NZ621583B2 - Ethynyl derivatives as metabotropic glutamate receptor modulators - Google Patents

Abstract

The disclosure relates to compounds of formula IA, IB and ID, wherein the unspecified functional groups are disclosed in the specification. These compounds act as allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5) and may have utility in the treatment or prevention of schizophrenia, cognitive diseases, fragile X syndrome or autism. Example compounds include: 2-Methoxy-2-methyl-N-(5-phenylethynyl-pyridin-2-yI)-propionamide, N-[5-(3-Fluoro-phenylethynyI)-pyridin-2-yl]-2-methoxy-2-methyl-propionamide, 2,2-Dimethyl-N-(5-phenylethynyl-pyrimidin-2-yl)-propionamide, 2,2,N-Trimethyl-N-(5-phenylethynyl-pyrimidin-2-yl)-propionamide, 2,2-Dimethyl-N-(6-phenylethynyl-pyridazin-3-yl)-propionamide and N-[6-(3-Chloro-phenylethynyl)-pyridazin-3-yl]-2,2-dimethyl-propionamide. hizophrenia, cognitive diseases, fragile X syndrome or autism. Example compounds include: 2-Methoxy-2-methyl-N-(5-phenylethynyl-pyridin-2-yI)-propionamide, N-[5-(3-Fluoro-phenylethynyI)-pyridin-2-yl]-2-methoxy-2-methyl-propionamide, 2,2-Dimethyl-N-(5-phenylethynyl-pyrimidin-2-yl)-propionamide, 2,2,N-Trimethyl-N-(5-phenylethynyl-pyrimidin-2-yl)-propionamide, 2,2-Dimethyl-N-(6-phenylethynyl-pyridazin-3-yl)-propionamide and N-[6-(3-Chloro-phenylethynyl)-pyridazin-3-yl]-2,2-dimethyl-propionamide.

Description

ETHYNYL DERIVATIVES AS METABOTROPIC GLUTAMATE RECEPTOR MODULATORS Described herein are ethynyl derivatives of formula I R R3 R3' Y N W R2 U O R1 I wherein Y is N or CH; with the proviso that Y can only be CH, if at least one of U, V or W are N; U is N or C-R4; V and W are independently N or CH; with the proviso that only one of U, V or W can be simultaneously nitrogen; R4 is hydrogen, methyl or halogen; R1 is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, lower alkoxy, CF3 or S-lower alkyl; R3/R3’ are ndently from each other hydrogen, lower alkyl or lower alkoxy; or R3 and R3’ form together a C3cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or to a pharmaceutically acceptable acid addition salt, to a racemic e, or to its corresponding omer and/or optical isomer and/or stereoisomer thereof.

It has now surprisingly been found that the nds of general formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 5).

In the central nervous system (CNS) the transmission of i takes place by the interaction of a neurotransmitter, which is sent out by a , with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms -controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and of these some even have pes. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or c neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer’s disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are ischemia, Huntington's chorea, amyotrophic l sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, thic sonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, y, vomiting, dyskinesia and depressions.

Disorders mediated full or in part by mGluR5 are for example acute, traumatic and c degenerative processes of the nervous system, such as Alzheimer’s disease, senile dementia, Parkinson’s e, Huntington’s chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12, (12)).

A new avenue for developing selective modulators is to fy compounds which act through allosteric mechanism, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site. Allosteric tors of mGluR5 have emerged recently as novel pharmaceutical entities offering this attractive ative. Allosteric tors have been described, for example in WO2008/151184, WO2006/048771, WO2006/129199 and WO2005/044797 and in Molecular Pharmacology, 40, 333 – 336, 1991; The Journal of Pharmacology and Experimental Therapeutics, Vol 313, No. 1, 199-206, 2005; In recent years there have been significant ages in understanding the pathophysiology of several ers of brain development, suggesting that protein sis at synapses is triggered by activation of group I metabotropic glutamate receptors. Such disorders include fragile X syndrome, autism, idiopatic autism, tuberous sclerosis complex er, neurofibromatosis type 1 or Rett syndrome (Annu. Rev. Med., 2011, 62, 31.1 – 31.19 and Neuroscience 156, 2008, 203-215). bed in the prior art are positive allosteric modulators. They are compounds that do not directly activate receptors by themselves, but markedly potentiate agonist-stimulated responses, increase potency and maximum of efficacy. The binding of these compounds increases the affinity of a glutamate-site agonist at its extracellular N-terminal binding site.

Allosteric modulation is thus an attractive mechanism for enhancing appropriate physiological receptor activation. There is a scarcity of selective allosteric modulators for the mGluR5 receptor. Conventional mGluR5 receptor modulators typically lack actory aqueous solubility and exhibit poor oral bioavailability.

Therefore, there remains a need for compounds that overcome these deficiencies and that effectively provide selective allosteric modulators for the mGluR5 receptor.

Compounds of formula I are distinguished by having le therapeutic ties. They can be used in the treatment or tion of disorders, ng to allosteric tors for the mGluR5 receptor.

The most preferred indications for compounds which are allosteric modulators are schizophrenia and cognition.

