Indian Patents. 205676:NICOTIN-OR ISONICOTIN BENZOTHIAZOLE DERIVATIVES

Title of Invention	NICOTIN-OR ISONICOTIN BENZOTHIAZOLE DERIVATIVES
Abstract	The present invention relates to compounds of the formula wherein R1,a and R are as described within.The compounds of the present invention have been found to be adenosine receptor ligands. Specifically,the compounds of the present invenstion have an affinity tothe A2A-receptor and are therefore useful in the treatment of diseaese related to this receptor.

Full Text	R" is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3; or A is -S- and R is lower alkyl; or A-R are together -piperazinyl, substituted by lower alkyl, -C(0)-lower alkyl or an oxo group, or is piperidinyl, substituted by lower alkoxy or hydroxy, or is morpholinyl, substituted by lower alkyl, or is -C4-6-cycloalkyl, -azetidin-1-yl, optionally substituted by hydroxy or lower alkoxy, thiomorpholine-l,l-dioxo, -tetrahydopyran or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl; and to pharmaceutically 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 Ap 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, A2A, 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 A\ 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 A2A 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 (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 ceils 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 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 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 reperfiision. 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 maybe 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 maybe 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: 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., 332, 39-41, (1999), Am. J. Physiol, 276, H1113-1116, (1999) or Naunyn Schmied, Arch. Pharmacol. 362, 375-381, (2000). Objects of the present invention are the compounds of formula IA and IB per se, the use of compounds of formula IA and IB and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the adenosine A? 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 IA and IB 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 maybe 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 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 4 — 6 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. Preferred are further compounds of formula IA, wherein Rl\js morpholinyl, A is -CH2- and R is pyrrolidinyl, -2-oxo-pyrroIidinyl, piperidinyl, which is optionally substituted by lower alkoxy or hydroxy, or is morpholinyl or alkoxy, for example the following compounds: N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-pyrrolidin-l-ylmethyl-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)2-(2-oxo-pyrrolidin-l-yl-methyl)-isonicotinamide) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-l- ylmethyl)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-piperidin-l-ylmethyl- isonicotinamide, 2-(4-hydroxy-piperidin-l-ylmethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)- isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-morpholin-4-ylmethyl- isonicotinamide, 2-methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide or 2-(4-hydroxy-piperidin-l-yl-methyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2- yl)-isonicotinamide Preferred compound of the present application are compounds of formula I A, wherein R1 is morpholinyl and A is -S-, for example the following compounds: N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylsulfanyl-isonicotinamideor 2-ethylsulfanyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide. Preferred compound of the present application are compounds of formula I A, wherein R1 is morpholinyl and A- R are together -piperazinyl, substituted by lower alkyl, -C(0)-lower alkyl or an oxo group, or is piperidinyl, substituted by lower alkoxy or hydroxy, or is morpholinyl, substituted by lower alkyl, or is -cyclohexyl, -azetidin-1-yl, which is optionally substituted by hydroxy or lower alkoxy, or is -tetrahydopyran, or is 1,1-dioxo-thiomorpholinyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, for example the following compounds: JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-l-yl)-isonicotinamide, 2-(4-acetyl-piperazin-l-yl)-N-(4-methox7-7-morpholin-4-yl-benzothiazol-2-yl)- isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-3-oxo-piperazin-l-yl)- isonicotinamide, commercially, for example from Maybridge Chemicals, or may be prepared according to methods well known in the art. The 2-haloisonicotinic acid of formula (1A) or 2-halonicotinic acid of formula (IB) may be converted to the corresponding acyl halide derivative of formula (2A) or (2B) by reacting a compound of formula (1A) or (IB) with an excess of a halogenating agent, such as oxalyl chloride or oxalyl bromide, or thionyl chloride or thionyl bromide, using a catalyst such as N,N-dimethylformamide or pyridine, in an organic solvent, prefereably dichloromethane or dichloroethane, at room temperature for about 2-16 hours, preferably 16 hours. The product of formula (2) is isolated by conventional means, and preferably reacted in the next step without further purification. Preparation of compounds of formula (4A) or (4B) The starting 2-amino-benzothiazole compounds of formula (3) maybe prepared according to methods disclosed in EP 00113219.0. The compounds of formula (4A) or (4B) are prepared by treating the 2-amino-benzothiazole compounds of formula (3) with a slight excess of the acyl halide compounds of formula (2A) or (2B) in a non-protic organic solvent, preferably a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine or triethylamine, at room temperature for 2-24 hours, preferably 24 hours. The product of formula (4A) or (4B) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Alternative preparation of compounds of formula (4A) or (4B) The compounds of formula (4A) or (4B) may also be prepared directly from compounds of formula (2A) or (2B). In this method, the compound of formula (2A) or 2(B) is treated with a stoichiometric equivalent of a peptide-coupling reagent, preferably O-(7-azabenzotriazol-l-yD-N,N,N'N'-tetramethyluroniumhexafluorophosphate (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine, at room temperature for 30-90 minutes. This mixture is then treated with a 2-amino-benzothiazole compoutnd of formula (3) in a solvent mixture, preferably a mixture of tetrahydrofuran, dioxane and N,N-dimethylformamide, at room temperature for 16-24 hours, preferably 24 hours. The product of formula (4) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. optionally substituted by hydroxy or lower alkoxy, or is morpholinyl, -N(R,,)-(CH2)m-C4-6-cycloalkyl) N(RJ,)-(CH2)m-C(0)0-lower alkyl, -N(R,>)-(CH2)m-C(0)OH, -2-oxo-pyrrolidinyl or -N(R")-C(0)0-lower alkyl, R" is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, and R in this scheme for compounds of formula IA3-2 is -(CHoJm-O-lower alkyl or alkyl; wherein R in this scheme for compounds of formula IB3-1 is -N(R")-(CH2)m-0-lower alkyl, -N(R")2> -S-lower alkyl or is acetidinyl, pyrrolidinyl or piperidinyl, which are optionally substituted by hydroxy or lower alkoxy, or is morpholinyl, -N(RM)-(CH2)m-C4.6-cycloalkyl, N(R")-(CH2)m-C(0)0-lower alkyl, -N(R,5)-(CH2)m-C(0)OH, -2-oxo-pyrrolidinyl, -N(R")-C(0)0-lower alkyl, R" is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, and R in this scheme for compounds of formula IB3-2 is -(CH2)m-0-lower alkyl or alkyl, R" is hydrogen or lower alkyl, and m is 1, 2 or 3. One method of preparation of compounds of formulae IA3-1 or IA3-2 and IB3-1 or IB3-2 is from the appropriately substituted benzothiazol-2-yl-amine (3) and 2-chloromethyl-isonicotinoyl chloride (4A1) or 2-chloromethyl-nicotinoyl chloride (4B1) as shown in reaction schemes 7 and 8 below. Preparation of compounds of formula IA or IB, wherein A is -CH?