Substituted 2-acyl-2-aminothiazoles

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

 

The present invention relates to new substituted N-acyl-2-aminothiazole formula (I)

or their pharmaceutically acceptable salts, where X, R and R1are as described in the text of this application. These compounds are believed to primarily are antagonists of adenosine 2B receptor and, thus, is effective in the treatment of diabetes, diabetic retinopathy, asthma and diarrhea.

Adenosine is a physiologically active substance, which is produced in many tissues and is a mediator of various functions, meeting in the form of four receptor subtypes, A1, A2A, AV and A3. All four receptors belong to the class of receptors, is fused to a G-protein (GPCR)that contain multiple spiral hydrophobic domains are located in the cell membrane, connecting through hydrophilic hydrophilic extracellular and intracellular parts of loops. A1 and A3 receptors fused with Gi and Go proteins, while A2A and UV receptors merged with Gs proteins. Due to these differences adenosine signals the increased levels of camp (cyclic adenosine monophosphate) inside the cell by acting on A2A - and UV receptors and signals the reduction via the A1 and A3 receptors. Additionally, adenosine increases the intracellular content of calcium ions is through the impact on AV-receptor, due to the fact that merged with Gq-proteins.

The compounds of formula I possess significant antagonistic activity against UV-receptor human, which is confirmed by the measurements when conducting research on cells SNO-AV-camp. These compounds also possess residual antagonistic activity against receptors A1 man and A2A person, which is confirmed by measurements at the radiological research associate with ligands.

The study of the role of functional activity AW-receptor in different cell types is complicated by the absence of selective AV agonists and antagonists for these three receptors. Usually about the functional activity against UV receptors conclude on the absence of the effect of selective agonists and antagonists for other three adenosine receptors, along with the manifestation of the response to NECA, strong and non-selective agonist adenosine receptor. Usually role in relation AV-receptor for this type of cells identified in the case, when there is the following clearly defined procedures agonistic activity: NECA (non-selective)>RIA (A1-selective agonist) > IB-MESA (A3-selective agonist)>GS-21680 (A2A-selective agonist).

The relative efficacy of adenosine in the four R the receptors is determined as follows: A1(EC 500.31 supranational μm)>A3(EC50-0,29 μm)>A2A(EC50a-0.7)>AW(EC50-24 μm), which assumes particular importance AW-receptor in the case of chronic stress during intense oxidative processes, including, but not limited to, hyperglycemia, activation of mast cells and inflammatory condition of the gastrointestinal tract. Despite the low antagonistic efficacy of adenosine in relation to UV-receptors, has been reported many compounds with high antagonistic efficiency in relation to AV receptors.

Using specific agonists and antagonists, the researchers of the company Eisai has shown the key role of antagonism against UV-receptors in the inhibition of the production of glucose by the liver, and also showed that the effective antagonist AV-receptor and inhibitor of the production of glucose by the primary hepatocyte mouse lead to lower glucose levels fasting and after food intake in mice line KK-Ay, the well-known model of type 2 diabetes. Thus, the compounds according to the present invention can be used for the prevention and/or treatment of type 2 diabetes.

AV receptors are also located in the plasma membranes of endothelial cells and has been found to stimulate their growth. Consequently, this leads to growth of new blood the blood vessels (angiogenesis). The object of the present invention is the prevention and/or treatment of diseases characterized by an abnormal growth of vessels such as diabetic retinopathy.

Analysis of immunofluorescent techniques using specific anti-UV of human antibodies indicates the presence AW receptors in the fat cells of the lung of a person obtained from asthmatics by bronchoalveolar lavage. Thus, the use of the compounds of formula I allows you to create a method of prevention and/or treatment of asthma, bronchospastic and allergic diseases, as well as other obstructive diseases of the Airways.

AV receptors found in the colon in basolateral domains of epithelial cells of the intestine, which leads to increased secretion of chloride ion as a reaction to inflammation of the gastrointestinal tract in diseases such as diarrhoea. Thus, the compounds of formula I allow you to create a method of treating inflammatory diseases of the gastrointestinal tract, including diarrhea.

Compounds according to the present invention also have significant antagonistic activity against A1 - and A2A-receptors, in addition to AV receptors. Thus, the compounds of formula I help to develop methods of treatment of diseases in comoriginal is antagonistic effects on adenosine A1, A2A and AV-receptors, for example to develop a method for the treatment of such diseases as depression, Parkinson's disease and high blood pressure (hypertension).

