HK1093021A - Benzothiazole derivatives and use thereof in the treatment of diseases related to the adenosine a2a receptor - Google Patents

Description

Benzothiazole derivatives and their use in the treatment of diseases related to the adenosine A2A receptor

The present invention relates to compounds of the general formula I:

wherein:

R¹is CF₃Lower alkyl, - (CH)₂)_nOH or- (CH)₂)_n-O-lower alkyl-substituted C_5，6-cycloalkyl or is 1-bicyclo [2.2.1]Hept-2-yl, 1- (7-oxa-bicyclo [2.2.1]]Hept-2-yl, 1- (5-exo-hydroxy-bicyclo [2.2.1]]Hept-2-exo-yl, 1- (5-exo-hydroxy-bicyclo [ 2.2.1)]Hept-2-endo-yl, or is 1-adamantan-1-yl;

R²is lower alkyl; or

R¹And R²Together with the N-atom forming the radical 8-oxa-3-aza-bicyclo [3.2.1]Octane;

n is 0 or 1;

and pharmaceutically acceptable acid addition salts thereof.

It has surprisingly been found that the compounds of formula I are adenosine receptor ligands. In particular, the compounds of the invention are of the formula A_2AGood affinity of the receptor for A₁-and A₃The receptor is highly selective.

Adenosine regulates a variety 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 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-1-methionine (SAM); structurally related to the coenzymes NAD, FAD and coenzyme a; and associated with RNA. Adenosine, together with these related compounds, is important in the regulation of many aspects of cellular metabolism and in the regulation of 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 rely on the G protein associated with the receptor. Each adenosine receptor subtype is generally characterized by the adenylate cyclase effector system, which utilizes cAMP as a second messenger. And G_iProtein-coupled A₁And A₃The receptor inhibits adenylate cyclase, resulting in a decrease in cellular cAMP levels, and G_sProtein-coupled A_2AAnd A_2BThe receptor activates adenylate cyclase, resulting in increased cellular cAMP levels. Known as A₁The receptor system involves the activation of phospholipase C and the modulation of potassium and calcium ion channels. In addition to being associated with adenylate cyclase, A₃The isoforms also stimulate phospholipase C and thus calcium ion channels.

A from different species (canine, human, rat, canine, chicken, bovine, guinea pig) were cloned₁The receptor (326-328 amino acids) has 90-95% sequence identity in mammalian species. A from canine, rat, human, guinea pig and mouse was cloned_2AReceptor (409-412 amino acids). A from human and mouse was cloned_2BReceptor (332 amino acids), human A_2BWith person A₁And A_2AThe receptor homology was 45%. Clone derived from humanRat, dog, rabbit and sheep A₃Receptor (317-320 amino acids).

A is proposed₁And A_2AReceptor subtypes play complementary roles in the regulation of the energy supply of adenosine. Adenosine, a metabolite of ATP, diffuses out of the cell and acts locally to activate adenosine receptors to reduce oxygen demand (A)₁) Or increasing the oxygen supply (A)_2A) And thus restore the energy supply in the tissue: and (4) balancing the requirements. The effects of these two subtypes are to increase the amount of oxygen available to the tissue and to protect cells from damage caused by a short-term oxygen imbalance. One important function of endogenous adenosine is to prevent damage in injury such as hypoxia, ischemia, hypotension and seizure activity.

In addition, adenosine receptor agonists are known to interact with rat A₃Mast cell binding of the receptor results in an increase in inositol triphosphate and intracellular calcium concentrations, thereby potentiating antigen-induced secretion of inflammatory mediators. Thus, A₃The receptors play a role in the modulation of asthma attacks and other allergies.

