WO1997019049A1

WO1997019049A1 - Glycine derivatives

Info

Publication number: WO1997019049A1
Application number: PCT/EP1996/005079
Authority: WO
Inventors: Roberto Pellicciari; Flavio Moroni; Manuel Koller
Original assignee: Novartis Ag; Sandoz-Patent-Gmbh; Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date: 1995-11-17
Filing date: 1996-11-18
Publication date: 1997-05-29
Also published as: AU7627496A; ITMI952383A0; ITMI952383A1; IT1276153B1

Abstract

Compounds of formula (I), wherein R, R1, R2 and X are as defined in the description, are useful as pharmaceuticals.

Description

GLYCINE DERIVATIVES

The present invention relates to glycine deriva¬ tives with affinity to metabotropic glutamate receptors. Metabotropic glutamate receptors ( GluR) are a family of proteins present in neurons and in the glia, which can interact with glutamate and bring about sig¬ nificant modifications in neurotransmission by interac¬ tion with protein G and the resulting regulation of the neosynthesis of second messengers or the modulation of ion channels both at the presynaptic and postsynaptic levels. Recent molecular biology studies have identified at least eight cDNAs which likewise code for mGluR subtypes. In general, on the basis of structural anal¬ ogies, the effector used and pharmacological properties, it is possible to divide the eight mGluRs into three groups:

1st group: comprises mGluRl and mGluR5 which are capable of stimulating phoβpholipase C and the inositol cycle. These receptors are stimulated by the antagonists in the following order of power: QUIS> IS, 3R-

ACPD>L-CCG1>>>>L-AP . 2nd group: comprises mGluR2 and mGluR3 which are capable of inhibiting the formation of cAMP induced by forskolin. The order of power of the agonists is as follows:

L-CCG1>1S, 3R-ACPD>QϋIS>>>>>L-AP4. 3rd group: comprises mGluR4, mGluR6, mGluR7 and mGluRβ which are also capable of inhibit- ing the formation of cAMP, but in the following order of power:L-AP4>>IS, 3R-

ACPD>>>>L-CCG1.

The various mGluRs are differentially distributed in the CNS and several subtypes may coexist in the same area and also in the same neuron. The final effect their activation has depends on the types of receptor present and may therefore be either an inhibitory effect or an excitatory effect. For example, in the cerebellum, thθ stimulation of mGluRl leads to activation of the calcium- dependent potassium channels and therefore to inhibition, whereas, in the hippocampus, activation of mGluR receptors can increase the neuronal excitability by inhibiting the voltage-operated potassium channels. Then there are mGluRs which are localized to the presynaptic level and are capable of regulating the release of the transmitter by means of particularly interesting mechan- isms. Thus, the stimulation of mGluR4 or mGluR7 can reduce the influx of Ca^2* into the nerve endings, thereby directly inhibiting the voltage-dependent channels and reducing the synaptic release of transmitter. A similar result can be obtained by stimulating the mGluR2 or mGluR3 receptors, which inhibit the formation of cAMP and in some way reducing the effects of depolarization on the release of the transmitter. In contrast, the stimulation of other mGluR subtypes (mGluRl and possibly also mGluR5) amplifies the depolarization-release of transmitter combination, especially in the presence of free fatty acids.