Some substituted N-allmynotes known from the prior art, for example, internationalinvestment described in U.S. patent 5480874; 2-amino-6-hydroxybenzothiazole in U.S. patent 4929623; 2-benzoylamino[1,2-d]thiazole - article in Synthetic Communications (1993), 23(17), 2347-53; benzamido - and 2-acetamidomalonate of benzothiazole - Indian Drugs, (1985), 23(3), 146-51, and some derivatives of acylaminoacyl in U.S. patent 5189049. In U.S. patent 4877876 described derivatives of 2-substituted 8H-indeno[1,2-d]thiazolo that are close in structure to the compounds according to the present invention.

More specifically, the present invention relates to compounds of formula (I)

or their pharmaceutically acceptable salts, where

X represents-CH2-, -CH2CH2-, -SNSN-, -(CH2)3and-O(CH2)-;

R represents an alkyl group, alkenylphenol group-other' or a 5 - or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms, with the specified ring system optionally substituted by one or more to cover the firs, selected from the group consisting of halogen, hydroxy, lower alkyl, atsetamidometil, alkoxycarbonylmethyl, nitrile groups, sulfonamide, alkylsulfonyl, alkoxy, benzyl, benzoyl, arylsulfonyl and acyl specified benzyl, benzoyl or arylsulfonyl optionally substituted with halogen, a group trihalogen-lower alkyl, lower alkyl, alkoxy, alkylsulfonyl or cyano;

R1selected from the group consisting of hydrogen, halogen, lower alkyl, alkoxy or nitrile group;

R' represents an alkyl group or 5 - or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms, with the specified ring system optionally substituted by one or more substituents, selected from the group consisting of halogen, lower alkyl, nitrile group, alkylsulfonyl, alkoxy and acyl.

Compounds according to the present invention showing the initial activity as agonists of adenosine AV receptors and thus can be used to treat diseases mediated by this receptor. Compounds according to the present invention can be used as active agents in the prevention and treatment of such diseases is s, as, for example, diabetes, diabetic retinopathy, asthma, and diarrhea. Secondary antagonism of adenosine A1 and A2A receptors allows the use of compounds according to the present invention in the case of depression, Parkinson's disease and high blood pressure (hypertension).

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, and their enantiomeric forms, obtaining the above-mentioned compounds, drugs containing these compounds, and receive them, as well as methods of using the above compounds for the control or prevention of diseases, in particular diseases, disabilities and disorders listed above, or for the preparation of the drugs.

The compounds of formula (I) individually are preferred, also individually preferred their physiologically acceptable salts, and the compounds of formula (I) are particularly preferred.

The compounds of formula (I) can contain one or more asymmetric atoms and may thus exist in the form of mixtures of enantiomers, mixtures of diastereomers or in the form of optically pure compounds.

Preferred compounds of formula (I)described above, characterized by formula (IA)

or provide the amount of pharmaceutically acceptable salt of this compound, where

X represents-CH2-, -CH2CH2-, -SNSN-, -(CH2)3and O(CH2)-;

R represents an alkyl group-other' or a 5 - or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms, with the specified ring system optionally substituted by one or more substituents, selected from the group consisting of halogen, lower alkyl, nitrile group, alkylsulfonyl, alkoxy and acyl, and

R' represents an alkyl group or 5 - or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms, with the specified ring system optionally substituted by one or more substituents, selected from the group consisting of halogen, lower alkyl, nitrile group, alkylsulfonyl, alkoxy and acyl.

Preferred are such compounds of formula (I)as described above, where R represents an alkyl group, alkenylphenol group or 5 - or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms, with the specified calcev the I system is optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxy, lower alkyl, atsetamidometil, alkoxycarbonylmethyl, nitrile groups, sulfonamide, alkylsulfonyl, alkoxy, benzyl, benzoyl, arylsulfonyl and acyl; specified benzyl, benzoyl or arylsulfonyl optionally substituted with halogen, a group trihalogen-lower alkyl, lower alkyl, alkoxy, alkylsulfonyl or cyano.

Also preferred are such compounds where X represents-CH2-. Other preferred compounds are such compounds where R1represents hydrogen, halogen or lower alkoxy. Hydrogen, halogen and lower alkoxy separately form the preferred embodiment of the invention in relation to R1.