Adenosine is a neuromodulator that is capable of modulating many aspects of brain physiological function. Endogenous adenosine, as an intermediate link between energy metabolism and neural activity, varies depending on behavioral states and (patho-) physiological conditions. Adenosine provides a powerful protective feedback mechanism under conditions of increased energy demand and reduced energy availability (e.g., hypoxia, hypoglycemia, and/or excessive neural activity). Interaction with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases, such as epilepsy, sleep, dyskinesias (parkinson's disease or huntington's chorea), alzheimer's disease, depression, schizophrenia or addiction. Neurotransmitter release increases after trauma such as hypoxia, ischemia and seizures. These neurotransmitters ultimately lead to neurodegeneration and nerve death, thereby causing brain damage and death of the individual. Thus, adenosine A, which mimics the central inhibitory effect of adenosine₁Agonists are useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant to inhibit glutamate excitationNeuronal firing (firing) is released and inhibited in sexual neurons. Adenosine agonists are therefore useful as antiepileptic agents. Adenosine antagonists stimulate CNS activity and have been shown to be effective cognitive enhancers. Selectivity A_2aAntagonists have the potential to treat various forms of dementia, such as alzheimer's disease, and to treat neurodegenerative disorders such as stroke. Adenosine A_2aReceptor antagonists modulate the activity of gabaergic neurons of the striatum and regulate smooth and well-coordinated movements, thus having therapeutic potential for the symptoms of parkinson's disease. Adenosine is also associated with a number of physiological processes involving sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamines, cocaine, opioids, alcohol, nicotine, cannabinoids). Drugs that act at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants and to treat drug abuse. They are also useful in the treatment of ADHD (attention deficit hyperactivity disorder).

An important role for adenosine in the cardiovascular system is as a cardioprotective agent. In response to ischemia and hypoxia, endogenous adenosine levels increase, protecting cardiac tissue during and after trauma (preconditioning). Adenosine A₁By action of agonists on A₁The receptor may provide protection against damage caused by myocardial ischemia and reperfusion. A. the_2aThe modulatory effects of receptors on adrenergic function may be associated with a number of diseases such as coronary heart disease and heart failure. In cases where it is desired to enhance the anti-adrenergic response, for example during acute myocardial ischemia, A_2aAntagonists may have therapeutic benefits. Selectivity A_2aReceptor antagonists may also enhance the therapeutic effects of adenosine in terminal ventricular arrhythmias.

Adenosine regulates many aspects of renal function, 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 are useful in the treatment of asthma and other allergies, as well as in the treatment of diabetes and obesity.

There are a number of documents describing the prior knowledge about adenosine receptors, such as 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 relates to the use of compounds of formula I per se, of compounds of formula I and of their pharmaceutically acceptable salts for the preparation of a medicament for the treatment of diseases associated with adenosine A₂The use of the compounds according to the invention in medicaments for the treatment of diseases which are dependent on the receptors, their preparation, medicaments based on the compounds according to the invention and their preparation as well as the use of the compounds of the formula I for the control or prevention of diseases which are modulated by the adenosine system, such as alzheimer's disease, parkinson's disease, huntington's chorea, neuroprotection, schizophrenia, anxiety, pain, respiratory deficiency (respirational deficiency), depression, drug addiction, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or against asthma, allergy, hypoxia, ischaemia, seizure and substance abuse. Furthermore, the compounds of the present invention are useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anti-epilepticsConvulsants and cardioprotective agents for conditions such as coronary heart disease and heart failure. The most preferred indications of the invention are those based on A_2ADisorders of receptor antagonist activity and disorders involving the central nervous system, such as Alzheimer's disease, certain depression, drug addiction, neuroprotection and Parkinson's disease, and the treatment or prevention of 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.

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.

Preferred compounds are those wherein R is¹Is CF₃Lower alkyl, - (CH)₂)_nOH or- (CH)₂)_n-O-lower alkyl-substituted C_5，6Cycloalkyl, such as the following compounds:

3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (4-trifluoromethyl-cyclohexyl) -urea,

(trans) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (4-methyl-cyclohexyl) -urea,

(trans) -1- (4-hydroxymethyl-cyclohexyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea,

(trans) -1- (4-methoxymethyl-cyclohexyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea or

(rac), (cis) -1- (3-hydroxymethyl-cyclopentyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea.

