7-aminobenzothiazole derivatives as ligands of adenosine receptor

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

 

The present invention relates to compounds of General formula

in which

R1, R2independently from each other represent hydrogen, lower alkyl, C3-6-cycloalkyl, tetrahydropyran-2,3 or 4-yl, piperidine-4-yl, optionally substituted lower alkyl,

-(CH2)n-O-lower alkyl, -(CH2)n-R NR'r", -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-C3-6-cycloalkyl, -(CH2)n-C(O)-NR'r R", -(CH2)nis phenyl, optionally substituted lower alkyl, lower alkoxy or NR'r R", or

-(CH2)n-pyridinyl, optionally substituted lower alkyl, lower alkoxy or NR'r R", or -(CH2)n-morpholinyl, -(CH2)n-tetrahydropyran-2,3 or 4-yl, -(CH2)n-piperidine-1 - or 4-yl, optionally substituted lower alkyl, or-C(O)-C5,6-cycloalkyl, -C(O)-tetrahydropyran-2,3 or 4-yl, --C(O)-morpholinyl, -C(O)-piperidine-1-yl or-C(O)-pyrrolidin-1-yl, or

R1and R2together with the N atom to which they are attached, form a ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl or azetidinone ring, optionally substituted lower alkyl or lower alkoxy;

R3represents lower alkoxy, phenyl, optionally substituted with halogen, -(CH2)n-halogen, or -(CH2/sub> )n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl, optionally substituted lower alkyl, halogen or morpholinium, or is morpholinyl, piperidine-1-yl, disubstituted in the 4-position a lower alkyl and -(CH2)nHE, or represents 2-azabicyclo[2,2,2]octane; n denotes 1 or 2;

R'/R" independently of one another represent hydrogen or lower alkyl, or together with the N atom can form azetidinol, pyrrolidinyloxy or piperidinyl group;

and their pharmaceutically acceptable acid additive salts.

It has been unexpectedly found that compounds of General formula I are ligands of adenosine receptor. Specifically, the compounds of the present invention have a high affinity to the receptor A2Aand high selectivity to the receptor A1and A3.

Adenosine modulates many physiological functions by interacting with specific receptors on the cell surface. The activity of adenosine receptors as a drug was first opened in 1982. Adenosine is related structurally and metabolically with bioactive nucleotides of adenosintriphosphate (ATP), adenosintriphosphate (ADP), adenosinemonophosphate (AMP) and cyclic adenosinemonophosphate (camp); biochemical methylated, agento the S-adenosyl-L-mational (SAM) and structurally with the coenzyme NAD, FAD and coenzyme A; and RNA. Adenosine and these related compounds together is important for regulating many aspects of cellular metabolism and modulation of various actions of the Central nervous system.

Receptors for adenosine are classified as receptor-A1, A2AAnd2Band a3referring to the family of receptors associated with G-protein. Activation of adenosine receptors adenosine triggers the transmission of the signal. These mechanisms are dependent on G-protein associated with the receptor. Each of the subtypes of adenosine receptors usually characterized by effector adenylate cyclase system, which uses camp as a secondary messenger. Receptors A1and A3associated with Gi; proteins that inhibit adenylate cyclase, which leads to a decrease in cellular camp levels, whereas receptors A2Aand a2Bcontact Gsproteins and activate adenylate cyclase, leading to an increase in cellular camp levels. It is known that the system of receptor-A1includes activation of phospholipase C and modulation of ion channels potassium and calcium. Subtype And3in addition to its binding to adenylate cyclase, also stimulates phospholipase C and, consequently, activates ion channels calcium.

Receptor-a1(326-328 amino acids) was cloned from various species (JI is th, human, rat, dog, chicken, bovine, Guinea pigs) with 90-95% sequence identity among mammals. Receptor-a2A(409-412 amino acids) was cloned from dog, rat, human, Guinea-pig and mouse. Receptor And2B(332 amino acids) was cloned from human and mouse with 45% homologically receptors And2Bthe man with the receptors of A1and A2Aman. Receptor And3(317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.

It is assumed that the receptor subtypes A1and A2Aplay additional roles in the regulation of adenosine supply of energy. Adenosine, which is a metabolic product of ATP diffuses from the cells and acts locally, activating adenosine receptors to reduce the need of oxygen (A1or increase oxygen delivery (A2A), and thus restoring the balance of energy supply: demand within the tissue. The actions of both subtypes should increase the amount of available oxygen in the tissues and to protect cells from damage caused by short-term volatility of oxygen. One of the important functions of endogenous adenosine is the prevention of damage at the time of injury such as hypoxia, ischemia, hypotension, and seizures.

In addition, it is known that St is the statements agonist adenosine receptor with fat cells, expressing the receptor of A3rats leads to increased concentrations inositoltrifosfata and intracellular calcium, which causes antigen-induced secretion of inflammatory mediators. Therefore, the receptor And3plays a role in mediolani asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that is able to modulate many aspects of the physiological functions of the brain. Endogenous adenosine, the Central link between energy metabolism and the activity of neurons, changes in behavior and (Pato)physiological conditions. In conditions of increased demand and reduced availability of energy (such as hypoxia, hypoglycemia and/or excessive activity of neurons), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine receptors represents a promising target for therapeutic use in numerous neurological and psychiatric diseases, such as epilepsy, sleep disorders and movement (Parkinson's disease or Huntington's, Alzheimer's, depression, schizophrenia or drug addiction. Increased release of neurotransmitters leads to injuries, such as hypoxia, ischemia and seizures. These neurotransmitters are ultimately responsible for the destruction and is ibel nerve cells, what causes brain damage or death of the individual. Agonists of the adenosine A1that mimic Central inhibiting action of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsive agent that inhibits the release of glutamate from stimulating neurons and inhibitory neural combustion. Agonists of adenosine can therefore be used as antiepileptic agents. Antagonists of adenosine to stimulate the Central nervous system and, as it turns out, are effective as enhancers of recognition. Selective antagonists And2ahave therapeutic activity in the treatment of various forms of dementia, such as Alzheimer's disease and neurodegenerative disorders, such as seizure. Antagonists of adenosine receptor And2amodulate the activity of veins GABA neurons and regulate smooth and well-coordinated movement, thus providing a possible treatment of symptoms of Parkinson's disease. Adenosine is also involved in numerous physiological processes, including calming effect, hypnosis, schizophrenia, anxiety, pain, respiration, depression and substance abuse (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Therefore, medicines, height is paudie as adenosine receptors, possess therapeutic activity as sedatives, muscle relaxants, antipsychotics, tranquilizers, analgesics, respiratory stimulants, antidepressants, and means for the treatment of drug abuse. They can also be used to treat ADHD (hyperactivity disorder attention deficit).

The important role of adenosine in the cardiovascular system is to use it as cardiotoxins agent. The levels of endogenous adenosine are increased in response to ischemia and hypoxia and protect cardiac tissue injury and after (pre-condition). Acting on A receptor1the agonists of the adenosine A1can protect from damage caused by myocardial ischemia and reperfusion. The modulating influence of receptors A2aon adrenergic function may be important for various diseases, such as coronary arterial disease and heart failure. Antagonists And2acan be used therapeutically in situations that require increased antiadrenergicheskoe response, such as acute myocardial ischemia. Selective receptor antagonists And2amay also increase the efficacy of adenosine in the elimination of the supraventricular arrhythmias.

Adenosine modulates many is specto kidney function, including the release of renin, the rate of glomerular filtration and blood flow through the kidneys. Compounds that are antagonists of the renal functions of adenosine, active as a renal protective agent. In addition, antagonists of the adenosine A3and/or And2Bcan be useful for the treatment of asthma and other allergic responses or for the treatment of diabetes and obesity.

Numerous documents describe the overall level of technology relative to the 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 object of the present invention are the compounds of formula IA and IB, the use of compounds of formula IA and IB and their pharmaceutically acceptable salts for the manufacture of medicines for the treatment of diseases associated with adenosine receptor And2receiving them, the medicinal product on the basis of the connection in accordance with the invention, and receipt of them, and also the use of compounds of formula IA and IB for the control or prevention of illnesses based on the modulation system of adenosine, so is x as Alzheimer's disease, Parkinson's disease, Huntington's disease, protecting nerve cells, schizophrenia, anxiety, pain, lack of breath, depression, addiction, such as the dependence on amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or for the treatment of asthma, allergic responses, hypoxia, ischemia, epileptic seizure and substance abuse. In addition, the compounds of the present invention can be useful as sedatives, muscle relaxants, anti-psychotic substances, anti-epileptics, anticonvulsants and cardiotoxin agents for diseases such as coronary arterial disease and heart failure. The most preferred indications in accordance with the present invention includes statements that are based on antagonistic activity of receptor-A2Aand which include disorders of the Central nervous system, for example, the treatment or prevention of Alzheimer's disease, certain depressive disorders, substance abuse, protect nerve cells and Parkinson's disease, and ADHD.

Used herein, the term "lower alkyl" denotes an alkyl group with a saturated linear or branched chain containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, etc. Preferred lower skillname groups are groups with 1-4 carbon atoms.

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

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

The term "pharmaceutically acceptable acid additive salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinea acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid, etc.

Preferred compounds of the present application are compounds of formula I in which one of R1/R2represents lower alkyl and the other represents -(CH2)n-O-lower alkyl, and R3represents phenyl, optionally substituted with halogen or -(CH2)n-halogen, for example, the following connections:

N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide,

4-fluoro-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide or

4-chloromethyl-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide.

Other preferred compounds are compounds in which one of R1/R2not only is em a lower alkyl, and the other represents -(CH2)n-O-lower alkyl, or R1and R2together with the N atom form the group of 2-oxa-5-azabicyclo[2,2,1]hept-5-yl and R3represents pyridinyl, substituted morpholine, for example, the following connections:

N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide or

N-[4-methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazole-2-yl]-2-methylethanolamine.