Another preferred implementation of the present invention relates to compounds of formula (I)as described above, where R is a lower alkyl, lower alkenyl, phenyl or heterocyclic ring system selected from the group which consists of tanila, pyridinyl, pyrazolyl, imidazolyl, Shrila or piperidinyl; specified phenyl or heterocyclic ring system optionally substituted with substituents in an amount of from 1 to 3, selected from the group consisting of halogen, hydroxy, nitrile, lower Alky is a, sulfonamide, lower alkylsulfonyl, lower alkoxycarbonyl, lower alkoxy-C(O)-NH-CH2-, benzyl, which is optionally substituted radical CF3, benzoyl, which is optionally substituted radical CF3or phenylsulfonyl, which is optionally substituted radical CF3.

Other preferred compounds as described above are those compounds where R is a lower alkenyl or heterocyclic ring system selected from the group which consists of tanila, pyridinyl, pyrazolyl, imidazolyl, Shrila or piperidinyl specified heterocyclic ring system optionally substituted with substituents in an amount of from 1 to 3, selected from the group consisting of halogen, hydroxy, nitrile, lower alkyl, sulfonamide, lower alkylsulfonyl, lower alkoxycarbonyl, lower alkoxy-C(O)-NH-CH2-, benzyl, which is optionally substituted radical CF3, benzoyl, which is optionally substituted radical CF3or phenylsulfonyl, which is optionally substituted radical CF3.

In the case of compounds of formula (I)as defined above, preferably R is not phenyl, 4-NO2-phenyl, or 4-Cl-phenyl, in particular in the case when X is-CH2and R1represents hydrogen. In addition, in the case of the of dinani formula (I), as defined above, preferably, when R is not phenyl, 4-NO2-phenyl, or 4-Cl-phenyl, in particular, if X is-CH2CH2and R1represents hydrogen or alkoxy. In addition, in the case of compounds of formula (I)as defined above, preferably, when R represents alkyl, in particular in the case when X represents-CH2CH2and R1represents hydrogen.

Each of the following as examples of the substituents X, R and R1as in the compounds mentioned below and in the examples, individually and in each of the combinations is preferred variant of the invention, preferably in specific combinations, which are listed above and in the examples.

Especially preferred compounds include the following compounds:

N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,

4-fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,

4-cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,

N-(8H-indeno[1,2-d]thiazol-2-yl)-4-methylbenzamide,

thiophene-2-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)amide,

N-(8H-indeno[1,2-d]thiazol-2-yl)nicotinamide,

N-(8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide,

(8H-indeno[1,2-d]thiazol-2-yl)amide 2-methyl-2H-pyrazole-3-carboxylic acid,

N-(6-chloro-8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide,

1H-pyrazole-4-carboxylic acid (8H-in the network[1,2-d]thiazol-2-yl)amide,

N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)isonicotinamide,

N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)isonicotinamide,

N-(4H-chromeno[4,3-d]thiazol-2-yl)isonicotinamide,

N-oil[1,2-d]thiazole-2-isonicotinamide,

triptorelin (8H-indeno[1,2-d]thiazol-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid,

tert-butyl ester 4-(8H-indenol[1,2-d]thiazole-2-ylcarbonyl)-

piperidine-1-carboxylic acid,

(8H-indeno[1,2-d]thiazol-2-yl)amide 3-(trifloromethyl)piperidine-4-carboxylic acid,

(9H-indeno[l,2-d]thiazol-2-yl)amide 1-(3-trifloromethyl)piperidine-4-carboxylic acid,

(8H-indeno[1,2-d]thiazole-2-alamid 1-(3-trifloromethyl)piperidine-4-carboxylic acid,

N-(8H-indeno[1,2-d]thiazol-2-yl)-3-perbenzoic,

N-(8H-indeno[1,2-d]thiazol-2-yl)-3-hydroxybenzamide,

N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylpent-5-unoiled,

N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylbutanoate,

N-(8H-indeno[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid,

N-(8H-indeno[l,2-d]thiazol-2-yl)-2-furosemid,

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-4-hydroxynicotinate,

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)(4-aminosulfonyl)benzamid,

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-(4-tert-butoxycarbonylmethyl)benzamid,

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)thiophene-3-carboxamide,

N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4-hydroxynicotinate,

N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)thiophene-3-carboxamide,

N-(45-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-4-hydroxynicotinate,

N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid,

N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)-4-hydroxynicotinate,

N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)thiophene-3-carboxamide,

N-(8H-indeno[1,2-d]thiazol-2-yl) 3-chloro-4-hydroxybenzamide and

N-(8H-indeno[1,2-d]thiazol-2-yl) (4-aminosulfonyl)benzamide.