The invention is as defined in the claims and relates to compounds of formulae IA, IB, and ID, as defined below, to processes of preparing such compounds, to pharmaceutical compositions containing such compounds and to their use for the manufacture of medicaments for the ent or prevention of diseases relating to all osteric modulators of mGluR5 receptors.

However, also described herein is the broader class of compounds of a I, which encompasses the compounds of formulae IA, IB and ID. This description is retained herein for its cal information.

Accordingly, also described herein are compounds of formula I and their pharmaceutically acceptable salts, in cases where this applies to mixtures of enantiomers or diastereomers or their enantiomerically or diastereomerically pure forms, these compounds as ceutically active substances, the processes for their production as well as their use in the treatment or prevention of ers, relating to allosteric modulators for the mGluR5 receptor, such as schizophrenia, cognition, fragile X syndrome or autism, and pharmaceutical compositions containing the compounds of formula I.

The following definitions of the l terms used in the present description apply irrespective of whether the terms in on appear alone or in combination.

As used herein, the term "lower alkyl" s a ted, i.e. tic hydrocarbon group including a straight or branched carbon chain with 1 – 4 carbon atoms. Examples for “alkyl” are methyl, ethyl, n-propyl, and isopropyl.

The term y” denotes a group -O-R’ wherein R’ is lower alkyl as defined above.

The term “ethynyl” denotes the group −C≡C-.

The term “heteroaryl” denotes a 5 or 6-membered aromatic ring, containing at least one N, O or S-heteroatom, for example pyridinyl, pyrimidinyl, pyrazolyl, zinyl, imidazolyl, triazolyl, thienyl or pyrazinyl.

The term "pharmaceutically acceptable salt" or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.

One embodiment of the invention are compounds of formula IA R R3 R3' N N R1 IA wherein R1 is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, lower alkoxy, CF3 or S-lower alkyl; R3/R3’ are independently from each other hydrogen, lower alkyl or lower alkoxy; or R3 and R3’ form together a C3cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or a pharmaceutically able acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof, with the ion of the compound N-(5-((1H-pyrrolo[2,3-B]pyridineyl)ethynyl)pyridineyl)acetamide.

Examples of compounds of formula IA are the followings: 2,2-Dimethyl-N-(5-phenylethynyl-pyridinyl)-propionamide N-(5-Phenylethynyl-pyridinyl)-butyramide oic acid (5-phenylethynyl-pyridinyl)-amide 3-Methyl-N-(5-phenylethynyl-pyridinyl)-butyramide (RS)Methyl-pentanoic acid (5-phenylethynyl-pyridinyl)-amide 2-Methylsulfanyl-N-(5-phenylethynyl-pyridinyl)-acetamide 2-Methoxy-N-(5-phenylethynyl-pyridinyl)-acetamide 3-Fluoro-phenylethynyl)-pyridinyl]-2,2-dimethyl-propionamide 2-Methoxymethyl-N-(5-phenylethynyl-pyridinyl)-propionamide N-[5-(3-Fluoro-phenylethynyl)-pyridinyl]methoxymethyl-propionamide N-[5-(2,5-Difluoro-phenylethynyl)-pyridinyl]methoxymethyl-propionamide or N-[5-(3-Chloro-phenylethynyl)-pyridinyl]-3,3,3-trifluoro-2,2-dimethyl-propionamide.

A further embodiment of the invention are compounds of formula IB R R3 R3' N N N O R1 IB wherein R1 is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, lower , CF3 or S-lower alkyl; R3/R3’ are independently from each other en, lower alkyl or lower alkoxy; or R3 and R3’ form together a C3cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding omer and/or optical isomer and/or stereoisomer thereof.

Specific examples from compounds of formula IB are the followings: 2,2-Dimethyl-N-(5-phenylethynyl-pyrimidinyl)-propionamide or 2,2,N-Trimethyl-N-(5-phenylethynyl-pyrimidinyl)-propionamide.

A further embodiment of the ion are compounds of formula ID R R3 R3' N N N R2 R1 ID wherein R1 is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower R is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, lower alkoxy, CF3 or S-lower alkyl; R3/R3’ are independently from each other hydrogen, lower alkyl or lower alkoxy; or R3 and R3’ form together a C3cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or a pharmaceutically able acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Examples of compounds of formula ID are the following: 2,2-Dimethyl-N-(6-phenylethynyl-pyridazinyl)-propionamide or N-[6-(3-Chloro-phenylethynyl)-pyridazinyl]-2,2-dimethyl-propionamide The preparation of compounds of formula I of the present ion may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the ing schemes 1 to 4. The skills required for carrying out the reaction and purification of the resulting ts are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before.

The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The on ce is not limited to the one yed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

The present compounds of formula I and their pharmaceutically acceptable salts may be prepared by methods, known in the art, for example by the process variant described below, which process ses a) reacting a compound of formula Y NH R1 3 with a le compound of a R3' R3 Cl R3' R2 OH O 4 or O 5 to a compound of formula R R3 Y N R3' U O R1 I wherein the substituents are described above, or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or b) reacting a nd of formula R R3 Y N R3' U O X V 6 with a suitable compound of formula R1 2 to a nd of formula R R3 Y N R3' U O R1 I wherein the substituents are described above, or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts, or c) reacting a compound of formula Y Y' R1 13 with a suitable compound of a R R3 NH R3' O to a compound of formula R R3 Y N R3' U O R1 I wherein the substituents are described above, or d) reacting a compound of a Y N R3' U O R1 I-1 with a suitable compound of formula R-hal to a compound of formula R R3 Y N R3' U O R1 I wherein R is halogen and the other substituents are described above, or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The preparation of compounds of formula I is further described in more detail in schemes 1 to 5 and in examples 1 –16.