In light of the above, regulation of the func¬ tioning of mGluR-controlled neuronal circuits in the hippocampus becomes particularly advantageous. Stimula- tion of the mGluR4 and mGluR7 receptors reduces trans¬ mission at the glutamatergic synapses level, whereas stimulation of mGluR5 can increase the excitability of the circuit, possibly also because it amplifies responses of ionotropic type. The consequences of a reduction in transmission and an increase in excitability are that low-intensity stimuli are blocked, while strong stimuli, capable of overcoming the presynaptic inhibi¬ tion, are amplified. In this way, the strategic location of the mGluRs leads to the formation of filtering systems capable of increasing the signal/noise ratio of the stimuli which converge on this neuronal circuit. Such systems, in which other types of mGluR also come into play, appear to operate both at the level of phenomena associated with learning and in regulating various sensory signals (for example in the olfactory pathways) . In the basal nuclei, the stimulation of mGluR2 and mGluR3 leads to a considerable reduction in the synaptic release of excitatory transmitter and may affect certain psychic and motor functions. Thus, the pharmacology of mGluRs appears to promise wide fields of therapeutic application since mGluRs appear to have an important role in the processes of neuroprotection and neurodegeneration, in controlling movement, and in the normal functioning of dopaminergic systems, in the onset of epileptic attacks, in the processes of central integration of pain, pres¬ sure, visual and sensory stimuli, and in learning. The fact that stimulation of the mGluR receptors can bring about an increase in the sensitivity of the ionotropic receptors for the same transmitter makes these receptors an ideal target for modifying synaptic excitatory func¬ tioning.

WO 93/08158 (Suntory Ltd.; 29.4.1993) describes enantiomers of 2-(2, 3-dicarboxycyclopropyl)gl cine as NMDA-receptor agonistε and their therapeutic use as anaestheticε, analgeεicε and antispastic agents.

It has now been found that cyclopropylglycine derivatives are endowed with affinity to metabotropic glutamate receptors. The compounds of the invention have the general formula (I) below

in which

R is hydrogen, halogen selected from chlorine , bromine , fluorine or iodine, hydroxy, C-_L-C^alkyl , C. -C,,alkoxy,

, Ci-Cjjhaloalkoxy, cyano , nitro , -COOR₁ (R_x being as defined below) , -CONR₃R₄

(R₃ and R₄ independently being hydrogen or C_j-C^alkyl ) , -PO ( OR₁ ) ₂ ( R₁ being as defined below) , -SO_jRi ( R_j^ being as defined below) or -NH-CO-R₅ ( R₅ being or phenyl ) , R₁ and R₂ , independently, are hydrogen, C. -C₄alkyl or benzyl , and

O

X is =CH- , =N- or =N^* -

The compounds of formula (I) have four asymmetric centres, which give rise to 16 enantiomers.

The invention comprises the individual enantio- meric forms as well as their racemic or diastereoisomeric mixtures. The invention moreover comprises the salts of the compounds (I) with acids or (when R₁ or R₂ = H) bases.

In a group of compounds of formula I, R is hydrogen, an halogen selected from chlorine, bromine, fluorine or iodine, hydroxy, C₁-C₄alkyl, C^C^alkoxy, C₁- C₄haloalkyl or C_j-C^haloalkoxy, R and R₂ are hydrogen and X is =CH- or =N- in ortho position to the bond which is linked to the cyclopropyl moiety.

Preferred compounds of formula (I) are those in which X is CH and R is hydrogen or a C^-C^ alkoxy group. Examples of C^C^ alkyl groups include methyl, ethyl, n-propyl, isopropyl and isobutyl, preferably methyl.

Examples of C₁-C₄ alkoxy groups include methoxy, ethoxy, n-propσxy and isopropoxy, preferably methoxy. Examples of C₁-C₄ haloalkyl groups include tri¬ fluoromethyl and pentafluoroethyl, preferably trifluoro¬ methyl.

Examples of C₁-C₄ haloalkoxy groups include trifluoromethoxy and difluoromethoxy, preferably tri- fluoromethoxy.

The formulae of 16 possible enantiomers of the compounds of formula (I) in which R is H, X is =CH- and R-_L is hydrogen are given below. The S configura ion of the carbon atom of the glycine residue is preferred and the configuration of compound 4.4 is particularly pre¬ ferred.

S Series R Series

The compounds of formula I wherein R_: and R₂ are H may be prepared by reaction of a compound of formula (II)

in which X and R are as defined above, with α-phenyl- glycinol and then with TMSCN, followed by oxidative cleavage with lead tetraacetate and acid hydrolysis. The compounds wherein K_λ and/or R₂ are alkyl or benzyl can be prepared from the free acids according to well known procedures.