Another preferred group of compounds is a group in which one of R1/R2represents-C(O)-lower alkyl and the other represents a lower alkyl, -(CH2)n-O-lower alkyl or benzyl, optionally substituted lower alkyl, and R3represents a phenyl or pyridinyl ring which is optionally substituted with halogen or lower alkyl, for example, the following connections:

N-{7-[acetyl-(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide,

N-[7-(acetylecholine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(acetylamino)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(acetylpenicillamine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(acetylpenicillamine)-4-methoxybenzothiazole-2-yl]-2-bromosalicylic or

N-{7-[acetyl-(2-methoxyethyl)amino]-4-methoxybenzothiazole-2-yl}-4-perbenzoic.

Other preferred connection what changes are connection, in which one of R1/R2represents lower alkyl and the other represents a lower alkyl or benzyl, optionally substituted lower alkoxy, and R3represents a phenyl or pyridinyl ring which is optionally substituted by morpholino, halogen or lower alkyl, for example, the following connections:

N-(7-dimethylamino-4-methoxybenzothiazole-2-yl)-4-perbenzoic,

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-methylethanolamine,

4-fluoro-N-{4-methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}benzamide,

N-{4-methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}-2-methylethanolamine,

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-bromosalicylic or

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-morpholine-4-isonicotinamide.

Other preferred compounds are compounds in which one of R1/R2represents lower alkyl and the other represents-CH2-C(O)-N(CH3)2or tetrahydropyran, and R3represents a phenyl or pyridinyl ring which is optionally substituted by morpholino, halogen or lower alkyl, for example, the following connections:

N-[7-(dimethylcarbamodithioato)-4-methoxybenzothiazole-2-yl]-4-CFT is benzamid,

N-[7-(dimethylcarbamoyl)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

4-fluoro-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}benzamide or

N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide.

The compounds of formula I in accordance with the present invention and their pharmaceutically acceptable salts can be obtained by methods known from the prior art, for example, as described below, which includes

a) reaction of compounds of formula

with the compound of the formula

or

obtaining the compounds of formula

where R1, R2and R3are as defined above, and

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

The compounds of formula I can be obtained in accordance with a variant of the method a) and in accordance with the following schemes 1-4.

Obtaining compounds of formula I

One way of preparing compounds of formula I consists in obtaining from compounds of formula (7), the receipt of which is shown below in the reaction scheme 1.

where R1, R2and R3are the same and, as specified above.

HATU is hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea.

Obtaining compounds of formula (3)

The source connection of pomarina formula (1) can be obtained commercially, for example, from Aldrich, or can be obtained by methods known from the prior art. Similarly, the amino compounds of the formula (2) can be obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art.

Connection pomarina formula (1) reacts with an excess of the amino compounds of the formula (2), or the corresponding chlorhydrate salt or bromhidrosis amine salt, in an organic solvent, preferably dioxane, containing a palladium catalyst, preferably palladium(II)acetate and a catalytic amount of phosphine ligand, preferably 2-(dicyclohexylphosphino)biphenyl, according to the methodology Buchwald and others (J. Am. Chem. Soc. 1998, 120, 9722). The reaction is carried out in the presence of a base such as cesium carbonate, sodium phosphate, triethylamine, or combinations thereof. The reaction is carried out at elevated temperature, preferably about 80-100°With, for about 2-24 hours, preferably about 16 hours. The product of formula (3) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (4)

The compounds of formula (4) can be obtained by hydrogenation of compounds of the formula (3) in the presence of a hydrogenation catalyst, preferably 10% palladium on coal. These reactions can be conducted in a variety of organic solvents, such as methanol, ethanol, dichloromethane or tetrahydrofuran, preferably in a mixture of methanol and dichloromethane, at room temperature and a pressure of one atmosphere or higher, preferably at one atmosphere, for 2-24 hours, preferably about 16 hours. The product of formula (4) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (5)

One way of preparing compounds of the formula (5) includes processing the compounds of formula (4) slight excess benzoylisothiocyanate in acetone at a temperature between room temperature and boiling temperature, preferably at room temperature for 30-60 minutes, preferably 30 minutes. The product of formula (5) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (6)

The compound of the formula (5) is treated with a stoichiometric amount of an alcoholate of an alkali metal in an appropriate alcoholic solvent, preferably a sodium methylate in methanol. Reacts the Yu was performed at room temperature for about 0.5-2 hours, preferably about 1 hour. The product of formula (6) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (7)

One way of preparing compounds of the formula (7) is in the handling of the compounds of formula (6) stoichiometric equivalent of bromine in a halogenated organic solvent, preferably chloroform. The reaction is carried out at elevated temperature, preferably at the boiling temperature of the solvent under reflux, for about 12-18 hours, preferably about 16 hours. The product of formula (7) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I

One way of preparing compounds of the formula I is in the treatment of compounds of formula (7) slight excess of the corresponding acylchlorides formula (8), which may be commercially available or may be obtained by methods known from the prior art. The reaction is carried out in an aprotic organic solvent, preferably in a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably N-ethyldiethanolamine or triethylamine, at room temperature for 2-24 hours, preferably 24 hours. The product of formula I distinguish normal IU is the ml and preferably purified by chromatography or recrystallization.

Alternative obtaining the compounds of formula I

An alternative method of preparing compounds of formula I includes processing the corresponding carboxylic acid of formula (9) stoichiometric equivalent binding peptide reagent, preferably of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiethanolamine at room temperature for 30-90 minutes, preferably 1 hour. This mixture then is treated with a compound of the formula (7) in a mixture of solvents, preferably in a mixture of tetrahydrofuran, dioxane and N,N-dimethylformamide at room temperature for 16-24 hours, preferably for 16 hours. The product of formula I produce with conventional methods, and preferably purified by chromatography or recrystallization.

Alternative obtaining compounds of formula (3)

An alternative method of preparing compounds of the formula (3) is a method of obtaining from the intermediate compounds of formula (14), the receipt of which is shown below in reaction scheme 2.

where R1and R2are as defined above, and X represents Br or I.

Obtaining compounds of formula (12)

Source arylamine formula (10) mouthbut obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art. Similarly, the source alkylidene or allylbromide the compounds of formula (11) can be obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art.

Connection arylamine formula (10) is reacted with the stoichiometric equivalent alkylidene or alkylbromides the compounds of formula (11) in an organic solvent, preferably N,N-dimethylformamide or acetonitrile containing a base, preferably potassium carbonate or N,N-diisopropylethylamine. The reaction is carried out at a temperature between room temperature and the boiling temperature of the solvent, for about 1-48 hours, preferably about 16 hours. The product of formula (12) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (14)

Source alkylidene or allylbromide the compounds of formula (13) can be obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art.

Connection arylamine formula (12) is reacted with the stoichiometric equivalent alkylidene or alkylbromides the compounds of formula (13) in an organic solvent, preferably N,N-dimethylformamide or acetonitrile is e, containing a base, preferably potassium carbonate or N,N-diisopropylethylamine. The reaction is carried out at a temperature between room temperature and the boiling temperature of the solvent, for about 1-48 hours, preferably about 16 hours. The product of formula (14) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (3)

The compound of formula (14) reacts with nitrous agent such as 65% nitric acid or potassium nitrate in 98% sulfuric acid, in an acid solvent such as acetic acid or 98% sulfuric acid. The reaction is carried out at a temperature between 20°s and 80°With, for about 2-16 hours. The product of formula (3) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Alternative obtaining compounds of formula (7)

An alternative method of preparing compounds of the formula (7) is receiving from the intermediate compounds of formula (20), the receipt of which is shown below in reaction scheme 3.

where R1and R2are as defined above.

Obtaining compounds of formula (16)

The original 2-aminobenzothiazole the compounds of formula (15) can be obtained commercially, for example, from Aldrich, or can be obtained by methods which, known from the prior art.

2-Aminobenzothiazole compound of the formula (15) is reacted with the stoichiometric equivalent of methylchloroform in an organic solvent, preferably dichloromethane, containing a base, preferably pyridine. The reaction is carried out at a temperature between 0°C and room temperature, preferably at 0°With, for about 1-2 hours, preferably about 1 hour. The product of formula (16) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (17)

The compound of formula (16) reacts with nitrous agent, preferably 65% nitric acid, in an acid solvent, preferably acetic acid. The reaction is carried out at elevated temperature, preferably about 70°With, for about 2-16 hours, preferably 4 hours. The product of formula (17) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (18)

The compounds of formula (18) can be obtained by hydrogenation of compounds of formula (17) in the presence of a hydrogenation catalyst, preferably oxides of platinum(IV). These reactions can be conducted in various organic solvents, such as methanol, ethanol, dichloromethane or tetrahydrofuran, site is preferably in a mixture of methanol and dichloromethane, at room temperature and at a pressure of one atmosphere or higher, preferably at one atmosphere, for 2-24 hours, preferably about 16 hours. The product of formula (18) was isolated by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (19)

One way of preparing compounds of the formula (19) is in the handling of the compounds of formula (18) by an excess of sodium hydroxide or potassium hydroxide in an aqueous solvent, preferably water-ethylene glycol. The reaction is carried out at elevated temperature, preferably about 100°C, for about 1 to 16 hours, preferably about 6 hours. The product of formula (19) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (20)

Source alkylated formula (11) can be obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art.

The compound of formula (19) is reacted with the stoichiometric equivalent alkylating the compounds of formula (11) in an organic solvent, preferably N,N-dimethylformamide, containing a base, preferably potassium carbonate. The reaction is carried out at a temperature between room temperature and the boiling temperature of the solvent for the Colo 1-48 hours preferably about 16 hours. The product of formula (20) was isolated by conventional methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (7)

Source alkylated formula (13) can be obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art.

The compound of formula (20) is reacted with the stoichiometric equivalent alkylating the compounds of formula (13) in an organic solvent, preferably N,N-dimethylformamide, containing a base, preferably potassium carbonate. The reaction is carried out at a temperature between room temperature and the boiling temperature of the solvent for about 1-48 hours, preferably about 16 hours. The product of formula (7) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Alternative obtaining compounds of formula (7), where R2represents-C(O)-lower alkyl, -C(O)-C5,6-cycloalkyl or-C(O)-tetrahydropyran-2,3 or 4-yl.

