying drawings, wherein: ers, colorants, odourants, salts, buffers, coating agents or antioxidants. They may contain a further therapeuti- - New use of glutamate antagonists (NMDA, AMPA cally active agent in addition to a antagonist of the and kainate receptor antagonists) and their physio- present invention. The further therapeutically active logically compatible salts for the preparation of agent may be a cytostatic agent, an immunomodulating 45 drugs for treatment of cancer is described. Active agent or physical measures such as irradiation, photo- combinations of NMDA, AMPA or kainate receptor modulation or hyperthermia. The agents of present antagonists with modes of therapy used in the treat- invention can also be combined with mono- or polyclo- ment of cancer are described. nal antibodies, antisense therapeutics, cancer vaccines, or gene therapy. 50 Examples [0038] The combination of an antagonist of the present invention and a further therapeutically active [0042] The tumor cell line SK-N-AS has been agent may be used simultaneously, separately or obtained from human neuroblastoma, a primary neur- sequentially to treat cancer. It may provide synergisti- oectodermal tumor. Agents active against tumor growth cally effective combination. A pharmaceutical composi- 55 in vitro have proved to also be effective anticancer tion within the scope of the present invention may be agents in vivo. adapted for administration by any appropriate route, for [0043] The surprising observation that the tumori- example by the oral (including buccal or sublingual), cidal effect of three different cytostatic agents, cisplatin,

8 15 EP 1 002 535 A1 16 vinblastin and thiotepa is significantly enhanced by two acid, amino-phenyl-acetic acid, amino- or desa- different AMPA antagonists, GYKI 52466 and NBQX mino- 2,3-benzodiazepine, 2,3-benzodiazepin-4- (2,3-dihydroxy-6-nitro-7-sulfaoylbenzo-(F)-quinoxaline) one, alkoxy-phenyl-benzodiazepine, acetyl-ami- and the NMDA antagonist MK 801 is described in the nophenyl-dihydro-methyl-dioxolo-benzodiazepine, following paragraphs. 5 benzothiadiazine, decahydroisoquinoline, β-carbo- [0044] Tumor cell line: SK-N-AS, obtained from line-3-carboxylic acid, fused cycloalkylquinoxaline- human neuroblastoma (European Collection of Cell dione, 4-hydroxypyrrolone, 4-hydroxy-pyrrolo- Cultures). Tumor cells were incubated in 96 well plates pyridazinone, indeno-pyrazine-carboxylic acid, indeno-pyrazinone, indoloneoxime, indolo-pyrazi- in culture medium in a CO2-incubator at 37°C. [0045] Exposure to agents: Tumor cells were 10 none, indolo-pyrazinone, imidazo-pyrazinone, imi- exposed to the following agents and concentrations: dazolo-quinoxalinone, isatine, isatinoxime, oxa- Cisplatin (10 µM), Vinblastin (1 µM), Thiotepa (10 µM) diazole, phenyl-azolophthalazine, phenylpyri- alone or in combination with MK 801 (10µM), GYKI dazino-indole-1,4-dione, quinoline, quinolone, qui- 52466 (10 µM) or NBQX (10 µM). nolonone, nitroquinolone, quinoxaline, quinox- [0046] Assessment of tumoricidal effect: Quantita- 15 alinedione, quinazolinone, 4-hydroxy-pyrrolo-pyri- tion of cell death was performed at 24, 48 or 72 hrs after dazinone, phenyl-azolophthalazine or sulphamate exposure to the agents of interest following staining of derivatives. the cells with trypan blue. This stain is taken up by necrotic cells. The numbers of necrotic cells/100 5. The use according to any of claims 1 to 4, counted cells served as quantitative measure for tumor- 20 wherein the inhibitor is L- dieth- icidal effect (% of tumor cell death). For each agent or ylester, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo- combination of agents and each time point 5 wells were (F)quinoxaline (NBQX), 6,7-dinitro-quinoxaline- analysed. Comparisons between groups was per- 2,3-dione (DNQX), 6-nitro-7-cyano-quinoxaline- formed by means of Student's t-test. 2,3-dione (CNQX), 6-(1-imidazolyl)-7-nitro-qui- 25 noxaline-2,3(1H, 4H)-dione (YM90K), [2,3-dioxo- Results 7(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1- quinoxalinyl]-acetic acid monohydrate (YM872), [0047] Each of the cytostatic agents tested pro- (3RS,4aRS,6RS,8aRS)-6-(2-(1H-tetrazole-5- duced a significant tumoricidal effect on its own at the yl)ethyl)-decahydroiso-quinoline-3-carboxylic acid concentrations used, which reached a peak for all three 30 (LY293558), 9-methyl-amino-6-nitro-hexahydro- agents after 72 hrs exposure time. The NMDA antago- benzo(F) quinoxalinedione (PNQX), 8-methyl-5-(4- nist MK 801 and the AMPA antagonists GYKI 52466 (N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetra- and NBQX significantly (P<0.05-0.001) potentiated hydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O- tumoricidal effect of cisplatin, vinblastin and thiotepa (3-hydroxybutyric acid-2-yl)oxime (NS 1209), 6,7- when used in combination with the cytostatic agents. 