Scheme 1 R 1. Bis-(tpp)-Pd(II)Cl2 Y NH Y NH W W Et3N, TPP, CuI, + THF or DMF, 2-16h, 70° U U R1 V X V 3 1 2 X = Cl, Br, I 2b. HATU or TBTU R R3 2a. Pyridine, DCM R3' Hunig's Base, DMF 2-16h, rt Y N 2-16h, rt W R2 OR U O R3 R3 V R3' R3' I Cl OH R1 R2 R2 5 O 4 An ethynyl compound of formula I can be obtained for e by Sonogashira coupling of an appropriate amine 1 with an appropriately substituted arylacetylene 2 to yield the corresponding ethynyl compound 3. Coupling of ethynyl nd 3 with an appropriately substituted acid chloride 4 with a base such as pyridine in a solvent like romethane or coupling with an appropriately substituted acid 5 with a base such as Hunig’s Base and a peptide coupling reagent such as HATU or TBTU in a t like DMF yield the desired ethynyl compounds of l formula I. It is also possible to introduce the R substituent at a later time point by tion of compounds of formula I, where R= H.

Scheme 2 1a. Pyridine, DCM 1b. HATU or TBTU Y NH Hunig's Base, DMF R W 2-16h, rt R3 R3' 2-16h, rt Y N U or W R2 X V R3 R3' R3 R3' U O 1 Cl X V R2 OH 4 R2 6 X = Cl, Br, I O O 5 X = Cl, Br, I 2. Bis-(tpp)-Pd(II)Cl2 R R3 R3' Et3N, TPP, CuI, Y N THF or DMF, 2-16h, 70° W R2 U O R1 I Generally speaking, the sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases, for example by first running the amide coupling to form an riately substituted amide derivative 6 followed by Sonogashira coupling with an appropriately substituted arylacetylene 2 using ures similar to those described in scheme 1. Introduction of the R substituent can also be realized at various points in the synthetic sequence via alkylation of the ponding intermediate where R= H.

Scheme 3 1. Bis-(tpp)-Pd(II)Cl2 N S N S Et3N, TPP, CuI + THF, 3h reflux N N R1 R1 8 7 2 3. Et3N, THF R 2. mCPBA N S N NH CH2Cl2, 4h rt 3h reflux R1 H N 9 2 R R1 11 4b. HATU or TBTU 4a. Pyridine, DCM R Hunig's Base, DMF R3 R3' 2-16h, rt 2-16h, rt N N or R2 R3 N O R3' R3 R3' Cl OH R2 R2 R1 O 4 O 5 An ethynyl pyrimidine compound of formula IB can be obtained by Sonogashira coupling of an appropriately substituted etylene 2 with 5-bromomethylsulfanylpyrimidine 7 to yield the corresponding methansulfanyl derivatives 8. Oxidation of the thioether compound with an oxidizing agent such as mCPBA in a solvent like dichloromethane yields the corresponding sulfonyl derivative 9. Reaction of the sulfonyl derivative with an appropriately substituted amine 10 in the ce of base such as triethylamine in a solvent like THF yields the desired (5-phenylethynyl-pyrimidinyl)-amine 11. Coupling of nd 11 with an appropriately tuted acid chloride 4 with a base such as pyridine in a solvent like dichloromethane or ng with an appropriately substituted acid 5 with a base such as Hunig’s Base and a peptide coupling reagent such as HATU or TBTU in a solvent like DMF yield the desired ethynyl pyrimidine compounds of general formula IB.

Scheme 4 1. Bis-(tpp)-Pd(II)Cl2 Y Y' Y Y' Et3N, TPP, CuI W W + R1 THF, 3h reflux U U V X V 2 R1 12 R R3 R3' 13 X, Y' = Hal N H R2 Cs2CO3, Tol H R3 R3' -16h, 100°C N H R2 2. Cs2CO3, xantphos O Pd2(dba)3, toluene 1h 90°C R R3 R3' H R3 R3' Y N Y N W R2 W R2 U O 3. R-Hal U O V NaH, DMF V R1 I R1 I-1 R= alkyl In certain cases it is also possible to selectively react a dihalogenated compound 12 with an acetylene derivative 2 to yield the adduct 13. The amido group can then be directly introduced via a nucleophillic addition (Y’ = preferably Cl, F) or a ium catalyzed coupling (Buchwald) reaction (Y’ = preferably Br or I). The R group can be introduced either directly in the ng step or via alkylation of compounds of general formula I-1. Of course, ing on X and Y’ the sequence of reactions can be ed by first introducing the amide group followed by the Sonogashira reaction (X = Cl, Br, I preferably Br, I) to introduce the acetylene moiety.

