HK1206715B - Ethynyl derivatives as modulators of mglur5 receptor activity - Google Patents

Description

Ethynyl derivatives as modulators of mGluR5 receptor activity

The present invention relates to ethynyl derivatives of formula I, or a pharmaceutically acceptable acid addition salt, a racemic mixture, or a corresponding enantiomer and/or optical isomer and/or stereoisomer thereof:

wherein

Y is N or CH;

R¹is fluorine or chlorine.

It has now surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor antagonists (NAM ═ negative allosteric modulators). The compounds of formula I are characterized by valuable therapeutic properties. They may be used for the treatment or prevention of mGluR5 receptor mediated disorders.

In the Central Nervous System (CNS), transmission of stimuli occurs through the interaction of neurotransmitters emitted by neurons with neuroreceptors.

Glutamate is the major excitatory neurotransmitter in the brain and has a unique role in a variety of Central Nervous System (CNS) functions. Glutamate-dependent stimulus receptors fall into two main classes. The first major class, the ionotropic receptors, forms ligand-controlled ion channels. Metabotropic glutamate receptors (mGluRs) belong to the second major class, and also belong to the G-protein coupled receptor family.

Currently, eight distinct members of these mglurs are known, and some of these members even have subtypes. These eight receptors can be subdivided into three subgroups based on their sequence homology, signal transduction mechanisms and agonist selectivity:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Negative allosteric modulators of metabotropic glutamate receptors belonging to the first group may be used for the treatment or prevention of acute and/or chronic neurological disorders such as Parkinson's disease, Fragile X syndrome, autistic disorders, cognitive disorders and memory deficits, as well as chronic and acute pain and gastroesophageal reflux disease (GERD).

Other treatable indications in this connection are: limited brain function resulting from shunt surgery or transplantation, poor cerebral blood supply, spinal cord injury, head injury, hypoxia resulting from pregnancy, cardiac arrest and hypoglycemia. Further treatable indications are ischemia, huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism (idiophatic parkinsonism) or parkinsonism caused by drugs and conditions which lead to glutamate-deficiency functions, such as, for example, muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction (nicotinoidism), opiate addiction, anxiety, vomiting, dyskinesia and depression.

Disorders that are wholly or partially mediated by mGluR5 are, for example, acute, traumatic and chronic degenerative processes of the nervous system, such as alzheimer's disease, senile dementia, parkinson's disease, huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychoses such as schizophrenia and anxiety, depression, pain and drug dependence (Expert opin.

Selective mGluR5 antagonists are particularly useful in the treatment of diseases requiring decreased activation of mGluR5 receptors, such as anxiety and pain, depression, fragile-X syndrome, autism spectrum disorders (autism spectrum disorders), parkinson's disease, and gastroesophageal reflux disease (GERD).

Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the above-mentioned compounds as pharmaceutically active substances and their preparation. Further objects of the invention are medicaments based on the compounds according to the invention and their manufacture as well as the use of the compounds for the control or prevention of mGluR5 receptor (NAM) mediated disorders such as anxiety and pain, depression, fragile-X syndrome, autism spectrum disorders, parkinson's disease and gastroesophageal reflux disease (GERD), and, respectively, for the manufacture of corresponding medicaments.

One embodiment of the invention are compounds of formula I wherein Y is N.

These compounds are

5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-chloro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide.

Another embodiment of the invention are compounds of formula I wherein Y is CH.

These compounds are

5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-chloro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide.

A particular embodiment of the invention consists of the following compounds:

5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-chloro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-chloro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

Compounds similar to those of the present invention have been generally described as positive allosteric modulators of the mGluR5 receptor. Surprisingly, it has been found that highly potent mGluR5 antagonists are obtained instead of mGluR5 positive allosteric modulators, which have a completely opposite pharmacology compared to positive allosteric modulators.

The main difference between positive and negative allosteric modulators can be seen in figure 1. At a fixed concentrationIn the presence of glutamate mGluR5 Positive Allosteric Modulators (PAMs) lead to increased receptor activity (Ca²⁺Mobilized), and allosteric antagonists (negative allosteric modulators, NAMs) result in a reduction in receptor activation. Figure 1 shows the general behaviour of NAM and PAM under the same conditions. In FIG. 1, PAM has a receptor affinity of about 10^-7M, and NAM have a receptor affinity of 10^-7M to 10^-8And M. These values can also be measured using a binding assay instead of radioligand (═ MPEP), see assay description.