- and R is -OfCI-Mm-O-lower alkvl or alkoxy One method of preparation of compounds of formula IA3-1, IA3-2, IB3-1 or IB3-2 is by-treatment of a compound of formula (4A1) or (4B1) with an excess of an appropriate alcohol of formula (5), which maybe commercially available or maybe prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a metal-hydride base, preferably sodium hydride or potassium hydride. These reactions maybe carried out in an ethereal solvent such as dioxane, tetrahydrofuran or l,2~dimethoxyethane, preferably dioxane, optionally containing a co-solvent such as N>N-dimethylformamide, or in the respective alcohol as solvent, at a temperature between room temperature and the reflux temperature of the solvent, preferably about 100 °C, for 2-72 hours, preferably 16 hours. The product of Formula I, where A is CH^O, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Preparation of compounds of formula IA or IB, wherein A is -CKh- and R is -N(R")-(CH2U-Q-lower alkvl -N(R"K or is acetidinyl pvrrolidinyl or piperidinvl which are optionally substituted by hydroxy or lower alkoxy or is morpholinvl -N(R"HCH2U-G^-cydoalkvl. -N(R"WCH2)m- C(Q)Q-lower alkvl -N(R"HCH? )m-C(0)OH, -2-oxo-pyrrolidinyl -N(R"VC(Q)0-lower alkvl R" is independently from each other hydrogen or lower alkvl and m is 1, 2 or 3 To prepare the compounds of formula IA or IB, wherein A is -CH2-, the 2-chloro-isonicotinamide intermediate of formula (4A1) or (4B1) is treated with a large excess of an appropriate amine of formula (9), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic amine or an aromatic amine. These reactions maybe carried out in the absence of added solvent, or optionally in the presence of a solvent such as NyN-dimethylformamide or N-methylpyrrolidone, at an elevated temperature, preferably about 60 °C, for 2-48 hours, preferably 4 hours. The product of formula I, where A is CH2, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Preparation of compounds of formula I, wherein A-R are together Q-g-cycloalkyl or tetrahydropyran. One method of preparation of compounds of formula IA4 or IB4 and IA5 or IB5 is shown in reaction schemes 9 and 10 below. as triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-methylphenol. The reaction is carried out at elevated temperature, preferably about 100 °C, for about 16-96 hours, preferably about 72 hours. The product of formula IA4 or IB4 is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Alternative preparation of compounds of formula IA4 or IB4 The starting boronic acid compounds of formula (8) maybe obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art. The compounds of formula IA4 or IB4 may alternatively be prepared by treating 2-bromo-isonicotinamide intermediates of formula (4A) or 2-bromo-nicotinamide intermediates of formula (4B) with an excess of a boronic acid compound of formula (8). The reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride, and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out in the presence of other additives such as triphenylphosphine, lithium chloride and 2,6-di-£er£-butyl-4-methylphenol. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100 °C, for about 16-96 hours, preferably about 48 hours. The product of formula IA4 or IB4 is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Preparation of compounds of formula 1A5 and 1B5 One method of preparation of compounds of formula IA5 or IB5 is by hydrogenation of a compound of formula IA4 or IB4 in the presence of a hydrogenation catalyst, preferably 10 % palladium on charcoal. These reactions maybe carried out in a mixture of organic solvents, preferably a mixture of methanol and dichloromethane, at room temperature and at a pressure of one atmosphere or above, preferably at one atmosphere, for 2-48 hours, preferably about 16 hours. The product of formula IA5 or IB5, where A is carbon, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. 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 IA and IB The compounds of Formula IA or IB may be basic, for example in cases where the residue A-R contains a basic group such as an aliphatic or aromatic amine moiety. In such cases the compounds of Formula IA or IB may be 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, famaric 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 maybe brought out of solution with a less polar solvent. The acid addition salts of the basic compounds of Formula IA and IB maybe 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 formulas IA and IB 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 and possess a high affinity towards the adenosine A2A receptor. The compounds were investigated in accordance with the test given hereinafter. Human adenosine A2A receptor The human adenosine A2A 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 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} Pharmacol 121, 353; InM) 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 \x\ of buffer A. Nonspecific binding was defined using xanthine amine congener (XAC; 2 \|iM). 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 Ki values calculated using the Cheng-Prussoff equation. the compounds of formula IA and IB 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 IA and IB can be processed with pharmaceutical^ 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, semisolid 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 IA and IB 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 IA and IB 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 IA and IB 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 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. The following preparation and examples illustrate the invention but are not intended to limit its scope. Example 1 2-(2-Methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)" isonicotinamide a) 2-Chloro-iV-(4-methoxy-7-morpholin-4-vl-benzothiazol-2-yl)--isonicotinamide To a stirred solution of 10.8 g (40.8 mmol) 4~methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 17.3 ml (102 mmol) N-ethyldiisopropylarnine in 500 ml THF at 5 °C was added dropwise over 90 minutes a solution of 7.90 g (44,9 mmol) 2-chloro-isonicotinoyl chloride in 250 ml dichloromethane and stirring continued at room temperature for 16 h. The reaction mixture was then quenched by addition of 30 ml methanol and concentrated in vacuo. The residue was then resuspended in ethyl acetate and washed sequentially with saturated sodium bicarbonate solution, 0.5 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo to ca 100 ml. The resulting suspension was then left standing at room temperature for 72 h and then 100 ml ether was added and the suspension stirred for 1 hour at room temperature. The crystals were collected by filtration and dried in vacuo to afford 9.79 g (59%) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yI)-isonicotinamide as a brown crystalline solid. ES-MS m/e (%): 429 (M{37Cl}+Na\ 11), 427 (M{35Cl}+Na+, 30). 407 (M{37Cl}+H+> 30), 405 (M{35C1}+H+, 100). b) 2-(2-Methoxy-ethoxy)-N-(4-methoxv-7-morpholin-4-vl-benzothiazol"2-vl)- isonicotinamide To a stirred solution of 0.058 ml (074 mmol) 2-methoxyethanol in 2 ml dioxane at room temperature was added 49 mg (1.24 mmol) sodium hydride (60% dispersion in mineral oil) and stirring continued for 10 minutes. 200 mg (0.49 mmol) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115 °C for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 1 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/toluene) afforded 109 mg (50%) 2-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamideas a yellow crystalline solid. ES-MS m/e (%): 467 (M+Na+, 16), 445 (M+H+, 100). In an analogous manner there was obtained: To a stirred solution of 0.52 ml (8.90 mmol) ethanol in 30 ml dioxane at room temperature was added 486 mg (11.1 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50 °C for 30 minutes. LOO g (2.23 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115 °C for 72 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was resuspended in dichloromethane, and washed sequentially with water and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in methanol and concentrated in vacuo to 2 ml, 20 ml ether added, and the resulting crystals were collected by filtration and dried in vacuo to afford 410 mg (44%) 2-ethoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 437 (M+Na+, 24), 414 (M+H+, 100). Analogously to Example 1 there were obtained: Example 4 2-Benzyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and benzyl alcohol in dioxane. ES-MS m/e (%): 499 (M+Na+> 40), 477 (M+H+, 100). Example 5 2-Methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 31), 401 (M+H+, 100). Example 6 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(pyridin-2-ylmethoxy)-isonicotinamide From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-hydroxymethylpyridine in dioxane. ES-MS m/e (%): 500 (M+Na+, 23), 478 (M+H+, 100). Example 7 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2- [methyl- (2-pyridin-2-yl-ethyl)-amino] -isonicotinamide A stirred suspension of 200 mg (0.45 mniol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, 1.23 ml (8.90 mmol) 2-(2-methylaminoethyl)pyridine and 290mg (0.89 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140 °C for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/100-2.5/97.5 methanol/dichlormoethane) followed by trituration in ether afforded 160 mg (71%)i\r-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino]-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 505 (M+H+, 100). In an analogous manner there were obtained: Example 8 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-pyridin-2-yl-ethylamino)-isonicotinamide From 2-bromo-N"-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-(2-aminoethyl)-pyridine in NMP. ES-MS m/e (%): 491 (M-t-H+, 100). Example 9 2-[(2-Methoxy-ethyl)-methyl-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-(2-methoxyethyl)-methylamine. ES-MS m/e (%): 458 (M+H+> 100). Example 10 N-(4-Methox),-7-morpholm-4-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-l-yl)-isonicotinamide and a small spatula-end of 2,6-di-ferf-butyl-4-methylphenoL The mixture was heated at 100 °C for 72 h and then concentrated in vacuo. Rough flash chromatography (2/98 methanol/dichloromethane) afforded 520 mg of an orange solid, comprising mainly 2-cyclohex-l-enyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, which was taken onto the next reaction step without further purification. ES-MS m/e (%): 451 (M+H\ 100). b) 2-Cvclohexvl-N-(4-methoxv-7-morpholin-4-yl-benzothiazoI-2-vl)-isonicotinamide