Title of Invention

BENZOTHIAZOLE DERIVATIVES AS ADENOSINE RECEPTOR LIGANDS

Abstract

The invention relates to compounds of the general formula (I) wherein R<1> is 1,4-dioxepanyl or tetrahydropyran-4-yl; R <2> is -N(R)-(CH2)n,-5-or 6 membered non aromatic heterocycle, optionally substituted by one or more substituents, selected from the group consisting of lower alkyl or -NR2, or is - (CH2)n-5-or 6 membered non aromatic heterocycle, optionally substituted by -(CH2)n-OH, lower alkyl, lower alkoxy, or is -CH2)n-5-or 6 membered aromatic heterocycle, optionally substituted by lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, -CH2N(R)(CH2)20CH3, -N(R)(CH2)20CH3, -CH2-morpholinyl or -CH2-pyrrolidinyl or is (CH2)n-cycloalkyl, optionally substituted by hydroxy, or is -N(R)-cycloalkyl, optionally substituted by hydroxy or lower alkyl, or is phenyl, optionally substituted by lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, -CH2-pyrrolidin-l-yl, -CH2-morpholinyl, -CH2N(R)(CH2)20CH3 or -CH2-N(R)C(0)-lower alkyl, or is l,4-dioxa-8-aza-spiro[4,5]decane, or is 2-oxa-5-aza-bicyclo[2.2.1]heptane, or is I-oxa-8-aza-spiro[4,5]decane, or is -N(R)-7-oxa-bicyclo [2.2. 11 hept-2-yl, or is 2-aza-bicyclo[2.2.2]decane; R is hydrogen or lower alkyl; n is 0 or 1; and pharmaceutically acceptable acid addition salts thereof for the treatment of diseases, which relate to the A2A receptor.

