HK1105199B - 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide - Google Patents

Description

4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

The present invention relates to 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide, a compound of formula I

And pharmaceutically acceptable acid addition salts thereof.

It has surprisingly been found that the compounds of formula I are high affinity, high selectivity adenosine A_2AReceptor antagonists of adenosine A_2AReceptor agonist-induced behavior has an effective and long-lasting in vivo oral antagonism.

This compound is generally described in WO 01/097786.

Adenosine regulates many physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is structurally and metabolically related to the biologically active nucleotides Adenosine Triphosphate (ATP), Adenosine Diphosphate (ADP), Adenosine Monophosphate (AMP), and cyclic adenosine monophosphate (cAMP); (ii) is associated with the biochemical methylating agent S-adenosyl-L-methionine (SAM); and are structurally related to the coenzymes NAD, FAD and coenzyme a; is related to RNA. Adenosine, together with these related compounds, has important roles in regulating many aspects of cellular metabolism and in regulating various central nervous system activities.

Adenosine receptors are classified as A₁、A_2A、A_2BAnd A₃Receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine triggers a signal transduction mechanism. These mechanisms depend on the G protein associated with the receptor. Each adenosine receptor subtype is traditionally characterized by an adenylate cyclase effector system, which uses cAMP as a second messenger. And G_iProtein-coupled A₁And A₃The receptor inhibits adenylate cyclase, causing a decrease in cellular cAMP levels, whereas A_2AAnd A_2BReceptors and G_sThe protein couples and activates adenylate cyclase, causing an increase in cellular cAMP levels. Known as A₁The receptor system activates phospholipase C and modulates potassium and calcium ion channels. A. the₃In addition to being associated with adenylate cyclase, the subtype also stimulates phospholipase C and activates calcium ion channels.

A₁The receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chicken, bovine, guinea pig) with 90-95% sequence identity in mammals. A. the_2AThe receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. A. the_2BThe receptor (332 amino acids) was cloned from human and mouse and shown to be homologous to human A₁And A_2AReceptor 45% homology. A. the₃The receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.

A₁And A_2AReceptor subtypes play a complementary role in the regulation of energy supply by adenosine. Adenosine, a metabolite of ATP, diffuses from the cell and is localizedActing to activate adenosine receptors to reduce oxygen demand (A)₁) Or increasing the oxygen supply (A)_2A) And thereby restoring the energy supply: balancing of needs within an organization. Both subtypes act to increase the amount of oxygen available to the tissue and protect cells from damage caused by a short-term oxygen imbalance. One of the important functions of endogenous adenosine is to prevent injury in traumas such as hypoxia, ischaemia, hypotension and seizure activity.

In addition, adenosine receptor agonists are known to interact with the expression rat A₃Mast cell binding of the receptor causes an increase in inositol triphosphate and intracellular calcium concentrations, which allows antigen-induced secretion of inflammatory mediators to occur. Thus, A₃Receptors play a role in mediating asthma attacks and other allergic reactions.

Adenosine is a neurotransmitter that regulates a wide range of physiological brain functions. Endogenous adenosine is an important link between energy metabolism and neuronal activity, which varies according to behavioral states and (patho-) physiological conditions. Adenosine provides a powerful protective feedback mechanism under conditions of increased energy demand and reduced available energy (e.g., hypoxia, hypoglycemia, and/or overactive neurons). Interaction with adenosine receptors is a desirable target for therapeutic intervention in a variety of neurological and psychiatric diseases, such as epilepsy, sleep, movement disorders (Parkinson's disease or Huntington's disease), Alzheimer's disease, depression, schizophrenia or addiction. Increased neurotransmitter release causes trauma such as hypoxia, ischemia and seizures. These neurotransmitters are ultimately responsible for neurodegeneration and nerve death, which leads to brain damage or death of the individual. Adenosine A₁Agonists mimic the important inhibitory effects of adenosine and are therefore useful as neuroprotective agents. Adenosine has been suggested as an endogenous anticonvulsant, inhibiting glutamate release from excited neurons and inhibiting neuronal firing. Thus, adenosine agonists may be useful as antiepileptic agents. In addition, adenosine antagonists have proven effective as cognitive enhancers. Selectivity A_2AAntagonists in the treatment of various forms of dementia such as Alzheimer's disease and neurodegenerative diseasesFor example, stroke, has therapeutic potential. Adenosine A_2AReceptor antagonists modulate the activity of striatal gabaergic neurons and regulate smooth and coordinated movements, thus providing a potential treatment for parkinson's disease. Adenosine is also involved in a variety of physiological processes associated with sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamines, cocaine, opioids, ethanol, nicotine, cannabinoids). Drugs that act at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants and for the treatment of drug abuse. They are also useful in the treatment of ADHD (attention deficit hyperactivity disorder).