FIG. 1 shows a schematic view of a: comparison of mGluR5 Positive Allosteric Modulators (PAMs) and mGluR5 antagonists (negative allosteric modulators ═ NAMs).

The indications which the compounds can address are not the same. mGluR5-NAM is beneficial for indications requiring reduced excessive receptor activity such as anxiety and pain, depression, fragile X syndrome, autism spectrum disorders, Parkinson's disease, and gastroesophageal reflux disease (GERD). mGluR5PAM, on the other hand, may be used in indications where normalisation of reduced receptor activity is required, such as psychosis (psychosis), epilepsy (epilepsy), schizophrenia (schizohrenia), Alzheimer's disease and related cognitive disorders, and tuberous sclerosis (tuberous sclerosis).

This difference can actually be shown, for example, in animal models of anxiety, such as in the rat Vogel drinking water conflict test (rat Vogel confluency driving test), in which the compounds of the invention show anxiolytic activity, whereas mGluR-PAM does not show activity in this animal model.

Biological assays and data:

intracellular Ca²⁺Mobilization assay

Generating a monoclonal HEK-293 cell line stably transfected with cDNA encoding the human mGlu5a receptor; for work with mGlu5 Positive Allosteric Modulators (PAMs), cell lines with low receptor expression levels and low constitutive receptor activity were selected to be able to distinguish agonist activity from PAM activity. Cells were cultured according to standard protocols (Freshney, 2000) in high glucose Dulbecco's Modified Eagle Medium supplemented with 1mM glutamine, 10% (vol/vol) heat-inactivated calf serum, penicillin/streptomycin, 50 μ g/ml hygromycin and 15 μ g/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland).

About 24 hours before the experiment, 5 × 10⁴Cells/well were seeded in poly-D-lysine coated 96-well plates with black/clear bottom. Cells were loaded with 2.5. mu.M Fluo-4AM in loading buffer (1xHBSS, 20mM HEPES) for 1hr at 37 ℃ and washed five times with loading buffer. Cells were transferred to a Functional Drug Screening System 7000(Hamamatsu, Paris, France) and 11 semilog serial dilutions of test compounds at 37 ℃ were added and cells were incubated for 10-30 minutes and fluorescence recorded online. After this pre-incubation step, the cells are added with EC₂₀The agonist L-glutamate at the corresponding concentration (typically about 80 μ M) and the fluorescence is recorded online; to illustrate the day-to-day variation in cellular responsiveness, the EC of glutamate was determined by recording the full dose response curve of glutamate immediately prior to each assay₂₀。

The response was measured as the peak increase in fluorescence minus the baseline (i.e., fluorescence without addition of L-glutamic acid), and the maximum stimulatory effect obtained with saturating concentrations of L-glutamic acid was normalized. Plot with% maximal stimulation using XLfit, a curve fitting program that iteratively plots the data using the Levenburg Marquardt algorithm. The single site competition assay equation used was y ═ a + ((B-a)/(1+ ((x/C) D))), where y is% maximal stimulatory effect, a is minimal y, B is maximal y, and C is EC₅₀X is the log10 of the concentration of competing compound and D is the slope of the curve (Hill Coefficient). From these curves, EC was calculated₅₀(concentration at which half maximal stimulation is achieved), hill coefficient and maximum response expressed as% maximal stimulatory effect obtained with saturating concentrations of L-glutamate.

During preincubation with PAM test Compounds(i.e., in applying EC)₂₀Prior to the concentration of L-glutamate) indicates agonist activity, and the absence of this signal indicates lack of agonist activity. In the addition of EC₂₀A decrease in the signal observed after the concentration of L-glutamic acid is indicative of the inhibitory activity of the test compound.

In the list of the following examples, all are shown having an EC of less than or equal to 100nM₅₀Corresponding results for compounds of value.