35 dichloro-2-(1H)-quinolinone-3-phosphonate (S This potentiation of the tumoricidal effect of the cyto- 17625-2), [1,2,3,4-tetrahydro-7-morpholinyl-2,3- static agents by the NMDA and the AMPA antagonists dioxo-6-(trifluoromethyl)quinoxalin-1 -yl]methyl- was most pominent after an exposure time of 72 hrs for phosphonate (ZK200775), 1-(4-aminophenyl)-4- cisplatin and thiotepa and 48 hrs for vinblastin (Figs. 1- methyl-7,8-methylene-dioxy-5H-2,3-benzodi- 3). 40 azepine (GYK152466), and 5-{2-[2- (N,N-dimethylamino)ethyl]oxy-phenyl}-3-phenyl- Claims 1,2,4-oxadiazol, 1-(4-aminophenyl)-3-methylcar- bamoyl-7,8-methylenedioxy-5H-2,3-benz odi- 1. The use of an inhibitor of the interaction of gluta- azepine (GYKI 53655). mate with the AMPA receptor complex in the manu- 45 facture of a medicament for treating cancer. 6. The use according to any of claims 1 to 2, wherein the inhibitor is an AMPA receptor channel blocker. 2. The use according to claim 1, wherein the type of cancer includes all kinds of cancer. 7. The use according to claim 6, wherein the AMPA 50 receptor channel blocker is fluorowillardiine, Joro 3. The use according to any preceding claim wherein spider toxin, NSTX spider toxin, argiotoxin, or their the inhibitor is an antagonist of the binding of gluta- derivatives. mate to the AMPA receptor. 8. The use of an inhibitor of the interaction of gluta- 4. The use according to any preceding claim, wherein 55 mate with the KA receptor complex in the manufac- the inhibitor is an L-glutamate derivative, an α- ture of a medicament for treating cancer. amino-3-hydroxy-5-methyl-4-isoxazolepropionate derivative, acid amide derivatives, amino alkanoic 9. The use according to claim 8, wherein the type of

9 17 EP 1 002 535 A1 18

cancer includes all kinds of cancer. to the NMDA receptor or NMDA receptor associ- ated binding sites such as e.g. glycine or polyamine 10. The use according to claim 8 and 9 wherein the binding sites. inhibitor is an antagonist of the binding of glutamate to the KA receptor. 5 18. The use according to claims 15 to 17, wherein the inhibitor is an L-glutamate derivative, a 4-hydroxy- 11. The use according to claims 8 to 10, wherein the 3-nitro-1,2-dihydroquinolon-2-one derivative, an inhibitor is an L-glutamate derivative, kainic acid indole derivative , a benzo-thiadiazine dioxide derivative, derivative, acid amide deriv- derivative, an indeno(1,2-b)pyrazin-3-one or corre- ative, aminoalkanoic acid derivative, aminophe- 10 sponding 2,3-dione, a quinoline derivative, an nyl(alkyl)acetic acid derivative, isatine, quinox- ethyl(phenyl-carbamoyl)-ethenyl)dichloroindole alinedione, fused cycloalkylquinoxalinedione, imi- carboxylate, a thienopyrazine 2,3-dione derivative, dazolo-quinoxalinone, phenyl-azolophthalazine, a 2-(2,3-dicarboxycyclopropyl) glycine, a 2-amino- pyridothiazines, quinazoline, quinazolinedione, qui- 3-substituted phenyl propionic acid derivative, 1- nolinone, 4-phosphonoalkyl-quinolinone, quinoxa- 15 carboxyalkylquinoxaline-2.3(1H,4H)dione deriva- linedione, or sulphamate derivative. tive, a thienyl-glycine derivative, a benzo-fused aza- cyclic compounds, an indole derivatives, a tricyclic 12. The use according to any of claims 8 to 11, wherein quinoxaline-diene derivative, a 3-hydroxy the inhibitor is 2,3-dihydroxy-6-nitro-7-sulfamoyl- anthranilic acid and salts, a decahydroisoquinoline benzo(F)quinoxaline (NBQX), 6,7-dinitro-quinoxa- 20 compound, a tri- or terta-substituted guanidine line-2,3-dione (DNQX), 6-nitro-7-cyano-quinoxa- derivatives, a D- or L-tryptophan derivative, a tetra- line-2,3-dione (CNQX), 