AU2002347055A1

AU2002347055A1 - Substituted Triazolopyridine Compounds

Info

Publication number: AU2002347055A1
Application number: AU2002347055A
Authority: AU
Inventors: Matthias Heinrich Nettekoven; Sebastien Schmitt
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2001-10-08
Filing date: 2002-10-04
Publication date: 2003-07-03
Anticipated expiration: 2022-10-04

Description

8-Amino-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid amide

The present invention relates to compounds of the general formula

wherein

R^l is -NR'R", wherein IV and R" are independently from each other lower alkyl, -(CH₂)„-C(O)NR^aR^b, -(CH₂)_n-heteiOaryl, -(CH₂)„-aryl, -(CH₂)„-CN,

-(CH₂)„-O-lower alkyl or -(CH₂)_n-i-"ycloalkyl, or R' and R" form together with the N-atom a five or six-membered none aromatic ring, which may contain one additional O or S heteroatom, and whose rings may be unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, -C(O)NR^''R^b or -(CH₂)_n-O-lower alkyl and

R' ¹ are independently from each other hydrogen or lower alkyl;

R^" is aryl or heteroaryl, unsubstituted or substituted ba lower alkyl or halogen;

n is 0, 1, 2 or 3;

and to their pharmaceutically acceptable salts.

It has surprisingly been found that the compounds of general formula I are adenosine receptor ligands.

Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and cόenzym A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.

The receptors for adenosine have been classified as A A_2A-. A_2B and A₃ receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine initiates signal transduction mechanism. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtyps has been classically characterised by the adenylate cyclase effector system, which utilises cAMP as a second messenger. The Ai and A₃ receptors, coupled with Gi proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A_2A and A_2B receptors couple to G_s proteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the Ai receptor system include the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A₃ subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and so activates calcium ion channels.

The Ai receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A_2A receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A_2B receptor (332 amino acids) was cloned from human and mouse with 45% homology of human A_2B with human Ai and A_2A receptors. The A₃ receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.

The Ai and A_2A receptor subtypes are proposed to play complementary roles in adenosine's regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (Ai) or increase the oxygen supply (A_2A) and so reinstate the balance of energy supply versus demand within the tissue. The actions of both subtyps is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischaemia, hypotension and seizure activity.

Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A₃ receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A₃ receptor plays a role in mediating asthmatic attacks and other allergic responses.

Adenosine is also a neuromodulator, possessing global importance in the modulation of molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischaemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine Aj agonists which mimic the central inhibitory effects of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitory neurons and inhibiting neuronal firing. Adenosine agonists therefore maybe used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A_2a-antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer's disease and are useful as neuroprotective agents. Adenosine A₂- receptor antagonists inhibit the release of dopamine from central synaptic terminals and reduce locomotor activity and consequently improve Parkinsonian symptoms. The central activities of adenosine are also implicated in the molecular mechanism underlying sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and substance abuse. Drugs acting at adenosine receptors therefore have also therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants and antidepressants.

An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischaemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus have potential as cardioprotective agents.

Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds, which antagonise the renal affects of adenosine, have potential as renal protective agents. Furthermore, adenosine A₃ and/or A_2B antagonists may be useful in the treatment of asthma and other allergic responses.

Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:

Bioorganic & Medicinal Chemistry, 6, (1998), 619-641, Bioorganic & Medicinal Chemistry, 6, (1998), 707-719, J. Med. Chem., (1998), 41, 2835-2845, J. Med. Chem., (1998), 41, 3186-3201, J. Med. Chem., (1998), 41, 2126-2133, J. Med. Chem., (1999), 42, 706-721, J. Med. Chem., (1996), 39, 1164-1171,

Arch. Pharm. Med. Chem., (1999), 332, 39-41.

Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention maybe useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents.The most preferred indications in accordance with the present invention are those, which base on the A_2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson's disease.

As used herein, the term "lower alkyl" denotes a saturated straight- or branched- chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1 - 4 carbon atoms.

The term "cycloalkyl" denotes a saturated carbocyclic group, containing 3 - 8 carbon atoms. A preferred cycloalkyl group is cyclohexyl.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "lower alkoxy" denotes a group wherein the alkyl residues is as defined above, and which is attached via an oxygen atom.