MPEP binding assay:

for binding experiments, cDNA encoding the human mGlu5a receptor was transiently transfected into EBNA cells using the method described by Schlaeger and Christensen [ Cytotechnology 15: 1-13(1998)]. The cell membrane homogenate was stored at-80 ℃ until the day of assay, at which time it was thawed and resuspended and polytronise in 15mM Tris-HCl, 120mM NaCl, 100mM KCl, 25mM CaCl₂，25mM MgCl₂To a final concentration of 20. mu.g protein/well in binding buffer at pH 7.4.

By adding twelve [ 2 ] to these films at 4 ℃ in 1h³H]The saturation isotherm was determined at MPEP concentrations (0.04-100nM) (total volume 200. mu.l). In [ 2 ]³H]Competition experiments were performed with fixed concentrations of MPEP (2nM) and 11 concentrations (0.3-10,000nM) were used to evaluate the IC of the test compounds₅₀The value is obtained. Incubation was performed at 4 ℃ for 1 h.

After the incubation was complete, the membranes were filtered on a unifilter (96-well white microplate with bound GF/C filter) with Filtermate 96 collector (Packard BioScience), preincubated in 0.1% PEI (in wash buffer) for 1h, Packard BioScience, Meriden, CT) and washed 3 times with cold 50mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 μ M MPEP. After addition of 45. mu.l microscint 40(Canberra Packard S.A., Z rich, Switzerland) and shaking for 20min, the radioactivity on the filtrate was counted on a Packardtop-count microplate scintillation counter with quenching correction (3 min).

In the list of the following examples, all are shown having an EC of less than or equal to 100nM₅₀Corresponding results for compounds of value.

Reference Compound 2
		1	42
2	24
		3	94
4	46

Comparison of the Compounds of the invention with reference Compounds 1 and 2

As can be seen in the table below, the compound of the invention (NAM) shows significantly different characteristics compared to the structurally similar reference compounds 1 and 2 (PAM).

The compounds of formula I can be prepared by the methods given below, the methods given in the examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. However, the reaction sequence is not limited to the sequence shown in the scheme, and the order of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, by the methods described in the references or examples listed in the specification, or by methods known in the art.

The compounds of the invention of formula I and pharmaceutically acceptable salts thereof may be prepared by methods known in the art, for example, the process variants described below, which comprise

Reacting a compound of formula 3 with a compound of formula 4

To form a compound of formula I

Wherein the substituents are as described above.

The preparation of compounds of formula I is further described in more detail in scheme 1 and examples 1-4.

Scheme 1

Ethynyl-pyridine or ethynyl-pyrimidine compounds of formula I may be obtained, for example, by the following methods: the Sonogashira coupling of 5-bromo-pyridine-2-carboxylic acid methyl ester or 5-bromo-pyrimidine-2-carboxylic acid methyl ester 1 with an appropriately substituted aryl acetylene 2 followed by saponification with a base such as LiOH to yield the corresponding acid 3, or the Sonogashira coupling of 5-bromo-pyridine-2-carboxylic acid or 5-bromo-pyrimidine-2-carboxylic acid 1 with an appropriately substituted aryl acetylene 2 to directly yield the corresponding acid 3. The corresponding acid 3 is reacted with t-butylethylamine 4 in the presence of a base such as Hunig's base and a peptide coupling reagent such as TBTU in a solvent such as bisReaction in an alkane, or the corresponding acid chloride prepared in situ in a solvent such as dichloromethane using oxalyl chloride and DMF (catalyzed), followed by reaction with tert-butyl ethylamine 4 in the presence of a base such as pyridine, yields the desired ethynyl compound of formula I (scheme 1).

The pharmaceutically acceptable salts of the compounds of formula I can be readily prepared according to methods known per se and taking into account the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric or citric acid, formic, fumaric, maleic, acetic, succinic, tartaric, methanesulfonic, p-toluenesulfonic acid and the like are suitable for forming pharmaceutically acceptable salts of the basic compounds of formula I. Compounds containing alkali or alkaline earth metals (e.g., sodium, potassium, calcium, magnesium, etc.), basic amines or basic amino acids are suitable for forming pharmaceutically acceptable salts of acidic compounds.