One important role of adenosine in the cardiovascular system is as a cardioprotective agent. In response to ischemia and hypoxia, endogenous adenosine levels increase and protect cardiac tissue during and after trauma (preconditioning). By acting on A₁Receptor, adenosine A₁Agonists protect the heart from damage caused by myocardial ischemia and reperfusion. A. the_2AThe modulatory effects of receptors on adrenergic function may be associated with a variety of disorders such as coronary artery disease and heart failure. A. the_2AAntagonists may have therapeutic benefit in situations where it is desirable to enhance an anti-adrenergic response, for example in acute myocardial ischemia. Selectivity A_2AReceptor antagonists may also enhance the efficacy of adenosine in terminating supraventricular arrhythmias.

Adenosine regulates a variety of renal functions, including renin release, glomerular filtration rate, and renal blood flow. Compounds that antagonize the renal effects of adenosine have potential as nephroprotective agents. In addition, adenosine A₃And/or A_2BThe antagonists may be used in the treatment of asthma and other allergic reactions or/and in the treatment of diabetes and obesity.

A number of documents describe the prior knowledge about 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)。

The invention concerns the use of a compound of formula I, per se, the use of said compound and its pharmaceutically acceptable salts for preparing a medicament for treating diseases associated with adenosine A_2AThe use of the compounds of the invention for the control or prevention of diseases which are based on the modulation of the adenosine system, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, drug addiction, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids or antiasthmatic, allergic responses, hypoxia, ischaemia, seizure and drug abuse. In addition, the compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants, and cardioprotective agents against disorders such as coronary artery disease and heart failure. The most preferred indications according to the invention are those based on A_2AIndications for receptor antagonist activity, including central nervous system disorders, e.g. treatment or prevention of Alzheimer's diseaseDefault, depression, drug addiction, neuroprotection and parkinson's disease, and ADHD.

The term "lower alkyl" as used herein denotes a saturated straight or branched alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred lower alkyl groups are those containing 1 to 4 carbon atoms.

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

The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

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

a) Reacting a compound of formula II

With a compound of the formula III,

to obtain a compound of formula I;

or

b) Reacting a compound of formula IV

With a compound of the formula V,

to obtain the compound of the formula I,

wherein L is a leaving group, e.g. halogen, -O-phenyl, -O-nitro-phenyl or-O-lower alkyl, and

if desired, the compound obtained is converted into a pharmaceutically acceptable acid addition salt.

The compounds of the formula I can be prepared according to process variants a) and b).

Additionally, in examples 1-7 and schemes 1, 2 and 3 below, the preparation of the compounds of formula I is described in more detail.

The starting materials are known compounds or compounds which can be prepared by methods known in the art.

Preparation of Compounds of formula I

One method for preparing the compound of formula (I) according to scheme 1 below is as follows: to a solution of intermediate 7- (morpholin-4-yl) -4-methoxy-benzothiazol-2-ylamine (II) (which may be prepared according to scheme 3) in dichloromethane is added a base such as pyridine or diisopropylethylamine in sequence with the compound of formula (III) and the resulting solution is stirred at ambient temperature for about 45 minutes. Saturated aqueous sodium bicarbonate was added and the organic phase was separated and dried.

Scheme 1

Another method for preparing the compounds of formula (I) is as follows: to a solution of a compound of formula (IV), which may be prepared according to methods known in the art and described in WO 01/97786, in an inert solvent such as dichloromethane, a base such as pyridine or diisopropylethylamine and a compound of formula (V) are added sequentially and the resulting solution is stirred at 45 ℃ for about 45 minutes. After cooling to ambient temperature, saturated aqueous sodium bicarbonate solution was added, and the organic phase was separated and dried.

Flow chart 2

Wherein L is a leaving group, such as halogen, -O-phenyl, -O-nitro-phenyl or-O-lower alkyl.

Flow chart 3

a is morpholine, Pd (Ac)₂2-biphenyl-dicyclohexylphosphine, K₃PO₄、DME；

b is H₂Palladium on carbon, methanol;

c is benzoyl isothiocyanate, acetone;

d is a solution of sodium methoxide in methanol;

e is trichloromethane containing bromine.