To a stirred solution of 585 mg (theoretically max 1.30 mmol) crude 2-cyclohex-l-enyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in 5 ml methanol and 10 ml dichloromethane was added 500 mg 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. Flash chromatography (1/19 methanol/dichloromethane) followed by trituration in ether and pentane afforded 125 mg (21%) 2-cyclohexyl-iV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 475 (M+Na+, 26), 453 (M+H+, 100). Analogously to Example 7 there were obtained: Example 25 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-3-oxo-piperazin-l-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and l-methyl-piperazin-2-one. ES-MS m/e (%): 505 (M+Na+, 31), 483 (M+H+, 100). Example 26 2-Azetidin-l-yl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidine. ES-MS m/e (%): 426 (M+H+, 100). Example 27 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-l-yl)-iso nicotinamide From2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100). Example 28 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(3-m isonicotinamide From 2-bromo-AT-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100). Example 29 2-(4-Ethyl-3-oxo-piperazin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and l-ethyl-piperazin-2-one. ES-MS m/e (%):519 (M+Na+, 28), 497 (M+H+, 100). Analogously to Example 24 there was obtained: Example 30 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with tri-n-butyl-(3,6-dihydro-2H-pyran-4-yl)-stannane>bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, lithium chloride and 2>6-di-terf-butyl-4-methylphenol in DMF. Then hydrogenation using palladium on charcoal in methanol and dichloromethane. ES-MS m/e (%): 477 (M+Na+, 16), 455 (M+H+, 100). Analogously to Example 7 there were obtained: Example 31 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-{(lS,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl}-isonicotinamide at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether afforded 270 mg (53%) 6-ethoxy-N-(4-methoxy-7-morpholin»4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 437 (M+Na+, 26), 415 (M+H+, 100). In an analogous manner there was obtained: Example 35 6-Methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamidewith sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M-J-Na+, 15), 401 (M+H+, 100). Example 36 6-(4-Acetyl-piperazin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide A stirred suspension of 200 mg (0.49 mmol) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide, 2.53 g (19.8 mmol) 1-acetylpiperazine and 290mg (0.89 mmol) cesium carbonate in 4 ml NMP in a thick-walled glass pressure tube fitted with a teflon cap was heated at 120 °C for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/99-4/96 methanol/dichlormoethane) followed by trituration in ether afforded 77 mg (31%) 6-(4-acetyl-piperazin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 519 (M+Na\ 26), 417 (M+H+> 100). Analogously to Example 34 there was obtained: Example 37 6-(2-Methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and 2-methoxyethanol in dioxane and DMF. ES-MS m/e (%): 467 (M+Na+, 24), 445 (M+H+, 100). Analogously to Example 36 there were obtained: Example 38 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-(4-methyl-piperazin-l-yl)-nicotinamide From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and 1-methyl-piperazine in NMP. ES-MS m/e (%): 469 (M+H+, 100). Example 39 6-[(2R,6S)-2,6-Dimethyl-morpholin-4-yl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamidewith cesium carbonate and cis-2,6-dimethyl-morpholine in NMP. ES-MS m/e (%): 506 (M+Na+, 31), 484 (M+H+, 100). Example 40 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-[(pyridin-2-ylmethyl)-amino]-nicotin amide From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamidewith cesium carbonate and 2-picolylamine. ES-MS m/e (%): 499 (M+Na+, 19), 477 (M+H+, 100). Example 41 6-(2-Methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and 2-methoxyethylamine. ES-MS m/e (%): 444 (M+H+, 100). Analogously to Example 34 there were obtained: Following the general method of example 46 the compounds of examples 47 - 62 were prepared. Example 47 2-[(2-Methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using 2-methoxy-ethylamine the title compound was prepared as yellow crystals (68 % yield). MS: m/e=458 (M+H+). Example 48 2-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-Wr-(4-methox)r-7-morpholin-4-yl-benzothiazoI-2-yl)-isonicotinamide Using N-ethyl-(2-methoxy-ethyl)-amine the title compound was prepared as off-white solid (76 % yield). MS: m/e=486 (M+H+). Example 49 2-{[(2-Ethoxy-ethyl)-ethyl-amino]-methyl}-JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using N-(2-ethoxy-ethyl)-ethyl-amine the title compound was prepared as brown solid (67 % yield). MS: m/e=500 (M+H+). Example 50 2-[(2-Ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using 2-ethoxy-ethylamine the title compound was prepared as yellow solid (44 % yield). MS: m/e=472 (M+H+). Example 51 2-[(Butyl-methyl-amino)-methyl]-iV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using N-butyl-methylamine the title compound was prepared as yellow solid (70 % yield). MS: m/e=470 (M+H+). Example 52 2-Butylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using bytylamine the title compound was prepared as yellow solid (58 % yield). MS: m/e=456 (M+H+). Example 53 2-Diethylaminomethyl-iV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using diethylamine the title compound was prepared as light yellow solid (55 % yield). MS: m/e=456 (M+H+). Example 54 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-pyrrolidin-l-ylmethyl-isonicotinamide Using pyrrolidine the title compound was prepared as yellow crystals (63 % yield). MS: m/e=454(M+H+). Example 55 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-piperidin-l-ylmethyl-isonicotinamide Using piperidine the title compound was prepared as off-white solid (56 % yield). MS: m/e=46S (M+H+). Example 56 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-morpholin-4-ylmethyl-isonicotinamide Using morpholine the title compound was prepared as light brown solid (76 % yield). MS: m/e=470 (M+H+). Example 57 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-l-ylmethyl)-isonicotinamide Using 4-methoxy-piperidine the title compound was prepared as light brown solid (99 % yield). MS: m/e=498 (M+H+). Example 58 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide Using methylamine the title compound was prepared as yellow crystals (30 % yield). MS: m/e=414 (M+H+). Example 59 2-Ethylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using ethylamine the title compound was prepared as yellow crystals (70 % yield). MS: m/e=428 (M+H+). Example 60 2-[(Cyclopropylmethyl-amino)-methyl]-N-(4-methoxy-7-morpholin--4-yl-benzothiazol-2-yl)-isonicotinamide Using C-cyclopropyl-methylamine the title compound was prepared as yellow crystals (70 % yield). MS: m/e=454 (M+H+). Example 61 2-Azetidin-l-yl-methyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using azetidine the title compound was prepared as yellow crystals (24 % yield). MS: rn/e=440 (M+H+). Example 62 4-{[4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-pyridin-2-yl-methyl]-amino}-butyric acid tert-butyl ester Using 4-amino-butyric acid tert-butyl ester in 10 parts tetrahydrofurane the title compound was prepared as light brown solid (43 % yield). MS: m/e=542 (M+H+). Example 69 (2-Chloromethyl-isonicotinoyl chloride (intermediate) Hydrolysis of 2-chloromethyl-isonicotinic acid methyl ester (derived as described by Scopes et al.> /. Med. Chem. 1992, 35, 492) with LiOH in MeOH and water and subsequent acid chloride formation with oxalyl chloride/dimethylformamide in dichloromethane gave the title compound as light brown oil in about 80% yield, which was used without further purification. Example 70 N-(4-Methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-pyrrolidin-l-yl-methyl-isonicotinamide Using 2-chloromethyl-N"-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-isonicotinamide and pyrrolidine the title compund was prepared as described for example 46 as light yellow crystals (67 % yield). MS: m/e=452 (M+H+). Example 71 N-(4-Methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-morpholin-4-yl-methyl-isonicotinamide Using 2-chloromethyl-N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-isonicotinamide and morpholine the title compund was prepared as described for example 1 as light yellow crystals (54 % yield). MS: m/e=46S (M+H+). Preparation of intermediates for examples 70 and 71. Example 72 2-Chloromethyl-N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-isonicotinamide (intermediate) Using 4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl-amine the title compound was prepared as described for 2-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as yellow crystals (70 % yield). MS: m/e=417 (M+H+). Example 73 2-(l,l-Dioxo-116-thiomorpholin-4-yl)-JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide a) N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2^ isonicotinamide A stirred suspension of 500 mg (1.11 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, 1.15 g (11.1 mmol) thiomorpholine and 