Further preferred are compounds wherein R is¹Is 1-bicyclo [2.2.1]Hept-2-yl, 1- (7-oxa-bicyclo [2.2.1]]Hept-2-yl, 1- (5-exo-hydroxy-bicyclo [2.2.1]]Hept-2-exo-yl, 1- (5-exo-hydroxy-bicyclo [ 2.2.1)]Hept-2-endo-yl or 1-adamantan-1-yl, for example the following compounds:

1- (endo) - (rac) -bicyclo [2.2.1] hept-2-yl-3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea,

(exo) - (+) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea,

(exo) - (-) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea,

(rac) - (endo) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea,

(rac) -1- (5-exo-hydroxy-bicyclo [2.2.1] hept-2-exo-yl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea,

(rac) -1- (5-rac-hydroxy-bicyclo [2.2.1] hept-2-in-yl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea or

1-adamantan-1-yl-3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea.

Wherein R is¹And R²Together with the N-atom forming the radical 8-oxa-3-aza-bicyclo [3.2.1]An example of a compound of octane is 8-oxa-3-aza-bicyclo [3.2.1]Octane-3-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide.

The compounds of formula I of the present invention and their pharmaceutically acceptable salts may be prepared according to methods known in the art, for example by a method comprising:

a) reacting a compound of formula II

With a compound of the formula III,

to obtain the compound of the formula I,

wherein R is¹And R²Have the meanings given above, or

b) Reacting a compound of formula IV

With a compound of the formula V,

to obtain the compound of the formula I,

wherein R is¹And R²L is a leaving group such as halogen, -O-phenyl or O-lower alkyl, and

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

In examples 1-13 and schemes 1 and 2 below, the preparation of the compounds of formula I is described in more detail.

The starting materials are known compounds or can be prepared according to methods known in the art.

Preparation of Compounds of formula I

The intermediate 7- (morpholin-4-yl) -4-methoxy-benzothiazol-2-ylamine (II) may be prepared according to the method disclosed in WO 01/97786. The preparation of compounds of formula (I) using intermediates of formula (II) is also described in WO 01/97786.

One method of preparing the compound of formula (I) according to scheme 1 below is as follows: to a solution of the compound of formula (II) in dichloromethane is added a base such as pyridine or diisopropyl-ethylamine, followed by the compound of formula (III), and the resulting solution is stirred at ambient temperature for about 45 minutes. Saturated aqueous sodium bicarbonate solution was added, the organic phase was separated and dried.

Scheme 1

Wherein R is¹And R²As described above.

An alternative process for preparing compounds of formula (I) is as follows: to a solution of a compound of formula (IV), which may be prepared according to methods well known in the art and as described in WO01/97786, in an inert solvent such as dichloromethane, a base such as pyridine or diisopropyl-ethylamine is added in succession with the compound of formula (V), and the resulting solution is stirred at 45 ℃ for about 45 minutes. After cooling to ambient temperature, saturated aqueous sodium bicarbonate solution was added, the organic phase was separated and dried.

Flow chart 2

Wherein R is¹And R²Such as byL is a leaving group such as halogen, -O-phenyl or O-lower alkyl, as defined above.

Isolation and purification of Compounds

The compounds and intermediates described herein can be isolated and purified, if desired, by any suitable method of isolation or purification, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer (thick-layer) chromatography, preparative low or high pressure liquid chromatography, or a combination of these methods. For a detailed description of suitable separation and isolation procedures, reference may be made to the preparations and examples below. However, other equivalent separation and isolation methods may of course also be used.

Salts of the compounds of formula I

The compounds of formula I may be basic, for example in the case where the group R contains a basic group such as an aliphatic or aromatic amine moiety. In this case, the compounds of the formula I can be converted into the corresponding acid addition salts.

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 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. 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 is added in a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The salt formed precipitates spontaneously or can be separated from the solution with a less polar solvent.

The acid addition salts of the basic 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 ligands, adenosine A_2AThe receptor has high affinity.

The compounds of the invention were investigated according to the tests given below.