6-(1-imidazolyl)-7-nitro- zolyl(alkyl)-cyclohexyl-aminoacid derivative, an quinoxaline-2,3(1H,4H)-dione (YM90K), [2,3-dioxo- octahydrophenanthrene derivative, a benzomor- 7(1H-imidazol-1 -yl)-6-nitro-1,2,3,4-tetrahydro-1- phan compound, a piperazinyl or piperidinyl-alkyl quinoxalinyl]-acetic acid monohydrate (YM872), 25 substituted isoxazole derivative, a decahydroisoqui- (3RS,4aRS,6RS,8aRS)-6-(2-(1H-tetrazole-5- noline-3-carboxylic ester or amide preparation, a yl)ethyl)-decahydroiso-quinoline-3-carboxylic acid compounds based on Conantokin-G peptide, a 3- (LY293558), 9-methyl-amino-6-nitro-hexahydro- heterocyclyl-alkyl-benzopyran-2-one derivative, a benzo(F)quinoxalinedione (PNQX), 8-methyl-5-(4- phosphono-alkyl imidazo-pyrimidine carboxylic acid (N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetra- 30 derivative, amantidine, memantine, rimantidine, a hydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-O- histogranin peptide or analogue, a nitrobenzoic (3-hydroxybutyric acid-2-yl)oxime (NS 1209), 6,7- acid derivative, e.g 4-((2-methoxycarbonyl-4-nitro- dichloro-2-(1H)-quinolinone-3-phosphonate phenyl)methyl)piperazine carboxylic acid, a (S17625-2), [1,2,3,4-tetrahydro-7-morpholinyl-2,3- diamine derivative with selective sigma recep- dioxo-6-(trifluoromethyl)quinoxalin-1-yl]methyl- 35 tor affinity, remacemide (2-amino-N-(1,2-diphe- phosphonate (ZK200775), 1-(aminophenyl)-4- nyl-1-methylethyl)acetamide), a phosphono-alkyl- methyl-7,8-methylenedioxy-5H-2,3-benzodi- idene- or phosphono-alkoxy-imino-piperidine acid, azepine (GYKI 52466), γ-D-glutamylaminomethyl- a benzothiadiazine carboxylic acid derivative, a sulphonate (GAMS), γ-D-glutamylglycine. dihydro-benzothiadiazine dioxide carboxylic acid 40 derivative, a 4-hydroxy 2(H) pyrrolone derivative, a 13. The use according to any of claims 8 to 9, wherein quinoxaline derivative, a tetrahydro-imidazo (1,2-a) the inhibitor is an KA receptor channel blocker. pyrimidines or its salt, a alpha-amino acid, a 4- hydroxy-pyrrolo(1,2-b)pyridazin-2(1H)-one deriva- 14. The use according to claim 13, wherein the KA tive, a nitroquinolone derivative, a 3-aryl-substd receptor channel blocker is fluorowillardiine, Joro 45 2(1H)quinolone, a 2(1H)-quinolone, a phosphonic spider toxin, NSTX spider toxin, argiotoxin, or their acid quinoline-2-carboxylic acid derivative, its per derivatives. hydro quinoline derivative or salt, a benzimida- zole(s) carrying 2 acidic groups, an N,N'-disubsti- 15. The use of an inhibitor of the interaction of gluta- tuted guanidine derivative, a tricyclic quinoxaline mate with the NMDA/glycine/polyamine recep- 50 dione, a 2-(2,3-dicarboxycyclopropyl) glycine stere- tor/ion channel complex in the manufacture of a oisomer, pregnenolone sulphate or one of its deriv- medicament for treating cancer. ative, an isatine derivative, a 3-amino-indolyl- derivative, 2-phenyl-1,3-propanediol dicarbamate 16. The use according to claim 1, wherein the type of (felbamate), a benzomorphan derivative, a dihydro- cancer includes all kinds of cancer. 55 thienopyridine derivative, an enantiomer of (ami- nophenyl)-heteroaryl ethylamine, a pyridazine- 17. The use according to claims 15 to 16 wherein the dione derivative, a 2H-1-benzopyran-2-one com- inhibitor is an antagonist of the binding of glutamate pound, a 4-sulphonylamino-quinoline derivative, a

10 19 EP 1 002 535 A1 20

R(plus)-3-amino-1-hydroxy-pyrrolidine-2-one, a 2- an 11-Exo-hydroxy MK 801 preparation including carboxy indole, a substd. imino-methano dibenzo electrochemical cyclisation step to form 5,10-imine (A,D)cycloheptene derivative, an indole-hydrazone, bridge in 5-methyl 5-oxyamino 5H-dibenzo (A,D) a piperazine derivative, a 4,6-disubstituted tryp- cycloheptene, a tetra hydro-isoquinoline or 2-ben- tophan and kynurenine derivative, a fluorenamine 5 zazepine derivative, an N-3-phenyl-propionyl-sub- compound, a diketo-pyrido pyrazine derivative or its std. spermine or related polyamine derivative, a 4a- salts, a 2-amino-3,4-dioxo-1-cyclobutene deriva- amino-fluorene compound or a heterocyclic ana- tive, a 2-acyl-amido derivative of 3,4-dihydro-3-oxo- logue, a cyclooctane-imine derivative, a R-3-amino- quinoxaline, a benzimidazole phosphono-ami- 1-hydroxy pyrrolidin-2-one or