The term "aryl" denotes phenyl or naphthyl. The preferred aryl group is phenyl.

The term "heteroaryl" denotes 5 or 6 membered rings with heteroatoms, such as O,

N or S, for example, pyridinyl, thiophenyl, furanyl or thiazolyl. The term "5 or 6 membered non aromatic ring" denotes rings, which may contain one additional heteroatom, such as O or S, in addition to the N atom, for example morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or 3,6-dihydro-2H-pyridin-l-yl.

The term "pharmaceutically acceptable acid addition salts" 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.

Compounds of formula I of the present invention, wherein R²is heteroaryl, such as furan-2-yl, substituted by bromo, are preferred. For example the following compounds:

[8-Amino-2-(5-bromo-furan-2-yl)-[l,2,4jtriazolo[l,5-a]pyridin-6-yl]-piperidin-l-yl- methanone,

[8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,41 triazolo[l,5-a]pyridin-6-yl]-pyrrolidin-l-yl- methanone,

[8-amino-2-(5-bromo-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]-(2-methyl- pyrrolidin-l-yl)-methanone, l-[8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l, 5-a]pyridine-6-carbonyl]- piperidine-3-carboxylic acid diethylamide,

[8-amino-2-(5-bromo-furan-2-yl)- [1,2,41 triazolo[l,5-a] pyridin-6-yl]-(3,5-dimethyl- piperidin-1-yl) -methanone, [8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4 ]triazolo[l, 5-a]pyridin-6-yl]-(2-methyl- piper idin- 1 -yl) -methanone,

[8-amino-2- ( 5-bromo-furan-2-yl)- [ 1 ,2,4 ] triazolo [ 1 ,5-a] pyridin-6-yl] -(2-methoxymethyl- pyrrolidin- 1 -yl) -methanone,

[8-amino-2-(5-bromo-furan-2-yl)-[l,2,4ltriazolo[l,5-a]pyridin-6-yl]-((S)-2- methoxymethyl-pyrrolidin-1-yl) -methanone, l-[8-amino-2-(5-bromo-furan-2-yl)-[ 1 ,2,4] triazolo [1,5-a] pyridine-6-carbonyl]- pyrrolidine-2-carboxylic acid (S)-dimethylamide,

8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l,5-a]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-methyl-amide, [8-amino-2-(5-bromo-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]-(3-methyl- piperidin-1-yl) -methanone,

8-amino-2-(5-bromo-furan-2-yl)- [1,2,4] triazolo[l,5-a]pyridine-6-carboxylic acid methyl- propyl-amide,

8-amino-2-(5-bromo-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid ethyl- (2-pyridin-2-yl-ethyl)-amide,

[8-amino-2-(5-bromo-furan-2-yl)-[l₎2,4|triazolo[l,5-a]pyridin-6-yl]-thiomorpholin-4-yl- methanone or

8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l,5-a]pyridine-6-carboxylic acid methyl- phenethyl-amide.

Further preferred are compounds, wherein R" is unsubstituted heteroaryl, such as furan-2-yl. Examples of this group are the following compounds:

(8-Amino-2-furan-2-yl-[l,2,4]triazolo[ l,5-a]pyridin-6-yl)-pyrrolidin-l-yl-methanone, (8-amino-2-furan-2-yl- [1,2,4] triazolo[ l ,5-a]pyridin-6-yl)-(2-R-methoxymethyl- pyrrolidin-l-yl)-methanone,

(8-amino-2-furan-2-yl-[l,2,4]triazolo| l,5-a]pyridin-6-yl)-(2-S-methoxymethyl- pyrrolidin-1-yl) -methanone or

8-amino-2-furan-2-yl-[ 1,2,4] triazolo [l,5-a]pyridine-6-carboxylic acid dibenzylamide.

