EP0843660A1

EP0843660A1 - Heterocyclic compounds, their preparation and use

Info

Publication number: EP0843660A1
Application number: EP96924801A
Authority: EP
Inventors: Jane Marie Lundbeck; Anders Kanstrup
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 1995-07-31
Filing date: 1996-07-31
Publication date: 1998-05-27
Also published as: WO1997005109A1; JPH11509847A; AU6514296A

Abstract

The present invention relates to therapeutically active heterocyclic compounds (Ia), a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases in the central nervous system related to the metabotropic glutamate receptor system.

Description

Heterocyclic compounds, their preparation and use .

The present invention relates to therapeutic active indolderivatives, a method for preparing the same, pharmaceutical compositions comprising the com- pounds and a method of treating diseases in the central nervous system therewith.

Recent molecular biological studies have clearly established the existence of two major types of glutamate receptors in the central nervous system namely the ionotropic and the metabotropic glutamate receptors. The latter is char¬ acterised by being G-protein-linked to changes in second messenger forma¬ tion and modulation of ion channel function, (Meldrum, B. (1991) Epilepsy Res. 10, 55-61 , Chapman, A. (1991) in Excitatory Amino Acids p. 265-286, Blackwell scientific publ. ltd., Oxford).

At present 8 different subtypes of the metabotropic glutamate receptors are described (MGIuR₁ to MGIuR₈) and in addition some spliced variants of the subtypes are reported.

The Metabotropic glutamate receptor subtypes MGIuR., and MGIuR₅ are coupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, CF. (1991) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J.J. and Krogsgaard Larsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P. (1993) Eur. J. Pharmacol. 245 ,299), while the others are coupled to cyclic AMP formation (Schoepp, D.D., Johnson, B.G. and Monn, J.A. (1992) J. Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem. 58, 1964-1966, Manzoni, O. et al. (1992) Eur. J. Pharmacol. 225, 357-358).

Compounds such as L-glutamate, quisqualate and ibotenate are known to act as non-selective agonists on the metabotropic glutamate receptors, while selective ionotropic glutamate receptor agonists such as NMDA, AMPA and kainate have little effect on these receptors. Recently a few compounds without activity at the ionotropic glutamate receptors but with activity at the metabotropic receptors have been identified.

These comprise trans-ACPD (trans 1S,3R-1-aminocyclopentane-1,3-dicar- boxylic acid), the partial agonist L-AP3 (L-2-amino-3-phosphonopropionic acid) (Palmer, E., Monaghan, D.T. and Cotman, C.W. (1989) Eur. J. Phar¬ macol. 166, 585-587, Desai, M.A. and Conn, P.J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D.D. et al. (1991), J. Neurochem. 56, 1789-1796, Schoepp D.D. and Johnson B.G. (1989), J. Neurochem. 53,1865-1613), L-AP4 (L-2-amino-4-phosphonobutyrate) which is an agonist at the MGIuR₄ receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) and some of the isomers of CCG (2-(carboxycyclopropyl)glycines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107, 539- 543).

Very few selective antagonists at the metabotropic glutamate receptors have been reported, however some phenylglycine derivatives S-4CPG (S-4-carboxyphenyl glycine), S-4C3HPG (S-4-carboxy-3-hydroxyphenyl glycine) and S-MCPG ( S-alpha methyl-4-carboxyphenyl glycine) have been reported to antagonise trans ACPD stimulated phosphoinositide hydrolysis and thus possibly acting as antagonists at the metabotropic glutamate receptors at the subtypes MGIuR₁ and MGIuR₅ (Thomsen, C. and Suzdak, P, (1993) Eur. J. Pharmacol. 245, 299).

Literature evidence suggests that compounds selective for the metabotropic glutamate receptors either as agonists or antagonists are useful in the treatment of different neurological diseases.

The use of compounds active at the metabotropic glutamate receptors for the treatment of epilepsy is corroborated by investigations of the influence of trans-ACPD in the formation of convulsions (Sacaan and Schoepp, (1992), Neurosci. lett. 139, 77) and that phosphoinositide hydrolysis mediated via MGluR is increased after kindling experiments in rats (Akiyama et al. (1992),Brain Res. 569, 71).

Trans-ACPD has been shown to increase release of dopamine in the rat brain which indicates that compounds acting on the metabotropic glutamate receptors might be usable for the treatment of Parkinson's disease and Huntington's Chorea (Sacaan et al. (1992), J. Neurochem. 59, 245).

The use of compounds active at the metabotropic glutamate receptors for treatment of neurological diseases such as senile dementia has been indicated by the findings of Zheng and Gallagher ((1992), Neuron 9, 163) and Bashir et al. ((1993), Nature 363, 347) who demonstrated that activation of metabotropic glutamate receptors are necessary for the induction of long term potentiation (LTP) in nerve cells (septal nucleus.hippocampus) and the finding that long term depression is induced after activation of metabotropic glutamate receptors in cerebellar granule cells (Linden et al. (1991), Neuron 7,81).

Investigations also show that in the treatment of deficiencies of mental and motoric performance seen after conditions of brain ischemia the metabotro¬ pic glutamate receptor active compounds may prove usable.