Each of the compounds mentioned above individually represents a preferred implementation of the present invention.

Preferred compounds of formula (I)as described above, are compounds selected from the group which consists of the following connections:

N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,

4-fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,

4-cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,

N-(8H-indeno[1,2-d]thiazol-2-yl)-4-methylbenzamide,

(8H-indeno[1,2-d]thiazol-2-yl)amide thiophene-2-carboxylic acid,

N-(8H-indeno[1,2-d]thiazol-2-yl)nicotinamide,

N-(8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide,

(8H-indeno[1,2-d]thiazol-2-yl)amide 2-methyl-2H-pyrazole-3-carboxylic acid,

N-(6-chloro-8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide,

1H-pyrazole-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)amide,

N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)isonicotinamide,

N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)isonicotinamide,

N-(4H-chromeno[4,3-d]thiazol-2-yl)isonicotinamide,

N-naphthas is[1,2-d]thiazole-2-isonicotinamide and

triptorelin (8H-indeno[1,2-d]thiazol-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid triptorelin.

Other preferred compounds of formula (I)as described above, are compounds selected from the group which consists of the following connections:

tert-butyl ester 4-(8H-indenol[1,2-d]thiazole-2-ylcarbonyl)piperidine-1-carboxylic acid,

(8H-indeno[1,2-d]thiazol-2-yl)amide 3-(trifloromethyl)piperidine-4-carboxylic acid,

(N-indeno[1,2-d]thiazol-2-yl)amide 1-(3-trifloromethyl)piperidine-4-carboxylic acid,

(8H-indeno[1,2-d]thiazole-2-alamid 1-(3-trifluoromethyl-

benzazolyl)piperidine-4-carboxylic acid,

N-(8H-indeno[1,2-d]thiazol-2-yl)-3-perbenzoic,

N-(8H-indeno[1,2-d]thiazol-2-yl)-3-hydroxybenzamide,

N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylpent-5-unoiled,

N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylbutanoate,

N-(8H-indeno[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid,

N-(8H-indeno[l,2-d]thiazol-2-yl)-2-furosemid and

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-4-hydroxynicotinic.

Other preferred compounds of formula (I)as described above, are compounds selected from the group which consists of the following:

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)(4-aminosulfonyl)benzamid,

N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)(4-tert-butoxycarbonylmethyl)benzamid,

N-(6-fluoro-8H-indeno[12-d]thiazol-2-yl)thiophene-3-carboxamide,

N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4-hydroxynicotinate,

N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)thiophene-3-carboxamide,

N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-4-hydroxynicotinate,

N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid,

N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)-4-hydroxynicotinate,

N-(5,6-dihydro-4H-3-thia-l-azabenzo[e]azulene-2-yl)thiophene-3-carboxamide,

N-(8H-indeno[1,2-d]thiazol-2-yl)-3-chloro-4-hydroxybenzamide and

N-(8H-indeno[1,2-d]thiazol-2-yl)(4-aminosulfonyl)benzamide.

It should be noted that compounds of General formula (I) according to the present invention can be subjected to derivatization by functional group with the receipt of this derivative, which is able to reverse the transformation of the parent compound in vivo.

Another variant of implementation of the present invention relates to a method for producing compounds of formula (I)as defined above, the method involves reacting the compounds of formula (II)

connection R-C(O)Cl, in which R, R1and X are as described above.

Suitable reaction conditions are indicated in schemes 1 and 2 and in the examples.

In addition, the present invention relates to compounds of formula (I)as defined above, which is produced by the method according to claim 9.

Unless otherwise stated, for the definition of the Oia and illustrations of the value and volume of various terms, used in the text of this application, the following definitions apply.

In the text of this application, the term "lower" is used to refer to groups containing one to six carbon atoms, preferably from one to four carbon atoms.

The term "alkyl" means a saturated aliphatic hydrocarbon group with a linear or branched chain. The alkyl groups preferably contain from 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, even more preferably from 1 to 10 carbon atoms. The lower alkyl groups described below are also preferred alkyl groups.

The term "lower alkyl" group means With1-C6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl, hexyl and the like, As a rule, lower alkyl preferably represents C1-C4alkyl and more preferably is C1-C3alkyl.