An alternative method of preparing compounds of the formula (7) from intermediates of formula (20) in the case when R2contains acyl group, i.e. where R2represents-C(O)-lower alkyl, -C(O)- C5,6-cycloalkyl or-C(O)-tetrahydropyran-2,3 or 4-yl, shown in the following scheme p is the action 4.

where R1is the same as defined above, and R2represents-C(O)-lower alkyl, -C(O)-C5,6-cycloalkyl, -C(O)-tetrahydropyran-2,3 or 4-yl.

Source acylchlorides formula (21) can be obtained commercially, for example, from Fluka, or can be obtained by methods known from the prior art.

The compound of formula (20) is reacted with the stoichiometric equivalent acylchlorides the compounds of formula (21) in an organic solvent, preferably in a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably pyridine. The reaction is carried out at a temperature between 0°C and room temperature, preferably at 0°C, for about 1 to 16 hours, preferably about 3 hours. The product of formula (7) is recovered by conventional methods, and preferably purified by chromatography or recrystallization.

Isolation and purification of compounds

Isolation and purification of these compounds and intermediate compounds can be produced, if necessary, any suitable procedure for the separation or purification, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick-layer chromatography, preparative liquid chromatography low or high pressure or comb the nation these procedures. Specific examples of suitable separation procedures and selection you can find below in the section Receiving and Examples. But, of course, can also be used by other equivalent procedures for separation or selection.

Salts of compounds of Formula I

The compounds of formula I may be the reason, for example, when the residue R contains a basic group, such as aliphatic or aromatic amino group. In such cases, the compounds of formula I can be converted to the corresponding acid additive salt.

The conversion is performed by processing at least the stoichiometric amount of the appropriate acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, mandlikova acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc. Usually free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol is whether the methanol and the like, and add the acid in this solvent. The temperature of the support between 0°s and 50°C. the Obtained salt is precipitated by themselves, or they can migrate into the solution of the less polar solvent.

Acid additive salts of basic compounds of formula I can be converted into the corresponding free base by treatment with at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, etc.

The compounds of formula I and their pharmaceutically acceptable additive salts have valuable pharmacological properties. Specifically, it was found that the compounds according to the present invention are ligands of adenosine receptor and have high affinity for the adenosine A2A receptor.

Compounds were tested in accordance with test below.

Adenosine receptor A2A person

Adenosine receptor A2A person recombinante expressed in cells of the Chinese hamster ovary (Cho)using the expression system of the virus semliki forest. Cells were collected, washed twice by centrifugation, homogenized and again washed by centrifugation. Received the washed membrane residue suspended in Tris buffer (50 mm)containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 the M MgCl 2(pH of 7.4) (buffer A). Test binding with [3H]-SCH-58261 (Dionisotti and others, 1997, Br J Pharmacol 121, 353; 1 nm) was performed in 96-cell dies in the presence of 2.5 μg of membrane protein, 0.5 mg of beads Ysi-poly-1-lysine SPA and 0.1 U adelaideans in the final volume of buffer And 200 µl. Nonspecific binding was determined with the help of the representatives of xanthinuria (KHAS; 2 μm). Compounds were tested at 10 concentrations ranging from 10 μm to 0.3 nm. All tests were performed twice and repeated at least twice. The test plates were incubated for 1 hour at room temperature before centrifugation and then bound peroxidase was determined by the ligand, using a scintillation counter Packard Topcount. The values of the IC50was calculated using the nonlinear fitting curve and the values of Ki was calculated using the equation of Cheng-Prussoff.

The preferred compounds show pKi>7,2.

# ExamplehA2 (pKi)# ExamplehA2 (pKi)
17,28207,21
27,42218,00
3the 7.43247,97
67,28257,28
107,9426
127,13287,31
147,41307,58
157,2132of 7.48
167,8135of 7.96
177,22377,25
197,88387,33

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicines, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. The introduction, however, can also be carried out rectally, for example in the form of suppositories, parenterally, e.g. in the form of injection solutions.

The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical compositions. For example, as carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or their salts, etc. Approach is asimi carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, depending on the nature of the active substance, however, typically do not require any carriers for soft gelatin capsules. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, glycerine, vegetable oil, etc. Suitable carriers for suppositories are, for example, natural or securing oils, waxes, fats, semi-liquid or liquid polyols and the like

Pharmaceutical compositions can also contain preservatives, soljubilizatory, stabilizers, moisturizing agents, emulsification, sweeteners, colorants, odorants, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically useful substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, and the method of production thereof, which includes the introduction of one or more compounds of the formula I and/or pharmaceutically acceptable acid additive salts and, optionally, one or more other therapeutically useful substances in herbal form of introduction together with one or more of therapeutic the ski inert media.

In accordance with the invention, the compounds of formula I and their pharmaceutically acceptable salts, are useful for the control or prevention of illnesses based on antagonistic activity of adenosine receptor, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, lack of breath, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be useful as sedatives, muscle relaxants, antipsychotics, anti-epileptics, anticonvulsants and cardiotoxin agents and to obtain the drugs.

The most preferred indications in accordance with the present invention are indications, 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, of course, must satisfy 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 the compounds of General formula I or the corresponding number f is rmaceuticals acceptable salt. The daily dosage may be administered as a single dose or divided doses, and, in addition, the upper limit if necessary may also be raised.

The composition of the tablets (wet granulation)
RoomComponentsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Anhydrous lactose DTG12510530150
3.Sta-Rx 150066630
4.Microcrystalline cellulose303030150
5.Magnesium stearate1111
The total number of167167167831

The way to obtain

1. Mixed components 1, 2, 3 and 4 and was granulated with purified water.

2. Dried granules at 50°C.

3. Punching granules through a suitable and is melchishua equipment.

4. Added component 5 and was stirred for three minutes.

was compressed on a suitable press.

The capsules composition
RoomComponentsmg/capsule
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Water lactose159123148---
3.Corn starch25354070
4.Talc10151025

5.Magnesium stearate1225
The total number of200200300600

The way to obtain

1. Mixed components 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Added components 4 and 5 and was stirred for 3 minutes.

3. Filled into a suitable capsule.

Example 1

N-{4-Methoxy-7-[(2-what ethoxyethyl)methylamino]benzothiazol-2-yl}benzamide

a) (2-Methoxyethyl)-(4-methoxyphenyl)methylamine

To a stirred solution of 1.00 g (7,29 mmol) N-methyl-n-anisidine in 15 ml of acetonitrile at 0°was added dropwise to 1.36 ml (8,02 mmol) of N-ethyldiethanolamine and 1.01 g (7,29 mmol) 2-bromatologia ether. The mixture was heated at 80°C for 2 days and then evaporated in vacuum. Express chromatography (1/9 ethyl acetate/hexane) yielded 1.20 g (84%) (2-methoxyethyl)-(4-methoxyphenyl)methylamine in the form of an orange oil. ES-MS m/e (%): 196 (M+N+, 100).

b) (2-Methoxyethyl)-(4-methoxy-3-nitrophenyl)methylamine

To a stirred solution of 600 mg (of 3.07 mmol) (2-methoxyethyl)-(4-methoxyphenyl)methylamine in 1.3 ml of concentrated sulfuric acid at room temperature was added 222 mg (3,69 mmol) of urea. After stirring for 1 h at room temperature was added dropwise a solution of 342 mg (3,38 mmol) of potassium nitrate in 0.6 ml of concentrated sulfuric acid and continued to stir for a further 16 hours the mixture is Then poured into water and was extracted five times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/9 ethyl acetate/hexane) resulted in the receipt of 260 mg (35%) (2-methoxyethyl)-(4-methoxy-3-nitrophenyl)methylamine in the form of an orange oil. ES-MS m/e (%): 241 (M+N+, 100).

C) 4-Methoxy-N1-(2-methoxyethyl)-N1-m is TELESOL-1,3-diamine

To a stirred solution of 2.50 g (10.4 mmol) (2-methoxyethyl)-(4-methoxy-3-nitrophenyl)methylamine in 100 ml of methanol was added at the tip of the spatula 10% palladium on coal and the mixture is then stirred for 16 hours at room temperature in a hydrogen atmosphere. Then the mixture was filtered and the filtrate was evaporated in vacuum, obtaining 1,90 g (87%) 4-methoxy-N1-(2-methoxyethyl)-N1-methylbenzo-1,3-diamine in the form of almost white crystalline solid. ES-MS m/e (%): 211 (M+N+, 100).

g) 1-Benzoyl-3-{2-methoxy-5-[(2-methoxyethyl)methylamino]phenyl}thiourea

To a stirred solution of 1.89 g (8,99 mmol) 4-methoxy-N1-(2-methoxyethyl)-N1-methylbenzo-1,3-diamine in 60 ml of acetone was added dropwise a solution of 1.38 ml of 10.3 mmol) benzoylisothiocyanate in 30 ml of acetone and continued stirring at room temperature for 30 minutes. Then the mixture was evaporated in vacuum. Rubbing in ether resulted in the receipt of 2.05 g (61%) of 1-benzoyl-3-{2-methoxy-5-[(2-methoxyethyl)methylamino]phenyl}thiourea as a yellow solid. ES-MS m/e (%): 374 (M+N+, 100).

e) N-{4-Methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide

To a stirred solution of 430 mg (1.15 mmol) of 1-benzoyl-3-{2-methoxy-5-[(2-methoxyethyl)methylamino]phenyl}thiourea in 8 ml of chloroform was added dropwise 0,059 ml (1.15 mmol) of bromine and the reaction mixture was heated at the boiling reverse chilling is the nickname for 18 hours. Then the mixture was cooled to room temperature, slowly poured into water and was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/4 ethyl acetate/hexane) yielded 120 mg (28%) of N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide as a yellow solid. ES-MS m/e (%): 394 (M+Na+, 14), 372 (M+N+, 100).