methionine hydroxa- noacid derivative, a quinoxaline phosphono-ami- 10 mate, a 10,11-dihydro-5H-dibenzo-cyclohepten- noacid derivative, a piperazine, piperidine or 5,10-imine compound, a polyhydro-10,11-dihydro- pyrrolidone derivative, ist salts and isomeric forms 5H-benzo(a,d)cyclohepten-5,10 imine derivative, a including stereoisomers, a 4-hydroxy-2(1H)-quino- 4-oxo-1,4-dihydroquinoline compound with 2- linone derivative, ist salts and prodrugs, a fused acidic groups, a heterocyclyl-alkene-phosphonic pyrazine derivative, a 2-phenyl or 2-thienyl-(2)-pipe- 15 acid compound, a phosphono gp-containing pyri- ridine derivative, a 3-amido or 3-sulphamido-indolyl dine 2-carboxylic acid, an alpha-amino-alpha-(3- derivative, a 3-aryl-4-hydroxy-2-(1H)-quinolone alkylphenyl)alkyl ethanoic acid, its esters or derivative, a 2-heterocyclyl-2-hydoxy-ethylamine amides, a 10,11-dihydro-5H-dibenzo-A,D-cyclo- derivative, a 1-aryl-2-aminomethyl pyrrolidine, its hepten-5,10-imine compound, a phosphorus con- optical isomers and acid-addn. salts, a 4,6- 20 taining unsatturated amino acid or its salts, a 5 Sub- dihalo indole-2-carboxylic acid derivative, a cyclic std.-1-,11-dihydro-5H-dibenzo-cyclohepten-5,10- amino-hydroxamate derivative, a tetracyclic amine imine or analogue, a heterocyclic phosphonic acid derivative, a 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivative or its salt, a substituted 4-(amino-carbo- derivative, a 2,4-dioxo-1,2,3,4-tetrahydroquinoline nyl-amino)quinoline derivative, a tricyclic quinoxa- derivative, a 3-phosphonopiperidine and p-pyrrolid- 25 line derivative, a butyryl-tyrosine spermine or one of ine derivative, a benzothieno (2,3-B)-pyrazine-2,3- its analogue, a tri- or tetra-substituted guanidine, a (1H,4H)-dione, a spiro dibenzosuberane derivative, quinoxalinylalkyl-aminoalkane phosphonic acid a benzomorphan derivative, a preparation of 3,4- derivative, a 2-(aminophenyl)-3-(2-carboxy-indol-3- disubstituted 2-isoxazoline(s) and isoxazoles(s), a yl)-propenoic acid derivative, a 6-piperidinylpropio- 3-indolyl thio-acetate derivative, an arginine- 30 nyl-2(3H)-benzoxazolone derivative, 6-(3-[4-(4- derived nitric oxide biosynthesis inhibitor, a dicyclic fluorobenzyl)piperidin-1-yl]propionyl)-3H-benzoxa- amine derivative, a spiroisoindole derivative, an imi- zol-2-one or one of its salts, an imidazo(1,2-a)pyrid- dazo(1,2-A)-pyridinylalkyl compound, a 1,2,3,4-tet- ine compound, a tetrahydroquinoline derivative or rahydro-9H-pyrido indole or benzothiophene one of ist salts, a 2-methyl-5,8-substituted 2,3,4,5- derivative, an indole-2,3-dione-3-oxime derivative, 35 tetra- or 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3- a 1-aryl-2-(aminomethyl)cyclopropanecarboxamide b]indole, a 3-aminoindolyl compound, a 6-pyrrolyl- derivative, a 4-phosphono-2-amino-alkenoic acid quinoxaline-2.3-dione derivative, an imidazolyl- derivative, a naphthopyran derivative, a beta- (mercaptoalkyl)-quinoxaline-dione compound, a 3- ketone, a beta oxime or beta hydrazine phospho- amidoindolyl derivative, a heterocyclyl-imidazolo- nate, a topa quinone aminoacid, kynurenic acid or a 40 quinoxalinone compound, a naphthyl-substituted derivative, a quinoline- or thienopyridine-carboxylic alpha-amino acid derivative, a 5-hetero-aryl-2,3- acid derivative, a 10,5-(imino-methano)-10,11-dihy- quinoxaline-dione derivative, a quinoxaline deriva- dro-5H-dibenzo(A,D)cycloheptene or a derivative, a tive, a 5H,10H-imidazo indeno 4-pyrazinone deriva- bicyclic amino-hydroxamate derivative, an indole-2- tive, a hydroxy-(aryl-substituted phenyl)-quinolone carboxylic acid derivative, a substituted adaman- 45 compound, an imidazo indolo pyrazinone deriva- tane derivative, a benzobicycloalkane derivative, a tive, a ((phenyl-amino)-(m)ethyl)-pyridine deriva- 2,4-disubstituted-1,2,3,4-tetrahydro-quinoline tive, a tetrahydro-isoquinoline derivative, a 4- derivative, a dihydro-alkyl-substituted-(immunom- substituted piperidine analogue, a 2-substituted ethano)-5H-dibenzo-cycloheptene, an aryl cyclo- piperidine derivative, a tri- or tetra-substituted gua- hexylamine, an N-substd. benzobicycloalkane 50 nidine derivative, a 3-Hydroxy-4-imidazolidinone, a amine, an isoquinoline phosphonate derivative, an 3-aminoquinoxalin-2-one derivative, rapamycin or a N,N'-disubstd.