Full Text

n is O or 1; and and pharmaceutical^ acceptable acid addition salts thereof It has surprisingly been found that the compounds of general formula I are adenosine receptor ligands. Specifically, the compounds of the present invention have a good affinity to the A2A-receptor and a high selectivity to the Ai- and A3 receptors. 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 coenzym 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 receptores for adenosine have been classified as Ai, A^ A2B 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 A2A and A2B receptors couple to Gs 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 A2A receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A2B receptor (332 amino acids) was cloned from human and mouse with 45 % homology of human A2B with human Ai and A2A receptors. The A3 receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep. The Ai and AIAreceptor 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 (A2A) and so reinstate the balance of energy supply: 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 a neuromodulator, able to modulate many aspects of physiological brain function. Endogenous adenosine, a central link between energy metabolism and neuronal activity, varies according to behavioural state and (patho)physiological conditions. Under conditions of increased demand and decreased availability of energy (such as hypoxia;, hypoglycemia, and/or excessive neuronal activity);, adenosine provides a powerful protective fedback mechanism. Interacting with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases such as epilepsy, sleep, movement disorders (Parkinson or Huntington's disease), Alzheimer's disease, depression, schizophrenia, or addiction 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 Ai . 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 may be used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A2a antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer's disease, and of neurodegenerative disorders, e.g. stroke. Adenosine A2a receptor antagonists modulate the activity of striatal GABAergic neurons and regulate smooth and well-coordinated movements, thus offering a potential therapy for Parkinsonian symptoms. Adenosine is also implicated in a number of physiological processes involved in sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Drugs acting at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants, and to treat drug abuse. They may also be used in the treatment of ADHD (attention deficit hyper-activity disorder). 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). By acting at the Ai receptor, adenosine Ai agonists may protect against the injury caused by myocardial ischemia and reperfusion. The modulating influence of A2a receptors on adrenergic function may have implications for a variety of disorders such as coronary artery disease and heart failure. A2a antagonists may be of therapeutic benefit in situations in which an enhanced antiadrenergic response is desirable, such as during acute myocardial ischemia. Selective antagonists at A2a receptors may also enhance the effectiveness of adenosine in terminating supraventricula arrhytmias. 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 A2B antagonists may be useful in the treatment of asthma and other allergic responses or and in the treament of diabetes mellitus and obesity. Numerous documents describe the current knowledge on adenosine receptors, for example the following publications: Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the adenosine A2 receptor, 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, Huntington's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, drug addiction, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or against 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 for disorders such as coronary artery disease and heart failure. The most preferred indications in accordance with the present invention are those, which base on the A2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of Alzheimer's disease, certain depressive disorders, drug addiction, neuroprotection and Parkinson's disease as well as ADHD. As used herein, the term "lower alky!" 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-butyi, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. 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 "cycloalkyT denotes a saturated carbocyclic group, containing 3-7 carbon atoms. The term "5-or 6 membered non aromatic heterocycle" denotes rings like morpholin, piperazin, piperidin, tetrahydropyran or tetrahydrofuran. The term "5-or 6 membered aromatic heterocycle" denotes rings like thiophene, imidazole, pyrazole or pyridine. 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. compound in the presence of a palladium catalyst, preferably dichloro(l,l'-bIs(diplienylpliosphino)ferrocene)palladium(II) dichloromethane adduct, and an inorganic base, preferably sodium carbonate- The reaction is carried out in a mixture of solvents, preferably a mixture of ethanol, toluene and water. The reaction is carried out at elevated temperature, preferably about SO °C, for about 0.1-2 hours, preferably about 20 minutes. The product of formula (XV) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. The starting vinyl bromide, vinyl iodide or vinyl triflate compounds maybe obtained commercially, for example from Fluka, or maybe prepared according to methods well known in the art. Preparation of compounds of formula (XVI) Compounds of formula (XVI) maybe prepared by hydrogenation of compounds of formula (XV) in the presence of a hydrogenation catalyst, preferably 10 % palladium on charcoal. These reactions maybe carried out in a variety of organic solvents, such as methanol, ethanol, or tetrahydrofuran, preferably methanol, at room temperature and at a pressure of one atmosphere or above, preferably at one atmosphere, for 16-72 hours, preferably about 72 hours. The product of formula (XVI) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Preparation