Scheme 5 R R3 R3' 1. Bis-(tpp)-Pd(II)Cl2 Y N Et3N, TPP, CuI R3 R3' W R2 Y N THF or DMF, 2-16h 70°C W R2 U O X V U O Si Si X = Cl, Br, I 14 2. Bis-(tpp)-Pd(II)Cl2 R R3 R3' Et3N, TPP, CuI, TBAF Y N THF or DMF, 1h 70°C W R2 U O Hal R1 16 I Compounds of formula I can be ed by Sonogashira coupling of an appropriately substituted amide tive 6 with ethynyltrimethylsilane 14 to yield the corresponding 5- trimethylsilanylethynyl- derivatives 15. Sonogashira coupling with in-situ desilylation of 15 and an appropriately substituted aryl-halogenide 16 yields the desired compounds of formula I (scheme 5).

List of Examples: Ex. Structure Name EC50 (nM) Eff. (%) mGlu5PAM N N 2,2-Dimethyl-N-(5- 1 O phenylethynyl-pyridin 19 72 yl)-propionamide N N O N-(5-Phenylethynyl- 2 70 52 pyridinyl)-butyramide N N Pentanoic acid (5- 3 ethynyl-pyridin 48 84 yl)-amide N N 3-Methyl-N-(5- 4 phenylethynyl-pyridin 71 83 yl)-butyramide N N (RS)Methyl-pentanoic acid (5-phenylethynyl- 48 75 nyl)-amide N N S 2-Methylsulfanyl-N-(5- 6 phenylethynyl-pyridin 18 47 yl)-acetamide N N methyl-N-(5- 7 N O phenylethynyl-pyrimidin- 56 59 2-yl)-propionamide N N 2,2,N-Trimethyl-N-(5- 8 N O phenylethynyl-pyrimidin- 52 74 2-yl)-propionamide N N 2,2-Dimethyl-N-(6- 9 O phenylethynyl-pyridazin- 6 73 3-yl)-propionamide N N O 2-Methoxy-N-(5- phenylethynyl-pyridin 49 43 yl)-acetamide N-[5-(3-Fluoro- N N phenylethynyl)-pyridin 11 O 15 44 F yl]-2,2-dimethylpropionamide N N O 2-Methoxymethyl-N- 12 O (5-phenylethynyl-pyridin- 77 68 2-yl)-propionamide N-[5-(3-Fluoro- N N O phenylethynyl)-pyridin 13 O 85 54 F yl]methoxymethylpropionamide N-[5-(2,5-Difluoro- N N O phenylethynyl)-pyridin 14 O 94 47 F yl]methoxymethyl- F propionamide N-[5-(3-Chloro- N N O F phenylethynyl)-pyridin 19 46 Cl yl]-3,3,3-trifluoro-2,2- dimethyl-propionamide 3-Chloro- N N N phenylethynyl)-pyridazin- 16 O 7 45 Cl 3-yl]-2,2-dimethylpropionamide Experimental n: Example 1 2,2-Dimethyl-N-(5-phenylethynyl-pyridinyl)-propionamide N N Step 1: 5-Phenylethynyl-pyridinylamine Bis-(triphenylphosphine)-palladium(II)dichloride (480 mg, 0.68 mmol, 0.05 equiv.) was dissolved in 50 ml THF. (3 g, 13.6 mmol) 2-Aminoiodopyridine and phenylacetylene (2.79 g, 27.3 mmol, 2.0 equiv.) were added at room temperature. Triethylamine (5.58 ml, 40.9 mmol, 3 equiv.), triphenylphosphine (111 mg, 0.41 mmol, 0.03 equiv.) and copper(I)iodide (70 mg, 0.41 mmol, 0.03 equiv.) were added and the mixture was stirred for 2 hours at 65°C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and three times with ethyl acetate. The organic layers were ed, dried over sodium sulfate and evaporated to dryness.

The crude product was suspended in dichloromethane, filtered and the solid evaporated to dryness. The desired 5-phenylethynyl-pyridinylamine (1.6 g, 62 % yield) was obtained as a light yellow solid, MS: m/e = 195.3 (M+H+).

Step 2: 2,2-Dimethyl-N-(5-phenylethynyl-pyridinyl)-propionamide N N (65 mg, 0.33 mmol) 5-Phenylethynyl-pyridinylamine (Example 1, step 1) was ved in dichloromethane (3 ml). Pyridine (52 mg, 53 µl, 0.67 mmol, 2 equiv.) and pivaloyl chloride (48 mg, 50 µl, 0.40 mmol, 1.2 equiv.) were added and the e was stirred for 2 hours at room temperature. The reaction mixture was ted with 1N HCl solution and twice with dichloromethane. The c extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with heptane:dichloromethane 50:50. The desired 2,2-dimethyl-N-(5-phenylethynylpyridinyl ionamide (40 mg, 43 % yield) was obtained as a light yellow solid, MS: m/e = 279.3 (M+H+).

Example 2 N-(5-Phenylethynyl-pyridinyl)-butyramide N N The title compound was obtained as a white solid, MS: m/e = 265.3 (M+H+), using chemistry r to that described in Example 1, step 2 from 5-phenylethynyl-pyridinylamine (Example 1, step 1) and butyryl chloride.