Human adenosine A_2AReceptors

Recombinant expression of human adenosine A in Chinese Hamster Ovary (CHO) cells using semliki forest virus expression System_2AA receptor. Cells were harvested, washed twice by centrifugation, homogenized and washed again by centrifugation. The final washed membrane pellet was suspended in a solution containing 120mM NaCl, 5mM KCl, 2mM CaCl₂And 10mM MgCl₂In Tris (50mM) buffer (pH 7.4) (buffer A). The [ alpha ], [ beta ] -n-ray-chain-like domain in a 96-well plate³H]The SCH-58261(Dionisotti et al 1997 Br J Pharmacol 121, 353; 1nM) binding assay was performed in the presence of 2.5. mu.g membrane protein, 0.5mg Ysi-poly-1-lysine SPA beads and 0.1U adenosine deaminase in a final volume of 200. mu.l buffer A. Non-specific binding was defined using the 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 at room temperature for 1 hour, after which centrifugation was performed and bound ligands were then determined using a PackardTopcount scintillation counter. Calculating IC using a non-linear fitting program₅₀Values, Ki values were calculated using the Cheng-Prussoff equation.

The compounds of the present application have pKi values in the range of 7.3 to 8.5, as described in the table below.

Example numbering	hA2(pKi)	Example numbering	hA2(pKi)
				1	7.7	8	8.0
2	7.8	9	7.9
				3	7.8	10	8.1
4	7.7	11	8.1
				5	8.4	12	7.3
6	8.1	13	8.0
				7	8.5

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. But may also be administered rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.

The compounds of formula I may be processed with pharmaceutically inert, inorganic or organic carriers to prepare pharmaceutical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as carriers for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. 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, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Medicaments containing 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 well as a process for their preparation, which comprises bringing one or more compounds of the formula I and/or pharmaceutically acceptable acid addition salts thereof 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 control or prevention of diseases based on adenosine receptor antagonistic activity, such as alzheimer's disease, parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiratory deficiency, depression, asthma, allergy, hypoxia, ischaemia, seizure and substance abuse. Furthermore, the compounds of the present invention are useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardioprotective agents, and for the preparation of corresponding medicaments.

The most preferred indications of the present invention are those which include central nervous system disorders, such as the treatment or prevention of certain depression, neuroprotection and parkinson's disease.

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

Tablet formulation (Wet granulation)

Item	Component (A)	mg/tablet
						1.2.3.4.5.	Lactose anhydrous DTGSTa-Rx 1500 microcrystalline cellulose magnesium stearate Total amount of Compound I	5mg51256301167	25mg251056301167	100mg100306301167	500mg500150301501831

Preparation method

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

2. The granules were dried at 50 ℃.

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

4. Adding item 5, mixing three times; compressed on a suitable tablet press.

Capsule preparation

Item	Component (A)	mg/capsule
						1.2.3.4.5.	Formula ICompound lactose-corn starch hydrate talc magnesium stearate	5mg515925101200	25mg2512335152200	100mg10014840102300	500mg500---70255600

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 suitable capsules.

The following preparations and examples serve to illustrate the invention, but are not intended to limit its scope.

Example 1

3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (4-trifluoromethyl-cyclohexyl) -urea

4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine was first reacted with phenyl chloroformate and then with methyl- (4-trifluoromethyl-cyclohexyl) -amine as described in WO01/97786 for benzyl (4-methoxy-7-phenyl-benzothiazol-2-yl) -carbamate. Conventional work-up, flash chromatography (silica gel with dichloromethane/methanol as eluent) and final evaporation of the solvent gave the title compound as white crystals (96% yield) m 157-. MS: 473(M + H) M/e⁺)。

The compounds of examples 2 to 12 were prepared according to the general procedure of example 1.

Example 2

(trans) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (4-methyl-cyclohexyl) -urea

The title compound was prepared as off-white crystals (70% yield) with melting point 171-. MS: 420(M + H) M/e⁺)。

Example 3

(trans) -1- (4-hydroxymethyl-cyclohexyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

The title compound was prepared as light brown crystals (42% yield) using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and (trans) - (4-hydroxymethyl-cyclohexyl) -methyl-amine. MS: 436(M + H)⁺) Melting point 190 ℃ (decomposition).