Example 2

4-Fluoro-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide

a) {2-Methoxy-5-[(2-methoxyethyl)methylamino]phenyl}thiourea

To a stirred suspension of 2.00 g (are 5.36 mmol) of 1-benzoyl-3-{2-methoxy-5-[(2-methoxyethyl)methylamino]phenyl}thiourea in 13 ml of methanol was added dropwise 0.15 ml (0.80 mmol) of 5.4 M solution of sodium methylate and continued stirring for 1 h at room temperature. Then the mixture was poured into water and was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (ethyl acetate) resulted in the receipt of 1.40 g (97%) of {2-methoxy-5-[(2-methoxyethyl)methylamino]phenyl}thiourea in the form of an amber oil. ES-MS m/e (%): 270 (M+H+, 100).

b) 4-Methoxy-N7-(2-methoxyethyl)-N7-methylbenzothiazol-2,7-diamine

To a stirred solution of 1.40 g (5,20 mmol) {2-methoxy-5-[(2-methoxyethyl)methylamino]phenyl}t is urea in 35 ml of chloroform was added dropwise with 0.27 ml (5,27 mmol) of bromine and the reaction mixture was heated at the boil under reflux for 18 hours. Then the mixture was cooled to room temperature, slowly poured into sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (ethyl acetate) resulted in the receipt of 984 mg (71%) 4-methoxy-N7-(2-methoxyethyl)-N7-methylbenzothiazol-2,7-diamine as an orange crystalline solid. ES-MS m/e (%): 268 (M+H+, 100).

b) 4-Fluoro-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide

To a stirred solution of 79 mg (0,56 mmol) 4-fermenting acid in 10 ml of THF was added 235 mg (of 0.62 mmol) HATU and 0.11 ml (of 0.62 mmol) of N-ethyldiethanolamine and continued stirring at room temperature for 1 hour. Then was added a solution of 150 mg (0,56 mmol) 4-methoxy-N7-methoxyethyl)-N7-methylbenzothiazol-2,7-diamine in 5 ml of dioxane and 1 ml of DMF and continued stirring at room temperature for 16 hours. The reaction mixture was then poured into 100 ml of 1 M hydrochloric acid and was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/4-1/1 ethyl acetate/hexane) followed by rubbing in hexane led to obtain 55 mg (25%) 4-fluoro-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide in the form of almost white what about the crystalline solid. ES-MS m/e (%): 390 (M+N+, 100).

Example 3

4-Chloromethyl-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide

To a stirred solution of 300 mg (1.12 mmol) of 4-methoxy-N7-(2-methoxyethyl)-N7-methylbenzothiazol-2,7-diamine and 1.12 ml (6,56 mmol) of N-ethyldiethanolamine in 10 ml of THF at room temperature was added dropwise a solution of 257 mg (1,36 mmol) of 4-(chloromethyl)benzoyl chloride in 3 ml of dichloromethane and continued stirring at room temperature for 16 hours. The reaction mixture is then evaporated in vacuum. Express chromatography (1/1 ethyl acetate/hexane) followed by rubbing in ether and hexane resulted in the receipt of 200 mg (42%) of 4-chloromethyl-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide as a pale yellow crystalline solid. ES-MS m/e (%): 422 (M {37Cl}+N+, 32), 420 (M {35Cl}+N+, 100).

Analogously to Example 2 were obtained:

Example 4

N-{4-Methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}-2-methylethanolamine

Of the hydrochloride of 2-methylethanolamine acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-N7-(2-methoxyethyl)-N7-methylbenzothiazol-2,7-diamine in dioxane and DMF. ES-MS m/e (%): 387 (M+N+, 100).

Example 5

2-Bromo-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}isonicotinamide

2 bromoisonicotinic acid, HATU and N-dietilico is Propylamine in THF, then the processing of 4-methoxy-N7-(2-methoxyethyl)-N7-methylbenzothiazol-2,7-diamine in dioxane and DMF. ES-MS m/e (%): 453 (M {81Br}+N+, 100), 451 (M {79Br}+N+, 71).

Example 6

N-{4-Methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide

Stir a suspension of 200 mg (0.44 mmol) of 2-bromo-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}isonicotinamide, of 0.38 ml (4,43 mmol) of the research and 289 mg (0.89 mmol) of cesium carbonate in 5 ml of N-methylpyrrolidone in a thick-walled glass tube under pressure, equipped with a Teflon lid was heated at 140°C for 24 hours. The reaction mixture was then cooled to room temperature and poured into water. The mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (ethyl acetate) followed by rubbing in the air has resulted in 100 mg (49%) of N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide in the form of a slightly yellow crystalline solid. ES-MS m/e (%): 458 (M+N+, 100).

Example 7

N-[4-Methoxy-7-{(1S, 4S-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}-benzothiazol-2-yl]-2-methylethanolamine

a) (1S,4S)-5-(4-Methoxy-3-nitrophenyl)-2-oxa-5-azabicyclo[2,2,1]heptane

To mix the solution 7,34 g (31,0 mmol) 4-bromo-2-nitroanisole 125 ml of dioxane was added a 5.25 g (37,2 mmol) of hydrochloride (1S,4S)-(+)-2-Aza-5-oxabicyclo[2,2,1]heptane, 1,109 g (3.10 mmol) of 2-(bicyclogermacrene)biphenyl, 14.2 g (a 43.4 mmol) of cesium carbonate, 696 mg (3.10 mmol) of palladium(II) acetate and the 5.65 ml (of 40.3 mmol) of triethylamine. The mixture was heated at the boil under reflux for 24 hours and then poured into water and was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/99 methanol/dichloromethane) resulted in the receipt of 5.10 g (66%) of (1S,4S)-5-(4-methoxy-3-nitrophenyl)-2-oxa-5-azabicyclo[2,2,1]heptane in the form of an orange oil. ES-MS m/e (%): 251 (M+N+, 100).

b) 2-Methoxy-5-{(1S,4S-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl}phenylamine

To mix the solution 5,01 g (20.0 mmol) of (1S,4S)-5-(4-methoxy-3-nitrophenyl)-2-oxa-5-azabicyclo[2,2,1]heptane in 375 ml of methanol and 62.5 ml of dichloromethane was added 500 mg of 10% palladium on coal and the mixture is then stirred for 3.5 hours at room temperature in a hydrogen atmosphere. Then the mixture was filtered and the filtrate was evaporated in vacuum, obtaining 4,30 g (98%) 2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}-phenylamine as a brown crystalline solid. ES-MS m/e (%): 221 (M+N+, 100).

C) 1-Benzoyl-3-[2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)} phenyl]thiourea

To mix the solution 4,20 g (19,1 mmol) 2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}phenylamine in 200 ml Aceto is and was added dropwise 2,88 ml (21,0 mmol) benzoylisothiocyanate and continued the stirring for 1 hour at room temperature. Then the mixture was evaporated in vacuum, obtaining 7.30 g (100%) of 1-benzoyl-3-[2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}phenyl]thiourea as a yellow solid. ES-MS m/e (%): 406 (M+Na+, 13), 384 (M+H+, 100).

g) [2-Methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}phenyl]thiourea

To a stirred suspension of 7.25 g (of 18.9 mmol) of 1-benzoyl-3-[2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}phenyl]thiourea in 350 ml of methanol was added dropwise 7,02 ml (37.8 mmol) of 5.4 M solution of sodium methylate and continued the stirring for 1 hour at room temperature. The obtained crystals were collected by filtration, receiving of 3.42 g (65%) [2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}phenyl]thiourea in the form of a beige solid. ES-MS m/e (%): 302 (M+Na+, 20), 281 (M+N+, 100).

d) 4-Methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazol-2-ylamine

To a stirred solution of 279 mg (1.00 mmol) [2-methoxy-5-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}phenyl]thiourea in 8 ml of chloroform at room temperature was added dropwise 0,051 ml (1.00 mmol) of bromine and the mixture was heated at the boil under reflux for 24 hours. Then the mixture was evaporated in vacuum and the residue suspended in water. Solution was added sodium bicarbonate to pH 10, and the crystals were collected by filtration. Express chromatography (5/95 methanol/dichloromethane) resulted floor is the increase of 91.5 mg (33%) 4-methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazole-2-ylamine in the form of almost white crystalline solid. ES-MS m/e (%): 278 (M+N+, 100).

e) N-[4-Methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazole-2-yl]-2-methylethanolamine

To a stirred solution of 111 mg (0.40 mmol) of 4-methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazole-2-ylamine and 0.26 ml (1.50 mmol) of N-ethyldiethanolamine in 20 ml of THF at room temperature was added dropwise a solution of 127 mg (0.66 mmol) of the hydrochloride of 2-methylisothiourea in 20 ml of dichloromethane and continued stirring at room temperature for 24 hours. The reaction mixture is then evaporated in vacuum. Express chromatography (3/97 methanol/ethyl acetate) followed by rubbing in ether resulted in the receipt of 142 mg (90%) N-[4-methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazole-2-yl]-2-methylethanolamine in the form of a yellow crystalline solid. ES-MS m/e (%): 419 (M+Na+, 17), 397 (M+H+, 100).

Example 8

Methyl ester {4-methoxy-7-[(pyridine-2-ylmethyl)amino]benzothiazol-2-yl}carboxylic acid

a) Methyl ester of (4-methoxybenzothiazole-2-yl)carboxylic acids

To a stirred solution of 23.6 g (131 mmol) of 2-amino-4-methoxybenzothiazole and 12.6 ml (157 mmol) of pyridine in 230 ml of dichloromethane at 0°With dropwise added to 10.6 ml (137 mmol) of methylchloroform and continued the stirring for 1 hour. Then the mixture was poured into 1 M hydrochloric acid and the organic phase was separated, washed the Li salt solution, dried over sodium sulfate and evaporated in vacuum, obtaining 31.0 g (99%) of the methyl ester (4-methoxybenzothiazole-2-yl)carboxylic acid as a white solid. ES-MS m/e (%): 239 (M+N+, 100).

b) Methyl ester of (4-methoxy-7-nitrobenzothiazole-2-yl)carboxylic acids

To a stirred solution of 13.6 g (to 57.1 mmol) of the methyl ester (4-methoxybenzothiazole-2-yl)carboxylic acid in 300 ml of acetic acid at room temperature was added 200 ml of 65% nitric acid and the mixture was heated at 70°C for 4 hours. Then the mixture was poured into stirred ice water and the resulting aqueous solution was filtered. The filter residue was dissolved in THF and was added 5 N sodium hydroxide solution to pH 8. Then this mixture was stirred for 1 hour, was filtered and the residue from the filter was dried in vacuum, obtaining to 7.61 g (47%) of the methyl ester (4-methoxy-7-nitrobenzothiazole-2-yl)carboxylic acid as a yellow crystalline solid. Meanwhile, the filtrate was separated into aqueous and organic phase and the organic phase was dried over sodium sulfate and evaporated in vacuum. The residue re-suspended in 200 ml of THF and 200 ml of methanol and heated at 70°With during the night. Then the mixture was cooled to room temperature and the resulting crystals were collected by filtration, washed with THF and dried in vacuum, obtaining extra is leitlinie 1.50 g (9%) of product as a yellow crystalline solid. ES-MS m/e (%): 306 (M+Na+, 28), 284 (M+H+, 100).

C) Methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carboxylic acids

To a stirred solution of 5.00 g (about 17.7 mmol) of the methyl ester (4-methoxy-7-nitrobenzothiazole-2-yl)carboxylic acid in 140 ml of methanol and 140 ml of dichloromethane was added 1.5 g of platinum oxide (IV) and then the mixture was stirred for 16 hours at room temperature in a hydrogen atmosphere. Then the mixture was filtered and the filtrate was evaporated in vacuum, obtaining a 4.03 g (90%) of the methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carboxylic acid as a gray crystalline solid. ES-MS m/e (%): 276 (M+Na+, 28), 254 (M+N+, 100).

d) Methyl ester {4-methoxy-7-[(pyridine-2-ylmethyl)amino]benzothiazol-2-yl}carboxylic acid

To a mixed solution of 40 mg (0.16 mmol) of the methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carboxylic acid in 2 ml DMF at room temperature was added 66 mg (0.47 mmol) of potassium carbonate and 40 mg (0.16 mmol) of bromhidrosis 2-(methyl bromide)of pyridine and the mixture was heated at 70°C for 16 hours. Then the mixture was evaporated in vacuum. Express chromatography (2/1 ethyl acetate/hexane) yielded 20 mg (37%) of methyl ester {4-methoxy-7-[(pyridine-2-ylmethyl)amino]benzothiazol-2-yl}carboxylic acid as a yellow solid. ES-MS m/e (%): 367 (M+Na+, 54), 345 (M+H+, 100).

Example 9

N-[-Methoxy-7-(4-methylbenzylamino)benzothiazol-2-yl]benzamide

and

Example 10

N-{7-[Acetyl-(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide

a) 4-Methoxy-3-nitrophenylamino

To a stirred solution of 30.0 g (244 mmol) of n-anisidine in 105 ml of concentrated sulfuric acid at 0°With added 17.6 g (292 mmol) of urea. After stirring for 1 hour and then was added dropwise a solution 27,1 g (268 mmol) of potassium nitrate in 47 ml of concentrated sulfuric acid over 1 hour, while the reaction mixture is maintained at 5-10°C. the mixture is Then poured into ice, and with stirring was added beads of sodium hydroxide to a pH of 14. Then added ethyl acetate and the phases were separated. The organic phase is washed with water and then with brine, dried over sodium sulfate and evaporated in vacuum, obtaining of 31.4 g (77%) of 4-methoxy-3-nitrophenylamino as an orange solid. EI-MS m/e (%): 169 (M+, 100), 153 ([M-CH3]+, 10), 92 (21).

b) (4-Methoxy-3-nitrophenyl)-bis-(4-methylbenzyl)Amin.

To a stirred solution of 5.00 g (29.7 mmol) of 4-methoxy-3-nitrophenylamino in 60 ml of acetonitrile at 0°added to 10.2 ml (59.5 mmol) of N-ethyldiethanolamine and 11.6 g (of 62.4 mmol) of 4-methylbenzylamine. Continued stirring at room temperature for 16 hours and then the mixture was dissolved in ethyl acetate and washed with 0.5 N hydrochloric acid and then with brine. Organic is ABC was dried over sodium sulfate and evaporated in vacuum, getting 10.4 g (93%) of (4-methoxy-3-nitrophenyl)-bis-(4-methylbenzyl)amine as an orange oil. ES-MS m/e (%): 399 (M+Na+, 18), 377 (M+H+, 100).

C) 4-Methoxy-N1,N1-bis-(4-methylbenzyl)benzene-1,3-diamine

To a stirred solution of 500 mg (of 1.33 mmol) (4-methoxy-3-nitrophenyl)-bis-(4-methylbenzyl)amine in 20 ml of ethanol at room temperature was added at 1.91 g (29.2 mmol) of powdered zinc and 147 mg (1,33 mmol) of calcium chloride and the mixture is then heated at 90°C for 16 hours. Then the mixture was filtered and the filtrate was dissolved in ethyl acetate and washed with 0.5 N sodium hydroxide solution and then with brine. The organic phase was dried over sodium sulfate and evaporated in a vacuum, getting 420 mg (91%) 4-methoxy-N1,N1-bis-(4-methylbenzyl)benzene-1,3-diamine as a dark brown oil. ES-MS m/e (%): 347 (M+N+, 100).

g) 1-Benzoyl-3-{5-[bis-(4-methylbenzyl)amino]-2-methoxyphenyl}thiourea

To a stirred solution of 400 mg (1.15 mmol) of 4-methoxy-N1,N1-bis-(4-methylbenzyl)benzene-1,3-diamine in 8 ml of acetone was added dropwise a solution of 0.18 ml (1,34 mmol) benzoylisothiocyanate in 4 ml of acetone and continued the stirring for 30 minutes at room temperature. Then the mixture was dissolved in ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/9 ethyl acetate/hexane) p is Evodia to obtain 320 mg (80%) of 1-benzoyl-3-{5-[bis-(4-methylbenzyl)amino]-2-methoxyphenyl}thiourea as a yellow oil. ES-MS m/e (%): 510 (M+N+, 100).

e) N-{7-[Bis-(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide

To a stirred solution of 500 mg (0.98 mmol) of 1-benzoyl-3-{5-[bis-(4-methylbenzyl)amino]-2-methoxyphenyl}thiourea in 7 ml of chloroform was added dropwise 0,050 ml (0.98 mmol) of bromine and the reaction mixture was heated at the boil under reflux for 18 hours. Then the mixture was dissolved in ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and evaporated in vacuum. Express chromatography (ethyl acetate/hexane) yielded 290 mg (58%) of N-{7-[bis-(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl} benzamide as a yellow solid. ES-MS m/e (%): 394 (M+Na+, 14), 508 (M+H+, 100).

e) 2,2,2-Trichlorethylene ether (2-benzoylamine 4-methoxybenzothiazole-7-yl-(4-methylbenzyl)carboxylic acids

To a stirred solution of 300 mg (0.59 mmol) of N-{7-[bis-(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide in 10 ml of acetonitrile was added dropwise to 0.60 ml (4,46 mmol) 2,2,2-trichlorethylphosphate and the reaction mixture was heated at 80°C for 72 hours. Then the mixture was evaporated in vacuum. Express chromatography (ethyl acetate/hexane) resulted in the receipt of 138 mg (40%) of 2,2,2-trichlorethylene ether (2-benzoylamine 4-methoxybenzothiazole-7-yl)-(4-methylbenzyl)carboxylic acid as yellow is solid substances. ES-MS m/e (%): 584 (M{37Cl37Cl37Cl}+H+, 5), 582 (M{37Cl37Cl35Cl}+H+, 32), 580 (M{37Cl35Cl35Cl}+H+, 100), 578 (M{35Cl35Cl35Cl}+H+, 92).

W) N-[4-Methoxy-7-(4-methylbenzylamino)benzothiazol-2-yl]benzamide and N-{7-[acetyl(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide

To a stirred solution of 100 mg (0,17 mmol) 2,2,2-trichlorethylene ether (2-benzoylamine 4-methoxybenzothiazole-7-yl)-(4-methylbenzyl)carboxylic acid in 3 ml of acetic acid at room temperature was added 90 mg (1,34 mmol) of the powder of activated zinc and the mixture was heated at 80°C for 16 hours. Then the mixture was filtered and the filtrate was evaporated in vacuum. Express chromatography (ethyl acetate/hexane) yielded 15 mg (21%) of N-[4-methoxy-7-(4-methylbenzylamino)benzothiazol-2-yl]benzamide as a yellow crystalline solid, ES-MS m/e (%): 426 (M+Na+, 27), 404 (M+H+, 100) and 10 mg (13%) of N-{7-[acetyl-(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide as a yellow crystalline solid, ES-MS m/e (%): 468 (M+Na+, 12), 446 (M+N+100).

Example 11

Dichlorhydrate 4-{[(2-methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide

A mixture of 100 mg (0.24 mmol) 4-chloromethyl-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}Bentham is Yes and 212 mg (of 2.38 mmol) of N-(2-methoxyethyl)of methylamine were treated with ultrasound at room temperature for 30 minutes. The reaction mixture then was evaporated in vacuum and the residue was purified accelerated chromatography (ethyl acetate). Containing the product fraction was evaporated in vacuum and the residue was stirred with HCl in ether and ethyl acetate. The obtained crystals were collected by filtration and was washed with ether, receiving 110 mg (91%) dichlorhydrate 4-{[(2-methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide as a white crystalline solid. ES-MS m/e (%): 473 (M+N+, 100).

Example 12

N-(7-Dimethylamino-4-methoxybenzothiazole-2-yl)-4-perbenzoic

a) 4-Methoxybenzothiazole-2,7-diamine

To a suspension 4,28 g (to 16.9 mmol) methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carboxylic acid in 100 ml of dioxane and 50 ml of ethylene glycol was added to 100 ml of 5 N NaOH and the mixture was heated at 100°C for 16 hours. After cooling to room temperature the reaction mixture was evaporated in vacuum and the residue was dissolved in 300 ml of tetrahydrofuran and stirred for 10 minutes. The mixture was filtered and the filtrate was evaporated in vacuum. The residue was treated with ether, receiving 2,73 g (83%) 4-methoxybenzothiazole-2,7-diamine as a brown solid. ES-MS m/e(%): 196 (M+N+, 100).