Example 3 Pentanoic acid nylethynyl-pyridinyl)-amide N N The title compound was obtained as a white solid, MS: m/e = 279.3 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-phenylethynyl-pyridinylamine (Example 1, step 1) and l chloride.

Example 4 3-Methyl-N-(5-phenylethynyl-pyridinyl)-butyramide N N The title compound was obtained as a white solid, MS: m/e = 279.3 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-phenylethynyl-pyridinylamine (Example 1, step 1) and isovaleroyl chloride.

Example 5 (RS)Methyl-pentanoic acid (5-phenylethynyl-pyridinyl)-amide N N The title compound was obtained as a white solid, MS: m/e = 293.3 , using chemistry r to that described in Example 1, step 2 from 5-phenylethynyl-pyridinylamine (Example 1, step 1) and (RS)methylvaleroyl chloride.

Example 6 2-Methylsulfanyl-N-(5-phenylethynyl-pyridinyl)-acetamide N N Step 1: N-(5-Bromo-pyridinyl)methylsulfanyl-acetamide N N (1 g, 5.78 mmol) 5-Bromopyridinamine was dissolved in DMF (40 ml) and HATU (2.64 g, 6.94 mmol, 1.2 ) was added. After 15 minutes at room temperature Hunig’s Base (6.0 ml, 34.7 mmol, 6 equiv.) and 2-(methylthio)acetic acid (736 mg, 6.94 mmol, 1.2 equiv.) were added.

The mixture was stirred for 72 hours at room temperature. The reaction mixture was evaporated and extracted three times with saturated Na2CO3 solution and three times with ethyl acetate. The c layers were extracted three times with 1N HCl solution and evaporated to dryness. The crude product was suspended in pentane, filtered and the solid evaporated to dryness. The desired N-(5-bromo-pyridinyl)methylsulfanyl-acetamide (312 mg, 21 % yield) was obtained as a yellow solid, MS: m/e = 258.9/260.8 (M+H+).

Step 2: 2-Methylsulfanyl-N-(5-phenylethynyl-pyridinyl)-acetamide N N The title compound was obtained as a white solid, MS: m/e = 283.1 (M+H+), using chemistry r to that described in Example 1, step 1 from N-(5-bromo-pyridinyl)methylsulfanyl- acetamide (Example 6, step 1) and phenylacetylene.

Example 7 2,2-Dimethyl-N-(5-phenylethynyl-pyrimidinyl)-propionamide N N N O Step 1: romo-pyrimidinyl)-2,2-dimethyl-propionamide N N N O The title compound was obtained as a white solid, MS: m/e = 258.0/259.9 , using chemistry similar to that described in Example 1, step 2 from 2-aminobromopyrimidine and pivaloyl chloride.

Step 2: 2,2-Dimethyl-N-(5-phenylethynyl-pyrimidinyl)-propionamide N N N O The title compound was obtained as a light yellow solid, MS: m/e = 280.1 (M+H+), using chemistry similar to that described in Example 1, step 1 from N-(5-bromo-pyrimidinyl)-2,2- dimethyl-propionamide (Example 7, step 1) and phenylacetylene.

Example 8 2,2,N-Trimethyl-N-(5-phenylethynyl-pyrimidinyl)-propionamide N N N O Step 1: 2-Methylsulfanylphenylethynyl-pyrimidine N S Bis-(triphenylphosphine)-palladium(II)dichloride (120 mg, 0.16 mmol, 0.05 equiv.) were ved in 50 ml THF and omethylsulfanyl-pyrimidine (840 mg, 4.1 mmol) and acetylene (410 µl, 4.1 mmol, 1 equiv.) were added at room temperature. Triethylamine (1.36 ml, 12.3 mmol, 3 equiv.), triphenylphosphine (28 mg, 0.12 mmol, 0.03 equiv.) and copper(I)iodide (19 mg, 0.08 mmol, 0.03 equiv.) were added and the mixture was stirred for 3 hours at 65°C. The reaction mixture was cooled and extracted once with saturated NaHCO3 solution and three times with ethyl acetate. The organic layers were ed, dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silicagel (heptane:ethyl acetate 100:0 -> 50:50). The desired 2- Methylsulfanylphenylethynyl-pyrimidine was ed as a light yellow solid (400 mg, 44%), MS: m/e = 227.3 (M+H+).

Step 2: 2-Methanesulfonylphenylethynyl-pyrimidine N S (360 mg, 1.60 mmol) 2-Methylsulfanylphenylethynyl-pyrimidine (Example 8, step 1) was dissolved in 20 ml of romethane and 3-chloroperbenzoic acid (870 mg, 3.50 mmol, 2.2 equiv.) was added in several portions at 0-5°C. The reaction mixture was stirred for 4 hours at room temperature. ted NaHCO3 solution was added and the mixture was extracted three times with ethyl acetate. The organic extracts were dried with sodium e, ed and evaporated. The crude product was purified by flash chromatography on silicagel (dichloromethane). The desired 2-methanesulfonylphenylethynyl-pyrimidine was obtained as a white solid (400 mg, 97%), MS: m/e = 259.2 (M+H+).