725 mg (2.23 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140 °C for 48 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether/ethyl acetate/hexane afforded 290 mg (55 %) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-thiomorpholin-4-yl-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 472 (M+H+, 100). b) 2-(U-Dioxo-116-thiomorpholin-4-vl)-iV-(4-methoxv-7-morpholin-4-yl- benzothiazol-2-vl)-isonicotinamide To a stirred solution of 500 mg (1.06 mmol) N-(4-methoxy~7-morpholin-4-yl~ benzothiazol-2-yl)-2-thiomorpholin-4-yl-isonicotinamide in 5 ml methanol and 5 ml dichloromethane at room temperature was added 652 mg (1.06 mmol) oxone and stirring was continued for 60 h. The reaction was then quenched by careful addition of 5 ml saturated aqueous sodium hydrogensulfite solution and the pH of the resulting mixture was then adjusted to pH by addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (0.5/99.5 methanol/dichloromethane) followed by trituration in ether afforded 90 mg (17%) 2-(l,l-Dioxo-ll6-thiomorpholin-4-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 504 (M+H+, 100). Analogously to Example 7 there were obtained: Example 74 2-(3-Hydroxy-azetidin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and azetidin-3-ol in NMP. ES-MS m/e (%): 442 (M+H+, 100). From 2-bromo-N-(4-methoxy-7-morphoIin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and cyclopentanol in dioxane and DMF. ES-MS m/e (%): 455 (M+H, 100). Example 86 2-(2-Dimethylamino-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and 2-dimethylaminoethanol in dioxane and DMF. ES-MS m/e (%): 458 (M+H+, 100). Example 87 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and N-(2-hydroxyethyl)morpholine in dioxane and DMF. ES-MS m/e (%): 500 (M+H+, 100). Analogously to Example 7 there were obtained: Example 88 2-(2-Dimethylamino-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2--yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-dimethylaminoethylamine. ES-MS m/e (%): 457 (M+H+, 100). Example 89 2-Cyclopentylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclopentylamine. ES-MS m/e (%): 454 (M+H+, 100). Example 95 2-(Cyclohexyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylcyclohexylamine. ES-MS m/e (%): 482 (M+H+, 100). Example 96 2-(Benzyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)*-isonicotinamide with cesium carbonate and JV-methylbenzylamine. ES-MS m/e (%): 490 (M+H+, 100). Example 97 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(methyl-phenethyl-amino)-isonicotinamide From 2-bromo-JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methyl-2-phenyiethylamine. ES-MS m/e (%): 504 (M+H+,100). Example 98 N-(4-Methoxy-7-rnorpholin-4-yl-benzothiazol-2-yl)-2-phenethylamino-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and phenylethylamine. ES-MS m/e (%): 490 (M+H+, 100). Example 99 2-[(2-Dimethylamino-ethyl)-methyl-amino]-N'-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate andN,N,N,-trimethylethylenediamine. ES-MS m/e (%): 471 (M+H+, 100). Example 100 iV-(4-Methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-l-yl)-isonicotinamide From2-bromo-N-(4-methoxy-7-piperi^ cesium carbonate and N-methylpiperazine. ES-MS m/e (%): 467 (M+H+, 100). Analogously to Example 1 there was obtained: Example 101 2-Methoxy-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide From 2-bromo-N-(4'methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane. ES-MS m/e (%): 392 (M+H+, 100). The following examples were made from intermediate 68(2-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide) in the manner for example 46: Example 102 2-(4-Hydroxy-piperidin-l-yl-methyl)-N-(4-methoxy-7-morpholiri-4-yl-benzothiazol-2-yl)-isonkotinamide Using 4-hydroxy-piperidine the title compound was prepared as yellow crystals (68 % yield), mp 125°C. MS: m/e=484 (M+H+). Example 103 2-Ethylsulfanylmethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using ethanethiol and N-ethyl-diisopropylamine (Ll.eq) and sodium methanolate (1 eq), the title compound was prepared as light brown crystals (41 % yield), mp 158-159°C. MS: m/e=445 (M+H+). Example 104 2-{[(2-Ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide Using N-(2-ethoxy)-methylethylamine the title compound was prepared as yellow crystals (41 % yield), mp 159-160°C. MS: m/e=486 (M+H+). example 105 (S)-2-(2-Methoxymethyl-pyrroM^ benzothiazol-2-yl)-isonicotinamide Using (S)-2-methoxymethyl)pyrrolidine the title compound was prepared as yellow solid (45 % yield), mp 110-113 °C. MS: m/e=498 (M+H+). Example 106 (S)-2-(3-Methoxymethyl-pyrrolidin-l-ylmethyl)-N-(4-methoxy-7-morphoUn-4-yl-benzothiazoI-2-yI)-isonicotinamide Using (S)-3-methoxymethyl)pyrrolidine the title compound was prepared as light-yellow solid (30 % yield), mp 93-96 °C. MS: m/e=498 (M+H+). Example 107 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-methyl-imidazol-l-ylmethyl)-isonicotinamide Using 2-methyl-imidazole and dioxane the title compound was prepared as light-brown solid (87 % yield), mp 264-265 °C. MS: m/e=465 (M+H+). Example 108 >-[(Acetyl-methyl~amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-sonicotinamide ^-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-sonicotinamide (207 mg> 0.5 mmol) is dissolved in dichloromethane (10 ml) and treated vith pyridine (0.07 ml, 0.85 mmol) and acetyl chloride (0.05 ml, 0.7 mmol) and stirred for 6 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate (10 ml) is dded, the layers are separated and the aqueous phase extracted twice with each 10 ml ichloromethane. The combined organic phases are dried with magnesium sulfate and vaporated. Recrystallization from ethyl acetate afforded the title compound as light-yellow 3lid (80 % yield), mp 228-230°C. MS: m/e=456 (M+H+). ollowing.the method of example 108 the compound of 109 was prepared. Example 109 •[(Methoxyacetyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-mzothiazol-2-yl)-isonicotinamide Using methoxyacetyl chloride the title compound was prepared as yellow solid (73 % yield), mp 210°C. MS: m/e=486 (M+H+). Compounds in accordance with claim 4, wherein R is -(Ct^n-pyndinyl, -(CH2)n-morpholinyl-or"(CH2)n-2-oxo-pyrrolidinyl. 8. Compounds in accordance with claim 7, which compounds are 2-benzyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(pyridin-2-ylmethoxy)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[2-(2-oxo-pyrrolidin-l-yl)-ethoxyj-isonicotinamide or N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide. 9. Compounds in accordance with claim 3, wherein A is -N(R')-. 10. Compounds in accordance with claim 9, wherein R is -(CH2)n-pyridinyl> -(CH2)n-piperidinylJ -(CH2)n-phenyl or -(CH2)n-morpholidinyl. 11. Compounds in accordance with claim 10, which compounds are N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino] -isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-pyridin-2-yl-ethylamino)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[(pyridin-2-ylmethyl)-amino]-isonicotinamide, 2-[ethyl-(2-pyridin-2-yl-ethyl)-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethylamino)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-piperidin-l-yl-ethyl)-amino] -isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-piperidin-l-yl-ethylamino)- isonicotinamide, 2-benzylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamideJ 2-(benzyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)- isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(methyl-phenethyl-amino)- isonicotinamide or N-(4»methoX)-7-morpholin-4-yl-benzothiazol-2-yl)-2-phenethylamino-isonicotinamide. N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-)d)-2-(tetrahydr'o-pyran-4-yl)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-{(lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl}-isonicotinamide, 2-(l,l-dioxo-ll6-thiomorpholin-4-yl)-N-(4-m yI)-isonicotinamide, 2-(3-hydroxy-azetidin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)- isonicotinamide, 2-(3-methoxy-azetidin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)- isonicotinamide or 2-(3-ethoxy-azetidin-l-yl)-N-(4-methoxy-7--morpholin-4-yl-benzothiazol-2-yl)- isonicotinamide. 23. Compounds in accordance with claim 2, wherein R1 is piperidinyl. 24. Compounds in accordance with claim 23, wherein A is -CH2- and R is pyrrolidinyl or morpholidinyl. 25. Compounds in accordance with claim 24, wherein the compounds are N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-pyrrolidin-l-yl-methyl-isonicotinamide or N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-morpholin-4-yl-methyl-isonicotinamide. 26. Compounds of formula IB in accordance with claim 1. 27. Compounds in accordance with claim 26, wherein R1 is morpholinyl. 28. Compounds in accordance with claim 27, wherein A is -O- and R is lower alkyl, -(CH2)2-0-lower alkyl or cycloalkyl. 29. Compounds in accordance with claim 28, which compounds are 6-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide> 6-isopropoxy-N-(4-methox)^7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide, 6-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide or 6-cyclohexyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide. 30. Compounds in accordance with claim 23, wherein A - R are together piperazinyl, substituted by lower alkyl.