Compounds of formula I of the present invention, wherein R² is heteroaryl, such as thiophen-2-yl, are also preferred. For example the following compound:

8-Amino-2-thiophen-2-yl-[ 1,2,4] triazolo I l,5-a]pyridine-6-carboxylic acid dibenzylamide. Further preferred are compounds, wherein R" is heteroaryl, such as furan-2-yl, substituted by methyl. Examples of this group are the following compounds:

[8-Amino-2-(5-methyl-furan-2-yl)-[ 1,2,4] triazolo [1, 5-a]pyridin-6-yl]-pyrrolidin-l-yl- methanone,

[8-amino-2-(5-methyl-furan-2-yl)-[ 1,2,41 triazolo [1, 5-a]pyridin-6-yl]-piperidin-l-yl- methanone,

[8-amino-2-(5-methyl-furan-2-yl)-[ 1,2,4] triazolo [ l,5-a]pyridin-6-yl] -(2-methyl- pyrrolidin-1-yl) -methanone or

8-amino-2-(5-methyl-furan-2-yl)-[l,2,4]triazolo[ l,5-a]pyridine-6-carboxylic acid methyl- propyl-amide. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises

reacting a compound of formula

with an amine of formula

HNR'R'^: III

to a compottnd of formula

wherein R , R and R have the significance given above, and

if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

In accordance with the above mentioned process variant for obtaining a compound of formula I (8-amino-2-(aryl or heteroaryl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]-piperidin- 1-yl-methanone), a solution of an amine of formula III (HNR'R") in dioxane is treated with trimethylaluminium in toluene and stirred for 1 h at room temperature. 8-Amino-2- (aryl or heteroaryl)-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester (II) in 1 ml dioxane is added and the mixture is heated to 90 °C for 72 h. HCI aq. is added and the volatiles are removed. The residue is taken up in 1 formic acid and methanol and purified by reversed phase preparative HPLC eluting with a gradient of acetonitrile and water.

The salt formation is effected at room temperatures in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids came into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrate, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.

In Examples 9 - 108 and in the following scheme 1 the preparation of compounds of formula I is described in more detail. Scheme 1

In accordance with scheme 1, the compound of formula V ( 6-hydroxy-5-nitro- nicotinic acid) is obtained as follows: To a solution of a compound of formula IV (6- hydroxy- nicotinic acid) in concentrated sulfuric acid is added a mixture of concentrated sulfuric acid and concentrated nitric acid below 20 °C and stirred for 1 h at room temperature and afterwards the solution is heated to 80 °C for 4 h. The mixture is then poured onto ice and the precipitae is collected and dried. The obtained compound of formula V is then mixed with POCI₃ and heated to 130 °C for 5 h and afterwards the excess POCI₃ is distilled under reduced pressure. The residue is cooled to 0 °C and 150 ml methanol were slowly added. The mixture is stirred for 2 h at 0 °C. After addition of a 25 % NH₃ aq. solution the mixture is stirred for 4 h at room temperature. The precipitate is filtered, washed once with diethyl ether and dried under vacuum to yield 6-amino-5- nitro-nicotinic acid methyl ester (VI). A suspension of 6-amino-5-nitro-nicotinic acid methyl ester in methanol and Pd/C (10 %) cat is then added and hydrogenated at room temperature during 14 h. The catalyst is filtered off and the solution is concentrated to yield 5,6-diamino-nicotinic acid methyl ester (VII). A mixture of (VII) in dioxane is treated with O-mesitylenesulfonylhydroxylamine (prepared from ethyl-o- mesitylenesulfonylacetohydroxamate and HClO ) for 1 h at room temperature. To thiophene-2-carboxaldehyde or another aldehye of formula R²CHO, wherein R² is an aryl or heteroaryl as described in the specification, molecular sieves 4 A is added and heated to 100 °C for 4 h before addition of KOH in methanol. The mixture is heated to 70 °C for 2 h and stirred at room temperature for 14 h. The volatiles are removed under reduced pressure and the residue is purified by flash column chromatography to yield 8-amino-2- (aryl or heteroaryl)-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester (II). To obtain a compound of formula I (8-amino-2-(aryl or heteroaryl)-[l₎2,4]triazolo[l,5- a]pyridin-6-yl]-piperidin- 1-yl-methanone a solution of an amine of formula III (HNR'R") in dioxane is treated with trimemylaluminium in toluene and stirred for 1 h at room temperature. 8-Amino-2-(aryl or heteroaryl)-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester (II) in 1 ml dioxane is added and the mixture is heated to 90 °C for 72 h. HCI aq. is added and the volatiles are removed. The residue is taken up in 1 formic acid and methanol and purified by reversed phase preparative HPLC eluting with a gradient of acetonitrile and water.

The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are adenosine receptor ligands.

The compounds were investigated in accordance with the tests given hereinafter.