Step 3: Methyl-(5-phenylethynyl-pyrimidinyl)-amine N N (100 mg, 0.38 mmol) 2-Methanesulfonylphenylethynyl-pyrimidine (Example 8, step 2), methylamine hydrochloride (52 mg, 0.77 mmol, 2 equiv.) and Et3N (220 µl, 1.55 mmol, 4 equiv.) were suspended in 1 ml THF and stirred for 1 hour at 65°C. The reaction mixture was concentrated in vacuo and the e was purified by flash chromatography by directly g the crude material onto a silica gel column and eluting with (heptane:ethyl acetate 100:0 -> 0:100). The desired methyl-(5-phenylethynyl-pyrimidinyl)-amine was obtained as a white solid (38 mg, 47 %), MS: m/e = 210.2 (M+H+).

Step 4: 2,2,N-Trimethyl-N-(5-phenylethynyl-pyrimidinyl)-propionamide N N N O The title compound was obtained as a white solid, MS: m/e = 294.0 (M+H+), using try similar to that described in Example 1, step 2 from methyl-(5-phenylethynyl-pyrimidinyl)- amine (Example 8, step 3) and pivaloyl chloride.

Example 9 2,2-Dimethyl-N-(6-phenylethynyl-pyridazinyl)-propionamide N N To a suspension of 3-chloro(phenylethynyl)pyridazine (CAS 777785) (200 mg, 0.93 mmol) and mide (113 mg, 1.12 mmol, 1.2 equiv.) in 4 ml of toluene were added cesium carbonate (364 mg, 1.12 mmol, 1.2 equiv.). The suspension was heated for 20 hours at 120°C and then allowed to cool to room temperature. Ethyl e (10 ml) was added and the unsoluble salts were filtered off. After tration in vacuum, the residue was purified by flash chromatography eluting with heptane ed by a heptane to 60% ethyl acetate/heptane gradient to yield 19 mg (7%) of the title compound as a light yellow solid, MS: m/e = 280.2 (M+H+).

Example 10 2-Methoxy-N-(5-phenylethynyl-pyridinyl)-acetamide N N The title compound was obtained as a white solid, MS: m/e = 267.0 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-phenylethynyl-pyridinylamine (Example 1, step 1) and 2-methoxyacetyl chloride.

Example 11 N-[5-(3-Fluoro-phenylethynyl)-pyridinyl]-2,2-dimethyl-propionamide N N Step 1: N-(5-Bromo-pyridinyl)-2,2-dimethyl-propionamide N N The title compound was obtained as a colorless oil, MS: m/e = 257.1/259.0 (M+H+), using try similar to that described in Example 1, step 2 from 2-aminobromopyridine and pivaloyl chloride.

Step 2: N-[5-(3-Fluoro-phenylethynyl)-pyridinyl]-2,2-dimethyl-propionamide N N The title compound was obtained as a yellow solid, MS: m/e = 297.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from N-(5-bromo-pyridinyl)-2,2-dimethylpropionamide (Example 11, step 1) and 3-fluorophenylacetylene.

Example 12 2-Methoxymethyl-N-(5-phenylethynyl-pyridinyl)-propionamide N N (100 mg, 0.515 mmol) 5-Phenylethynyl-pyridinylamine (Example 1, step 1) was dissolved in dichloromethane (5 ml) and 2-methoxymethylpropionic acid (91 mg, 0.77 mmol, 1.5 equiv.), 2-bromoethyl pyridinium luoroborate (CAS 8789) (211 mg, 0.77 mmol, 1.5 equiv.) and Hunig’s Base (0.26 ml, 1.54 mmol, 3 ) were added. The mixture was d for 14 hours at room temperature. The reaction mixture was extracted with saturated Na2CO3 solution and dichloromethane. The organic layer was dried over sodium sulfate and evaporated to dryness.

The crude product was purified by prep HPLC to afford the desired 2-methoxymethyl-N-(5- phenylethynyl-pyridinyl)-propioamide (70 mg, 46 % yield) was obtained as a yellow oil, MS: m/e = 295.2 (M+H+). e 13 N-[5-(3-Fluoro-phenylethynyl)-pyridinyl]methoxymethyl-propionamide N N Step 1: N-(5-Iodo-pyridinyl)methoxymethyl-propionamide N N The title compound was obtained as a ess oil using chemistry similar to that described in Example 12 from 2-aminoiodopyridine and 2-methoxymethylpropionic acid.

Step 2: 2-Methoxymethyl-N-(5-trimethylsilanylethynyl-pyridinyl)-propionamide N N The title compound was obtained as a yellow oil, MS: m/e = 290.8 (M+H+), using try similar to that described in Example 1, step 1 from N-(5-iodo-pyridinyl)methoxymethylpropionamide (Example 13, step 1) and hylsilylacetylene.