Trans-ACPD has been shown to be a neuroprotective agent in an MCAO model in mice (Chiamulera et al. (1992), Eur. J. Pharmacol. 215, 353), and it has been shown to inhibit NMDA induced neurotoxicity in nerve cell cultures (Koh et al., (1991), Proc. Natl. Acad. Sci. USA 88, 9431).

Also in the treatment of pain the metabotropic glutamate receptor active compounds seem of interest, proved by the fact that antagonists at the metabotropic glutamate receptors antagonises sensory synaptic response to noxious stimuli of thalamic neurons (Eaton, S.A. et al. (1993), Eur. J. Neuro¬ sci. 5, 186).

The above findings support that compounds acting on the metabotropic glutamate receptors are useful for the treatment of epilepsy, neurological diseases such as senile dementia, Parkinson's disease, Huntington's Cho¬ rea, pain and deficiencies of mental and motoric performance seen after conditions of brain ischemia.

We have now discovered a series of new indolderivatives which are potent antagonists at the metabotropic glutamate receptors.

The present invention relates to compounds of formula la

wherein

R^1a is C^-alkyl optionally substituted with halogen; C₂.₆-alkenyi;

C₂.₆-alkynyl; C₃.₆-cycloalkyl; C^-alkyl substituted with C₃.₆-cycloalkyl; carboxy;

-COR^10a; -COOR^10a; C^-alkyl substituted with dimethylamino; -R^10a-O-R ^a; -R^10a-O-R^11a-O-R ^2a; phenylsulfonyl; benzoyl; benzyl; or phenyl; each of which aromatic group is optionally substituted with C^-alkyl, C^-alkoxy, halogen, carboxy or nitro; wherein R^10a, R^11a, and R^12a are independently C^-alkyl;

R^2a is halogen; C^-alky! substituted with C₃.₆-cycloalkyl; C₃.₆-cycloalkyl; C₂.₆-alkenyl; C₂.₆-alkynyl; benzyl; C^-alkyl substituted with dimethylamino; -R^10a-O-R^11a; -R^10a-O-R^11a-O-R^12a; wherein R^10a, R^11a and R^12a are independ- ently C₁₄-alkyl; -O optionally substituted with C₃.₆-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C_1-6-alkyl substituted with C₃.₆-cycloalkyl or dimethylamino, -R^10a-O-R^11a, -R ^0a-O-R^11a-O-R^12a, wherein R^10a, R^11a and R^12a are independently C^-alkyl; -S optionally substituted with C,.₆-alkyl, C₃.₆-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl,

C^-alkyl substituted with C₃.₆-cycloalkyl or dimethylamino, -R^10a-O-R^11a, -R^10a-O-R^11a-O-R^12a, wherein R^10a, R^11a and R^12a are independently C^-alkyl; -N optionally substituted with one or two C^-alkyl which alkyl group(s) is/are optionally substituted with hydroxy, morpholino, amino unsubstituted or N-mono or disubstituted with C_1-6-alkyl, phenyl, phenyl¬ sulfonyl or benzyl; morpholino; piperidino; or piperazino optionally N-substituted with C^-alkyl;

R^3a and R^4a are independently H; -CN; -COR^13a; -COOR^13a; -SOR ^3a; or -SO₂R^13a; wherein R^13a is C,.₆-alkyl optionally substituted with C₃.₆-cycloalkyl, C₃.₆-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyl substituted with dimethylamino, -R ^0a-O-R ^1a or -R^10a-O-R^11a-O-R^12a wherein R^10a, R^11a and R^12a are independently C^-alkyl; -NH substituted with -COR^14a wherein R^14a is H or C,__β-alkyl; -CONH optionally substituted with H or C^-alkyl; or 1-methyl- 2-imidazolyl; provided that R^3a and R^4a cannot both be H;

R^5a is H or C^-alkyl; provided that R^5a is not H when either R^3a or R^4a is H;

R^6a, R^7a, R^8a and R^9a are independently H; nitro; amino; halogen; tri- fluoromethyl; trifluoroacetyl; sulfo; carboxy; carbamoyl; sulfamoyl;

-COR^10a or -COOR^10a wherein R^10a is as defined above; C^-alkoxy; or C^-alkyl optionally substituted with halogen; or a salt thereof with a pharma¬ ceutically acceptable acid or base.

These salts include pharmaceutically acceptable acid addition salts, phar¬ maceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo¬ roacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magne¬ sium and the like.

The term "C^-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methyl- pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.

The term "C^-alkoxy" as used herein, alone or in combination, refers to a monovalent substituent comprising a lower alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy.

The term "C₂.₆-alkenyl" as used herein refers to an unsaturated hydrocarbon chain having 2-6 carbon atoms and one double bond such as e.g. vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.

The term "C₃.₆-cycloalkyl" as used herein refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopro¬ pyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "C₂.₆-alkynyl" as used herein refers to unsaturated hydrocarbons which contain triple bonds, such as e.g. -C≡CH, -C=CCH_3l -CH₂C*≡CH, -CH₂CH₂C≡CH, -CH(CH₃)C≡H, and the like. The term "halogen" means fluorine, chlorine, bromine and iodine.