Furthermore, the invention relates to medicaments containing one more compounds of the invention and pharmaceutically acceptable excipients for the treatment and prevention of mGluR5 receptor mediated disorders (NAM), such as anxiety and pain, depression, fragile-X syndrome, autism spectrum disorders, parkinson's disease and gastroesophageal reflux disease (GERD). The invention also relates to the use of the compounds according to the invention and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment and prevention of mGluR5 receptor mediated disorders (NAM) as described above.

The compounds were tested for pharmacological activity using the following method:

cDNA encoding rat mGlu5a receptor was transiently transfected into EBNA cells using the method described by e. -j.schlaeger and k.christensen (Cytotechnology 1998, 15, 1-13). After incubation of mGlu5a transfected EBNA cells with Fluo 3-AM (obtainable by FLUKA, 0.5. mu.M final concentration) for 1 hour at 37 ℃ followed by 4 washes with assay buffer (DMEM supplemented with Hank's salt and 20mM HEPES), [ Ca ] was performed on the cells²⁺]And i, measuring. Performed using a fluorescence imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, Calif., USA) [ Ca²⁺]And i, measuring. When a compound is evaluated as an antagonist, the compound is tested against 10 μ M glutamate as an agonist.

Using a given IC₅₀And Hill coefficient, using iterative non-linear curve fitting Software Origin (Microcal Software inc., north ampton, MA, USA) to fit inhibition (antagonist) curves.

The Ki values for the test compounds are given. The Ki value is defined by the formula:

wherein, IC₅₀Values are those concentrations of test compound in μ M at which 50% of the compound's effect is antagonized. [ L ]]Is the concentration of EC₅₀The values are the concentration of the compound in μ M that produces about 50% stimulation.

The compounds of the invention are mGluR5a receptor antagonists. The activity of the compound of formula I measured in the above assay is K_i＜100μM。

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, may be used in the aqueous injection solutions of the water-soluble salts of the compounds of formula I, but in general this is not essential. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain additional other therapeutically valuable substances.

As mentioned before, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as are processes for the preparation of such medicaments, which processes comprise: bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will of course be fitted to the individual requirements in each particular case. In general, an effective dose for oral or parenteral administration is 0.01-20 mg/kg/day, with a dose of 0.1-10 mg/kg/day being preferred for all indications mentioned. Accordingly, the daily dose for an adult having a body weight of 70kg is 0.7-1400 mg/day, preferably 7-700 mg/day.

The following examples are provided to further illustrate the invention:

example 1

5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

Step 1: 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid methyl ester

Bis- (triphenylphosphine) -palladium (II) dichloride (406mg, 580. mu. mol, 0.05 eq.) was dissolved in 25ml DMF. Methyl 5-bromo-pyridine-2-carboxylate (2.5g, 11.6mmol) and 3-fluorophenylacetylene (2.22g, 18.5mmol, 1.6 equiv.) are added at room temperature. Triethylamine (3.5g, 4.84ml, 34.7mmol, 3 equiv.), triphenylphosphine (91mg, 347. mu. mol, 0.03 equiv.) and copper (I) iodide (66mg, 347. mu. mol, 0.03 equiv.) were added and the mixture was stirred at 80 ℃ for 20 h. The reaction mixture is cooled and utilizedThe adsorbent is evaporated toAnd (5) drying. The crude product was purified by flash chromatography on silica gel (70g) eluting with an ethyl acetate: heptane gradient from 0: 100 to 80: 20. The desired 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid methyl ester was obtained (1.95g, 66% yield) as a light yellow solid, MS: 256.3(M + H) M/e⁺)。

Step 2: 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid

At room temperature, (1.9g, 7.44mmol) methyl 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylate (example 1, step 1) was dissolved in THF (30ml) and water (30ml) and LiOH (357mg, 24.9mmol, 2 equiv) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 2.5 with 4N HCl and THF was evaporated, forming a yellow suspension. The suspension was cooled to 0-5 ℃ and filtered. The crystals were washed with cold water and evaporated to dryness. The desired 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid (1.71g, 95% yield) was obtained as a light yellow solid, MS: 239.9(M + H)⁺)。