-guanidine compound, a phosphono- derivative e.g. 1,3-Diels Alder adduct with phenyl- propenyl piperidine carboxylic acid compound, triazoline-dione, 1-amino-1-cyclobutanecarboxylic (2R,3S,4S)-alpha-carboxy-cyclo-propyl-glycine, a acid, a thiamorphinan derivative, a pyrido[4,3- pyrrolidine derivative, a dihydroxy-fused hetero- 55 b]indole derivative, 4-phenyl carbamoyl methylene cyclyl quinoxaline derivative, a hydrogenated deriv- tetrahydro quinoline-2-carboxylic acid or a deriva- ative of MK 801 and analogues, a 5-substd. 10,11- tive thereof, (3R,4S)-3-(4-(4-fluorophenyl)-4- dihydro 5H-dibenzo (a,d) cycloheptene 5,10-imine, hydroxy-piperidin-1-yl)-chroman-4,7-diol, a phenol

11 21 EP 1 002 535 A1 22 derivative, an indeno-pyrazin-4-one, a 2,3-dioxo- noalkyl-cyclopropane N,N-diethyl carboxamide 1,2,4,5-tetrahydro-quinoxalinyl derivative, a 4,5- compound, a dexanabinol derivative, a substi- bridged quinoxalinedione or quinolone, (1S,2S)-1- tuted chroman derivative, a sulphonamide quina- (4-hydroxyphenyl)2-(4-hydroxy 4-phenyl piperidin- zoline-2-4-dione compound, a 6-and 8-aza-, and 1-yl) 1-propanol methane sulphonate trihydrate, a 5 6,8-diaza-1,4-dihydro-quinoxaline-2,3-dione deriv- 4-sulphanimide-quinoline derivative, a methano- ative, a substituted quinoline derivative, a tetrazoly- benzocyclodecen-13-amine compound, a deriva- lalkyl cyclohexyl aminoalkanoic acid, a tricyclic tives of pregnenolone sulphate, a quinoxalinyl- indole 2-carboxylic acid derivative, a 6-substd-7H- (alkane,alkene,or alkyne)-phosphonic acid or one imidazo-8-pyrazinone derivative, a quinoxaline of ist esters, a diarylalkylamine related to spider 10 dione derivative or one of its radiolabelled com- and wasp venom toxins, a piperazine R-alpha-car- pounds, a tricyclic pyridazinopyridine derivative, an boxylic acid derivative, an imidazo-indeno-pyrazin- N-substituted heterocyclylidenemethyl-indole car- 4-one derivative, a pyridazino-quinoline deriva- boxylic acid derivative, a 3-aza-8-substituted-bicy- tive, a 1-substd. or 1,3-di-substd. 1,3-diaryl-gua- clo(3.3.0)octane-2-carboxylic acid derivative, an nidine compound, an aza-cycloalkyl-fused 15 ethano-heterocyclo-isoquinolinium salt, a phenyl quinoxaline-dione, a 3-substd. 2-carboxy-indole alkanolamine derivative, a dihydrobenzothiadi- derivative or intermediate, a (2R)-N-trityl-4-oxo-5- azinedioxide carboxylic acid derivative, a methyl- (dimethyl phosphono)-nor-valinate ester, a butenylmethyl(hydroxy-propyl)carbazoledione, an kynurenic acid derivative, an indole carboxylic acid imidazo pyrazinone derivative, an imidazo-(1,2- derivative, a 6-(tetrazolyl or isoxazolyl)-decahydroi- 20 a)pyrazine-4-one, a benzazepine-dione derivative, soquinoline-3-carboxylic acid derivative, a phenyl- disulfiram, a 3-(indol-3-yl)-propenoic acid deriva- or pyridinyl-thieno-pyridinone derivative, a fused tive, a 1,2,3,4-tetrahydro-quinoline-2,3,4-trione-3 or cycloalkyl-quinoxaline-dione derivative, a pyri- 4-oxime compound, a peptide antagonist at NMDA dazino-quinoline derivative, a 1-Alpha-amino-3- receptors, a 2-amino-2-phenyl(alkyl)-acetic acid biphenyl-propanoic acid derivative, a 3-(Indol-3- 25 derivative, 6-halo-tryptophan or a 4-halo-kynure- yl)propenoic acid derivative, a spiro-heterocycle- nine, a 6-tetrazolyl or isoxazolyl-decahydro-isoquin- imidazo-indeno-pyrazine-4-one derivative, a 2-het- oline-3-carboxylic acid derivative, or an imidazolyl- erocyclyl-3-indolylpropenoic acid derivative, a pipe- or salts thereof. ridinoalkyl heterocyclic ketone or alcohol compound, a pyrrolyl-tetrahydro-benzoquinoxahne- 30 19. The use according to any of claims 15 dione derivative, a 7-imidazolyl or dialkylamino,tet- to 18, wherein the inhibitor is 3-(2-car- rahydroquinoxaline dione compound, a dibenzocy- boxypiperazin-4-yl)-propyl-1-phosphonate cloheptene, a quinoxaline derivative, an aryl-thio- (CPP), 2-(carboxypiperazine-4-yl)-1-propenyl-1- quinoxaline derivative, a heterocyclic substd. imida- phosphonic acid (D-CPPene), 2-amino-5-pen- zolo-quinoxaline derivative, a 1,4-dihydro-quinoxa- 35 tanoic acid (AP5), 2-amino-7-heptanoic acid line-2,3-dione derivative, an oxa- or thia- (AP7), (CGS19755), (1S,2S)-1-(4- aliphatically