Step 3: N-[5-(3-Fluoro-phenylethynyl)-pyridinyl]methoxymethyl-propionamide N N 2-Methoxymethyl-N-(5-trimethylsilanylethynyl-pyridinyl)-propionamide (Example 13, step 2) (90 mg, 0.31 mmol) was dissolved in THF (8 ml). 1-Fluoroiodobenzene (83 mg, 0.37 mmol, 1.2 equiv.), Et3N (130 µl, 0.93 mmol, 3 equiv.), riphenylphosphine)- palladium(II)dichloride (11 mg, 15 µmol, 0.05 equiv.) and copper(I)iodide (1.8 mg, 10 µmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70°C. TBAF 1M in THF (370 µl, 0.37 mmol, 1.2 equiv.) was added dropwise at 70°C. The reaction mixture was stirred for 1 hour at 70°C, filtered through celite and the filtrate evaporated to dryness. The crude product was purified by flash chromatography with a silica gel column eluting with heptane:ethyl acetate 100:0 -> 90:10. The desired N-[5-(3-fluoro-phenylethynyl)-pyridinyl] methoxymethyl-propionamide (64 mg, 66% yield) was obtained as a yellow oil, MS: m/e = 313.0 (M+H+). e 14 N-[5-(2,5-Difluoro-phenylethynyl)-pyridinyl]methoxymethyl-propionamide N N F The title compound was obtained as a white solid, MS: m/e = 331.0 (M+H+), using chemistry similar to that described in Example 13, step 3 from 2-methoxymethyl-N-(5- trimethylsilanylethynyl-pyridinyl)-propionamide (Example 13, step 2) and 1,4-difluoro nzene.

Example 15 N-[5-(3-Chloro-phenylethynyl)-pyridinyl]-3,3,3-trifluoro-2,2-dimethyl-propionamide N N Step 1: 3,3,3-Trifluoro-N-(5-iodo-pyridinyl)-2,2-dimethyl-propionamide N N The title compound was obtained as a yellow oil: m/e = 359.4 (M+H+), using chemistry similar to that described in Example 12 from 2-aminoiodopyridine and 3,3,3-trifluoro-2,2- dimethylpropanoic acid.

Step 2: N-[5-(3-Chloro-phenylethynyl)-pyridinyl]-3,3,3-trifluoro-2,2-dimethyl-propionamide N N The title compound was obtained as a light yellow oil, MS: m/e = 367.5 , using chemistry similar to that described in Example 1, step 1 from 3,3,3-trifluoro-N-(5-iodo-pyridin- 2-yl)-2,2-dimethyl-propionamide le 15, step 1) and 3-chlorophenylacetylene.

Example 16 N-[6-(3-Chloro-phenylethynyl)-pyridazinyl]-2,2-dimethyl-propionamide N N Step 1: N-(6-Chloro-pyridazinyl)-2,2-dimethyl-propionamide N N The title compound was ed as a white solid, MS: m/e = 214.2/216.2 (M+H+), using chemistry similar to that described in Example 1, step 2 from 3-aminochloropyridazine and pivaloyl chloride.

Step 2: N-[6-(3-Chloro-phenylethynyl)-pyridazinyl]-2,2-dimethyl-propionamide N N The title compound was obtained as a light yellow solid, MS: m/e = 314.5/316.5 (M+H+), using chemistry similar to that bed in Example 1, step 1 from N-(6-chloro-pyridazinyl)-2,2- dimethyl-propionamide (Example 16, step 1) and 3-chlorophenylacetylene.

Biological Assay and Data: Intracellular Ca2+ mobilization assay A onal HEK-293 cell line stably transfected with a cDNA encoding for the human mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow the differentiation of tic versus PAM activity. Cells were cultured according to standard protocols (Freshney, 2000) in co’s ed Eagle Medium with high glucose supplemented with 1 mM ine, 10% (vol/vol) heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50 µg/ml hygromycin and 15 µg/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland).

About 24 hrs before an experiment, 5x104 cells/well were seeded in poly-D-lysine coated, black/clear-bottomed 96-well plates. The cells were loaded with 2.5 µM AM in loading buffer (1xHBSS, 20 mM HEPES) for 1 hr at 37°C and washed five times with loading buffer.

The cells were transferred into a Functional Drug Screening System 7000 atsu, Paris, France), and 11 half logarithmic serial dilutions of test compound at 37°C were added and the cells were incubated for 10-30 min. with on-line recording of fluorescence. ing this pre- incubation step, the t L-glutamate was added to the cells at a concentration corresponding to EC20 (typically around 80 µM) with on-line recording of fluorescence; in order to t for day-to-day variations in the responsiveness of cells, the EC20 of glutamate was determined immediately ahead of each experiment by recording of a full dose-response curve of glutamate.

Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence without addition of L-glutamate), normalized to the maximal stimulatory effect obtained with ting concentrations of L-glutamate. Graphs were plotted with the % maximal stimulatory using XLfit, a curve fitting program that iteratively plots the data using Levenburg Marquardt algorithm. The single site competition analysis equation used was y = A + ((B-A)/(1+((x/C)D))), where y is the % maximal atory effect, A is the minimum y, B is the maximum y, C is the EC50, x is the log10 of the concentration of the competing nd and D is the slope of the curve (the Hill Coefficient). From these curves the EC50 (concentration at which half maximal stimulation was achieved), the Hill coefficient as well as the maximal response in % of the maximal stimulatory effect obtained with saturating concentrations of L-glutamate were calculated.