of compounds of formula CXVTO The intermediate 4-methox7-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine of formula (XVII) maybe prepared starting from 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine (XVI) according to methods disclosed in WO01/97786. The preparation of compounds of formula lb using the intermediate of formula (XVII) is also described in WO01/97786. wherein R1 and R are as defined above, L is a leaving group such as halogen, -O-phenyl or O-lower alkyL> and R3 is -(CH2)ir5-or 6 membered non aromatic heterocycle, optionally substituted by one or more substituents, selected from the group consisting of lower alkyl or -NR2, or is cycloalkyl, optionally substituted by hydroxy or lower alkyl, or is In accordance with scheme 3, compounds of formula Ic maybe prepared in usual-manner from intermediates of formula IV (known compounds, described in WO01/97786), as described in more detail in the examples. . Isolation and purification of the compounds Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and Isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Salts of compounds of formula I The compounds of formula I maybe basic, for example in cases where the residue R contains a basic group such as an aliphatic or aromatic amine moiety. In such cases the compounds of formula I maybe converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent. The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. The compounds of formula I and their pharmaceutical^ usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are adenosine receptor ligands and possess a high affinity towards the adenosine A2A receptor. The compounds were investigated in accordance with the test given hereinafter. Human adenosine A^ receptor The human adenosine A2A. receptor was recombinant^ expressed ki 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 NaCl, 5 mM KCl, 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; 1 nM) binding assay was carried out in 96-well plates in the presence of 2.5 jig of membrane protein, 0.5 mg of Ysi-poly-Hysine SPA beads and 0.1 U adenosine deaminase in a final volume of 200 |ol of buffer A. Non-specific binding was defined using xanthine amine congener (XAQ 2 fxM). Compounds were tested at 10 concentrations from 10 \xM - 0.3 nM. AH assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for Ihour at room temperature before centrifugation and then bound ligand determined using a Packard Topcount scintillation counter. IC5o values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation. The pKi value of compounds of the present application are in the range of 7.5 to 9.0. The preferred compounds show a pKi > 8.5. 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 cceptable 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 maybe 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 pharmaceuticallacceptable salt thereof. The daily dosage maybe 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. Following the general method of example 1 the compounds of examples 2 to 7 were prepared. Example 2 Piperidine-l~carboxyKcacid(7-[l,4]dioxepan-6-yl-^^ amide Using 7-[l?4]dioxepan-6-7l-4-metliox7-benzothia2ol-2-ylamine, phenyl chloroformate and piperidine, the title compound was prepared as light yellow powder. MS: m/e-392(M+H+). Example 3 l-Cyclohexyl-3-(7-[l?4]dioxepan-6-yl-4-mellioxy-benzothiazol-2-yl)-l-methyl-iirea Using 7-[l34]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine; phenyl chloroformate and cyclohexyl-methylamine, the title compound was prepared as light off-white powder. MS:m/e=420(M+H+). Example 4 4-Hydroxymethyl-piperidine-l-carboxylicacid (7-[l,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide Using 7-[l,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-piperidine, the title compound was prepared as off-white powder. MS:m/e^422(M+H+). Example 5 3-(7-[ 1,4] Dioxepan-6-yl-4-methoxy-ben^ piperidin-4-yl) -urea Using 7-[l;4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamineJ phenyl chloroformate and l-methyl-4-(methylamino)piperidine> the title compound was prepared as light brown powder. MS; m/e= 435(M+H+). Example 6 l,4-Dioxa-8-aza-spiro[4.5] decane-8-carboxylic acid (7-[l)4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide N-(7-[l,4]Dioxepan-6-yl-4-methoxy4)enzolhiazol^^ pyrrolidine were reacted as described for 2-(2-meliioxy-ethylamixLo)-N-(4-niethoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isoiiicotmainide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown solid. MS; m/e^ 455(M+H+). Example 47 N-(7-[l,4]Dioxepan-6-yl-4-me^ isonicotinamide 2-Chloromethyl-N-(7-[I,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide and 2s7-(2-methoxyethyl)-methylamine were reacted as described for 2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4 benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light yellow solid (48% yield). Mp 108-111 °C, MS: m/e= 469(M+H+). Example 48 N-(7-[l,4]Dioxepan~6-yl-4-methoxy-benzo^ amino] -methyl}-isonicotin amide 2-Chloromethyl-N-(7-[l34]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide and pyrrolidine were reacted as described for 2-{ [(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown solid (56% yield). Mp 100-107 °C, MS: m/e= 487(M+H+). Example 49 2-Bromo-N- (7- [ 1,4] dioxepan-6-yl-4-methox7-benzothiazol-2-yl)-isonicotinamide Using 7-[l,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-bromo-isonicotinic acid, the title compound was prepared in the same manner as descried for 5-methyl-thiophene-2-carboxylic acid (7-[ 1,4]dioxepan~6~yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as off-white powder. MS: m/e= 452(M+H+). Example 50 (£rans)-2-(4-Hydroxy-cyclohexyl)-N^ benzothiazol-2-yl] -acetamide Using 4-methoxy-7-(tetrahydro-pyxan-4-yl)-benzotliLazol-2-ylamine and (4-hydroxy- ■ cyclohexyl)~acetic acid, the title compound was prepared in the same manner as descried for N-[4-meth.ox7-7-(te1xahydTO-pyran-4-yl)-benzoth.iazol-2-yll-2-(tetrahydro-p}T:an-4-yl)-acetamide and obtained as white crystals (25 % yield). Mp 120-145 °C? MS: m/e= 405(M+H+). Example 51 (I?)