bridged quinoxaline derivative, an aza- hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- aliphatically bridged quinoxaline-2,3-dione com- 1-propanol (CP101606), 5-nitro-6,7-dichloro-qui- pound, a 3-amido- or 3-sulphamido-indole com- nox-alinedione (ACEA1021), pyridazino[4,5-b]quin- pound, a 3,5-disubstd. phenyl-naphthalene 40 oline-1,4,10(5H)-trione,7-chloro-2,3-dihydro-2-(4- derivative, an imidazo (1,2-a)indeno (1,2-e) pyra- methoxy-2-methylphenyl)-, monosodium salt zine-2-carboxylic acid derivative, a 3-phenyl-fused (ZD9379), 1H-indole-2-carboxylic acid, 4,6- ring pyridine-dione derivative, a 2-phenyl-pyri- dichloro-3-[3-oxo-3-(phenylamino)-1-propenyl]-, dazino-indole-dione derivative, a 4,6-disubstd. monosodium salt (GV150526), 1-aminocyclopro- kynurenine compound, a phosphono derivative of 45 panecarboxylic acid (ACPC), (SL820715), imidazo(1,2-a)pyrimidine-2-carboxamide, a tetrahy- , aminophosphovaleric acid, memantine dro-quinoxaline-dione derivative with N-(alkyl)carb- (1-amino-3,5-dimethyladamantane), 3-(4-chloroph- onyl-amino- or ureido group, a tryptophan enyl)glutamic acid, (+)-beta-cyclazocine, (-)-beta- derivative, a hetero-aliphatic or hetero-araliphatic cyclazocine, DL-(E)-2-amino-4-methyl-5-phos- substd. quinolone derivative, an imidazo-pyridine 50 phono-3-pentanoic acid (CGP 37849), 3-[(RS)-2- dicarboxylic acid derivative, a composition contain- carboxypiperazin-4-yl]propyl-1-phosphonic acid, ing pyrazolo-quinoline derivatives, an ethanodihyd- ketamine, phencyclidine, , dextrometh- robenzoquinolizinium salt, an oxopyridinyiquinox- orphan, N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-meth- aline derivative, an indeno-triazolo-pyrazin-4-one ylguanidine hydrochloride (, CNS1102), derivative, an imidazo-indeno-pyrazinone deriva- 55 , (+)-alpha-phenyl-2-pyridine-ethanamide tive, an imidazo-indeno-pyrazin-4-one derivative, (FPL 15896AR), 5-aminocarbonyl-10,11-dihydro- an imidazo(1,2-a)pyrazine-4-one derivative, a 5H- 5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI), indeno-pyrazine-2,3-dione derivative, a phenyl-ami- bis(3-aminopropyl)nonanediamine (TE393), N-(3-

12 23 EP 1 002 535 A1 24 aminopropyl)octanediamine, magnesium salts, methyl]piperidine-2-carboxylic acid (LY 233053), 2- 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7- amino-6-phosphonohexanoic acid, D-2-amino-5- phosphono-heptanoic acid, 3-amino-1-hydroxy-2- phosphonovaleric acid (5-APV), (+-)-2-Amino-N- pyrrolidinone (HA 966), D-(E)-4-(3-phosphonoprop- ethyl-alpha-(3-methyl-2-thienyl)benzeneethan- 2-enyl)piperazine-2-carboxylic acid (CGP 40116), 5 amine 2HCl (8319), desipramine, [3H]N-(1-(2- (+/-)(E)-2-amino-4-methyl-5-phosphono-3-penten- thienyl)-cyclohexyl)-3,4-piperidine (TCP), 4- oate ethylester (CGP39551), (+)-(3S,4S)-7- (phosphonomethyl)-phenylglycine (PD 129635), 3- hydroxy-delta 6-tetrahydrocannabinol-(1,1)-dimeth- (phosphonomethyl)phenylalanine (PD 130527), ylheptyl (HU 211), (+)-1-methyl-1-phenyl-1,2,3,4- tiletamine, arginine vasopressin, O-phosphohomo- tetrahydro-isoquinoline hydrochloride (FR115427), 10 serine, D-(E)-2-amino-4-methyl-5-phosphono-3- (+/-)-6-phosphonomethyl-decahydroisoquinolin-3- pentenoic acid (CAS 137424-81-8), [+/-]-5-aminoc- carboxylic acid (LY274614), 3-isoquinolinecarboxy- arbony-10,11-dihydro-5H-dibenzo[a,d]cycloheptan- lic acid, decahydro-6-(1H-tetrazol-5-ylmethyl)- 5,10-imine (ADCI), 7-chlorokynurenate, ketoprofen, ,[3R-(3alpha,4alpha,6beta,8alpha)] (LY 233536), [(S)-Alpha-phenyl-2-pyridine-ethanamine dihydro- 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonohep- 15 chloride] ARL 15896AR, ((3S,4aR, 6R, 8aR)-6-[2- tanoate (NPC 12626), (2R,4R,5S-2-amino-4,5- (1 H-tetrazol-5-yl)-ethyl]-1,2,3,4,4a,5,6,7,8,8a-dec- (1,2-cyclohexyl)-7-phosphono-heptanoic acid ahydroiso-quinoline-3 -carboxylic acid) (LY293558). (NPC 17742), procyclidine, D-(E)-2-amino-4- methyl-5-phosphono-3-pentenoic acid (CGP 20. The use according to any of claims 15 to 16, 40116), (+)5-methyl-10,11-dihydro-5H-dibenzo- 20 wherein the inhibitor is an NMDA receptor channel [a,d]cyclohepten-5,10-imine, D,L-(E)-2-amino-4- blocker. propyl-5-phosphono-3-pentenoic acid, D-norvaline- 4-oxo-5-phosphono (MDL-100453), cis-4-(phos- 21. The use according to claim 20, wherein the