C) 4-Methoxy-N7,N7-dimethylbenzothiazole-2,7-diamine

To a stirred solution of 2.00 g (1,02 mmol) 4-methoxybenzothiazole-2,7-diamine in 30 ml DMF at room temperature until alali of 4.25 g (of 3.07 mmol) of potassium carbonate and the mixture was heated to 50° C. Then was added dropwise a solution of 0.64 ml (1,02 mmol) iodomethane in 10 ml of DMF for more than 3 hours and continued stirring for another 1 hour at 50°C. Then the mixture was filtered and the filtrate was evaporated in vacuum. Express chromatography (20/1 dichloromethane/methanol) resulted in the receipt of 600 mg (26%) 4-methoxy-N7,N7-dimethylbenzothiazole-2,7-diamine in the form of a yellow solid, ES-MS m/e (%): 224 (M+N+, 100); 540 mg (25%) 4-methoxy-N7-methyl-benzothiazole-2,7-diamine in the form of a yellow solid, ES-MS m/e (%): 210 (M+N+, 100) and 340 mg (17%) of recovered starting material.

g) N-(7-Dimethylamino-4-methoxybenzothiazole-2-yl)-4-perbenzoic

To a stirred solution of 41 mg (0.29 mmol) of 4-fermenting acid in 1 ml of THF was added 128 mg (0.34 mmol) HATU and 0.10 ml (0,56 mmol) of N-ethyldiethanolamine and continued stirring at room temperature for 2.5 hours. Then added 50 mg (0.22 mmol) of 4-methoxy-N7,N7-dimethylbenzothiazole-2,7-diamine and continued stirring at room temperature for 16 hours. The reaction mixture is then evaporated in vacuum. Express chromatography (ethyl acetate/hexane) resulted in the receipt of 64 mg (83%) of N-(7-dimethylamino-4-methoxybenzothiazole-2-yl)-4-fermentated in the form of a white crystalline solid. ES-MS m/e (%): 346 (M+N+, 100).

In a similar way have been received:

Example 13

N-(7-Diethylamino-4-IU is oxybisethanol-2-yl)-4-perbenzoic

4-methoxybenzothiazole-2,7-diamine with potassium carbonate and iodomethane in DMF, followed by treatment of 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 374 (M+N+, 100).

Example 14

N-[7-(Benzylmethylamine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and benzylbromide in DMF, followed by treatment of 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 422 (M+N+, 100).

Example 15

4-Fluoro-N-[4-methoxy-7-(methylpyridin-2-ylmethylamino)benzothiazol-2-yl]benzamide

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and 2-(methyl bromide)pyridinemethanol in DMF, followed by treatment of 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 423 (M+N+, 100).

Example 16

N-[7-(Benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-methylethanolamine

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and benzylbromide in DMF, followed by treatment of the hydrochloride of 2-methylethanolamine acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 419 (M+H+, 100).

Example 17

N-[7-(Dimethylcarbamodithioato)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and 2-iodine-N, N-dimethylacetamide in DMF, followed by treatment of 4-fermenting acid, HATU and N-etelvino what propylamino in THF. ES-MS m/e (%): 417 (M+N+, 100).

Example 18

N-(7-Diethylamino-4-methoxybenzothiazole-2-yl)-2-methylethanolamine

4-methoxybenzothiazole-2,7-diamine with potassium carbonate and iodomethane in DMF, followed by treatment of the hydrochloride of 2-methylethanolamine acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 371 (M+N+, 100).

Example 19

N-[-7-Acetylethanolamine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

a) N-(2-Amino-4-methoxybenzothiazole-7-yl)-N-methylacetamide

To a stirred solution of 120 mg (or 0.57 mmol) 4-methoxy-N7-methylbenzothiazol-2,7-diamine in 1 ml dichloromethane and 1 ml of tetrahydrofuran at 0°With added and 0.09 ml (1.15 mmol) of pyridine. Then was added dropwise a solution of 0.04 ml (or 0.57 mmol) acetylchloride in 1 ml dichloromethane and continued stirring for 3 hours at 0°C. the mixture is Then evaporated in vacuum. Express chromatography (30/1 dichloromethane/methanol) yielded 60 mg (42%) of N-(2-amino-4-methoxybenzothiazole-7-yl)-N-methylacetamide in the form of a light brown crystalline solid, ES-MS m/e (%): 252 (M+N+, 100).

b) N-[7-(Acetylecholine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

To a stirred solution of 31 mg (0.22 mmol) of 4-fermenting acid in 2 ml of THF was added 89 mg (0.23 mmol) HATU and 0.07 ml (0.44 mmol) of N-ethyldiethanolamine and continued stirring at room temperature for 2 hours. Then EXT is ulali 28 mg (0.11 mmol) of N-(2-amino-4-methoxybenzothiazole-7-yl)-N-methylacetamide and continued stirring at 50° C for 16 hours. The reaction mixture is then evaporated in vacuum. Express chromatography (dichloromethane/methanol 50/1) and then rubbing in ether resulted in the receipt of 10 mg (24%) of N-[7-(acetylecholine)-4-methoxybenzothiazole-2-yl]-4-fermentated in the form of a white crystalline solid. ES-MS m/e (%): 374 (M+N+, 100).

Analogously to Example 12 was obtained:

Example 20

N-[7-(Dimethylcarbamoyl)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

From N7-ethyl-4-methoxybenzothiazole-2,7-diamine with potassium carbonate and 2-iodine-N,N-dimethylacetamide in DMF, followed by treatment of 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 431 (M+N+, 100).

Analogously to Example 19 were obtained:

Example 21

N-[7-(Acetylamino)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

From N7-ethyl-4-methoxybenzothiazole-2,7-diamine with pyridine and acetylchloride in dichloromethane and THF, then treatment 4-fermenting acid, HATU and N-methylmorpholine in THF. ES-MS m/e (%): 388 (M+N+, 100).

Example 22

N-[7-(Acetylamino)-4-methoxybenzothiazole-2-yl]-2-methylethanolamine

From N7-ethyl-4-methoxybenzothiazole-2,7-diamine with pyridine and acetylchloride in dichloromethane and THF, then treatment of the hydrochloride of 2-methylethanolamine acid, HATU and N-methylmorpholine in THF. ES-MS m/e (%): 385 (M+N+, 100).

Analogously to Example 12 was obtained:

23

N-[7-(Benzylideneamino)-4-methoxybenzothiazole-2-yl-4-perbenzoic

From N7-ethyl-4-methoxybenzothiazole-2,7-diamine with potassium carbonate and benzylbromide in DMF, followed by treatment of 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 436 (M+N+, 100).

Analogously to Example 19 were obtained:

Example 24

N-[7-(Acetylpenicillamine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic

From N7-benzyl-4-methoxybenzothiazole-2,7-diamine with pyridine and acetylchloride in dichloromethane and THF, then treatment 4-fermenting acid, HATU and N-methylmorpholine in THF. ES-MS m/e (%): 450 (M+N+, 100).

Example 25

N-[7-(Acetylpenicillamine)-4-methoxybenzothiazole-2-yl-2-bromosalicylic

From N7-benzyl-4-methoxybenzothiazole-2,7-diamine with pyridine and acetylchloride in dichloromethane and THF, then treatment 2-bromoisonicotinic acid, HATU and N-methylmorpholine in THF. ES-MS m/e (%): 513 (M{81Br}+H+, 90), 511 (M{79Br}+H+, 100).

Example 26

N-{7-[Acetyl-(2-methoxyethyl)amino]-4-methoxybenzothiazole-2-yl}-4-perbenzoic

From 4-methoxy-N7-(2-methoxyethyl)benzothiazole-2,7-diamine with pyridine and acetylchloride in dichloromethane and THF, then treatment 4-fermenting acid, HATU and N-methylmorpholine in THF. ES-MS m/e (%): 418 (M+N+, 90), 100).

Example 27

N-{7-[Acetyl-(2-methoxyethyl)amino]-4-methoxybenzothiazole-2-yl}-2-bromosalicylic

From 4-methoxy-N7-(2-meth is xitil)benzothiazole-2,7-diamine with pyridine and acetylchloride in dichloromethane and THF, then the processing of 2-bromoisonicotinic acid, HATU and N-methylmorpholine in THF. ES-MS m/e (%): 481 (M{81Br}+H+, 100), 479 (M{79Br}+H+, 99).

Example 28

4-Fluoro-N-{4-methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}benzamide

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and 4-methoxybenzylamine in DMF, followed by treatment of 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 452 (M+H+, 100).

Example 29

2-Bromo-N-{4-methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}isonicotinamide

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and 4-methoxybenzylamine in DMF, followed by treatment 2-bromoisonicotinic acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 515 (M{81Br}+H+, 100), 513 (M{79Br}+H+, 81).

Example 30

N-{4-Methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}-2-methylethanolamine

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and 4-methoxybenzylamine in DMF, followed by treatment of the hydrochloride of 2-methylethanolamine acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 449 (M+N+, 100).

Example 31

4-Fluoro-N-{4-methoxy-7-[methyl(2-oxo-2-piperidine-1-retil)amino]benzothiazol-2-yl}benzamide

4-methoxybenzothiazole-2,7-diamine with potassium carbonate and 2-iodine-1-morpholine-4-ratanana in DMF, followed by treatment with a carbonate is Aliya and iodomethane in DMF, then processing 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 457 (M+N+, 100).

Example 32

N-[7-(Benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-bromosalicylic

From 4-methoxy-N7-methylbenzothiazol-2,7-diamine with potassium carbonate and benzylbromide in DMF, followed by treatment 2-bromoisonicotinic acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 485 (M{81Br}+H+, 98), 483 (M{79Br}+H+, 100).