And step 3: 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid (example 1, step 2) was dissolved in bis (ethyl acetate) (100mg, 0.41mmol) at room temperatureTo an alkane (1ml) and Hunig's base (217. mu.l, 1.24mmol, 3 equiv.), tert-butylethylamine (63mg, 0.62mmol, 1.5 equiv.), and TBTU (146mg, 0.45mmol, 1.1 equiv.) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and saturated NaHCO₃The solution was extracted and extracted twice with a small amount of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layer onto a silica gel column and eluting with an ethyl acetate heptane gradient from 0: 100 to 0: 100. Desired 5- (3-fluoro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide (102mg, 76% yield) was obtained as a pale yellow oil, MS: 325.3(M + H)⁺)。

Example 2

5- (3-chloro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

Step 1: 5- (3-chloro-phenylethynyl) -pyridine-2-carboxylic acid

Using chemistry similar to that described in example 1, step 1, the title compound was obtained from 5-bromo-pyridine-2-carboxylic acid and 3-chlorophenylacetylene as a white solid, MS: 258.4/260.4(M + H)⁺)。

Step 2: 5- (3-chloro-phenylethynyl) -pyridine-2-carboxylic acid tert-butyl-ethyl-amide

Using chemistry similar to that described in example 1, step 3, the title compound was obtained from 5- (3-chloro-phenylethynyl) -pyridine-2-carboxylic acid (example 2, step 1) and tert-butylethylamine as a pale yellow oil, MS: 341.5/343.5(M + H)⁺)。

Example 3

5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

Step 1: 5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid

Using chemistry similar to that described in example 1, step 1, the title compound was obtained from 5-bromo-pyrimidine-2-carboxylic acid and 3-fluorophenylacetylene as a light yellow solid, MS: 243.4(M + H)⁺)。

Step 2: 5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid (example 3, step 1) (100mg, 0.41mmol) was suspended in dichloromethane (1ml) and DMF (10 μ l). Oxalyl chloride (40 μ l, 0.45mmol, 1.1 equiv) was added dropwise at room temperature and the mixture was stirred at reflux for 1 hour. The reaction mixture was then added to a mixture of diisopropylethylamine (235 μ l, 1.34mmol, 3.3 equivalents) and tert-butylethylamine (43mg, 0.41mmol, 1 equivalent) in THF (2 ml). The mixture was stirred at room temperature for 16 hours and atThe evaporation to dryness was carried out in the presence of an adsorbent. The crude product was purified by flash chromatography using a 20g silica gel column eluting with heptane: ethyl acetate 100: 0- > 0: 100.Desired 5- (3-fluoro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide was obtained (97mg, 78% yield) as a white solid, MS: 326.5(M + H)⁺)。

Example 4

5- (3-chloro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

Step 1: 5- (3-chloro-phenylethynyl) -pyrimidine-2-carboxylic acid

Using chemistry similar to that described in example 1, step 1, the title compound was obtained from 5-bromo-pyrimidine-2-carboxylic acid and 3-chlorophenylacetylene as a white solid, MS: m/e 259.4/261.4(M + H)⁺)。

Step 2: 5- (3-chloro-phenylethynyl) -pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide

Using chemistry similar to that described in example 3, step 2, the title compound was obtained from 5- (3-chloro-phenylethynyl) -pyrimidine-2-carboxylic acid (example 4, step 1) and tert-butylethylamine as a white solid, MS: 342.6/344.6(M + H)⁺)。

Claims (6)

1. A compound of formula I, or a pharmaceutically acceptable acid addition salt thereof,

wherein

Y is N or CH;

R¹is fluorine or chlorine.

2. A compound of formula I according to claim 1, wherein Y is N.

3. A compound of formula I according to claim 1, wherein Y is CH.

4. A process for the preparation of a compound of formula I as claimed in claim 1, which process comprises:

reacting a compound of formula 3

With a compound of formula 4

To form a compound of formula I

Wherein R is¹And Y is as defined in claim 1.

5. A pharmaceutical composition comprising a compound according to any one of claims 1-3 and a pharmaceutically inert carrier.

6. Use of a compound according to any one of claims 1-3 for the preparation of a medicament for the treatment of anxiety and pain, depression, fragile-X syndrome, autism spectrum disorders, parkinson's disease and gastroesophageal reflux disease.