NMDA phonomethyl)-2-piperidinecarboxylic acid, D,L-(E)- receptor channel blocker is dizocilpine (MK801), 2-amino-4-propyl-5-phosphono-3-pentenoic acid 25 memantine, budipine, flupirtine, remacemide, (CGP 39653), conantokin-T, conantokin-G, γ-L- phencyclidine, tiletamine, ketamine, carvedilol, apti- glutamyl-L-aspartate, (+/-)-(2SR,4SR)-4-(1H-tetra- ganel (CNS1102), remacemide (FPL12924AA), 7- zol-5-ylmethyl)piperidine-2-carboxylic acid, DL- hydroxy- Delta (6)-tetrahydrocannabinol 1,1- (E)-2-amino-4-methyl-5-phosphono-3-pentanoic dimethylheptyl (Dexanabinol; HU211), 1-[1-(2- acid (CGP 37849), (+/-)-3-carboxy-5-phosphono- 30 thienyl)cyclohexyl]piperidine (TCP), or their deriva- 1,2,3,4-tetrahydroisoquinoline (SC 48981), tives. 1,2,3,4-tetrahydro-5-(2-phosphonoethyl)-3-isoquin- oline-carboxylic acid, (1S,2S)-1-(4-Hydroxyphe- 22. The use according to any of claims 1 to 2, 8 to 9, nyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol and 15 to 16 wherein the inhibitor is a glutamate (CP-101,606,1), (3R,4S)-3-[4-(4-fluorophenyl)-4- 35 release inhibitor. hydroxypiperidin-1- yl]chroman-4,7-diol (12a, CP- 283,097) , ifenprodil derivatives 1-piperidineetha- 23. The use according to claim 22, wherein the gluta- nol,4-hydroxy-alpha-(4-hydroxyphenyl)-beta- mate release inhibitor is i.e. riluzole, lamotrigine, methyl-4-phenyl-,[R-(R*,R*)] (CP-101,581) and 1- diphenylhydantoin, tetrodotoxin, agatoxin-gluta- piperidineethanol,4-hydroxy-alpha-(4-hydroxyphe- 40 mate-release-inhibitor (AG-GI), [5-(2,3,5-trichlo- nyl)-beta-methyl-4-phenyl-(alphaS,betaS) (CP- rophenyl)]-2,4-diamino-pyrimidine (BW1003C87), 98,113), (+/-)-(E)-beta-cyclazocine, D-α-aminoadi- (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS- pate (DAA), salts, , dextropropoxy- 153) and 4-amino-2-(4-methyl-1-piperazinyl)-5- phene, [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (2,3,5-trichlorophenyl)pyrimidine (BW619C89) or (TCP), 2-phenyl-1,3-propane-diol dicarbamate (fel- 45 any other agent that decreases the release of gluta- bamate), kynurenic acid, , Flupir- mate from nerve endings and prevents glutamate tine (Katadolon), (laughing gas), from binding to its binding sites and from triggering 4-{3-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- the signal that would occur as a result of binding of yl]-2-hydroxy-propoxy}-benzamide (Ro 8-4304), glutamate to its binding sites. N1,N4,N8-tri-benzyl-spermidine (TB-3-4), 1(-)- 50 3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydr- 24. The use according to any of claims 1 to 2, 8 to 9, oiso-qu inoline-3-carboxylic acid (LY235959), 2H- and 15 to 16 wherein the inhibitor is a glutamate 1,2,4-benzothiadiazine-1-dioxide-3-carboxylic acid synthesis inhibitor. (RPR 104632), dizocilpine maleate {(+)-5-methyl- 10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10- 55 25. The use according to claim 24, wherein the gluta- imine maleate} ((+)MK-801), 2R, 4R, 5S-(2- mate synthesis inhibitor is gabapentin, L-canaline, amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic phenylsuccinate, spermidine, putrescine, gen- acid) (NPC 17742), cis-(+/-)-4-[(2H-tetrazol-5-yl) tamicin, orthovanadate, vanadyl sulphate, vanadyl

13 25 EP 1 002 535 A1 26

acetylacetonate, methionine sulphoximine, chloro- 33. The use according to claim 32, wherein a preferred quine, amodiaquine, quinacrine, chinidine, chinine, antibody which binds specifically to the AMPA, kai- α-monofluoromethylputrescine and (R,R)-delta- nate or NMDA receptor or a part thereof, or to gluta- methyl-α-acetylenic-putrescine, or any other agent mate is monoclonal or polyclonal or derivative which interacts with glutamate synthesis or metab- 5 thereof. olism and prevents activation of its receptors by glutamate. 