Human adenosine A_2A receptor

The human adenosine A_2A receptor was recombinantly expressed in Chinese hamster ovary (CHO) cells using the semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenised and again washed by centrifugation. The final washed membrane pellet was suspended in a Tris (50 mM) buffer containing 120 mM NaCI, 5 mM KCI, 2 mM CaCl₂ and 10 mM MgCl₂ (pH 7.4) (buffer A). The [³H]-SCH- 58261 (Dionisotti et al., 1997, Br. J. Pharmacol. 121, 353) binding assay was carried out in 96-well plates in the presence of 2.5 μg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and 0.1 U adenosine deaminase in a final volume of 200 μl of buffer A. Nonspecific binding was defined using xanthine amine congener (XAC; 2 μM). Compounds were tested at 10 concentrations from 10 μM - 0.3 nM. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for lhour at room temperature before centrifugation and then bound ligand determined using a Packard

Topcount scintillation counter. IC₅₀ values were calculated using a non-linear curve fitting program and Kj values calculated using the Cheng-Prussoff equation.

In accordance with the invention, it has been shown that compounds of formula I have a high affinity toward the A_2A receptor. In the table below are described specific values of prepared compounds. Preferred compounds are those, wherein the hA2a Kj is less than 100 nM, foe example the followings:

The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I 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, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.

The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids 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 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, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, 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.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

In accordance with the invention compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the adenosine receptor antagonistic activity, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents and for the production of corresponding medicaments.

The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson's disease.

The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

Intermediates

Example 1

8-Amino-2-thiophen-2-yl-[ 1,2,4] triazolo [l,5-a]pyridine-6-carboxylic acid methyl ester a) 6-Hydroxy-5-nitro-nicotinic acid

To a solution of 30 g (0.217 mol) 6-hydroxy-nicotinic acid in 50 ml concentrated sulfuric acid was added 60 ml of a 1:1 mixture of cone, sulfuric acid and cone nitric acid below 20 °C and stirred for 1 h at room temperature and afterwards heated to 80 °C for 4 h. The mixture was poured onto ice and the formed precipitae was collected and dried to yield 14.2 g (36 %) of the title compound as a yellow amorphous solid. MS m/e (%): 184 (MH⁺, 100)

IH-NMR (300 MHz, DMSO-d6): δ = 13.3 (s, br, 2H, COOH / OH), 8.65 (d, J = 2.5 Hz, 1H, H-4), 8.38 (d, J = 2.5 Hz, 1H, H-2).

b) 6-Amino-5-nitro-nicotinic acid methyl ester

A mixture of 14.2 g (78 mmol) 6-hydroxy-5-nitro-nicotinic acid in 50 ml POCl₃ was heated to 130 °C for 5 h and afterwards the excess POCI₃ was distilled under reduced pressure. The residue was cooled to 0 °C and 150 ml methanol were slowly added. The mixture was stirred for 2 h at 0 °C. After addition of 300 ml of a 25 % NH₃ aq. solution the mixture was stirred for 4 h at room temperature. The precipitate was filtered washed once with diethyl ether and dried under vacuum to yield 5.97 g (39 %) of the title compound as a yellow solid.

MS m/e (%): 197 (MH⁺, 100)

IH-NMR (300 MHz, DMSO-d6): δ = 8.83 (d, J = 2.1 Hz, 1H, H-4), 8.72 (d, J = 2.1 Hz, 1H, H-2), 8.38 (s, br, 2H, NH₂), 3.85 (s, 3H, OCH₃).

c) 5,6-Diamino-nicotinic acid methyl ester

A suspension of 5.97 g (30 mmol) 6-amino-5-nitro-nicotinic acid methyl ester in 30 ml methanol and 600 mg Pd/C ( 10 %) cat was added and hydrogenated at room temperature during 14 h. The catalyst was filtered off and the solution was concentrated to yield 4.74 g (94 %) of the title compound as white amorphous solid.