Isolation and purification of Compounds

Isolation and purification of the compounds and intermediates described herein may be accomplished by any suitable isolation or purification method, if desired, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography, or a combination of these methods. Specific illustrations of suitable separation and isolation procedures can be obtained with reference to the preparations and examples below. However, other equivalent separation or isolation methods may of course also be used.

Salts of the compounds of formula I

The conversion to the corresponding acid addition salt is accomplished by treatment with at least a stoichiometric amount of a suitable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, as well as organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Generally, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, etc., and the added acid is dissolved in a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.

Basic acid addition salts of compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.

The compounds of formula I and their pharmaceutically acceptable addition salts possess valuable pharmacological properties. In particular, it has been found that the compounds of the present invention are adenosine receptor ligandsBody, adenosine A_2AThe receptor has a high affinity.

The compounds were studied according to the tests given below.

Description of the experiments

Human A recombinantly expressed in Chinese Hamster Ovary (CHO) cells_2AReceptor evaluation of 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide p A using the semiki forest Virus expression System_2AThe affinity of the receptor. Cells were harvested, washed twice by centrifugation, homogenized and washed again by centrifugation. The final washed cell membrane pellet was suspended in Tris (50mM) buffer containing 120mM NaCl, 5mM CaCl₂And 10mM MgCl₂(pH7.4) (buffer A). In the presence of a buffer containing about 2.5. mu.g of membrane protein, 0.5mg of Ysi-poly-1-lysine SPA beads and 0.1U of adenosine deaminase in a final volume of 200. mu.L in a 96-well plate³HSCH-58261(Dionisotti et al, 1997, Br J Pharmacol 121, 353; 1nM) binding assay. Nonspecific binding was defined by xanthine amine congener (XAC; 2. mu.M). Compounds were tested at 10 concentrations ranging from 10. mu.M to 0.3 nM. All assays were performed in duplicate and repeated at least twice. The assay plates were incubated for 1 hour at room temperature prior to centrifugation, and bound ligands were then determined using a Packard Topcount scintillation counter. Calculation of IC Using a non-Linear Curve fitting program₅₀Values and Ki values were calculated using the Cheng-Prussoff equation.

Test results

4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide was found to be recombinant human adenosine A_2AHigh affinity, potent, selective antagonists of the receptor. It is to human A_2AThe affinity (pKi) of the receptor for A is 8.3_2ASelectivity of receptor alignment A₁、A_2BAnd A₃The selectivity of the receptor is two orders of magnitude greater. Further studies evaluated 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholine-4)-yl-benzothiazol-2-yl) -amides are selective for a variety of neurotransmitter transporters, ion channels, and enzyme targets. Shows 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide p_2AThe receptor selectivity is more than 1000-fold greater than the selectivity for the target tested.

Antagonizing NECA-stimulated (non-specific adenosine receptor agonist) expression of human A coupled to G protein G alpha 16 by study compounds_2ACa in CHO cells of the receptor²⁺The ability to flow was evaluated for in vitro activity. 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide inhibits A_2AMediated reaction, pIC₅₀It was 8.83(Hill slope 0.6). 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide antagonizes NECA-stimulated expression of human A coupled to G protein G.alpha.16_2ACa in CHO cells of the receptor²⁺Flow, pIC₅₀It was 5.22(Hill slope 0.7). Thus, in this functional assay, 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide was shown to be human a_2AThe receptor selectivity is for human A₁The selectivity of the acceptor is > 4000 times.

4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide was found to be a potent, long-acting, orally active antagonist in vivo. It antagonizes APEC (adenosine A) administered subcutaneously at 0.01mg/kg in rats_2AReceptor agonists) induced hypokinesia (hypopolocomotion). The calculated dose of the compound to inhibit 50% APEC-induced hypokinesia following oral administration was 0.5 mg/kg. A plasma concentration of 290ng/mL was required to fully antagonize this APEC-induced hypokinesia. This antagonism lasts for several hours and the functional half-life in this model is about 8 hours.

Pharmacokinetic parameters have been evaluated in rats and dogs. In rats, the compound had a half-life of 4 hours, a clearance of 11ml/min/kg and a distribution volume of 1.4L/kg after intravenous administration; the oral bioavailability was 77% after 5mg/kg administration to rats. In dogs, following intravenous administration, the half-life of the molecule was 2.2 hours, clearance was 8ml/min/kg, and volume of distribution was 1.2L/kg; the oral bioavailability after 5mg/kg administration to dogs was 88%.