It is to be understood that the invention extends to both the (E) and the (Z) stereoisomeric forms of the compounds of formula I as well as mixtures of the two.

The preferred compounds of the present invention are those in which R^1a is benzyl optionally substituted with C^-alkyl. C^-alkoxy, halogen, carboxy or nitro, and/or R^3a and R ^a are independently -CN; -COR^13a or -COOR^13a; wherein R^13a is C^-alky! optionally substituted with C₃.₆-cycloalkyl, C_3.6- cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyl substituted with dimethylamino, -R^10a-O-R^11a or -R^10a-O-R^11a-O-R^12a wherein R^10a, R^11a and R^12a are independently C^-alkyl.

The invention also relates to methods of preparing the above mentioned compounds. These methods comprise

a) reacting a compound of formula lla

prepared by well known methods, wherein R^1a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above, with a N,N-dimethyl amide, preferably dimethylfor¬ mamide or dimethylacetamide, and POX₃, wherein X is chlorine or bromine, using Vilsmeyer-Hack conditions, to form a compound of formula Ilia

wherein X is chlorine or bromine, and R^1a, R^5a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above; and subsequently

b) reacting a compound of formula Ilia, wherein X is chlorine or bromine, and R^1a, R^5a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above, with a compound R^14a-CH₂-R^15a wherein R^{1 a} and R^15a are independently -CN; -COR^13a; -COOR^13a; -SOR^13a; or -SO₂R^13a; wherein R^13a have the meanings defined above, either in the presence or absence of an added base, prefer¬ able triethylamine, piperidine or potassium carbonate, to form a compound of formula IVa,

wherein R^1a, R^5a, R^6a, R^7a, R^8a, R^9a, R^14a and R^15a have the meanings defined above, or

c) reacting a compound of formula Va,

prepared by well known methods, wherein R^1a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above and R^16a is C,.₆-alkyl optionally substituted with C₃.₆-cycloalklyl; C₃.₆-cycloalkyl; C₂.₆-alkenyl; C₂.₆-alkynyl; phenyl; benzyl; C^-alkyl substituted with dimethylamino; R ^0a-O-R^11a; -R^10a-O-R^11a-O-R^12a; wherein R^10a, R^11a and R^12a are independently C^-alkyl; with a N,N-dimethyl amide, preferably dimethylformamide or dimethylacetamide, and POX₃, wherein X is chlorine or bromine, using Vilsmeyer-Hack condi¬ tions, to form a compound of formula Via,

wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, and subsequently

d) reacting a compound of formula Via wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, with a compound R^14a-CH₂-R^15a wherein R^14a and R^15a are independently -CN; -COR^13a;

-COOR^13a; -SOR^13a; or -SO₂R^13a; wherein R^13a have the meanings defined above, either in the presence or absence of an added base, preferable triethylamine, piperidine or potassium carbonate to form a compound of for¬ mula Vila,

wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a, R^14a, R^15a and R^16a have the meanings defined above, or

e) reacting a compound of formula Via, wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, with a compound R^14a-CH₂- PO(R^17a)₂, wherein R^3a have the meaning defined above, and R^17a is -O-alkyl, under Wittig or Horner-Emmons conditions, to form a compound of formula Villa,

(Villa)

wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a, R^14a and R^16a have the meanings defined above, or

f) reacting a compound of formula Via, wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, with a compound R^14a-CH(R ^a)- PO(R^17a)₂, wherein R^14a have the meanings defined above and R^17a is -O- alkyl, under Wittig or Horner-Emmons conditions, to form a compound of for¬ mula IXa,

wherein R^1a, R^4a, R^5a, R^6a, R^7a, R^8a ,R^9a, R^14a, and R^16a have the meanings defined above, or

g) reacting a compound of formula Ilia, wherein X is chlorine or bromine, and R^1a, R^5a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above, with an alkali metal salt of a compound HO-R^18a or HS-R^18a, prepared previously or in situ, wherein R^18a is C^-alky! optionally substituted with C₃.₆-cycloalkyl, C_3.6- cycloalkyl, C_2-6-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alky! substituted with dimethylamino, R^10a-O-R^11a, -R^10a-O-R^11a-O-R^12a; wherein R^10a, R^11a and R^12a are independently C_1-6-alkyl, to form a compound of formula Xa,

wherein Y^a is -O- or -S-, and R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a, and R^18a have the meanings defined above, and subsequently

h) reacting a compound of formula Xa, wherein Y^a is -O- or -S-, and R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a, and R^18a have the meanings defined above, under the conditions defined in paragraphs b, d, e, or f, to give a compound of formula Xla,

wherein Y^a, R^1a, R^3a ,R^4a, R^5a, R^6a, R^7a, R^8a ,R^9a, and R^18a have the meanings defined above, or

i) reacting a compound of formula formula Via, wherein R^1a, R^5a, and R^16a have the meanings defined above, and at least one of R^6a, R^7a, R^8a, or R^9a is H with well known reactive substrates leading to aromatic substitution using the reaction conditions known in the art, to form a compound of formula Via, wherein R^6a, R^7a, R^8a, or R^9a have the meanings defined above provided that at least one of R^6a, R^7a, R^8a, or R^9a is not H.