Example 33

2-Bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-ylmethyl)amino]benzothiazol-2-yl}isonicotinamide

a) (4-Methoxy-3-nitrophenyl)methyl(tetrahydropyran-4-ylmethyl)Amin

To mix the solution 4,70 g (20.0 mmol) of 4-bromo-2-nitroanisole in 100 ml of dioxane was added a 4.03 g (a 24.3 mmol) of the hydrochloride of methyl(tetrahydropyran-4-ylmethyl)amine (1:1), 0,710 g (20.0 mmol) of 2-(dicyclohexylphosphino)biphenyl, 16.5 g (50,65 mmol) of cesium carbonate and 227 mg (1.0 mmol) of palladium (II)acetate. The mixture was heated at the boil under reflux for 24 hours and then poured into water and was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/1 hexane/ethyl acetate) led to obtaining 3.5 g (62%) of (4-methoxy-3-nitrophenyl)methyl(tetrahydropyran-4-ylmethyl)amine as a red oil. ES-MS m/e (%): 281 (M+N+, 100).

b) 4-Methoxy-N1-mate the-N1-(tetrahydropyran-4-ylmethyl)benzene-1,3-diamine

To a stirred solution of 3.5 g (12.5 mmol) of (4-methoxy-3-nitrophenyl)methyl(tetrahydropyran-4-ylmethyl)amine in 230 ml of methanol was added 70 mg of 10% palladium on coal and the mixture is then stirred for 18 hours at room temperature in a hydrogen atmosphere. Then the mixture was filtered and the filtrate was evaporated in vacuum, obtaining 2.20 g (70%) 4-methoxy-N1-methyl-N1-(tetrahydropyran-4-ylmethyl)benzene-1,3-diamine as a dark brown oil. ES-MS m/e (%): 251 (M+N+, 100).

C) 1-Benzoyl-3-{2-methoxy-5-[methyl(tetrahydropyran-4-ylmethyl)amino]phenyl}thiourea

To a stirred solution of 1.70 g (6.8 mmol) of 4-methoxy-N1-methyl-N1-(tetrahydropyran-4-ylmethyl)benzene-1,3-diamine in 30 ml of acetone was added dropwise 1.0 ml (7,50 mmol) benzoylisothiocyanate and continued the stirring for 1 hour at room temperature. Then the mixture was evaporated in vacuum and the residue was subjected to column chromatography (1/1 hexane/ethyl acetate)to give 2.0 g (71%) of 1-benzoyl-3-{2-methoxy-5-[methyl(tetrahydropyran-4-ylmethyl)amino]phenyl}thiourea as a yellow oil. ES-MS m/e (%): 436 (M+Na+, 13), 414 (M+N+, 100).

g) {2-Methoxy-5-[methyl(tetrahydropyran-4-ylmethyl)amino]phenyl}thiourea

To a stirred suspension of 2.0 g (4.8 mmol) of 1-benzoyl-3-{2-methoxy-5-[methyl(tetrahydropyran-4-ylmethyl)amino]phenyl}thiourea in 15 ml of methanol was added dropwise 0.4 ml (to 7.25 mmol) 5.4 M solution methylate is the atrium and continued the stirring for 18 hours at room temperature. Then the mixture was evaporated in vacuum and the residue was subjected to column chromatography (1/1 hexane/ethyl acetate)to give 1.5 g (100%) of {2-methoxy-5-[methyl(tetrahydropyran-4-ylmethyl)amino]phenyl}thiourea in the form of a beige oil. ES-MS m/e (%): 310 (M+N+, 100).

d) 4-Methoxy-N7-methyl-N7-(tetrahydropyran-4-ylmethyl)benzothiazole-2,7-diamine

1.5 g (of 0.53 mmol) {2-methoxy-5-[methyl(tetrahydropyran-4-ylmethyl)amino]phenyl}thiourea was dissolved in 15 ml of chloroform, and at room temperature was slowly added to 0.025 ml (0.5 mmol) Br2. After 24 hours boiling under reflux the mixture was evaporated in vacuum and the residue suspended in water. Solution was added sodium bicarbonate to pH 10, and the crystals were collected by filtration. They were subjected to column chromatography (1/1 hexane/ethyl acetate)to give 0.16 g (10%) 4-methoxy-N7-methyl-N7-(tetrahydropyran-4-ylmethyl)benzothiazole-2,7-diamine as a brown solid. ES-MS m/e (%): 308 (M+N+, 100).

e) 2-Bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-ylmethyl)amino]benzothiazol-2-yl}isonicotinamide

To a stirred solution of 99 mg (0.49 mmol) of 2-bromoisonicotinic acid in 3 ml of THF was added 195 mg (0.51 mmol) HATU and 0.11 ml (0.98 mmol) of N-methylmorpholine and continued stirring at 30°C for 5 hours. Then added 75 mg (0.24 mmol) of 4-methoxy-N7-methyl-N7-(tetrahydropyran-4-ylmethyl)benzothiazole-2,7-diamine and continued per smeshivanie at 40° C for 16 hours. The reaction mixture was then dissolved in ethyl acetate and washed successively with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic phase was dried over sodium sulfate and evaporated in vacuum. Express chromatography (methanol/dichloromethane) followed by rubbing in ether/hexane resulted in the receipt of 17 mg (14%) of 2-bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-ylmethyl)amino]benzothiazol-2-yl}isonicotinamide in the form of a white crystalline solid. ES-MS m/e (%): 493 (M{81Br)+H+, 100), 491 (M{79Br}+H+, 95).

A similar method was obtained:

Example 34

4-Fluoro-N-{4-methoxy-7-[methyl(tetrahydropyran-4-ylmethyl)amino]benzothiazol-2-yl}benzamide

From 4-methoxy-N7-methyl-N7-(tetrahydropyran-4-ylmethyl)benzothiazole-2,7-diamine with 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 430 (M+N+, 100).

Analogously to Example 6 were obtained:

Example 35

N-[7-(Benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-morpholine-4-isonicotinamide

From N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-bromosalicylic with morpholine and cesium carbonate. ES-MS m/e (%): 490 (M+N+, 100).

Example 36

2-Bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}isonicotinamide

a) (4-Methoxy-3-nitrophenyl)methyl(tetrahydropyran-4-yl)AMI is

To a stirred solution of 7.50 g (32,0 mmol) 4-bromo-2-nitroanisole in 200 ml of dioxane was added 6,86 g (45,0 mmol) of the hydrochloride of methyl(tetrahydropyran-4-yl)amine (1:1), 1.13 g (3.0 mmol) of 2-(dicyclohexylphosphino)biphenyl, 14,75 g (45,0 mmol) of cesium carbonate and 360 mg (2.0 mmol) of palladium (II)acetate. The mixture was heated at the boil under reflux for 72 hours and then poured into water and was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Express chromatography (1/2 hexane/ethyl acetate) resulted in the receipt of 1.59 g (18,5%) (4-methoxy-3-nitrophenyl)methyl(tetrahydropyran-4-yl)amine as a red solid. ES-MS m/e (%): 267 (M+N+, 100).

b) 4-methoxy-N1-methyl-N1-(tetrahydropyran-4-yl)benzene-1,3-diamine

To a stirred solution of 0.73 g (2,74 mmol) (4-methoxy-3-nitrophenyl)methyl(tetrahydropyran-4-yl)amine in 50 ml of methanol was added 15 mg of 10% palladium on coal and the mixture is then stirred for 18 hours at room temperature in a hydrogen atmosphere. Then the mixture was filtered and the filtrate was evaporated in vacuum, obtaining 0,3520 g (54%) 4-methoxy-N1-methyl-N1-(tetrahydropyran-4-ylmethyl)benzene-1,3-diamine in the form of an almost white solid. MP.: 97-99°C.

C) 1-Benzoyl-3-{2-methoxy-5-[methyl(tetrahydropyran-4-yl)amino]phenyl}thiourea

To mix the solution 0,330 g (1 mmol) 4-methoxy-N1-methyl-N1-(tetrahydropyran-4-ylmethyl)benzene-1,3-diamine in 5 ml of acetone was added dropwise 0.2 ml (1.50 mmol) benzoylisothiocyanate and continued stirring for 16 hours at room temperature. Then the mixture was evaporated in vacuum and the residue was subjected to column chromatography (1/1 hexane/ethyl acetate)to give 0.31 g (56%) of 1-benzoyl-3-{2-methoxy-5-[methyl(tetrahydropyran-4-yl)amino]phenyl}thiourea as a yellow solid. ES-MS m/e (%): 422 (M+Na+, 13), 400 (M+H+, 100).

g) {2-Methoxy-5-[methyl(tetrahydropyran-4-yl)amino]phenyl}thiourea

To a stirred suspension of 1.7 g (4.2 mmol) of 1-benzoyl-3-{2-methoxy-5-[methyl(tetrahydropyran-4-yl)amino]phenyl}thiourea in 13 ml of methanol was added dropwise to 0.78 ml (6,35 mm) 5.4 M solution of sodium methylate and continued the stirring for 18 hours at room temperature. Then the mixture was evaporated in vacuum and the residue was subjected to column chromatography (1/1 hexane/ethyl acetate)to give 0.6 g (51%) of {2-methoxy-5-[methyl(tetrahydropyran-4-yl)amino]phenyl}thiourea as a yellow solid. ES-MS m/e (%): 296 (M+H+, 100).

d) 4-Methoxy-N7-methyl-N7-(tetrahydropyran-4-yl)benzothiazole-2,7-diamine

0.28 g (0.95 mmol) {2-methoxy-5-[methyl(tetrahydropyran-4-yl)amino]phenyl}thiourea was dissolved in 15 ml of chloroform and slowly added 0.05 ml (1.0 mmol) Br2at room temperature. After 24 hours boiling under reflux the mixture was evaporated in vacuum and the residue suspended in water. Solution was added sodium bicarbonate to pH 10, and the crystals were collected by filtration. They were subjected to column is cromatografia (ethyl acetate), getting 0.11 g (41%) 4-methoxy-N7-methyl-N7-(tetrahydropyran-4-yl)benzothiazole-2,7-diamine in the form of an almost white solid. ES-MS m/e (%): 294 (M+H+, 100).

e) 2-Bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}isonicotinamide

To a stirred solution of 103 mg (0.51 mmol) 2-bromoisonicotinic acid in 3 ml of THF was added 204 mg (0,53 mmol) HATU and 0.11 ml (1,02 mmol) N-methylmorpholine and continued stirring at 30°C for 7 hours. Then added 75 mg (0.26 mmol) of 4-methoxy-N7-methyl-N7-(tetrahydropyran-4-yl)benzothiazole-2,7-diamine and continued stirring at 40°C for 16 hours. The reaction mixture was then dissolved in ethyl acetate and washed sequentially with saturated sodium bicarbonate solution and saline. The organic phase was dried over sodium sulfate and evaporated in vacuum. Express chromatography (methanol/dichloromethane) followed by rubbing in ether/pentane resulted in the receipt of 77 mg (63%) of 2-bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}isonicotinamide in the form of a white crystalline solid. ES-MS m/e (%): 479 (M{81Br}+H+, 100), 477 (M{79Br}+H+, 95).