Full Text

R" is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3;
or
A is -S- and R is lower alkyl;
or
A-R are together
-piperazinyl, substituted by lower alkyl, -C(0)-lower alkyl or an oxo group, or is piperidinyl, substituted by lower alkoxy or hydroxy, or is morpholinyl, substituted by lower alkyl, or is -C4-6-cycloalkyl, -azetidin-1-yl, optionally substituted by hydroxy or lower alkoxy, thiomorpholine-l,l-dioxo, -tetrahydopyran or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl;
and to pharmaceutically 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 Ap 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, A2A, 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 A\ 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 A2A 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 (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 ceils 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 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 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 reperfiision. 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 maybe 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 maybe 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:
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., 332, 39-41, (1999),
Am. J. Physiol, 276, H1113-1116, (1999) or
Naunyn Schmied, Arch. Pharmacol. 362, 375-381, (2000).
Objects of the present invention are the compounds of formula IA and IB per se, the use of compounds of formula IA and IB and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the adenosine A? 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 IA and IB 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 maybe 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 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 4 — 6 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.

Preferred are further compounds of formula IA, wherein Rl\js morpholinyl, A is -CH2- and R is pyrrolidinyl, -2-oxo-pyrroIidinyl, piperidinyl, which is optionally substituted by lower alkoxy or hydroxy, or is morpholinyl or alkoxy, for example the following compounds:
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-pyrrolidin-l-ylmethyl-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)*2-(2-oxo-pyrrolidin-l-yl-methyl)-isonicotinamide)
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-l-
ylmethyl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-piperidin-l-ylmethyl-
isonicotinamide,
2-(4-hydroxy-piperidin-l-ylmethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-
isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-morpholin-4-ylmethyl-
isonicotinamide,
2-methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
or
2-(4-hydroxy-piperidin-l-yl-methyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-
yl)-isonicotinamide
Preferred compound of the present application are compounds of formula I A, wherein R1 is morpholinyl and A is -S-, for example the following compounds: N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylsulfanyl-isonicotinamideor 2-ethylsulfanyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide.
Preferred compound of the present application are compounds of formula I A, wherein R1 is morpholinyl and A- R are together -piperazinyl, substituted by lower alkyl, -C(0)-lower alkyl or an oxo group, or is piperidinyl, substituted by lower alkoxy or hydroxy, or is morpholinyl, substituted by lower alkyl, or is -cyclohexyl, -azetidin-1-yl, which is optionally substituted by hydroxy or lower alkoxy, or is -tetrahydopyran, or is 1,1-dioxo-thiomorpholinyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, for example the following compounds:
JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-l-yl)-isonicotinamide, 2-(4-acetyl-piperazin-l-yl)-N-(4-methox7-7-morpholin-4-yl-benzothiazol-2-yl)-
isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-3-oxo-piperazin-l-yl)-
isonicotinamide,

commercially, for example from Maybridge Chemicals, or may be prepared according to methods well known in the art.
The 2-haloisonicotinic acid of formula (1A) or 2-halonicotinic acid of formula (IB) may be converted to the corresponding acyl halide derivative of formula (2A) or (2B) by reacting a compound of formula (1A) or (IB) with an excess of a halogenating agent, such as oxalyl chloride or oxalyl bromide, or thionyl chloride or thionyl bromide, using a catalyst such as N,N-dimethylformamide or pyridine, in an organic solvent, prefereably dichloromethane or dichloroethane, at room temperature for about 2-16 hours, preferably 16 hours. The product of formula (2) is isolated by conventional means, and preferably reacted in the next step without further purification.
Preparation of compounds of formula (4A) or (4B)
The starting 2-amino-benzothiazole compounds of formula (3) maybe prepared according to methods disclosed in EP 00113219.0.
The compounds of formula (4A) or (4B) are prepared by treating the 2-amino-benzothiazole compounds of formula (3) with a slight excess of the acyl halide compounds of formula (2A) or (2B) in a non-protic organic solvent, preferably a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine or triethylamine, at room temperature for 2-24 hours, preferably 24 hours. The product of formula (4A) or (4B) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of formula (4A) or (4B)
The compounds of formula (4A) or (4B) may also be prepared directly from compounds of formula (2A) or (2B). In this method, the compound of formula (2A) or 2(B) is treated with a stoichiometric equivalent of a peptide-coupling reagent, preferably O-(7-azabenzotriazol-l-yD-N,N,N'N'-tetramethyluroniumhexafluorophosphate (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine, at room temperature for 30-90 minutes. This mixture is then treated with a 2-amino-benzothiazole compoutnd of formula (3) in a solvent mixture, preferably a mixture of tetrahydrofuran, dioxane and N,N-dimethylformamide, at room temperature for 16-24 hours, preferably 24 hours. The product of formula (4) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.

optionally substituted by hydroxy or lower alkoxy, or is morpholinyl, -N(R,,)-(CH2)m-C4-6-cycloalkyl) N(RJ,)-(CH2)m-C(0)0-lower alkyl, -N(R,>)-(CH2)m-C(0)OH, -2-oxo-pyrrolidinyl or -N(R")-C(0)0-lower alkyl, R" is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, and R in this scheme for compounds of formula IA3-2 is -(CHoJm-O-lower alkyl or alkyl;

wherein R in this scheme for compounds of formula IB3-1 is -N(R")-(CH2)m-0-lower alkyl, -N(R")2> -S-lower alkyl or is acetidinyl, pyrrolidinyl or piperidinyl, which are optionally substituted by hydroxy or lower alkoxy, or is morpholinyl, -N(RM)-(CH2)m-C4.6-cycloalkyl, N(R")-(CH2)m-C(0)0-lower alkyl, -N(R,5)-(CH2)m-C(0)OH, -2-oxo-pyrrolidinyl, -N(R")-C(0)0-lower alkyl, R" is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, and R in this scheme for compounds of formula IB3-2 is -(CH2)m-0-lower alkyl or alkyl, R" is hydrogen or lower alkyl, and m is 1, 2 or 3.
One method of preparation of compounds of formulae IA3-1 or IA3-2 and IB3-1 or IB3-2 is from the appropriately substituted benzothiazol-2-yl-amine (3) and 2-chloromethyl-isonicotinoyl chloride (4A1) or 2-chloromethyl-nicotinoyl chloride (4B1) as shown in reaction schemes 7 and 8 below.

Preparation of compounds of formula IA or IB, wherein A is -CH?- and R is -OfCI-Mm-O-lower alkvl or alkoxy
One method of preparation of compounds of formula IA3-1, IA3-2, IB3-1 or IB3-2 is by-treatment of a compound of formula (4A1) or (4B1) with an excess of an appropriate alcohol of formula (5), which maybe commercially available or maybe prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a metal-hydride base, preferably sodium hydride or potassium hydride. These reactions maybe carried out in an ethereal solvent such as dioxane, tetrahydrofuran or l,2~dimethoxyethane, preferably dioxane, optionally containing a co-solvent such as N>N-dimethylformamide, or in the respective alcohol as solvent, at a temperature between room temperature and the reflux temperature of the solvent, preferably about 100 °C, for 2-72 hours, preferably 16 hours. The product of Formula I, where A is CH^O, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of formula IA or IB, wherein A is -CKh- and R is -N(R")-(CH2U-Q-lower alkvl -N(R"K or is acetidinyl pvrrolidinyl or piperidinvl which are optionally substituted by hydroxy or lower alkoxy or is morpholinvl -N(R"HCH2U-G^-cydoalkvl. -N(R"WCH2)m- C(Q)Q-lower alkvl

-N(R"HCH? )m-C(0)OH, -2-oxo-pyrrolidinyl -N(R"VC(Q)0-lower alkvl R" is independently from each other hydrogen or lower alkvl and m is 1, 2 or 3
To prepare the compounds of formula IA or IB, wherein A is -CH2-, the 2-chloro-isonicotinamide intermediate of formula (4A1) or (4B1) is treated with a large excess of an appropriate amine of formula (9), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic amine or an aromatic amine. These reactions maybe carried out in the absence of added solvent, or optionally in the presence of a solvent such as NyN-dimethylformamide or N-methylpyrrolidone, at an elevated temperature, preferably about 60 °C, for 2-48 hours, preferably 4 hours. The product of formula I, where A is CH2, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of formula I, wherein A-R are together Q-g-cycloalkyl or tetrahydropyran.
One method of preparation of compounds of formula IA4 or IB4 and IA5 or IB5 is shown in reaction schemes 9 and 10 below.

as triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-methylphenol. The reaction is carried out at elevated temperature, preferably about 100 °C, for about 16-96 hours, preferably about 72 hours. The product of formula IA4 or IB4 is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of formula IA4 or IB4
The starting boronic acid compounds of formula (8) maybe obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The compounds of formula IA4 or IB4 may alternatively be prepared by treating 2-bromo-isonicotinamide intermediates of formula (4A) or 2-bromo-nicotinamide intermediates of formula (4B) with an excess of a boronic acid compound of formula (8). The reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride, and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out in the presence of other additives such as triphenylphosphine, lithium chloride and 2,6-di-£er£-butyl-4-methylphenol. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100 °C, for about 16-96 hours, preferably about 48 hours. The product of formula IA4 or IB4 is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of formula 1A5 and 1B5
One method of preparation of compounds of formula IA5 or IB5 is by hydrogenation of a compound of formula IA4 or IB4 in the presence of a hydrogenation catalyst, preferably 10 % palladium on charcoal. These reactions maybe carried out in a mixture of organic solvents, preferably a mixture of methanol and dichloromethane, at room temperature and at a pressure of one atmosphere or above, preferably at one atmosphere, for 2-48 hours, preferably about 16 hours. The product of formula IA5 or IB5, where A is carbon, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
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 IA and IB
The compounds of Formula IA or IB may be basic, for example in cases where the residue A-R contains a basic group such as an aliphatic or aromatic amine moiety. In such cases the compounds of Formula IA or IB may be 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, famaric 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 maybe brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of Formula IA and IB maybe 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 formulas IA and IB 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 and possess a high affinity towards the adenosine A2A receptor.
The compounds were investigated in accordance with the test given hereinafter.
Human adenosine A2A receptor
The human adenosine A2A 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 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} Pharmacol 121, 353; InM) 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 \x\ of buffer A. Nonspecific binding was defined using xanthine amine congener (XAC; 2 |iM). 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 Ki values calculated using the Cheng-Prussoff equation.

the compounds of formula IA and IB 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 IA and IB can be processed with pharmaceutical^ 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, semisolid 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 IA and IB 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 IA and IB 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 IA and IB 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 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.

The following preparation and examples illustrate the invention but are not intended to limit its scope.
Example 1
2-(2-Methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)" isonicotinamide
a) 2-Chloro-iV-(4-methoxy-7-morpholin-4-vl-benzothiazol-2-yl)--isonicotinamide
To a stirred solution of 10.8 g (40.8 mmol) 4~methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 17.3 ml (102 mmol) N-ethyldiisopropylarnine in 500 ml THF at 5 °C was added dropwise over 90 minutes a solution of 7.90 g (44,9 mmol) 2-chloro-isonicotinoyl chloride in 250 ml dichloromethane and stirring continued at room temperature for 16 h. The reaction mixture was then quenched by addition of 30 ml methanol and concentrated in vacuo. The residue was then resuspended in ethyl acetate and washed sequentially with saturated sodium bicarbonate solution, 0.5 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo to ca 100 ml. The resulting suspension was then left standing at room temperature for 72 h and then 100 ml ether was added and the suspension stirred for 1 hour at room temperature. The crystals were collected by filtration and dried in vacuo to afford 9.79 g (59%) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yI)-isonicotinamide as a brown crystalline solid. ES-MS m/e (%): 429 (M{37Cl}+Na\ 11), 427 (M{35Cl}+Na+, 30). 407 (M{37Cl}+H+> 30), 405 (M{35C1}+H+, 100).
b) 2-(2-Methoxy-ethoxy)-N-(4-methoxv-7-morpholin-4-vl-benzothiazol"2-vl)-
isonicotinamide
To a stirred solution of 0.058 ml (074 mmol) 2-methoxyethanol in 2 ml dioxane at room temperature was added 49 mg (1.24 mmol) sodium hydride (60% dispersion in mineral oil) and stirring continued for 10 minutes. 200 mg (0.49 mmol) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115 °C for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 1 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/toluene) afforded 109 mg (50%) 2-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamideas
a yellow crystalline solid. ES-MS m/e (%): 467 (M+Na+, 16), 445 (M+H+, 100). In an analogous manner there was obtained:

To a stirred solution of 0.52 ml (8.90 mmol) ethanol in 30 ml dioxane at room temperature was added 486 mg (11.1 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50 °C for 30 minutes. LOO g (2.23 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115 °C for 72 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was resuspended in dichloromethane, and washed sequentially with water and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in methanol and concentrated in vacuo to 2 ml, 20 ml ether added, and the resulting crystals were collected by filtration and dried in vacuo to afford 410 mg (44%) 2-ethoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 437 (M+Na+, 24), 414 (M+H+, 100).
Analogously to Example 1 there were obtained:
Example 4
2-Benzyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and benzyl alcohol in dioxane. ES-MS m/e (%): 499 (M+Na+> 40), 477 (M+H+, 100).
Example 5
2-Methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 31), 401 (M+H+, 100).
Example 6
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(pyridin-2-ylmethoxy)-isonicotinamide
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-hydroxymethylpyridine in dioxane. ES-MS m/e (%): 500 (M+Na+, 23), 478 (M+H+, 100).

Example 7
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2- [methyl- (2-pyridin-2-yl-ethyl)-amino] -isonicotinamide
A stirred suspension of 200 mg (0.45 mniol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, 1.23 ml (8.90 mmol) 2-(2-methylaminoethyl)pyridine and 290mg (0.89 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140 °C for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/100-2.5/97.5 methanol/dichlormoethane) followed by trituration in ether afforded 160 mg (71%)i\r-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino]-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 505 (M+H+, 100).
In an analogous manner there were obtained:
Example 8
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-pyridin-2-yl-ethylamino)-isonicotinamide
From 2-bromo-N"-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-(2-aminoethyl)-pyridine in NMP. ES-MS m/e (%): 491 (M-t-H+, 100).
Example 9
2-[(2-Methoxy-ethyl)-methyl-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-(2-methoxyethyl)-methylamine. ES-MS m/e (%): 458 (M+H+> 100).
Example 10
N-(4-Methox),-7-morpholm-4-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-l-yl)-isonicotinamide

and a small spatula-end of 2,6-di-ferf-butyl-4-methylphenoL The mixture was heated at 100 °C for 72 h and then concentrated in vacuo. Rough flash chromatography (2/98 methanol/dichloromethane) afforded 520 mg of an orange solid, comprising mainly 2-cyclohex-l-enyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, which was taken onto the next reaction step without further purification. ES-MS m/e (%): 451 (M+H\ 100).
b) 2-Cvclohexvl-N-(4-methoxv-7-morpholin-4-yl-benzothiazoI-2-vl)-isonicotinamide
To a stirred solution of 585 mg (theoretically max 1.30 mmol) crude 2-cyclohex-l-enyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in 5 ml methanol and 10 ml dichloromethane was added 500 mg 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. Flash chromatography (1/19 methanol/dichloromethane) followed by trituration in ether and pentane afforded 125 mg (21%) 2-cyclohexyl-iV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 475 (M+Na+, 26), 453 (M+H+, 100).
Analogously to Example 7 there were obtained:
Example 25
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-3-oxo-piperazin-l-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and l-methyl-piperazin-2-one. ES-MS m/e (%): 505 (M+Na+, 31), 483 (M+H+, 100).
Example 26
2-Azetidin-l-yl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidine. ES-MS m/e (%): 426 (M+H+, 100).
Example 27
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-l-yl)-iso nicotinamide

From2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100).
Example 28
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(3-m isonicotinamide
From 2-bromo-AT-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-piperidine. ES-MS m/e (%): 484 (M+H+, 100).
Example 29
2-(4-Ethyl-3-oxo-piperazin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and l-ethyl-piperazin-2-one. ES-MS m/e (%):519 (M+Na+, 28), 497 (M+H+, 100).
Analogously to Example 24 there was obtained:
Example 30
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with tri-n-butyl-(3,6-dihydro-2H-pyran-4-yl)-stannane>bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, lithium chloride and 2>6-di-terf-butyl-4-methylphenol in DMF. Then hydrogenation using palladium on charcoal in methanol and dichloromethane. ES-MS m/e (%): 477 (M+Na+, 16), 455 (M+H+, 100).
Analogously to Example 7 there were obtained:
Example 31
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-{(lS,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl}-isonicotinamide

at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether afforded 270 mg (53%) 6-ethoxy-N-(4-methoxy-7-morpholin»4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 437 (M+Na+, 26), 415 (M+H+, 100).
In an analogous manner there was obtained:
Example 35
6-Methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamidewith sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M-J-Na+, 15), 401 (M+H+, 100).
Example 36
6-(4-Acetyl-piperazin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide
A stirred suspension of 200 mg (0.49 mmol) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide, 2.53 g (19.8 mmol) 1-acetylpiperazine and 290mg (0.89 mmol) cesium carbonate in 4 ml NMP in a thick-walled glass pressure tube fitted with a teflon cap was heated at 120 °C for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/99-4/96 methanol/dichlormoethane) followed by trituration in ether afforded 77 mg (31%) 6-(4-acetyl-piperazin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 519 (M+Na\ 26), 417 (M+H+> 100).
Analogously to Example 34 there was obtained:
Example 37 6-(2-Methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide

From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and 2-methoxyethanol in dioxane and DMF. ES-MS m/e (%): 467 (M+Na+, 24), 445 (M+H+, 100).
Analogously to Example 36 there were obtained:
Example 38
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-(4-methyl-piperazin-l-yl)-nicotinamide
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and 1-methyl-piperazine in NMP. ES-MS m/e (%): 469 (M+H+, 100).
Example 39
6-[(2R,6S)-2,6-Dimethyl-morpholin-4-yl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamidewith cesium carbonate and cis-2,6-dimethyl-morpholine in NMP. ES-MS m/e (%): 506 (M+Na+, 31), 484 (M+H+, 100).
Example 40
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-[(pyridin-2-ylmethyl)-amino]-nicotin amide
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamidewith cesium carbonate and 2-picolylamine. ES-MS m/e (%): 499 (M+Na+, 19), 477 (M+H+, 100).
Example 41
6-(2-Methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and 2-methoxyethylamine. ES-MS m/e (%): 444 (M+H+, 100).
Analogously to Example 34 there were obtained:

Following the general method of example 46 the compounds of examples 47 - 62 were prepared.
Example 47
2-[(2-Methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using 2-methoxy-ethylamine the title compound was prepared as yellow crystals (68 % yield). MS: m/e=458 (M+H+).
Example 48
2-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-Wr-(4-methox)r-7-morpholin-4-yl-benzothiazoI-2-yl)-isonicotinamide
Using N-ethyl-(2-methoxy-ethyl)-amine the title compound was prepared as off-white solid (76 % yield). MS: m/e=486 (M+H+).
Example 49
2-{[(2-Ethoxy-ethyl)-ethyl-amino]-methyl}-JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using N-(2-ethoxy-ethyl)-ethyl-amine the title compound was prepared as brown solid (67 % yield). MS: m/e=500 (M+H+).
Example 50
2-[(2-Ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using 2-ethoxy-ethylamine the title compound was prepared as yellow solid (44 % yield). MS: m/e=472 (M+H+).
Example 51
2-[(Butyl-methyl-amino)-methyl]-iV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using N-butyl-methylamine the title compound was prepared as yellow solid (70 % yield). MS: m/e=470 (M+H+).

Example 52
2-Butylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using bytylamine the title compound was prepared as yellow solid (58 % yield). MS: m/e=456 (M+H+).
Example 53
2-Diethylaminomethyl-iV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using diethylamine the title compound was prepared as light yellow solid (55 % yield). MS: m/e=456 (M+H+).
Example 54
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-pyrrolidin-l-ylmethyl-isonicotinamide
Using pyrrolidine the title compound was prepared as yellow crystals (63 % yield). MS: m/e=454(M+H+).
Example 55
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-piperidin-l-ylmethyl-isonicotinamide
Using piperidine the title compound was prepared as off-white solid (56 % yield). MS: m/e=46S (M+H+).
Example 56
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-morpholin-4-ylmethyl-isonicotinamide
Using morpholine the title compound was prepared as light brown solid (76 % yield). MS: m/e=470 (M+H+).
Example 57
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-l-ylmethyl)-isonicotinamide

Using 4-methoxy-piperidine the title compound was prepared as light brown solid (99 % yield). MS: m/e=498 (M+H+).
Example 58
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide
Using methylamine the title compound was prepared as yellow crystals (30 % yield). MS: m/e=414 (M+H+).
Example 59
2-Ethylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using ethylamine the title compound was prepared as yellow crystals (70 % yield). MS: m/e=428 (M+H+).
Example 60
2-[(Cyclopropylmethyl-amino)-methyl]-N-(4-methoxy-7-morpholin--4-yl-benzothiazol-2-yl)-isonicotinamide
Using C-cyclopropyl-methylamine the title compound was prepared as yellow crystals (70 % yield). MS: m/e=454 (M+H+).
Example 61
2-Azetidin-l-yl-methyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using azetidine the title compound was prepared as yellow crystals (24 % yield). MS: rn/e=440 (M+H+).
Example 62
4-{[4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-pyridin-2-yl-methyl]-amino}-butyric acid tert-butyl ester
Using 4-amino-butyric acid tert-butyl ester in 10 parts tetrahydrofurane the title compound was prepared as light brown solid (43 % yield). MS: m/e=542 (M+H+).

Example 69
(2-Chloromethyl-isonicotinoyl chloride (intermediate)
Hydrolysis of 2-chloromethyl-isonicotinic acid methyl ester (derived as described by Scopes et al.> /. Med. Chem. 1992, 35, 492) with LiOH in MeOH and water and subsequent acid chloride formation with oxalyl chloride/dimethylformamide in dichloromethane gave the title compound as light brown oil in about 80% yield, which was used without further purification.
Example 70
N-(4-Methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-pyrrolidin-l-yl-methyl-isonicotinamide
Using 2-chloromethyl-N"-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-isonicotinamide and pyrrolidine the title compund was prepared as described for example 46 as light yellow crystals (67 % yield). MS: m/e=452 (M+H+).
Example 71
N-(4-Methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-morpholin-4-yl-methyl-isonicotinamide
Using 2-chloromethyl-N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-isonicotinamide and morpholine the title compund was prepared as described for example 1 as light yellow crystals (54 % yield). MS: m/e=46S (M+H+).
Preparation of intermediates for examples 70 and 71.
Example 72
2-Chloromethyl-N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-isonicotinamide
(intermediate)
Using 4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl-amine the title compound was prepared as described for 2-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as yellow crystals (70 % yield). MS: m/e=417 (M+H+).
Example 73
2-(l,l-Dioxo-116-thiomorpholin-4-yl)-JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide

a) N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2^
isonicotinamide
A stirred suspension of 500 mg (1.11 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, 1.15 g (11.1 mmol) thiomorpholine and 725 mg (2.23 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140 °C for 48 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether/ethyl acetate/hexane afforded 290 mg (55 %) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-thiomorpholin-4-yl-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 472 (M+H+, 100).
b) 2-(U-Dioxo-116-thiomorpholin-4-vl)-iV-(4-methoxv-7-morpholin-4-yl-
benzothiazol-2-vl)-isonicotinamide
To a stirred solution of 500 mg (1.06 mmol) N-(4-methoxy~7-morpholin-4-yl~ benzothiazol-2-yl)-2-thiomorpholin-4-yl-isonicotinamide in 5 ml methanol and 5 ml dichloromethane at room temperature was added 652 mg (1.06 mmol) oxone and stirring was continued for 60 h. The reaction was then quenched by careful addition of 5 ml saturated aqueous sodium hydrogensulfite solution and the pH of the resulting mixture was then adjusted to pH by addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (0.5/99.5 methanol/dichloromethane) followed by trituration in ether afforded 90 mg (17%) 2-(l,l-Dioxo-ll6-thiomorpholin-4-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 504 (M+H+, 100).
Analogously to Example 7 there were obtained:
Example 74
2-(3-Hydroxy-azetidin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and azetidin-3-ol in NMP. ES-MS m/e (%): 442 (M+H+, 100).

From 2-bromo-N-(4-methoxy-7-morphoIin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and cyclopentanol in dioxane and DMF. ES-MS m/e (%): 455 (M+H*, 100).
Example 86
2-(2-Dimethylamino-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and 2-dimethylaminoethanol in dioxane and DMF. ES-MS m/e (%): 458 (M+H+, 100).
Example 87
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith sodium hydride and N-(2-hydroxyethyl)morpholine in dioxane and DMF. ES-MS m/e (%): 500 (M+H+, 100).
Analogously to Example 7 there were obtained:
Example 88
2-(2-Dimethylamino-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2--yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-dimethylaminoethylamine. ES-MS m/e (%): 457 (M+H+, 100).
Example 89
2-Cyclopentylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclopentylamine. ES-MS m/e (%): 454 (M+H+, 100).