Specific examples of the compounds of formula la are the following:

Ethyl 2-cyano-3-(1 -benzyl-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1 -methyl-2-chloro-3-indolyl)acrylate, 3-(1-Methyl-2-chloro-3-indolyl)-2-methylsulfonyl-acrylonitrile, 3-(1-Benzyl-2-chloro-3-indolyl)-2-methylsulfonylacrylonitrile,

3-(1-Cyclopropylmethyl-2-chloro-3-indolyl)-2-(1-methyl-2-imidazolylsulfonyl) acrylonitrile,

3-(1-Methyl-2-chloro-3-indolyl)-2-(2-propylsulfonyl)acrylonitrile, 3-(1-Benzyl-2-methylthio-3-indolyl)-2-methylsulfonyl-acrylonitril, Ethyl 2-cyano-3-(1 -(4-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(3-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(2-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(3-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(2-methoxybenzyl)-2-chloro-3-indolyl)acrylate,

Ethyl 2-ethoxycarbonyl-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-ethoxycarbonyl-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-benzyl-2-chloro-3-indolyl)acrylonitrile, Ethyl 2-cyano-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)acrylonitrile, Ethyl 2-cyano-3-(1 -(4-chlorobenzyl)-2-chloro-3-indolyl)acrylonitrile Ethyl 2-cyano-3-(1 -methyl-2-chloro-3-indolyl)acrylonitrile, Methyl 3-(1-benzyl-2-chloro-3-indolyl)-2-methoxycarbonylacrylate, Methyl 3-(1 -(4-methoxybenzyl)-2-chloro-3-indolyl)- 2-methoxycarbonylacrylate, Methyl 3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)-2-methoxycarbonylacrylate, Methyl 3-(1-methyl-2-chloro-3-indolyl)-2-methoxycarbonylacrylate, 3-(1-benzyl-2-chloro-3-indolyl)-2-ethoxycarbonylacrylamide, 3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)-2-ethoxycarbonylacrylamide, 3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)-2-ethoxycarbonylacrylamide, 2-Ethoxycarbonyl-3-(1-methyl-2-chloro-3-indolyl)acrylamide, 2-Ethoxycarbonyl-3-(1-benzyl-2-chloro-3-indolyl)-N-methylacrylamide, 2-Ethoxycarbonyl-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)-N- methylacrylamide,

2-Ethoxycarbonyl-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)-N- methylacrylamide, 2-Ethoxycarbonyl-3-(1-methyl-2-chloro-3-indolyl)-N-methylacrylamide.

The pharmacological properties of the compounds of the invention can be illustrated by determining their effects in different conventional radioligand binding assays or in functional in vitro assays.

The compounds of the invention were studied in an in vitro assay for meas¬ uring inhibition of Pl-hydrolysis in BHK 570 cells expressing mGluR^ receptors.

Principle

The metabotropic glutamate receptor (mGluR) is selectively activated by trans-aminocyclopentane dicarboxylic acid and is coupled to the hydrolysis of inositol phosphates via a GTP-binding protein. At the molecular level, cDNAs encoding eight subtypes of the mGluR family have been isolated. The first subtype isolated (Houamed et al., 1991 , Science 252, 1318), termed the mGluRlα, has been shown to be coupled to Pl-hydrolysis when expressed in baby hamster kidney cells (BHK) (Thomsen et al., Brain Res. (in press)). In these cells no stimulation by 1 mM quisqualate or glutamate was observed with control BHK cells whereas a 6-8 fold increase over basal Pl-hydrolysis was seen with BHK cells expressing mGluRlα. Cell culture

BHK570 cells expressing mGluRlα are cultured in DMEM (4.5 g/l glucose, 2mM glutamin); 5% foetal calf serum; 0.10 mg/ml neomycin; 0.5 mg/ml G418; 1 μM methotrexate; 50 μg/ml gentamycin. Cells are subcultured every 5 days using 0.05% trypsin/EDTA in PBS.

Inositol phosphate formation

The protocol for Pl-hydrolysis was measured using a modification of a method previously described (Berridge et al., 1982, Biochem. J. 206,587). Cells were plated in 16 mm wells (24 well multidish, Costar) with 1 confluent 100 mm dish per multidish. Replace the medium 24 h before the experiment with 500 μl fresh growth medium containing 4μCi/ml myo-[2-³H]inositol (specific activity 18 Ci/mmol, Amersham). The cells were washed twice with Krebs-Henseleit buffer (Sigma cat. # 3753: glucose 2.0 g/l, MgSO₄ 0.141 g/l, KHPO₄ 0.16 g/l, KCI 0.35 g/l, NaCI 6.90 g/l and NaHCO₃ 2.1 g/l) supple¬ mented with 10 mM LiCI and 2.5 mM CaCI₂. The buffer was equilibrated with 5% CO₂, 95% air to pH 7.5 at 37°C. Following 5 min of preincubation in the above buffer, buffer or test compounds were added and cells were incubated for 30 min at 37°C. In antagonist studies, add test compounds 5 min prior to agonist stimulation. Pl-formation was stopped by placing the cells on ice and quickly aspirating the media. The wells were washed once with ice-cold Krebs-Henseleit buffer and subsequently 1 ml ice-cold 10% perchloric acid was added to each well. Place the cells on ice for 20 min. In Nunc minisorp test tubes (75 x 12 mm, cat. # 443990): add 250 μl of 10 mM EDTA, pH 7.0 + 5% Universal Indicator (Merck). Transfer the PCA extract to each tube containing the pH-indicator. Neutralize the samples with 1.5 M KOH + 60 mM HEPES to pH 7.5 (~ 1100-1200 μl). Centrifugate (6.000 rpm, 5 min, 0°C). They can be stored frozen at this point. Fractions of inositolphosphates were separated using ion-exchange columns (Amersham, RPN 1908) according to the method provided by Amersham. Separation of inositol phosphates on ion-exchange columns