By using various enantiomers of the aldehydes (II) and of R- or S-α-phenylglycinol, the desired enantiomers may be prepared.

Schemes 1-4 for the preparation of compounds (I) in which X = CH and R = H are given below. Further compounds (I) can be obtained by identical methods, starting with appropriate aldehydes (II).

Aldehydes (II) can be prepared according to the following schemes 5 and 6, again with reference to compounds in which X is CH and R is hydrogen. Obviously, further aldehydes of formula (II) can be prepared in a similar manner, starting with the appropriate E-cinnamyl or E-pyridylvinyl alcohols.

SCHEME 1

SCHEME 2 inol

SCHEME 3

The compounds of formula (I) and their pharmaceutically acceptable salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro, particularly affinity to metabotropic glutamate receptors (mGluRs) as indicated above, and are therefore useful as pharmaceuticals.

The agents of the invention were evaluated as mGluR antagonists in the following tests: 1) Antagonism of the phospholipase C-stimulatory action by 1S,3R-ACPD (300 μM) on slices of rat cortex. Active molecules in this test are considered to be mGluRl or mGluR5 antagonists (group 1) .

2) Antagonism of the action of L-CCG1 (3 μM) on the formation of cAMP induced by forskolin (30 μM) on slices of rat stria. Active molecules in this test are con¬ sidered to be mGluR2 or mGluR3 antagonists (group 2) .

3) Antagonism of the action of L-AP4 (10 μM) on the formation of cAMP induced by forskolin (30 μM) on slices of rat cerebellum. Active molecules in this test are considered to be mGluR4, ιtιGluR7 and mGluRβ antagonists (group 3) .

The agents of the invention show significant activity in these tests at about 0.01 to about lOOuM. The molecules active on group 1 mGluRs were then tested for their potentiation of the release of transmit¬ ter from slices of cortex and the molecules active on group 2 were tested for their inhibition of the release of transmitter from slices of rat stria. The methods used for the experiments reported above are described in: ombardi et al. British J. Pharmacol . 19933, 110, 1407- 1412.

The agents of the invention, and in particular compound 4_4, display selective antagonist activity towards the mGluRs of the second group by antagonizing the effect of L-CCG-1 on the production of cAMP and on the release of transmitter from slices of stria, with an IC₅₀ of 10 μM. The effect is selective since the action of IS, 3R ACDP on phospholipase C is not modified.

Furthermore, the compounds of the invention may act as mGluR-agonists. Agonistic activity can be shown in the following way: 1) Stimulation of phospholipase C in BHK cells which are transfected with mGluRs of group I;

2) Decrease of forskolin-stimulated cAMP-formation in transfected BHK cells expressing one of the mGluRs of class XI or 111. The agents of the invention show significant activity in these tests at about 0.01 to about lOOμM. Compound 44, for example, acts as an agonist at mGluR4 with an EC50 < 200 μM.

The compounds of the invention are therefore useful in disorders which are linked to metabotropic excitatory amino acid receptors. Such disorders include cerebral ischemia (e.g. due to stroke or cardiac arrest during bypass surgery) , head trauma, subarachnoid haemorrage, Alzheimers disease, Huntingtons Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, Parkinson syndrom, convulsive disorders (e.g. epilepsy), muscular spasms, chronic and neuropathic pain, cognitive disorders such as memory deficits, schizophrenia, anxiety, emesis and drug abuse. For the therapeutic uses envisaged, the compounds of the invention will be formulated in appropriate dosage forms, using conventional techniques and excipients. The dosage will be determined by the doctor in charge, based on the pharmaceutical and pharmacodynamic properties of the compounds. An indicated daily dosage will lie within the range from about 1 mg to about lg, conveniently administered, for example, in divided doses up to four times a day.

In accordance with the foregoing, the present invention also provides a pharmaceutical composition comprising an agent of the invention, in association with a pharmaceutical carrier or diluent.

The invention furthermore provides an agent of the invention for use as a pharmaceutical, particularly in disorders linked to metabotropic glutamate receptors, e.g. in the treatment of the above-mentioned disorders.