Example 4

(trans) -1- (4-methoxymethyl-cyclohexyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

The title compound was prepared as a white solid (73% yield) m.p. 141-. MS: 450(M + H) M/e⁺)。

Example 5

(rac), (cis) -1- (3-hydroxymethyl-cyclopentyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

The title compound was prepared as a light yellow solid (58% yield) with melting point 115-. MS: 421(M + H) M/e⁺)。

Example 6

1- (endo) - (rac) -bicyclo [2.2.1] hept-2-yl-3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and (inner) - (rac) - (bicyclo [2.2.1]]Hept-2-yl) -methyl-amine the title compound was prepared as a white solid (65% yield), mp 199-. MS: 417(M + H) as M/e⁺)。

Example 7

(exo) - (+) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and (-) - (exo) -methyl- (7-oxa-bicyclo [2.2.1]Hept-2-yl) -amine the title compound was prepared as light yellow crystals (82% yield), mp 202 and 204 ℃. MS: m/e ═ 419(M + H)⁺)。

Example 8

(outer) - (-) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and (+) - (exo) -methyl- (7-oxa-bicyclo [2.2.1]Hept-2-yl) -amine the title compound was prepared as light yellow crystals (82% yield), mp 202-. MS: m/e ═ 419(M + H)⁺)。

Example 9

(rac) - (endo) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and (rac) - (endo) -methyl- (7-oxa-bicyclo [ 2.2.1)]Hept-2-yl) -amine the title compound was prepared as white crystals (47% yield), mp 191-193 ℃. MS: m/e ═ 419(M + H)⁺)。

Example 10

(rac) -1- (5-exo-hydroxy-bicyclo [2.2.1] hept-2-exo-yl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and 5- (exo) -methylamino-bicyclo [2.2.1]Heptane-2- (exo) -alcohol the title compound was prepared as white crystals (10% yield), MS: m/e 433(M + H)⁺) Melting point 189 ℃.

Example 11

(rac) -1- (5-rac-hydroxy-bicyclo [2.2.1] hept-2-in-yl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and 5- (endo) -methylamino-bicyclo [2.2.1]Heptane-2- (exo) -alcohol the title compound was prepared as white crystals (12% yield), MS: m/e 433(M + H)⁺) Melting point 189 ℃.

Example 12

1-adamantan-1-yl-3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea

The title compound was prepared as white crystals (76% yield) with melting point 165-. MS: 458(M + H)⁺)。

Example 13

8-oxa-3-aza-bicyclo [3.2.1] octane-3-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide

Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and 8-oxa-3-aza-bicyclo [3.2.1]Octane the title compound was prepared as white crystals (67% yield), m.p. 229-. MS: 405(M + H) M/e⁺)。

Intermediates：

Example 14

Methyl- (4-trifluoromethyl-cyclohexyl) -amine

The title compound was prepared from 4-trifluoromethyl-cyclohexylamine (DE2630562) by introducing an ethoxycarbonyl group under standard conditions (ethyl chloroformate/diisopropyl-ethylamine) and finally reducing with lithium aluminium hydride in tetrahydrofuran under standard conditions to give the title compound as a pale yellow oil, MS: m/e 168(M + H)⁺). The title compound can be crystallized as the hydrochloride by using an ethanol solution of hydrogen chloride. White crystals, melting point 202-204 ℃.

Example 15

1-methyl-4- (cis) -methylamino-cyclohexanol

The title compound was prepared from (cis) -4-amino-1-methyl-cyclohexanol (WO9607657) in exactly the same way as described for methyl- (4-trifluoromethyl-cyclohexyl) -amine. White crystals, melting point 123-: 144(M + H) M/e⁺)。

Example 15

(-) - (exo) -methyl- (7-oxa-bicyclo [2.2.1] hept-2-yl) -amine hydrochloride

By benzylation under standard conditions (benzyl bromide/diisopropyl-ethylamine), treatment with preparative chiral HPLC (Chrialpak AD with 2% isopropanol in heptane as eluent) and finally deprotection under standard conditions (chloroethylchloroformate/methanol) from (rac) -methyl- (7-oxa-bicyclo [ 2.2.1)]Hept-2-yl) -amine (j.med.chem.1971, 14, 698) the title compound was prepared as a white solid. [ alpha ] to]_D-6.2(c ═ 0.23, dichloromethane).