Prepare columns with 5 ml 1 M KHCO₃ and wash with 15 ml dist. water. Adjust vacuum so that the flow-rate does not exceed 5 ml/min.

Add 4 ml dist. water and subsequently 1 ml [³H]lnsP sample. Wash with 5 ml dist. water. IP1 to IP4 fractions may be collected with 5 ml 0.05; 0.10; 0.17 and 0.25 M KHCO₃, respectively. Usually IP1 and IP2 fractions are collected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold (Packard).

Testprocedure

Testcompounds are dissolved in DMSO, DMSO and Pluronic F-127 or ethanol and diluted in assay buffer. Glutamate (10 μM and 1000 μM) and buffer alone are included as a control.

Results

The stimulation by 10 μM shall represent a submaximal stimulation. The response by 10 μM glutamate should exceed 3-fold the basal level and should be below maximal stimulation (glutamate at 1 mM). The results are calculated relative to the stimulation by 10 μM glutamate and a dose re¬ sponse curve is generated.

Examples of test results obtained by testing a compound of the present invention in the above mentioned assay appear from the following Table 1.

Table 1

Compound No. IC₅₀ (μM)

1 2.2 The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 10 mg to about 70 mg per day. In choosing a regimen for patients suffering from a disease in the central nervous system related to the metabotropic glutamate receptor system it may frequently be necessary to begin with a dosage of from about 30 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, form in which admin¬ istered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramus¬ cular or intranasal, the oral route being preferred.

Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable carrier. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, mag¬ nesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinyl- pyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dis¬ solved in polyhydroxy lated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.

A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:

Active compound 5.0 mg

Lactosum 67.8 mg Ph.Eur.

Avicel® 31.4 mg Amberiite® 1.0 mg

Magnesii stearas 0.25 mg Ph. Eur. The invention will now be described in further detail with reference to the following examples.

EXAMPLE 1a

Ethyl 2-cyano-3-(1-benzyl-2-chioro-3-indolyl)acrylate (1a)

To 5.83 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 200 ml of abs. EtOH, was added 6.1 g of ethyl 2-cyanoacetate and 6.6 g of triethy¬ lamine. After 4 days with stirring, the solution was added to water, and the precipitate collected by filtration and dried to give (1a). Yield 6.72g of (1a), m.p. 130-131°C.

EXAMPLE 2a

Ethyl 2-cyano-3-(1-methyl-2-chloro-3-indolyl)acrylate (2a)

To 2 g of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 50 ml of abs. EtOH, was added 2.3 g of ethyl 2-cyanoacetate and 4.2 g of triethylamine. After 19 hours with stirring, the solution was added to 200 ml of water, and the precipitate collected by filtration and dried to give (2a). Yield 2.68 g of (2a), m.p. 131-132°C.

EXAMPLE 3a

3-(1-Methyl-2-chloro-3-indolyl)-2-methylsulfonylacrylonitrile (3a)

To 550 mg of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 730 mg of methylsulfonylacetonitril and 1.2 g of triethyl¬ amine. After 24 hours another 300 mg of methylsulfonylacetonitril was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (3a). Yield 630 mg of (3a), m.p. 180°C.

EXAMPLE 4a

3-(1-Benzyl-2-chloro-3-indolyl)-2-methylsulfonylacrylonitrile (4a)

To 1 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 930 mg of methylsulfonylacetonitril and 1.6 g of triethylamine. After 24 hours another 1 g of methylsulfonylacetonitril and 0.3 g of triethy¬ lamine was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (4a). Yield 1.1 g of (4a), m.p. 206°C.

EXAMPLE 5a

3-(1-Cyclopropylmethyl-2-chloro-3-indolyl)-2-(1-methyl-2-imidazolylsul- fonyl)acrylonitrile (5a)

To 1 g of 1-cyclopropylmethyl-2-chloroindole-3-carbaldehyde, dissolved in 50 ml of MeOH, was added 880 mg of 1-methylimidazol-2-ylsulfonylacetonitril and 1.6 ml of triethylamine. The mixture was stirred for 24 hours. The pre¬ cipitate was collected by filtration to give (5a). Yield 1.45 g of (5a), m.p. 214°C.

EXAMPLE 6a

3-(1-Methyl-2-chloro-3-indolyl)-2-(2-propylsulfonyl)acrylonitrile (6a)

To 1 g of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of MeOH, was added 820 mg of propan-2-propylsulfonylacetonitril and 1.6 ml of triethylamine. After 24 hours another 300 mg of methylsulfonylacetonitril was added, and the mixture was stirred for 48 hours. The precipitate was col¬ lected by filtration to give (6a). Yield 1.13 g of (6a), m.p. 141 C.