Example 95
2-(Cyclohexyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylcyclohexylamine. ES-MS m/e (%): 482 (M+H+, 100).
Example 96
2-(Benzyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)*-isonicotinamide with cesium carbonate and JV-methylbenzylamine. ES-MS m/e (%): 490 (M+H+, 100).
Example 97
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(methyl-phenethyl-amino)-isonicotinamide
From 2-bromo-JV-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methyl-2-phenyiethylamine. ES-MS m/e (%): 504 (M+H+,100).
Example 98
N-(4-Methoxy-7-rnorpholin-4-yl-benzothiazol-2-yl)-2-phenethylamino-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate and phenylethylamine. ES-MS m/e (%): 490 (M+H+, 100).
Example 99
2-[(2-Dimethylamino-ethyl)-methyl-amino]-N'-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamidewith cesium carbonate andN,N,N,-trimethylethylenediamine. ES-MS m/e (%): 471 (M+H+, 100).
Example 100
iV-(4-Methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-l-yl)-isonicotinamide

From2-bromo-N-(4-methoxy-7-piperi^
cesium carbonate and N-methylpiperazine. ES-MS m/e (%): 467 (M+H+, 100).
Analogously to Example 1 there was obtained:
Example 101
2-Methoxy-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide
From 2-bromo-N-(4'methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane. ES-MS m/e (%): 392 (M+H+, 100).
The following examples were made from intermediate 68(2-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide) in the manner for example 46:
Example 102
2-(4-Hydroxy-piperidin-l-yl-methyl)-N-(4-methoxy-7-morpholiri-4-yl-benzothiazol-2-yl)-isonkotinamide
Using 4-hydroxy-piperidine the title compound was prepared as yellow crystals (68 % yield), mp 125°C. MS: m/e=484 (M+H+).
Example 103
2-Ethylsulfanylmethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using ethanethiol and N-ethyl-diisopropylamine (Ll.eq) and sodium methanolate (1 eq), the title compound was prepared as light brown crystals (41 % yield), mp 158-159°C. MS: m/e=445 (M+H+).
Example 104
2-{[(2-Ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Using N-(2-ethoxy)-methylethylamine the title compound was prepared as yellow crystals (41 % yield), mp 159-160°C. MS: m/e=486 (M+H+).

example 105
(S)-2-(2-Methoxymethyl-pyrroM^ benzothiazol-2-yl)-isonicotinamide
Using (S)-2-methoxymethyl)pyrrolidine the title compound was prepared as yellow solid (45 % yield), mp 110-113 °C. MS: m/e=498 (M+H+).
Example 106
(S)-2-(3-Methoxymethyl-pyrrolidin-l-ylmethyl)-N-(4-methoxy-7-morphoUn-4-yl-benzothiazoI-2-yI)-isonicotinamide
Using (S)-3-methoxymethyl)pyrrolidine the title compound was prepared as light-yellow solid (30 % yield), mp 93-96 °C. MS: m/e=498 (M+H+).
Example 107
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-methyl-imidazol-l-ylmethyl)-isonicotinamide
Using 2-methyl-imidazole and dioxane the title compound was prepared as light-brown solid (87 % yield), mp 264-265 °C. MS: m/e=465 (M+H+).
Example 108
>-[(Acetyl-methyl~amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-sonicotinamide
^-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-sonicotinamide (207 mg> 0.5 mmol) is dissolved in dichloromethane (10 ml) and treated vith pyridine (0.07 ml, 0.85 mmol) and acetyl chloride (0.05 ml, 0.7 mmol) and stirred for 6 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate (10 ml) is dded, the layers are separated and the aqueous phase extracted twice with each 10 ml ichloromethane. The combined organic phases are dried with magnesium sulfate and vaporated. Recrystallization from ethyl acetate afforded the title compound as light-yellow 3lid (80 % yield), mp 228-230°C. MS: m/e=456 (M+H+).
ollowing.the method of example 108 the compound of 109 was prepared.
Example 109
•[(Methoxyacetyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-mzothiazol-2-yl)-isonicotinamide

Using methoxyacetyl chloride the title compound was prepared as yellow solid (73 % yield), mp 210°C. MS: m/e=486 (M+H+).

Compounds in accordance with claim 4, wherein R is -(Ct^n-pyndinyl, -(CH2)n-morpholinyl-or"(CH2)n-2-oxo-pyrrolidinyl.
8. Compounds in accordance with claim 7, which compounds are 2-benzyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(pyridin-2-ylmethoxy)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[2-(2-oxo-pyrrolidin-l-yl)-ethoxyj-isonicotinamide or
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide.
9. Compounds in accordance with claim 3, wherein A is -N(R')-.
10. Compounds in accordance with claim 9, wherein R is -(CH2)n-pyridinyl> -(CH2)n-piperidinylJ -(CH2)n-phenyl or -(CH2)n-morpholidinyl.
11. Compounds in accordance with claim 10, which compounds are N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino] -isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-pyridin-2-yl-ethylamino)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[(pyridin-2-ylmethyl)-amino]-isonicotinamide,
2-[ethyl-(2-pyridin-2-yl-ethyl)-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethylamino)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-piperidin-l-yl-ethyl)-amino] -isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-piperidin-l-yl-ethylamino)-
isonicotinamide, 2-benzylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamideJ
2-(benzyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-
isonicotinamide, N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(methyl-phenethyl-amino)-
isonicotinamide or N-(4»methoX)-7-morpholin-4-yl-benzothiazol-2-yl)-2-phenethylamino-isonicotinamide.

N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-)d)-2-(tetrahydr'o-pyran-4-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-{(lS,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl}-isonicotinamide,
2-(l,l-dioxo-ll6-thiomorpholin-4-yl)-N-(4-m
yI)-isonicotinamide,
2-(3-hydroxy-azetidin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-
isonicotinamide,
2-(3-methoxy-azetidin-l-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-
isonicotinamide or
2-(3-ethoxy-azetidin-l-yl)-N-(4-methoxy-7--morpholin-4-yl-benzothiazol-2-yl)-
isonicotinamide.
23. Compounds in accordance with claim 2, wherein R1 is piperidinyl.
24. Compounds in accordance with claim 23, wherein A is -CH2- and R is pyrrolidinyl or morpholidinyl.
25. Compounds in accordance with claim 24, wherein the compounds are
N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-pyrrolidin-l-yl-methyl-isonicotinamide or
N-(4-methoxy-7-piperidin-l-yl-benzothiazol-2-yl)-2-morpholin-4-yl-methyl-isonicotinamide.
26. Compounds of formula IB in accordance with claim 1.
27. Compounds in accordance with claim 26, wherein R1 is morpholinyl.
28. Compounds in accordance with claim 27, wherein A is -O- and R is lower alkyl, -(CH2)2-0-lower alkyl or cycloalkyl.
29. Compounds in accordance with claim 28, which compounds are
6-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide>
6-isopropoxy-N-(4-methox)^7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide,
6-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide
or 6-cyclohexyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide.
30. Compounds in accordance with claim 23, wherein A - R are together piperazinyl, substituted by lower alkyl.

Documents:

1079-chenp-2004-abstract.pdf

1079-chenp-2004-claims duplicate.pdf

1079-chenp-2004-claims original.pdf

1079-chenp-2004-correspondnece-others.pdf

1079-chenp-2004-correspondnece-po.pdf

1079-chenp-2004-description(complete) duplicate.pdf

1079-chenp-2004-description(complete) original.pdf

1079-chenp-2004-form 1.pdf

1079-chenp-2004-form 26.pdf

1079-chenp-2004-form 3.pdf

1079-chenp-2004-form 5.pdf

1079-chenp-2004-others document.pdf

1079-chenp-2004-pct.pdf

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Patent Number

205676

Indian Patent Application Number

1079/CHENP/2004

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

09-Apr-2007

Date of Filing

17-May-2004

Name of Patentee

M/S. F. HOFFMANN-LA ROCHE AG

Applicant Address

124GRENZACHERSTRASSE, CH-4070 BASEL

Inventors:

#	Inventor's Name	Inventor's Address
1	JAKOB-ROETNE,ROLAND	BASELBLICK 37, 79595 INZLINGEN
2	NORCROSS,,ROGER ,DAVID	20 ALTE SALINE CH-4310
3	RIEMER,CLAUS	OPTIZSTRASSE 5, 79110 FREIBURG
4	FLOHR,ALEXANDER	142 ST, GALLER-RING, CH4054 BASEL

PCT International Classification Number

A61K 31/4439

PCT International Application Number

PCT/EP02/12562

PCT International Filing date

2002-11-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	1127312.5	2001-11-19	EUROPEAN UNION