Moreover the present invention provides the use of an agent of the invention for the manufacture of a medicament for the treatment of the above-mentioned disorders.

In still a further aspect the invention provides a method for the treatment of disorders linked to metabotropic glutamate receptors, e.g. for the above- mentioned disorders, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.

The examples which follow further illustrate the invention. Example 1.

(2S.l'S.2'S.3'R)-2-(2' -carboxy-3 ' -phenylcvclopropyl) - σlvcine a) 6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one A solution of cis-3-phenyl-2-propen-l-yl diazo- acetate (1 g, 4.95 mmol) in anhydrous toluene (165 ml) was added to a refluxing solution of bis(N- t-butylsalicylaldiminato)copper (II) (0.104 g, 0.25 mmol) in anhydrous toluene (165 ml) with stir- ring under an argon atmosphere for 12 hours. After cooling, the reaction mixture was evaporated and the residue subjected to flash chromatography, eluting with petroleum ether containing from 10 to 40% of ethyl acetate, to give the title compound. (0.75 g, 87%), m.p. 112-3°C; ^-NM (CDC1₃) δ 2.60 (2H, m,

1-CH and 5-CH) , 2.78 (IH, t, J=8.8 Hz, 6-CH) , 4.05 (IH, dd, J=0.6 Hz, J=9.8 Hz, 4-CH , 4.35 (IH, dt, 3=2 . 1 Hz, J=9.8 Hz, 4-CH_b) , 7.20-7.35 (5H, m, aro¬ matic) b) 2-Hydroxymethyl-3-phenylcyclopropanecarboxylic acid (4-morpholinyl)amide

A 2.0 M solution of trimethylaluminium in hexane (22.35 ml) was added dropwise over 20 minutes to a solution of morpholine (3.9 ml) in anhydrous CH₂C1₂ (108 ml) with stirring at room temperature under an argon atmosphere. The stirring was continued for 20 minutes after the addition of a solution of the compound obtained in a) (2.59 g, 14.88 mmol) in anhydrous CH₂C1₂ (67 ml) over 20 minutes, and the resulting mixture was then heated at 40°C for 20 hours. The reaction mixture was acidified cautiously with I HCl, the organic phase was separated out and the aqueous phase was extracted with CH₂C1₂ (2 x 60 ml) . The combined organic phases were dried over anhydrous Na₂S0₄ and, after evaporation of the solvent, the residue (3.7 g) was subjected to flash chromatography, eluting with CH₂Cl₂/methanol (95/5) to give the title compound. (3.50 g, 90%), m.p. 103°C; ϊ-NMR (CDC1₃) δ 2.00 (2H, m, 1-CH and 2-CH) ,

2.50 (IH, t, J=5.5 Hz, 3-CH) , 3.40-3.80 (8H, , morpholine), 3.90-4.15 (2H, m, CH-OH) , 7.15-7.40

(5H, , aromatic) c) A solution of the compound obtained in b) (3.40 g, 13.03 mmol) in anhydrous tetrahydrofuran (200 ml) was added dropwise over 30 minutes to a solution of lithium hexamethyldisilazide, prepared by adding a 1.5 M solution of butyllithium in hexane (26 ml) to a solution of anhydrous hexamethyldiεilazane (8.3 ml) in tetrahydrofuran (200 ml). The addition was carried out at room temperature under an argon atmosphere. Stirring was continued for 1 hour, after which the reaction mixture was diluted with satu¬ rated NH,C1 (500 ml) and extracted with CH₂C1₂ (3 x 200 ml) . The combined organic extracts were then dried (Na₂S0₄) and evaporated to give a residue which was subjected to flash chromatography, eluting with CH₂C1₂/methanol (95/5) to give the epimer of the compound obtained in b) . (3.00 g, 88%); ¹H-NMR (CDC1₃) δ 2.05 (2H, m, 2-CH and OH), 2.25 (IH, t,