A similar method was obtained:

Example 37

4-Fluoro-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}benzamide

From 4-methoxy-N7-methyl-N7-(tetrahydropyran-4-ylmethyl)besot the azole-2,7-diamine with 4-fermenting acid, HATU and N-ethyldiethanolamine in THF. ES-MS m/e (%): 416 (M+H+, 100).

Analogously to Example 6 were obtained:

Example 38

N-{4-Methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide

From 2-bromo-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}isonicotinamide with morpholine and cesium carbonate. ES-MS m/e (%): 484 (M+N+, 100).

1. Compounds of General formula

in which R1, R2independently from each other represent hydrogen, lower alkyl, tetrahydropyran-2,3 or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'r R", -(CH2)nis phenyl, optionally substituted lower alkyl, lower alkoxy or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyran-2,3 or 4-yl, -C(O)-piperidine-1-yl or

R1and R2together with the N atom to which they are attached, form a ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl;

R3represents lower alkoxy, phenyl, optionally substituted with halogen, -(CH2)n-halogen, or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl, optionally substituted lower alkyl, halogen or morpholinyl;

n denotes 1 or 2;/p>

R'/R" independently of one another represent hydrogen or lower alkyl,

and their pharmaceutically acceptable acid additive salt.

2. The compounds of formula I according to claim 1, where one of R1/R2represents lower alkyl and the other represents -(CH2)n-O-lower alkyl, and R3represents phenyl, optionally substituted with halogen or -(CH2)n-halogen.

3. The compounds of formula I according to claim 2 where the compound is a N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide, 4-fluoro-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide or 4-chloromethyl-N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}benzamide.

4. Compounds according to claim 1, where one of R1/R2represents lower alkyl and the other represents -(CH2)n-O-lower alkyl, or R1and R2together with the N atom form the group of 2-oxa-5-azabicyclo[2,2,1]hept-5-yl, and R3represents pyridinyl, substituted morpholine.

5. Compounds according to claim 4 where the compound is a N-{4-methoxy-7-[(2-methoxyethyl)methylamino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide or N-[4-methoxy-7-{(1S,4S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)}benzothiazole-2-yl]-2-methylethanolamine.

6. Compounds according to claim 1, where one of R1/R2represents-C(O)-neither the Chille alkyl, and the other represents a lower alkyl, -(CH2)n-O-lower alkyl or benzyl, optionally substituted lower alkyl, and R3represents phenyl, optionally substituted with halogen or pyridinyl, optionally substituted with halogen or lower alkyl.

7. Compounds according to claim 6, where the connection is a

N-{7-[acetyl(4-methylbenzyl)amino]-4-methoxybenzothiazole-2-yl}benzamide,

N-[7-(acetylecholine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(acetylamino)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(acetylpenicillamine)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(acetylpenicillamine)-4-methoxybenzothiazole-2-yl]-2-bromosalicylic or

N-{7-[acetyl-(2-methoxyethyl)-amino]-4-methoxybenzothiazole-2-yl}-4-perbenzoic.

8. Compounds according to claim 1, where one of R1/R2represents lower alkyl and the other represents a lower alkyl or benzyl, optionally substituted lower alkoxy, and R3represents phenyl, optionally substituted with halogen or pyridinyl, optionally substituted by morpholino, halogen or lower alkyl.

9. Connection of claim 8, where the connection is a

N-(7-dimethylamino-4-methoxybenzothiazole-2-yl)-4-perbenzoic,

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-the l]-4-perbenzoic,

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-methylethanolamine,

4-fluoro-N-{4-methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}benzamide,

N-{4-methoxy-7-[(4-methoxybenzyl)methylamino]benzothiazol-2-yl}-2-methylethanolamine,

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-bromosalicylic or

N-[7-(benzylmethylamine)-4-methoxybenzothiazole-2-yl]-2-morpholine-4-isonicotinamide.

10. Compounds according to claim 1, where one of R1/R2represents lower alkyl and the other represents-CH2-C(O)-N(CH3)2or tetrahydropyran, and R3represents phenyl, optionally substituted with halogen or pyridinyl, optionally substituted by morpholino, halogen or lower alkyl.

11. Connection of claim 10, where the connection is a

N-[7-(dimethylcarbamodithioato)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

N-[7-(dimethylcarbamoyl)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

4-fluoro-N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}benzamide or

N-{4-methoxy-7-[methyl(tetrahydropyran-4-yl)amino]benzothiazol-2-yl}-2-morpholine-4-isonicotinamide.

12. A drug that has affinity to the adenosine receptor And2Acontaining one or more compounds will love claims 1 to 11, and pharmaceutically acceptable excipients.

13. The drug is indicated in paragraph 12 for the treatment of diseases related to the adenosine receptor.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to the production of derivatives of 3-amino-2-mercaptobenzoic acid of the formula I, in which X represents fluorine, n = 0 or 1, Z represents CO-a or CS-A1A represents hydrogen, halogen, OR1or SR2, A1denotes hydrogen or or1, R1and R2denote hydrogen, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical with an open chain, containing not more than 8 carbon atoms; the interaction of the compounds of formula II in which T represents hydrogen, C1-C6alkyl, C3-C6alkenyl,3-C6quinil,3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; with aqueous strong base

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to organic chemistry, in particular to the synthesis of substituted 6-hydroxybenzothiazole containing labile fragments

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate

Benzothiazoles // 2293736

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3- or 4-yl, cyclohex-1-enyl, cyclohexyl, or it represents 1,2,3,6-tetrahydropyridin-4-yl or piperidin-4-yl that are optionally substituted with -C(O)CH3 or -C(O)OCH3 in position 1 at nitrogen atom (N); R2 represents lower alkyl, piperidin-1-yl substituted with hydroxy-group optionally, or it represents phenyl optionally substituted with -(CH2)n-N(R')-C(O)-(CH2)n-NR'2, -(CH2)n-halogen, lower alkyl or -(CH2)n-N(R')-(CH2)n-O-lower alkyl, or it represents morpholinyl or pyridinyl that is substituted optionally with halogen atom, -N(R')-(CH2)n-O-lower alkyl, lower alkyl, lower alkoxy-group, morpholinyl or -(CH)n-pyrrolidinyl; n = 0, 1 or 2; R' represents hydrogen atom or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicament possessing affinity to adenosine A2A-receptors and containing one or some compounds of the general formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds.

17 cl, 47 ex

FIELD: medical engineering.

SUBSTANCE: pill taken per os comprises pharmaceutically active agent selectable from (S,S)-Reboxetin or its salt and Pramipexol or its salt. The pharmaceutically active agent is taken in the amount of 0.01% by mass to 25% by mass of composition. It is dispersed in matrix composed of hydrophilic polymer and starch having rupture strength of at least approximately 0.15 kN·cm-2, at least approximately 0.175 kN·cm-2 or at least approximately 0.2 kN·cm-2, when having solid substance usable for producing pills where hydrophilic polymer takes approximately 20-70% by mass and starch is available in the amount of approximately 25-75% by mass. Method involves determining starch usability and composition applicability for treating the cases of disorders and states selected from depressive psychosis, neuropathic pains and Parkinson disease. Starch of specified rupture strength allows pill to withstand high speed pelletization operation and to provide prolonged drug release and to take a pill once a day.

EFFECT: controlled and prolonged drug action; enhanced effectiveness of treatment.

21 cl, 9 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

FIELD: medicine, veterinary science, pharmacy.

SUBSTANCE: invention relates to an agent used in treatment of dermatomycosis. Agent comprises 2-mercaptobenzothiazole, glycerol and dimethylsulfoxide. Invention provides enhancing effectiveness in treatment of patients with trichophytosis and microsporia disease. Proposed agent is harmless, useful in using, allows reducing treatment period and decreases the labor intensity in its using.

EFFECT: improved and valuable properties of agent.

4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 8,8a-dihydro-3aH-indeno[1,2-d]thiazoles and to their physiologically acceptable salts and physiologically functional derivatives also. Invention describes compounds of the formula (I): wherein R1 and R1' mean independently of one another H, F, Cl, Br, J; R2 and R3 means H; R4 means phenyl hat can be replaced with hydroxyl group (OH); R5 means hydrogen atom (H); R6 means OH. Also, invention describes a method for preparing these compounds. Compounds can be used as anorexic agents for prophylaxis and treatment of obesity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 2 tbl, 1 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to polycyclic dihydrothiazole and to their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein R1 and R1' mean independently of one another atoms of hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) and iodine (J); R2 and R3 mean hydrogen atom (H); R4 means (CH2)n-R5 wherein n can be = 0-6; R5 means phenyl that can be substituted with NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl being phenyl ring up to twice-fold can be substituted with chlorine atom (Cl), (CH2)m-SO2-NH2, (CH2)-SO2-NH-(C1-C6)-alkyl, (CH2)m-SO2-N-[(C1-C6)-alkyl]2 or (CH2)m-SO2-N-[=CH-N(CH3)2] wherein m can be = 0-6, and a method for their preparing. Compounds are useful, for example, as anorexic agents used in prophylaxis or treatment of obesity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 12 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles and their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein r1 and R1' mean independently of one another atoms H, F, Cl, Br and J; R2 means hydrogen atom (H); R3 means chlorine (Cl), bromine (Br) atom; R4 means phenyl, and a method for their preparing. Compounds can be used, for example, as anorectics for prophylaxis or obesity treatment.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 2 tbl, 1 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

Up!