MS m/e (%): 167 (MH⁺, 100)

IH-NMR (300 MHz, DMSO-d6): δ = 7.95 (d, J = 1.5 Hz, 1H, H-4), 7.16 (d, J = 1.5 Hz, 1H, H-2), 6.25 (s, br, 2H, NH₂), 4.91 (s, br, 2H, NH₂), 3.74 (s, 3H, OCH₃).

d) 8-Amino-2-thiophen-2-yl- 1,2,41 triazolo f l-5-a]pyridine-6-carboxylic acid methyl ester

A mixture of 1.114 g (6.66 mmol) 5,6-diamino-nicotinic acid methyl ester in 40 ml dioxane was treated with 1.578 g (7.33 mmol) O-mesitylenesulfonylhydroxylamine (prepared from ethyl-o-mesitylenesulfonyiacetohydroxamate and HClO (70 %)) for 1 h at room temperature. 0.897 g (8 mmol) thiophene-2-carboxaldehyde and molecular sieves 4 A was added and heated to 100 °C for 4 h before addition of 1.6 ml 5M KOH in methanol. The mixture was heated to 70 °C for 2 h and stirred at room temperature for 14 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane to yield after evaporation 0.88 g (48 %) of the title compound.

MS m/e (%): 275.3 (MH⁺, 100)

IH-NMR (300 MHz, DMSO-d6): δ = 8.65 (d, J = 1.4 Hz, 1H, H-5), 7.81 (dd, J_x = 3.5 Hz, J₂ = 1 Hz, 1H, thiophene H-2), 7.76 (dd, = 4.8 Hz, J₂ = 1 Hz, 1H, thiophene H-4), 7.24 (dd, Ji = 4.8 Hz, h = 3.5 Hz, 1H, thiophene H-3), 7.09 (d, J = 1.4 Hz, 1H, H-7), 6.31 (s, br, 2H, NH₂), 3.88 (s, 3H, OCH₃). Example 2

8-Amino-2-phenyl-[ 1,2,4] triazolo [l,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 269 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene- sulfonylhydroxylamine, and benzaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.

Example 3

8-Amino-2-thiazol-2-yl-[ 1,2,4] triazolo [l,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 276.1 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene- sulfonylhydroxylamine, and thiazole-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n- hexane.

Example 4

8-Amino-2-(5-methyl-thiophen- 2-yl)-[ 1,2,4] triazolo [l,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 289.2 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene- sulfonylhydroxylamine, and 5-methylthiophene-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.

Example 5

8-Amino-2-furan-2-yl-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 259.1 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene- sulfonylhydroxylamine, and furan-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n- hexane.

IH-NMR (300 MHz, DMSO-d6): δ = 8.65 (d, J = 1.5 Hz, 1H, H-5), 7.92 (dd, Ji = 1.7 Hz, J₂ = 0.8 Hz, 1H, furan H-5), 7.16 (dd, J_t = 3.4 Hz, J₂ = 0.8 Hz, 1H, furan H-3), 7.08 (d, J = 1.5 Hz, 1H, H-7), 6.73 (dd, Ji = 3.4 Hz, J₂ = 1.7 Hz, 1H, furan H-4), 6.35 (s, br, 2H, NH₂), 3.89 (s, 3H, OCH₃).

Example 6

8-Amino-2-(5-methyl-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 273.2 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, 0-mesitylene- sulfonylhydroxylamine, and 5-methylfuran-2-carboxaldehyde. The purification was performed by flash column chromatogr phy on silica eluting with a mixture of ethyl acetate and n-hexane.

Example 7

8-Amino-2-(5-bromo-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 338.2 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene- sulfonylhydroxylamine, and 5-bromofuran-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.

Example 8

8-Amino-2-pyridin-2-yl- [ 1 ,2,4] triazolo [ 1 ,5-a]pyridine-6-carboxylic acid methyl ester

The title compound, MS m/e (%): 270.3 (M⁺, 100), was prepared in accordance with the general method of example 1 from 5,6-Diamino-nicotinic acid methyl ester, O-mesitylene- sulfonylhydroxylamine, and pyridine-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n- hexane.