J=5.0 Hz, 1-CH), 2.85 (IH, dd, J=5.0 Hz, J=12.0 Hz, 3-CH), 3.50-3.90 (8H, m, morpholine ring), 3.85 (2H, dd, J=6.7 Hz, J=12.0 Hz, CH₂OH) , 7.15-7.40 (5H, m, aromatic) . d) 2-Formyl-3-phenylcyclopropanecarboxylic acid (4-morpholinyl)amide

PCC (4.20 g, 19.48 mmol) was added to a solution of the compound obtained in c) (3.00 g, 11.49 mmol) in anhydrous CH₂C1₂ (130 ml) and the resulting mixture was stirred at room temperature under an argon atmosphere for 16 hours. The reaction mixture was then diluted with ethyl ether and filtered and the solvent was evaporated off. Flash chromatography of the residue and elution with ethyl acetate/petroleum ether (8/2) gave the title compound. (1.90 g, 64%), m.p. 89°C; ^-N R (CDCl₃) δ 2.78-2.90 (IH, m, 2-CH) , 3.12 (IH, t, J=4.9 Hz, 1-CH) , 3.35 (IH, dd, J=6.4 Hz, J=9.4 Hz, 3-CH), 6.60-3.90 (8H), m, mor- pholine ring, 7.18-7.40 (5H, m, aromatic), 9.20 (IH, d, J=5.1 Hz, CHO) . e) R-Phenylglycine (0.45 g, 3.28 mmol) was added to a solution of the aldehyde (0.85 g, 3.28 mmol) in methanol (32.8 ml) and the resulting mixture was stirred at room temperature for 2 hours. After cooling to 0°C, TMSCN (0.65 g, 6.56 mmol) was added and the resulting mixture was stirred for 12 hours at room temperature. Evaporation of the solvent gave a residue which was subjected to medium-pressure chromatography, eluting with CH₂C1₂/methanol (98/2) to give the compound of formula:

(3.00 g, 2%), m.p. 123-4°C 'H-NMR (CDCl₃) δ 2.20 (2H, m, CHCO and CH-CHN) , 2.80 (IH, d, J=9.6 Hz, CHCN) , 3.10 (2H, m, CHPh and OH), 3.40-3.90 (10H, m, mor- pholine and CH₂OH) , 3.95 (IH, dd, J=3.8 and 13.5 Hz, CH-CH₂OH), 6.70-7.40 (10H, 2 x m, aromatic). Subsequent elution with the same solvent gave the compound of formula

(0.450 g, 33%), m.p. 146-7°C; ^-NMR (CDC1₃) δ 2.25

(2H, m, CHCO and CH-CHN) , 2.60 (IH, d, J=8.0 Hz,

CHCN) , 2.90 (2H, m, CHPh and OH) , 3.50-4.00 (11H, m, morpholine, CH₂OH and CH-CH₂OH) , 6.90-7.40 (10H, 2 x , aromatic) . f) (2S,l'S,2'S,3'R)-2-(2' -Carboxy-3 ^■ -phenylcyclo- propyl)glycine

Lead tetraacetate (0.360 g, 0.81 mmol) was added to a solution of the compound obtained in e) , formula (IV) (0.300 g, 0.74 mmol) in an anhydrous methanol/methylene chloride mixture (12 ml, 1/1); after 10 minutes, water (10 ml) was added and the resulting mixture was filtered through Celite. After evaporation of the solvent, the residue was refluxed in 6N HCl (30 ml) for 12 hours. The reaction mixture was washed with CH₂C1₂ (2 x 10 ml) and evaporated. The residue was subjected to chromatography on an ion exchange resin of Dowex 50 x 2 200 type: elution with 10% pyridine gave the title compound. (0.110 g, 63%), m.p. 221°C; ^XH-NMR (D₂0+DC1) δ 215 (IH, td, J=5.2 and 9.3 Hz, l'-CH), 2.50' (IH, t, J=5.2 Hz, 2'-CH), 3.05 (IH, dd, J=5.2 and 9.3 Hz, 3 ' -CH) , 3.20 (IH, d, J=10.2 Hz, 2-CH), 7.30 (5H, br ε, aromatic); ¹³C-NMR (D₂0+DC1 δ 22.90 (C-l'), 27.76 (C-2 ' ) , 31.33