Positive signals obtained during the pre-incubation with the PAM test compounds (i.e. before application of an EC20 concentration of L-glutamate) were tive of an agonistic activity, the absence of such signals were trating the lack of agonistic activities. A depression of the signal observed after on of the EC20 concentration of L-glutamate was indicative of an inhibitory activity of the test compound.

In the list of examples above are shown the corresponding results for compounds which all have EC50< 100 nM..

The compounds of formula (I) and ceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft ne capsules, solutions, emulsions or sions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula (I) and ceutically acceptable salts thereof can be processed with ceutically inert, nic or organic rs for the production 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, dragées and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, olid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, s, sucrose, invert sugar, glucose and the like. Adjuvants, such as ls, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not ary. 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, lizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

As mentioned r, medicaments ning a compound of formula IA, IB or ID or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an aspect of the present invention. Also described is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically le substances into a cal dosage form together with one or more therapeutically inert carriers.

As further mentioned earlier, the use of the compounds of formula IA, IB or ID for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases is also an aspect of the present invention.

The dosage can vary within wide limits and will, of course, be fitted to the individual ements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg ingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

Pharmaceutical compositions comprising compounds of the invention: Tablets of the following composition are produced in a conventional manner: mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch 35 nylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250

Claims (5)

Claims

1. Ethynyl derivatives of formulla 1A, IB and ID 83?:13 IB and 3 R3 N i R Ni’ \ R2 / O (N é R1 is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, lower alkoxy, CF3 or S-lower alkyl; RB/Ry are independently from each other hydrogen, lower alkyl or lower alkoxy; or an oxetane-ring; or R3 and R3, form together a ycloalkyl-, tetrahydrofuran- or its corresponding or a pharrnaceutically acceptable acid addition salt, a racemic mixture, enantiomer and/or optical isomer and/or stereoisomer thereof, with the exception of the nd N—(S—((1H—pyrrolo[2,3-B]pyridine—Z-yl)ethynyl)pyridine—2—yl)acetamide.

2. Ethynyl derivatives of formula IA according to claim 1, which compounds are 2,2~Dimethyl-N—(5-phenylethynyl—pyridinyl)—propionamide N—(5-?henylethynyl-pyridin-2~yl)-butyramide Pentanoic acid (5-phenylethynyl-pyridin—2—yl)—amide 3-Methyl‘N-(S—phenylethynyl-pyridin-E—yl)—butyramide (RS)—2-Methyl—pentanoic acid (5~phenylethynyl-pyridin~2—yl)-amide 2-Methylsulfanyl-N-(5~phenylethynyI—pyridinyl)—acetamide 2-Methoxy-N-(S-phenylethynyl-pyridinyl)-acetamide N-[S-(3—Fluoro-phenylethynyl)-pyridin—2~yl]-2,2-dimethyl-propionamide Z-Methoxy-Z-methyl-N-(5-pher1ylethynyl-pyridinyl)-propionamide N-[S -(3 -Fluoro-phenyi ethynyl)-pyridin—2—yl]methoxymethyl-propionamid e N-[S-(2,5-Difluoro-phenylethynyl)-pyridin—Z—yl]~2-methoxymethyl-propionamide or N-[5-(3-Chloro—phenylethynyl)-pyridin-Z-yl]—3,3,3-trifluoro-2,2-dimethyl-propionamide.

3. Ethynyl derivatives of formula IB according to claim 1, which compounds are 2,2-Dimethyl-N~(5vphenylethynykpyrimidin-2—yl)-propionamide or 2,2,N-Trimethyl-N45-phenylethynyl-pyrimidiny])-propionamide.

4. l tives of formula ID according to claim 1, which compounds are 2,2-Dimethyl-N~(6-phenyl ethynyl-pyridazin-3 -yl)-propionamide or N-[6-(3-Chloro-phenylethynyl)-pyridaz'm—3~yl]-2,2-dimethyl—propionamide

5. A process for preparation of a compound of formula I as described in any one of claims 1 to 4, comprising the variant a) reacting a compound of a R F3 8 N NH N NH N NH ‘ ‘Y N' ‘ l I ’N ' / / / R‘ / / / 3A, R‘ 3B or R‘ 3D with a suitable compound of formula 01$}:3' R3 H071)<R23. R R 4 or O 5 to a compound of formulas 3R3 3 3' R3! RR R I N71><R2 l NYNWXRZ / O /N O 1 1% R R 1A ~ IE or ‘3 R3 R3' N,N\ NW><R2 / o R ID wherein the substituents are described in claim 1, or if desired, converting the compounds obtained into pharmaceutically able acid addition salts, or b) reacting a compound of formulas ‘3 R3 R3. 3 R3 ”WI/b ‘ R3' N N N‘s/F .N N \ BfiRs' XU 2 R XLNY NJN x R R2 o o 0 6A, 6Bor 6D to a compound of formulas . ’3 R3 .5 R3 N N 2 N N 2 \ R \ R l a??? i / O /\Ti\i/ O 1 // 1 R R M [B or ’3 R3 R3I N,N\ N R2 / O R ID wherein the substituents are described in claim 1, or if desired, converting the compounds ed into phannaceuticaliy acceptable acid addition salts, or c) ng a compound of formulas N Y. N Y‘ N Y: r; i / /