EXAMPLE 7a

1 -Benzyl-2-methylthioindole-3-carbaldehyde (7a)

To 5 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in MeOH, was added 2.5 g of sodium methylmercaptan, and the mixture was stirred over¬ night. The precipitate was collected by filtration, washed with MeOH and water to give (7a). Yield 5.15 g of (7a).

EXAMPLE 8a

3-(1-Benzyl-2-methylthio-3-indolyl)-2-methylsulfonylacrylonitril (8a)

To 1 g of (7a), dissolved in 50 ml of MeOH, was added 850 mg of methylsul¬ fonylacetonitril and 1.5 ml triethylamine. After 24 hours of stirring another 300 mg of methylsulfonylacetonitril was added. After further 24 hours with stirring the precipitate was collected by filtration, washed with MeOH and water, to give (8a). Yield 990 mg of (8a), m.p. 125-126°C.

EXAMPLE 9a

Ethyl 2-cyano-3-(1 -(4-chlorobenzyl)-2-chloro-3-indolyl)acrylate (9a)

To 608 mg of 1-(4-chlorobenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (9a). Yield 650 mg of (9a). M.p. 179-80°C (sample recryst. from EtOH).

EXAMPLE 10a

Ethyl 2-cyano-3-(1 -(3-chlorobenzyl)-2-chloro-3-indolyl)acrylate (10a)

To 500 mg of 1-(3-chlorobenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 500 mg of potassium carbonate and 0.19 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (10a). Yield 510 mg of (10a). M.p. 130.5-132°C (sample recryst. from EtOH).

EXAMPLE 11a

Ethyl 2-cyano-3-(1-(2-chlorobenzyl)-2-chloro-3-indolyl)acrylate (11a)

To 608 mg of 1-(2-chlorobenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (10a). Yield 590 mg of (11a). M.p. 139.5-140.5°C (sample recryst. from EtOH).

EXAMPLE 12a

Ethyl 2-cvano-3-(1-(4-methoxybenzvπ-2-chloro-3-indolvnacrylate (12a)

To 600 mg of 1-(4-methoxybenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (12a). Yield 620 mg of (12a). M.p. 153-4°C (sample recryst. from EtOH).

EXAMPLE 13a

Ethyl 2-cyano-3-(1-(2-methoxybenzyl)-2-chloro-3-indolyl)acrylate (13a)

To 600 mg of 1-(2-methoxybenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (12a). Yield 630 mg of (12a). M.p. 126-8°C (sample recryst. from EtOH/water). EXAMPLE 14a

Ethyl 2-ethoxycarbonyl-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)acrylate (14a)

To 500 mg of 1-(4-Chlorobenzyl)-2-chloroindole-carbaldehyde, dissolved in 15 ml of a solvent which consisted of 5 % piperidine and 2 % acetic acid in absolute ethanol, was added 0.28ml of diethyl malonate . After stirring for 3 days the solvent was removed by evaporation, and the product dissolved in 25 ml of ether plus 25 ml of 1 N HCI. The organic phase was separated, and washed with 25 ml 1 N HCI, 25 ml water, 25 ml of saturated NaHCO3 solu¬ tion, dried (MgSO4) and evaporated to give an oil. Purification by column chromatography (methylene chloride on silica 60) gave (14a) as an oil which slowly crystallized. Yield 210 mg. M.p. 98-99°C (sample recryst. from EtOH/water).

EXAMPLE 15a

Ethyl 2-ethoxycarbonyl-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)acrylate (15a)

To 460 mg of 1-(4-methoxybenzyl)-2-chloroindole-carbaldehyde, dissolved in 15 ml of a solvent which consisted of 5 % piperidine and 2 % acetic acid in absolute ethanol, was added 0.26ml of diethyl malonate . After stirring for 3 days the solvent was removed by evaporation, and the product dissolved in 25 ml of ether plus 25 ml of 1 N HCI. The organic phase was separated, and washed with 25 ml 1 N HCI, 25 ml water, 25 ml of saturated NaHCO3 solu¬ tion, dried (MgSO4) and evaporated to give an oil. Purification by column chromatography (methylene chloride on silica 60) gave (15a) as an oil. 1 H-NMR (CDCI3): 8.03 (s, 1 H); 7.50 (m, 1 H); 7.20 (m, 3H); 7.02 (d, 2H); 6.78 (d, 2H); 5.30 (s, 2H); 4.32 (q, 2H); 4.24 (q, 2H); 3.71 (s, 3H); 1.33 (t, 3H); 1.11 (t, 3H).