(C-3^>) 51.50 (C-2), 127.66, 128.57), 128.57, 128.94, 133.26 (aromatic), 169.69, 175.27 (CO); [α]_D ²°-108 (c 0.15, 2.5N HCl) . Example 2 In a similar manner to Example 1, starting with the appropriate aldehydes of formula (II) and using, depending on the case, R- or S-o-phenylglycinol as indicated in the above schemes 1-4, the following compounds were obtained:

(2R,l^,S,2'S,3'R)-2-(2* -Carboxy-3 ^• -phenylcyclopropyl) - glycine; Dowex 50WX2-200 (10% pyridine); 86% yield; m.p. 240-l°C; ^-N R (D₂0) δ 1.95 (IH, td, J=5.4, 8.9 and 10.8 Hz, l'-CH), 2.55 (IH, t, J=5.4 Hz, 2 ' -CH) , 2.85 (IH, dd, J=5.4 and 8.9 Hz, 3*-CH), 3.00 (IH, d, J=10.8 Hz, 2-CH), 7.20-7.35 (5H, m, aromatic); ¹³C-NMR (D₂0+DC1) δ

23.90, 27.78, 29.97, 50.40, 128.03, 128.43, 129, 17, 132.76, 170.81, 175.24; [θ]_D ²⁰ -74 (c 0.30, 2.5N HC1).

(2R, l'R,2'R,3'S). 2-(2' -Carboxy-3 ' -phenylcyclopropyl) - glycine; Dowex 50WX2-200 (10% pyridine); 74% yield; m.p. 221-3°C; ^- M (D₂0) δ 2.10 (IH, dt, J=5.0 and 10.5 Hz, l'-CH), 2.40 (IH, t, J=5.0 Hz, 2 ' -CH) , 3.00 (2H, m, 3 ^■ -CH and 2-CH) , 7.30 (5H, d, aromatic); ¹³C-NMR (D-O+DCl) δ

22.91, 27.83, 31.39, 51.49, 127.69, 128.59, 128.96, 133.28, 169.70, 175.25; [θ]_D ²⁰ +100 (c 0.20, 2.5N HCl). (2S, 1 'R,2 'R, 3 *S) -2- (2 ' -Carboxy-3 ' -phenylcyclopropyl) - glycine; 70% yield; [α]_D ²⁰ +72 (c 0.30, 2.5N HCl). (2R,l'R,2^,S,3^,S)-2-(2* -Carboxy-3 ' -phenylcyclopropyl) - glycine; Dowex 50WX2-200 (10% pyridine); 48% yield; m.p. 219-220°C; ^XH-NMR (D₂0) δ 1.80 (IH, dt, J=9.4 and 11.9 Hz, l'-CH), 2.49 (IH, t, J=9.4 Hz, 2 ' -CH) , 2.75 (IH, t, J=9.4 Hz, 3--CH), 4.10 (IH, d, J=11.9 Hz, 2-CH) , 7.10- 7.30 (5H, , aromatic); ¹³C-NMR (D₂0+DC1) δ 23.99, 24.54, 28.51, 49.00, 127.86, 129.20, 129.71, 133.33, 171.27, 175.24; [<X]_D ²⁰ +20 (c 0.50, 2.5N HC1).

(2R, 1 'S, 2 'R, 3 ^«R) -2- (2 ' -Carboxy-3 ' -phenylcyclopropyl) - glcyine; Dowex 50 X2-200 (10% pyridine); 53% yield; m.p. 219-220°C; "Η-NMR (D-O) δ 1.90 (IH, dt, J=8.8 and 11.5 Hz, l'-CH), 2.55 (IH, t, J=8.8 Hz, 2'-CH), 2.80 (IH, t, J=8.8 Hz, 3'-CH), 4.15 (IH, d, J=11.5 Hz, 2-CH) , 7.10-7.30 (5H, m, aromatic); ¹³C-NMR (D₂0+DC1) δ 23.46, 24.20, 28.54, 49.16, 127.61, 128.95, 129.49, 132.94, 171.05, 173.98; [α]_D ^2D -17 (c 0.60, 2.5N HCl).