IH-NMR (300 MHz, DMSO-d6): δ = 8.75 (dd, Ji = 2 Hz, J₂ = 0.6 Hz, 1H, pyridine H-6), 8.70 (d, J = 1.5 Hz, 1H, H-5), 8.25 (dd, J, = 7.8 Hz, J₂ = 0.6 Hz, 1H, pyridine H-3), 8.00 (dd, Ji = 7.8 Hz, h = 2 Hz, 1H, pyridine H-4), 7.54 (dd, J_! = 7.8 Hz, J₂ = 1.2 Hz, 1H, pyridine H-5), 7.09 (d, J = 1.5 Hz, 1H, H-7), 6.41 (s, br, 2H, NH₂), 3.89 (s, 3H, OCH₃). Pharmaceutically actice compounds

Example 9

[8-Amino-2-(5-bromo-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]-piperidin-l-yl- methanone

A solution of 20 mg (0.24 mmol) piperidine in 1 ml dioxane was treated with 0.24 ml (0.24 mmol) trimethylaluminium in toluene and stirred for 1 h at room temperature. 20 mg (0.06 mmol) 8-Amino-2-(5-bromo-furan-2-yl)- [1,2,4] triazolo [l,5-a]pyridine-6-carboxylic acid methyl ester in 1 ml dioxane was added and the mixture was heated to 90 °C for 72 h. 0.5 ml IN HCI aq. was added and the volatiles were removed. The residue was taken up in 1.5 ml formic acid and 0.5 ml methanol and purified by reversed phase preparative HPLC eluting with a gradient of acetonitrile and water. The elution solvents were evaporated to obtain 7 mg (29 %) of the title compound. MS m/e (%): 391.3 (MH⁺, 100)

IH-NMR (500 MHz, DMSO): δ = 8.21 (s, IH, H-5), 7.14 (dd, J_x = 3.5 Hz, IH, furan H-4), 6.82 (d, J = 3.5 Hz, IH, furan H-3), 6.56 (s, IH, H-7), 6.26 (s, br, 2H, NH₂), 1.62 (m, 4H, NCH₂), 1.52 (m, 6H, CH2).

According to example 9 further [l,2,4]triazolo[l,5-a]pyridin-6-carboxamide derivatives have been synthesised from the esters described in example 1-8 and the respective amine. The results are compiled in the following list comprising example 10 to example 108.

Tablet Formulation (Wet Granulation)

Item Ingredients mg/tablet

5mg 2 255 mg 100 mg 500 mg

1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150

3. Sta-Rx 1500 6 6 6 30

4. Micro crystalline Cellulose 30 30 30 150

5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50 °C.

3. Pass the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation

Item Ingredients mg/capsule

5mg 25 mg 100 mg 500 mg

1. Compound of formula I 5 25 100 500

2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70

4. Talc 10 15 10 25

5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

Claims

1. A compound of the general formula

wherein

R¹ is -NR'R", wherein R' and R" are independently from each other lower alkyl, -(CH₂)_n-C(O)NR^aR^b, -(CH₂)„-heteroaryl, -(CH₂)„-aryl, -(CH₂)_n-CN, -(CH₂)„-O-lower alkyl or -(CH₂)_n-cycloalkyl, or R' and R" form together with the N-atom a five or six-membered none aromatic ring, which may contain one additional O or S heteroatom, and whose rings may be unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, -C(O)NR''R or -(CH₂)_n-O-lower alkyl and R^aR ¹ are independently from each other hydrogen or lower alkyl;

R² is aryl or heteroaryl, unsubstituted or substituted ba lower alkyl or halogen;

n is 0, 1, 2 or 3;

and its pharmaceutically acceptable salts.

2. A compound of formula I in accordance with claim 1, wherein R²is heteroaryl.

3. A compound of formula I in accordance with claim 2, wherein R" is furan-2-yl, substituted by bromo.

4. A compound of formula I in accordance with claim 3, wherein the compound is [8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l,5-a]pyridin-6-yl]-piperidin-l-yl- methanone, [8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l,5-a]pyridin-6-yl]-pyrrolidin-l-yl- methanone, [8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo [1,5-a] pyridin-6-yl]-(2-methyl- pyrrolidin-l-yl)-methanone, l-[8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo [1,5-a] pyridine-6-carbonyl]- piperidine-3-carboxylic acid diethylamide, [8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,41 triazolo[ 1,5-a] pyridin-6-yl]-(3,5-dimethyl- piperidin- 1 -yl) -methanone,

[8-amino-2-(5-bromo-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]-(2-methyl- piperidin-l-yl)-methanone,

[8-amino-2-(5-bromo-furan-2-yl)-[l,2,4|triazolo[l,5-a]pyridin-6-yl]-(2-methoxymethyl- pyrrolidin-1-yl) -methanone,