Claims

1. A compound of formula la

wherein

R^1a is C^-alkyl optionally substituted with halogen; C₂.₆-alkenyl; C₂.₆-alkynyl; C₃.₆-cycloalkyl; C^-alkyl substituted with C₃.₆-cycloalkyl; carboxy; -COR^10a; -COOR^10a; C_1-6-alkyl substituted with dimethylamino; -R^10a-O-R^11a; -R^10a-O-R^11a-O-R^12a; phenylsulfonyl; benzoyl; benzyl; or phenyl; each of which aromatic group is optionally substituted with C_1-6-alkyl, C,.₆-alkoxy, halogen, carboxy or nitro; wherein R^10a, R^11a, and R^12a are independently C,_.6-alkyl;

R^2a is halogen; C^-alkyl substituted with C₃.₆-cycloalkyl; C₃.₆-cycloalkyl; C₂.₆-alkenyl; C₂.₆-alkynyl; benzyl; C^-alkyl substituted with dimethylamino; -R^10a-O-R^11a; -R^10a-O-R^11a-O-R^12a; wherein R^10a, R^11a and R^12a are independ¬ ently C^-alkyl; -O optionally substituted with C^-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyl substituted with C₃.₆-cycloalkyl or dimethylamino, -R^10a-O-R^11a, -R^10a-O-R^11a-O-R^12a, wherein R^10a, R^11a and R^12a are independently C^-alkyl; -S optionally substituted with C^-alkyl, C₃.₆-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyl substituted with C₃.₆-cycloalkyl or dimethylamino, -R^10a-O-R^11a, -R^10a-O-R^11a-O-R^12a, wherein R^10a, R^11a and R^12a are independently C^e-alkyl; -N optionally substituted with one or two C^-alkyl which alkyl group(s) is/are optionally substituted with hydroxy, morpholino, amino unsubstituted or N-mono or disubstituted with C,._β-alkyl, phenyl, phenyl- sulfonyl or benzyl; morpholino; piperidino; or piperazino optionally N-substituted with C_1-6-alkyl;

R^3a and R^4a are independently H; -CN; -COR ^3a; -COOR^13a; -SOR^13a; or -SO₂R ^3a; wherein R^13a is C,.₆-alkyl optionally substituted with C₃.₆-cycloalkyl, C₃.₆-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyl substituted with dimethylamino, -R^10a-O-R^11a or -R^10a-O-R^11a-O-R^12a wherein R^10a, R^11a and R^12a are independently C_1-6-alkyl; -NH substituted with -COR^14a wherein R^14a is H or C_1-6-alkyl; -CONH optionally substituted with H or C^-alkyl; or 1-methyl- 2-imidazolyl; provided that R^3a and R^4a cannot both be H;

2. A compound according to claim 1 wherein R^1a is benzyl optionally substi¬ tuted with C_1-6-alkyl, C^-alkoxy, halogen, carboxy or nitro.

3. A compound according to claim 1 or 2 wherein R^3a and R^4a are independ¬ ently -CN; -COR^13a or -COOR^13a; wherein R^13a is C^-alkyl optionally substi- tuted with C₃.₆-cycloalkyl, C₃.₆-cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyl substituted with dimethylamino, -R^10a-O-R^11a or -R^10a-O-R^11a- O-R^12a wherein R^10a, R^11a and R^12a are independently C^-alkyl.

4. A compound according to claim 1 selected from the following:

Ethyl 2-cyano-3-(1 -benzyl-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1 -methyl-2-chloro-3-indolyl)acrylate, 3-(1-Methyl-2-chloro-3-indolyl)-2-methylsulfonyl-acrylonitrile, 3-(1-Benzyl-2-chloro-3-indolyl)-2-methylsulfonylacrylonitrile, 3-(1-Cyclopropylmethyl-2-chloro-3-indolyl)-2-(1-methyl-2-imidazolylsulfonyl) acrylonitrile,

3-(1-Methyl-2-chloro-3-indolyl)-2-(2-propylsulfonyl)acrylonitrile, 3-(1-Benzyl-2-methylthio-3-indolyl)-2-methylsulfonyl-acrylonitril, Ethyl 2-cyano-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(3-chiorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(2-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(3-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1-(2-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-ethoxycarbonyl-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-ethoxycarbonyl-3-(1 -(4-methoxybenzyl)-2-chloro-3-indolyl)acrylate, Ethyl 2-cyano-3-(1 -benzyl-2-chloro-3-indolyl)acrylonitrile, Ethyl 2-cyano-3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)acrylonitrile, Ethyl 2-cyano-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)acrylonitrile Ethyl 2-cyano-3-(1-methyl-2-chloro-3-indolyl)acrylonitrile, Methyl 3-(1 -benzyl-2-chloro-3-indolyl)-2-methoxycarbonylacrylate, Methyl 3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)- 2-methoxycarbonylacrylate,

Methyl 3-(1-(4-chiorobenzyl)-2-chloro-3-indolyl)-2-methoxycarbonylacrylate, Methyl 3-(1-methyl-2-chloro-3-indolyl)-2-methoxycarbonylacrylate, 3-(1-benzyl-2-chloro-3-indolyl)-2-ethoxycarbonylacrylamide,

3-(1-(4-methoxybenzyl)-2-chloro-3-indolyl)-2-ethoxycarbonylacrylamide, 3-(1-(4-chlorobenzyl)-2-chioro-3-indolyl)-2-ethoxycarbonylacrylamide, 2-Ethoxycarbonyl-3-(1-methyl-2-chloro-3-indolyl)acrylamide, 2-Ethoxycarbonyl-3-(1-benzyl-2-chloro-3-indolyl)-n-methylacrylamide, 2-Ethoxycarbonyl-3-(1-(4-methoxybenzyl)-2-chloro-3-indoIyl)-N- methylacrylamide, 2-Ethoxycarbonyl-3-(1-(4-chlorobenzyl)-2-chloro-3-indolyl)-N- methylacrylamide,

2-Ethoxycarbonyl-3-(1-methyl-2-chloro-3-indolyl)-N-methylacrylamide.