(2S, 1 ' S, 2 'R, 3 'R) -2- (2 ' -Carboxy-3 ' -phenylcyclopropyl) - glycine; 48% yield; [α]_D ⁰-21 (c 0.50, 2.5N HCl). (2S, 1 'R, 2 *S, 3 'S) -2- (2 ' -Carboxy-3 ' -phenylcyclopropyl) - glycine; 55% yield; [α] ²⁰ +18 (c 0.40, 2.5N HCl). (2S,l'S,2 'S, 3 ^,R)-2- (2 ' -Carboxy- 3 ' -o -methoxyphenyl - cyclopropyl ) glycine .

(0.100 g, 82%), m.p. 219-20°C; ^-N R (D₂0+DC1) δ 2.15 (IH, td, J=5.8 and 10.3 Hz, l'-CH), 2.40 (IH, t, I J=5.8 Hz, 2'-CH), 2.9-3.10 (2H, m, 3 ' -CH and 2-CH) , 3.80 (3H, ε, OMe), 6.90-7.40 (4H, m, aromatic); [α]_D ²⁰ -81 (c 0.15, 2.5N HCl) .

Claims

1. A compound of formula I

wherein

R is hydrogen, halogen selected from chlorine, bromine, fluorine or iodine, hydroxy,

C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄- haloalkoxy, cyano, nitro, -COOR₁ (R_x being as defined below), -CONR₃R₄ (R₃ and R₄ independently being hydrogen or C₁-C₄alkyl), -PO(OR₁)₂ (R₁ being as defined below), -SO₃R₁ (R₁ being as defined below) or -NH-CO-R₅ (R₅ being C₁-C₄alkyl or phenyl), R₁ and R₂, independently, are hydrogen,

C₁-C₄alkyl or benzyl, and

X is =CH-, =N- or

or a salt thereof.

2. A compound of formula I according to claim 1 wherein R is hydrogen, an halogen selected from chlorine, bromine, fluorine or iodine, hydroxy, C₁-C₄alkyl, C₁- C₄alkoxy, C₁-C₄haloalkyl or C₁-C₄haloalkoxy, R₁ and R₂ are hydrogen and X is =CH- or =N- in ortho position to the bond which is linked to the cyclopropyl moiety, or a salt thereof.

3. A compound of claim 1 wherein R is hydrogen or C₁- C₄alkyl, R₁ and R₂ are hydrogen and X is =CH-.

4 . The compound of formula

and its salts .

5. A compound of anyone of claims 1 to 4, in free or pharmaceutically acceptable salt form, for use as a pharmaceutical.

6. A compound of anyone of claims 1 to 4, in free or pharmaceutically acceptable salt form, for use in disorders linked to metabotropic glutamate receptors.

7. A compound of anyone of claims 1 to 4, in free or pharmaceutically acceptable salt form, for use in the treatment of cerebral ischemia, head trauma, subarachnoid haemorrage, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, Parkinson syndrome, convulsive disorders, muscular spasms, pain, cognitive disorders, schizophrenia, anxiety, emesis and drug abuse.

8. A pharmaceutical composition comprising a compound of anyone of claims 1 to 4 in free or pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent.

9. The use of a compound of anyone of claims 1 to 4 in free or pharmaceutically acceptable salt form, as a pharmaceutical for the treatment of disorders linked to metabotropic glutamate receptors.

10. The use of a compound of anyone of claims 1 to 4 in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of disorders linked to metabotropic glutamate receptors.

11. A method for the treatment of disorders linked to metabotropic glutamate receptors in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of anyone of claims 1 to 4 in free or pharmaceutically acceptable salt form.