[8-amino-2-(5-bromo-furan-2-yl)-[l,2,4|triazolo[l,5-a]pyridin-6-yl]-((S)-2- methoxymethyl-pyrrolidin-l-yl)-methanone, l-[8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l,5-a]pyridine-6-carbonyl]- pyrrolidine-2-carboxylic acid (S)-dimethylamide, 8-amino-2-(5-biOmo-furan-2-yl)-[l,2,4| triazolo[l,5-a]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-methyl-amide,

[8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4] triazolo[l,5-a]pyridin-6-yl]-(3-methyl- piperidin-l-yl)-methanone,

8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,4 ] triazolo[ 1,5-a] pyridine-6-carboxylic acid methyl- propyl-amide,

8-amino-2-(5-bromo-furan-2-yl)-[ 1,2,41 triazolo [ 1,5-a] pyridine-6-carboxylic acid ethyl-

(2-pyridin-2-yl-ethyl)-amide,

[8-amino-2-(5-bromo-furan-2-yl)- [ 1,2,4] triazolo [ 1,5-a] pyridin-6-yl]-thiomorpholin-4-yl- methanone or 8-amino-2-(5-bromo-furan-2-yl)-[l,2,4|triazolo[l,5-a]pyridine-6-carboxylic acid methyl- phenethyl-amide.

5. A compound of formula I in accordance with claim 2, wherein R² is unsubstituted furan-2-yl.

6. A compound of formula I in accordance with claim 5, wherein the compound is (8-amino-2-furan-2-yl-[ 1,2,4] triazolo [l ,5-a]pyridih-6-yl)-pyrrolidin- 1-yl-methanone,

(8-amino-2-furan-2-yl- [1,2,4] triazolo [ 1,5-a] pyridin-6-yl)-(2-R-methoxymethyl- pyrrolidin- 1 -yl) -methanone,

(8-amino-2-furan-2-yl-[ 1,2,4] triazolo| l,5-a]pyridin-6-yl)-(2-S-methoxymethyl- pyrrolidin-l-yl)-methanone or 8-amino-2-furan-2-yl-[ 1,2,4] triazolo [ 1,5-a] pyridine-6-carboxylic acid dibenzylamide.

7. A compound of formula I in accordance with claim 2, wherein R² is thiophen-2-yl.

8. A compound of formula I in accordance with claim 7, wherein the compound is 8-amino-2-thiophen-2-yl- [1,2,4] triazolo [ 1,5-a] pyridine-6-carboxylic acid dibenzylamide.

9. A compound of formula I in accordance with claim 2, wherein R² is furan-2-yl, substituted by methyl.

10. A compound of formula I in accordance with claim 9, wherein the compound is [8-amino-2-(5-methyl-furan-2-yl)-[ 1,2,4 ] triazolo [1, 5-a]pyridin-6-yl]-pyrrolidin- 1-yl- methanone, [8-amino-2-(5-methyl-furan-2-yl)-[l,2,4|triazolo[l,5-a]pyridin-6-yl]-piperidin-l-yl- methanone,

[8-amino-2-(5-methyl-furan-2-yl)-[ 1,2,4] triazolo [ 1,5-a] pyridin-6-yl] -(2-methyl- pyrrolidin-l-yl)-methanone or

8-amino-2-(5-methyl-furan-2-yl)-[ 1,2,41 triazolo[l,5-a]pyridine-6-carboxylic acid methyl- propyl-amide.

11. A compound of formula I in accordance with claim 1, wherein R is aryl.

12. A compound of formula I in accordance with claim 11, wherein R² is phenyl.

13. A medicament containing one or more compounds of formula I as claimed in any one of claims 1 - 12 and pharmaceutically acceptable excipients.

14. A medicament according to claim 13 for the treatment of diseases related to the adenosine receptor.

15. A process for preparing a compound of formula I as defined in claim 1, which process comprises

reacting a compound of formula

with an amine of formula

HNR'R" III to a compound of formula

wherein R , R and R have the significance given above, and

16. A compound according to any one of claims 1 - 12, whenever prepared by a process as claimed in claim 15 or by an equivalent method.

17. The use of a compound in any one of claims 1 - 12 for the treatment of diseases.

18. The use of a compound in any one of claims 1 - 12 for the manufacture of corresponding medicaments for the treatment of diseases related to the adenosine A_2A receptor.

19. The invention as hereinbefore described.