In summary, 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide was found to be a high affinity, high selectivity adenosine a_2AReceptor antagonists, pair A_2AReceptor agonist-induced behavior has an effective and long-lasting in vivo oral antagonism.

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

The compounds of formula I may be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules, lactose, corn starch and derivatives thereof, talc, stearic acid or its salts and the like can be used. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, in the case of soft gelatin capsules, depending on the nature of the active substance, no carriers are often required. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

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

According to the invention, the compounds of formula I and their pharmaceutically acceptable salts are useful in the treatment or prevention of adenosine A-based diseases_2ADiseases with receptor antagonistic activity, such as alzheimer's disease, parkinson's disease, huntington's chorea, neuroprotection, schizophrenia, anxiety, pain, respiratory defects, depression, ADHD (attention deficit hyperactivity disorder), amphetamine, cocaine, opioids, ethanol, nicotine, drug addiction of the cannabinoids, or for the treatment of asthma, allergic reactions, hypoxia, ischaemia, seizure, substance abuse, or for use as muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardioprotective agents.

The most preferred indications of the invention are those which include disorders of the central nervous system, for example the treatment or prevention of parkinson's disease, ADHD, depression and drug addiction.

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

The following preparation methods and examples are illustrative of the present invention but are not intended to limit the scope thereof.

Example 1

4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide (I)

To a solution of phenyl (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -carbamate (3.2g, 8.3mmol) and N-ethyl-diisopropyl-amine (4.4mL, 25mmol) in chloroform (50mL) was added a solution of 4-hydroxy-4-methyl-piperidine in chloroform (3mL) and tetrahydrofuran (3mL), and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was then cooled to ambient temperature and extracted with saturated aqueous sodium carbonate (15mL) and water (2 x 5 mL). Finally drying over magnesium sulfate, evaporation of the solvent and recrystallization from ethanol gave the title compound as white crystals (78% yield), mp 236 ℃. MS: 407(M + H) M/e⁺)。

Example 2

(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -carbamic acid phenyl ester (IV)

To a suspension of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (26.5g, 100mmol) in dichloromethane (56mL) and pyridine (56mL, 700mmol) was added phenyl chloroformate (15.7mL, 125mmol) at 0-5 ℃ and the reaction mixture was warmed to ambient temperature. After 1 h, water (7.2mL, 400mmol) was added and the reaction mixture was heated to 45 ℃ for 1 h. Ethyl acetate (250mL) and 2M HCl (125mL) were then added and the organic phase was separated. After removal of the solvent, recrystallization from tert-butyl methyl ether and finally from ethanol, the title compound is obtained as a white solid (80% yield), mp 166-168 ℃. MS: 386(M + H)⁺)。

Example 3

4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (II)

A solution of (2-methoxy-5-morpholin-4-yl-phenyl) -thiourea (5.0g, 19mmol) in chloroform (130mL) was treated with bromine (960. mu.L) and the mixture was refluxed for 18 h. After removal of volatile components under vacuum, the product was recrystallized from THF (2.8g, 57%). MS: 266M/e (M)⁺)。

Example 4

(2-methoxy-5-morpholin-4-yl-phenyl) -thiourea

1-benzoyl-3- (2-methoxy-5-morpholin-4-yl-phenyl) -thiourea (8.0g, 21mmol) was suspended in methanol (260mL), treated with 6mL sodium methoxide (5.4M in methanol) and the mixture was stirred until a white precipitate formed. The mixture was concentrated in vacuo, the crystals were isolated by filtration and washed with methanol and hexane (5.0g, 86%). MS: 268 (M/e)⁺)。

Example 5

1-benzoyl-3- (2-methoxy-5-morpholin-4-yl-phenyl) -thiourea

To a solution of 2-methoxy-5-morpholin-4-yl-aniline (4.6g, 22mmol) in acetone (140mL) was added a solution of benzoyl isothiocyanate (3.4mL, 25mmol) in acetone (80mL) and the reaction mixture was stirred at ambient temperature for a further 30 min. After removal of volatile components under vacuum, the product was isolated by flash chromatography (silica gel, eluent ethyl acetate/n-hexane 1: 4, then 1: 2) as a yellow solid (8.0g, 97%). MS: 272 (M/e) ═ M/e⁺)。