The enantiomer (+) - (exo) -methyl- (7-oxa-bicyclo [2.2.1] hept-2-yl) -amine hydrochloride was obtained from the early eluting fraction of the resolution.

Claims (14)

1. A compound of the general formula I:

wherein:

R¹is CF₃Lower alkyl, - (CH)₂)_nOH or- (CH)₂)_n-O-lower alkyl-substituted C_5，6-cycloalkyl or is 1-bicyclo [2.2.1]Hept-2-yl, 1- (7-oxa-bicyclo [2.2.1]]Hept-2-yl, 1- (5-exo-hydroxy-bicyclo [2.2.1]]G-2-exo-yl, 1- (5-exo-hydroxy-bicyclo [2.2.1]Hept-2-endo-yl, or is 1-adamantan-1-yl;

R²is lower alkyl; or

R¹And R²Together with the N-atom forming the radical 8-oxa-3-aza-bicyclo [3.2.1]Octane;

n is 0 or 1;

and pharmaceutically acceptable acid addition salts thereof.

2. A compound of formula I in accordance with claim 1, wherein R¹Is CF₃Lower alkyl, - (CH)₂)_nOH or- (CH)₂)_n-O-lower alkyl-substituted C_5，6-a cycloalkyl group.

3. The compound of claim 2, wherein the compound is:

3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (4-trifluoromethyl-cyclohexyl) -urea,

(trans) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (4-methyl-cyclohexyl) -urea,

(trans) -1- (4-hydroxymethyl-cyclohexyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea,

(trans) -1- (4-methoxymethyl-cyclohexyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea or (rac), (cis) -1- (3-hydroxymethyl-cyclopentyl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea.

4. A compound of formula I in accordance with claim 1, wherein R¹Is 1-bicyclo [2.2.1]Hept-2-yl, 1- (7-oxa-bicyclo [2.2.1]]Hept-2-yl, 1- (5-exo-hydroxy-bicyclo [2.2.1]]Hept-2-exo-yl, 1- (5-exo-hydroxy-bicyclo [ 2.2.1)]Hept-2-endo-yl or 1-adamantan-1-yl.

5. The compound of claim 4, wherein the compound is:

1- (endo) - (rac) -bicyclo [2.2.1] hept-2-yl-3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea,

(exo) - (+) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea,

(exo) - (-) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea,

(rac) - (endo) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-1- (7-oxa-bicyclo [2.2.1] hept-2-yl) -urea,

(rac) -1- (5-exo-hydroxy-bicyclo [2.2.1] hept-2-exo-yl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea,

(rac) -1- (5-rac-hydroxy-bicyclo [2.2.1] hept-2-in-yl) -3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea or

1-adamantan-1-yl-3- (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -1-methyl-urea.

6. A compound of formula I in accordance with claim 1, wherein R¹And R²Together with the N-atom forming the radical 8-oxa-3-aza-bicyclo [3.2.1]Octane.

7. A compound of formula I according to claim 6, wherein the compound is 8-oxa-3-aza-bicyclo [3.2.1] octane-3-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl) -amide.

8. A process for the preparation of a compound of formula I as defined in claims 1 to 7, which process comprises:

a) reacting a compound of formula II

With a compound of the formula III,

to obtain the compound of the formula I,

wherein R is¹And R²Has the meaning given in claim 1, or

b) Reacting a compound of formula IV

With a compound of the formula V,

to obtain the compound of the formula I,

wherein R is¹And R²L is a leaving group such as halogen, -O-phenyl or O-lower alkyl, as defined in claim 1, and

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

9. A compound according to any one of claims 1 to 7, whenever prepared by a process as claimed in claim 6 or by an equivalent method.

10. A medicament containing one or more compounds as claimed in any one of claims 1 to 7 and pharmaceutically acceptable excipients.

11. The medicament of claim 10, which is a medicament for treating a disease associated with an adenosine receptor.

12. Use of a compound according to any one of claims 1 to 7 for the treatment of a disease.

13. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament corresponding for the treatment of adenosine a_2AThe use in the preparation of a medicament for treating a receptor-related disease.

14. The invention as hereinbefore described.