34. The use according to any preceding claim wherein the inhibitor is combined with one or more of: a 26. The use according to any of claims 1 to 2, 8 to 9, cytostatic agent (such as alkylating agents e.g. and 15 to 16 wherein the inhibitor is an agent accel- 10 nitrogen mustard, chlorambucil, melphalan, cyclo- erating glutamate uptake. phosphamide, busulfan, nitrosoureas, BCNU, CCNU, methyl-CCNU; such as antimetabolites e.g. 27. The use according to claim 26, wherein the antifolates, pyrimidine and purine analogs including agent accelerating glutamate uptake is γ- e.g. methotrexate, 5-fluorouracil, azathioprine, glutamyl-transpeptidase, or any other agent which 15 cytosine arabinoside, 6-thioguanine, 6-mercaptop- decreases synaptic concentration of glutamate by urine; such as natural products based anticancer activating uptake mechanism for glutamate. drugs including e.g. doxorubicin, daunorubicin, daunomycin, actinomycin D, bleomycin, mitox- 28. The use according to any of claims 1 to 2, 8 to 9, antrone, neocarzinostatin, procarbazine, mitomycin and 15 to 16 wherein the inhibitor is an agent that 20 C, vinblastine, vincristine, etoposide; such as inter- interacts with glutamate itself and prevents its bind- calating drugs e.g. cisplatin, carboplatin; and other ing to glutamate receptors. anticancer drugs such as e.g. dacarbazine), an immunomodulating agent (e.g. corticosteroids as 29. The use according to claim 28, wherein the e.g. prednisone and methylprednisolone; interfer- agent that interacts with glutamate is D-serine, 25 ons such as interferon-a (IFN-α), IFN-β, IFN-γ, and D-cycloserine, γ-L-glutamylglutamate, N-phtha- other potential modulators such as e.g. interleukins lamoyl-L-glutaminic acid, (R,S)-2-amino-3-[5-tert- (IL-1 - IL7)); and with physical measures such as butyl-3-(phosphonomethoxy)-4-isoxazolyl]propi- irradiation, or hyperthermia. The agents of present onic acid, α-N-acetylaspartylglutamate, 1-aminoc- invention can also be combined with mono- or poly- yclopropanecarboxylic acid, aminocyclobutane 30 clonal antibodies, antisense therapeutics, cancer cyrboxylic acid, (+,R)-3-amino-1-hydroxy-2-pyrroli- vaccines, and gene therapy. dine (HA966) and D,L-threo-3-hydroxyasparate, or any other agent which changes conformational 35. A method of screening for an agent useful in treat- state of glutamate and therefore decreases its bind- ing cancer, determining whether or not said agent is ing to receptors. Furthermore such agents include 35 an inhibitor of the interaction of glutamate with the soluble forms of AMPA, kainate or NMDA receptors AMPA, kainate, or NMDA receptor complex on or parts thereof which can be used to circulate and tumor cells. to bind to glutamate and therefore decrease its binding capability to the receptors. 36. A pharmaceutical composition comprising an inhib- 40 itor as described in any of claims 1 to 34 and a 30. The use according to any of claims 1 to 2, 8 to 9, pharmaceutically acceptable carrier. and 15 to 16 wherein the inhibitor is a glutamate transporter activator that decreases the concentra- 37. A combined preparation of an inhibitor as described tion of glutamate and prevents its binding to the in any of claims 1 to 34 and one or more of: a cyto- AMPA, kainate or NMDA receptors. 45 static agent (such as alkylating agents e.g. nitrogen mustard, chlorambucil, melphalan, cyclophospha- 31. The use according to claim 30, wherein the agent mide, busulfan, nitrosoureas, BCNU, CCNU, that blocks glutamate transporter is 12-O-tetrade- methyl-CCNU; such as antimetabolites e.g. anti- canoylphorbol-13-acetate and phorbol-12-myr- folates, pyrimidine and purine analogs including istate 13-acetate, or any other agent which 50 e.g. methotrexate, 5-fluorouracil, azathioprine, accelerates the function of glutamate transporters. cytosine arabinoside, 6-thioguanine, 6-mercaptop- urine; such as natural products based anticancer 32. The use according to any of claims 1 to 2, 8 to 9, drugs including e.g. doxorubicin, daunorubicin, and 15 to 16 wherein the inhibitor is an antibody daunomycin, actinomycin D, bleomycin, mitox- interacting with AMPA, kainate, or NMDA receptors 55 antrone, neocarzinostatin, procarbazine, mitomycin of parts of it or with glutamate and prevents binding C, vinbiastine, vincristine, etoposide; such as inter- of glutamate to its receptors. calating drugs e.g. cisplatin, carboplatin; and other anticancer drugs such as e.g. dacarbazine), an

14 27 EP 1 002 535 A1 28 immunomodulating agent (e.g. corticosteroids as e.g. prednisone and methylprednisolone; interfer- ons such as interferon-α (IFN-α), IFN-β, IFN-γ, and other potential modulators such as e.g. interleukins (IL-1 - IL7). 5

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