Example 6

2-methoxy-5-morpholin-4-yl-anilines

4- (4-methoxy-3-nitro-phenyl) -morpholine (6g) was hydrogenated over palladium on charcoal (10%, 600mg) in dichloromethane (100mL) and methanol (600mL) for 12 h. The catalyst was removed by filtration and the solution was evaporated under vacuum. Purification by flash chromatography (silica gel, eluent ethyl acetate/hexanes 1: 1) afforded the product as an off-white solid (4.6g, 88%). MS: 209(M + H) M/e⁺)。

Example 7

4- (4-methoxy-3-nitro-phenyl) -morpholine

4-bromo-2-nitroanisole (8.5g, 36mmol), morpholine (3.8mL, 44mmol), potassium phosphate (11g, 51mmol), 2-biphenyl-bis (biphenyl) and the likeCyclohexylphosphine (960mg, 2.7mmol) and palladium (II) acetate (411mg, 1.8mmol) were dissolved in dimethoxyethane (80mL) and stirred at 80 ℃ for 96 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate (50mL) and filtered through dicalite. Flash chromatography on silica gel (eluent dichloromethane/methanol 99: 1) afforded the product as a red solid (6.0g, 69%). MS: 238 (M/e)⁺)。

Tablet formulation(Wet granulation)

Item Composition (I) mg/tablet

5mg 25mg 100mg 500mg

525100500 Compound of formula I

2 lactose anhydrous DTG 12510530150

3 Sta-Rx 1500 6 6 6 30

4 microcrystalline cellulose 303030150

5 magnesium stearate 1111

Total 167167167831

Preparation method

1. Items 1, 2, 3 and 4 were mixed and granulated with purified water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Add item 5 and mix for 3 minutes; tabletting on a suitable tabletting machine.

Capsule preparation

Item Composition (I) mg/capsule

5mg 25mg 100mg 500mg

525100500 Compound of formula I

2 aqueous lactose 159123148-

3 corn starch 25354070

4 Talc powder 10151025

5 magnesium stearate 1225

Total 200200300600

Preparation method

1. Items 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

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

3. Fill into a suitable capsule.

Claims (13)

1. The compound of formula I4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

Or a pharmaceutically acceptable acid addition salt thereof.

2. A medicament comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

3. A medicament according to claim 2 for the treatment or prophylaxis of adenosine a_2AA receptor associated disease.

4. A medicament according to claim 3 for the treatment or prevention of alzheimer's disease, parkinson's disease, huntington's chorea, neuroprotection, schizophrenia, anxiety, pain, depression, attention deficit hyperactivity disorder, drug addiction to cocaine, ethanol, or for the treatment of allergic reactions, ischemia, seizures, drug abuse, or for use as antipsychotics, antiepileptics and cardioprotectors.

5. A medicament according to claim 4 for the treatment or prevention of Parkinson's disease, attention deficit hyperactivity disorder, depression and drug addiction.

6. A process for the preparation of a compound of formula I as defined in claim 1, which process comprises

a) Reacting a compound of formula II

With a compound of the formula III,

to obtain a compound of formula I;

or

b) Reacting a compound of formula IV

With a compound of the formula V,

to obtain the compound of the formula I,

wherein L is a leaving group, and

if desired, the compound obtained is converted into a pharmaceutically acceptable acid addition salt.

7. The method of claim 6, wherein the leaving group is halogen, -O-phenyl, -O-nitro-phenyl, or-O-C_1-6An alkyl group.

8. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of diseases associated with adenosine a_2AA receptor associated disease.

9. The use of a compound as claimed in claim 8 for the preparation of a medicament for the treatment or prophylaxis of alzheimer's disease, parkinson's disease, huntington's chorea, neuroprotection, schizophrenia, anxiety, pain, depression, attention deficit hyperactivity disorder, drug addiction to cocaine, ethanol, or for the treatment of allergic reactions, ischemia, seizures, drug abuse, or for use as antipsychotics, antiepileptics and cardioprotectors.

10. The use of a compound as claimed in claim 9 in the manufacture of a medicament for the treatment of parkinson's disease.

11. Use of a compound as claimed in claim 9 in the manufacture of a medicament for the treatment of attention deficit hyperactivity disorder.

12. The use of a compound as claimed in claim 9 in the manufacture of a medicament for the treatment of depression.

13. Use of a compound as claimed in claim 9 in the manufacture of a medicament for the treatment of cocaine, ethanol drug addiction.