5. A method of preparing a compound according to claim 1 , CHARACTER¬ IZED IN

a) reacting a compound of formula lla

b) reacting a compound of formula Ilia, wherein X is chlorine or bromine, and R^1a, R^5a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above, with a compound R^{1 a}-CH₂-R^15a wherein R^14a and R^15a are independently -CN; -COR^13a; -COOR^13a; -SOR^13a; or -SO₂R^13a; wherein R^13a have the meanings defined above, either in the presence or absence of an added base, prefer¬ able triethylamine, piperidine or potassium carbonate, to form a compound of formula IVa,

c) reacting a compound of formula Va,

prepared by well known methods, wherein R^1a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above and R^16a is C_1-6-alkyl optionally substituted with C₃.₆-cycloalklyl; C₃.₆-cycloalkyl; C₂.₆-alkenyl; C₂.₆-alkynyl; phenyl; benzyl; C^-alkyl substituted with dimethylamino; R^10a-O-R ^1a; -R^10a-O-R^11a-O-R ^2a; wherein R^10a, R^11a and R^12a are independently C^-alkyl; with a N.N-dimethyl amide, preferably dimethylformamide or dimethylacetamide, and POX₃, wherein X is chlorine or bromine, using Vilsmeyer-Hack condi¬ tions, to form a compound of formula Via,

wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, and subsequently ' d) reacting a compound of formula Via wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, with a compound R^14a-CH₂-R ^5a wherein R^{1 a} and R^15a are independently -CN; -COR ^3a; -COOR^13a; -SOR ^3a; or -SO₂R^13a; wherein R^13a have the meanings defined above, either in the presence or absence of an added base, preferable triethylamine, piperidine or potassium carbonate, to form a compound of for¬ mula Vila,

(Villa)

wherein R ^a, R^5a, R^6a, R^7a, R^8a ,R^9a, R^14a and R^16a have the meanings defined above, or

f) reacting a compound of formula Via, wherein R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a and R^16a have the meanings defined above, with a compound R^{1 a}-CH(R ^a)- PO(R^17a)₂, wherein R^{1 a} have the meanings defined above and R^17a is -O- alkyl, under Wittig or Horner-Emmons conditions, to form a compound of for¬ mula IXa,

g) reacting a compound of formula Ilia, wherein X is chlorine or bromine, and R^1a, R^5a, R^6a, R^7a, R^8a, and R^9a have the meanings defined above, with an alkali metal salt of a compound HO-R^18a or HS-R^18a, prepared previously or in situ, wherein R^18a is C^-alkyl optionally substituted with C₃.₆-cycloalkyl, C₃.₆- cycloalkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, phenyl, benzyl, C^-alkyi substituted with dimethylamino, R^10a-O-R^11a, -R^10a-O-R^{1 a}-O-R^12a; wherein R^10a, R^11a and R^12a are independently C^-alkyl. to form a compound of formula Xa,

wherein Y^a is -O- or -S-, and R^1a, R^5a, R^6a, R^7a, R^8a ,R^9a, and R ^8a have the meanings defined above, and subsequently

i) reacting a compound of formula formula Via, wherein R^1a, R^5a, and R ^6a have the meanings defined above, and at least one of R^6a, R^7a, R^8a, or R^9a is H with well known reactive substrates leading to aromatic substitution using the reaction conditions known in the art, to form a compound of formula Via, wherein R^6a, R^7a, R^8a, or R^9a have the meanings defined above provided that at least one of R^6a, R^7a, R^8a, or R^9a is not H.

6. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 4 together with a pharmaceutically acceptable carrier or diluent.

7. A pharmaceutical composition according to claim 5 in the form of an oral dosage unit or parenteral dosage unit.

8. A pharmaceutical composition according to claim 6, wherein said dosage unit comprises from about 1 to about 100 mg of a compound according to any one of claims 1 to 4.

9. A compound according to any one of claims 1 to 4 for treating a disease in the central nervous system via the metabotropic glutamate receptor system.

10. A compound according to any one of claims 1 to 4 for treating epilepsy, senile dementia, Parkinson's disease, Huntington's Chorea, pain or defici¬ encies of mental and motoric performance seen after conditions of brain ischaemia.

11. A method of treating a disease in the central nervous system via the metabotropic glutamate receptor system comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 4.

12. A method according to claim 10 wherein said disease is epilepsy, senile dementia, Parkinson's disease, Huntington's Chorea, pain or deficiencies of mental and motoric performance seen after conditions of brain ischemia.

13. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for treatment of a disease in the central nerv¬ ous system via the metabotropic glutamate receptor system.

14. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for treatment of epilepsy, senile dementia, Parkinson's disease, Huntington's Chorea, pain or deficiencies of mental and motoric performance seen after conditions of brain ischaemia.