-Tetrahydrq-furan-2-carboxylic acid [4-methoxy-7~(tetrahydxo-pyran-4-yl)-benzothiazol-2-yl]-amide Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzotiuazol-2-ylamine and (.R)-tetrahydro-furan-2-carboxylic acid> the title compound was prepared in the same manner as descried for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide and obtained as off-white solid (62 % yield). Mp 158-161 °C, MS: m/e= 363(M+H+). Example 52 4-Hydroxymethyl-piperidine- 1-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl] -amide Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-piperidine, the title compound was prepared as white crystals (87 % yield). Mp. 202-203.5 °C, MS: m/e= 406(M-fH+). Example 53 l-(l-Dimethylanuno-pi^^^ b enzothiazol-2-yl] -1 -methyl-urea Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothdazol-2-ylamine, phenyl chloroformate andN^N^N'-Trimethyl-piperidine-l^-diamine, the title compound was prepared as white crystals (77 % yield). Mp. 167-170 °C, MS: m/e= 448(M+H+). i iddition of the solution, the reaction mixture was heated at reflux for 2 hrs. The resulting ^rey solution was cooled to 0 °C and a solution of l,4-dioxepan-6-one (prepared as described in US4410354) (5.08 g, 0.044 mol) in THP (25 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was acidified to pH = 1 with IN HC1 and extracted with ether (2 x 250 mL). The ether extracts were washed with water, dried (MgSC^), filtered and concentrated to give a sticky brown solid (9.45 g). This was purified by column chromatography on silica gel eluting with ethyl acetate-hexanes. The relevant fractions were concentrated to give the desired product (6.21 g, 63 %). Example 58 6- (4-methoxyphenyl)- [ 1,4] -dioxepane (IX) To a solution of 6-(4-methoxyphenyl)-[l,4]-dioxepan-6-ol (6.20 g, 0.028 mol) in CH2CI2 was added triethylsilane (3.53 g> 0.031 mol) and trifluoroacetic acid (35.1 g, 0.31 mol). The reaction mixture was allowed to stir overnight. The reaction was basified with K2CO3 solution until pH = 10. The organic layer was dried (MgS04), filtered and evaporated to dryness to give the desired product as a red oil (5.84 g, 100 %). Example 59 6-(4-methoxy-3-nitro-phenyl)-l>4-dioxepane (X) A solution of 6-(4-methoxyphenyl)-l,4-dioxepane (5.84 g> 0.028 mol) and acetic anhydride (40 mL) in a 100 mL three-necked flask was heated to 65 °C. The heat was removed and the copper (II) nitrate (7.7 g, 0.033 mol) was added portionwise over 2 hrs whilst the temperature was maintained between 60-70 °C {caution: exothermic). When the addition was complete the blue suspension was stirred at 65 °C for an additional 1.5 hr. Water (400 mL) was added and the reaction mixture was stirred for 1 hour then solid K2CO3 was added until pH = lO.The mixture was extracted with ethyl acetate (3 x 150 mL). The combined organics were dried (MgSC^X filtered and evaporated to give a red oil (7.37 g). The crude material was purified by column chromatography eluting with 20 %-30 % EtOAc-hexanes. The relevant fractions were combined and concentrated to give the desired product as an orange oil (5.80 g, 83 %). MS: m/e= 254(M+H+). Example 60 7- [ 1,4] Dioxepan-6-yl-4-methox7-benzothiazol-2-ylamine (XI) %) 2-metliox7-5-(tetrahydro-pyran-4-7l)-phenylamiiie as an off-white crystalline solid.. ES-MS m/e (%): 208 (M+H+, 100). d) l-Benzovi-3-[2-methoxv-5--(tetrahydro-pyran-4--ylVphenyl]-thiourea To a stirred solution of 1.11 g (14.6 mmol) ammonium rhodanide in 60 ml acetone was added dropwise 1.54 ml (13.3 mmol) benzoyl chloride and the mixture heated at reflux for 10 minutes. A solution of 2.75 g (13.3 mmol) 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine in 30 ml acetone was then added dropwise and the reaction mixture heated at reflux for a further 10 minutes. The mixture was then cooled to room temperature, poured onto sodium bicarbonate solution, and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 3.25 g (66 %) l-benzoyl-3-[2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea as a white solid. ES-MS m/e (%): 371 (M+H+, 100). e) f 2-Methoxy-5-(tetrahydro-pyran-4-ylVphenyll-thiourea To a stirred solution of 3.25 g (8.77 mmol) l-benzoyl-3-[2-methoxy-5~(tetrahydro-pyran-4-yl)-phenyl]-thiourea in 45 ml methanol was added dropwise 0.25 ml (1.32 mmol) 5.3 M sodium methylate solution and stirring continued for 1 h at room temperature. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 1.90 g (81 %) [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea as a white foam. ES-MS m/e (%): 267 (M+IT, 100). f) 4-Methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl-amine To a stirred solution of 1.90 g (7.13 mmol) [2-methoxy-5-(tetrahydro-pyran-4~yl)-phenyl]-thiourea in 20 ml acetic acid heated to 80 °C was added dropwise 1.45 ml (8.27 mmol) hydrobromic acid (5.7 M solution in acetic acid) and stirring continued for 30 min at 80 °C. 0.56 ml (7.85 mmol) DMSO was then added dropwise and the reaction mixture stirred for a further 30 min at 80 °C The mixture was then cooled to room temperature, poured slowly onto sodium bicarbonate solution, and ethyl acetate added. The mixture was stirred for 10 minutes at room temperature and the resulting crystals collected by filtration, washing with ethyl acetate. The mother liquor phases were separated and the organic phase concentrated in vacuo to 5 ml. The resulting second crop of crystals was collected by filtration and combined with the first crop to afford 920 mg (49 %) 4-mefhoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 265 (M+H*", 100). wherein R and R~ have the significances given above, or b) reacting a compound of formula with a compound of formula to a compound of formula wherein R1 and R are as defined above, L is a leaving group such as halogen, -O-phenyl or 12. The use of a compound in any one of claims I to 6 for the manufacture of corresponding medicaments for the treatment of diseases related to the adenosine A2A receptor.

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3057-chenp-2005-form 3.pdf

3057-chenp-2005-form 5.pdf

3057-chenp-2005-pct.pdf