The term "trihalogen-lower alkyl" means a lower alkyl group which is substituted 3 halogen atoms. CF3a preferred group trihalogen-lower alkyl.

The term "alkoxy" means-O-alkyl. "Lower alkoxy" means-O-lower alkyl.

The term "alkenyl" refers to a hydrocarbon group with a linear or branched chain, including the setup portion of the olefinic bond and up to 7, preferably up to 4, carbon atoms, such as a band like 2-propenyl.

The term "carbocyclic" refers to 5 - or 6-membered saturated or unsaturated carbon-containing ring system, such as aryl ring system.

The term "heterocyclic" refers to 5 - or 6-membered ring system which may comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur, for example to such a ring system, as tetrahydropyridine, dihydrofuran, dihydropyran, furyl, pyrrolyl, pyridyl, 1,2-, 1,3 - and 1,4-diazines, thienyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazole or imidazolyl. Heterocyclic group may be optionally substituted aryl group. As mentioned above, the heterocyclic group may be substituted by various substituents, and in the case of benzyl, sensornogo and arylsulfonyl Vice-mentioned substituents may be optionally substituted with halogen, trigalogenmetany lower alkyl, lower alkyl, alkoxy, alkylsulfonyl or cyano.

The term "halogen" means an atom selected from chlorine, fluorine and bromine.

The term "effective amount" refers to an amount that is effective to prevent, mitigate or eliminate the symptoms of disease or prolong the life of the subject, which produces the t treatment.

The term "heteroatom" means an atom selected from N, O and S.

The term "IC50" refers to a concentration of a particular compound required to inhibit 50% of specific measured activity. IC50can be measured, in particular, thus, as described below.

The term "aryl" means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably 5 - to 6-membered aromatic ring system. An example of such a radical is phenyl.

The term "acyl" means-C(O)-C1-C6-alkyl, -C(O)H or C(O)-O alkyl.

The term "pharmaceutically acceptable ester" refers to esterified in the usual manner to the compound of formula I containing a carboxy group specified ester retains the biological activity and properties of the compounds of formula I and is cleaved in vivo (in the body) with formation of a corresponding active carboxylic acid.

Information concerning esters, as well as information on the use of esters for the delivery of pharmaceutically active compounds, can be found in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985), and in H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995), pp.108-109; Krogsgaard-Larsen et al., In Textbook of Drug Design and Development (2d Ed. 1996), pp.152-191.

The term "pharmaceutically acceptable salt" relation is seeking to well-known additive salts with acids or bases, which retain the biological activity and properties of the compounds according to the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic. Examples of the additive salts with acids include salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and an additive salts with acids, obtained using organic acids, such as p-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid (butanedioate), citric acid, malic acid, lactic acid, fumaric acid, etc. are Examples of additive salts with bases include salts obtained by using hydroxides of ammonium, potassium, sodium and Quaternary ammonium hydroxides, such as a hydroxide of Tetramethylammonium. Chemical modification of pharmaceutically active compounds (i.e. medicines) to obtain this salt is a technique well known in the field of pharmaceutical chemistry and used to enhance the physical and chemical stability, gyros is obecnosci, flowability and solubility of compounds. See, for example, H.Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995), pp.196, 1456-1457.

The term "pharmaceutically acceptable," such as pharmaceutically acceptable carrier, filler, etc. refers to the agent, a pharmacologically acceptable and substantially non-toxic to the patient, which impose a particular connection.

The term "substituted" means that the substitution can be carried out in one or more of the terms and unless otherwise specified, the substituents in each case, the substitution is independently selected from the concrete possibilities of substitution.

The compounds of formula (I) can be obtained using the methods described below, using the methods described in the examples or by analogous methods. Suitable reaction conditions for carrying out a specific stage of the interaction is known to the person skilled in the art from the prior art. Source materials are either commercially available or can be obtained using the methods described below or in the examples, or using methods known from the prior art.

The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, couples who naturalnego or local injection. They can be introduced, for example, orally, such as tablets, tablets with sheath, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of solutions for injection or infusion, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.

Obtaining pharmaceutical preparations can be carried out using methods known to the person skilled in the art, through the introduction of the described compounds of formula (I) and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically important compounds in the pharmaceutical composition of the drug with a suitable non-toxic, inert, therapeutically compatible solid or liquid carrier, if necessary, with conventional pharmaceutical ancillary medicinal substances.

Suitable substances-the media are not only inorganic substances, but also organic matter. For example, in as matter-carriers for tablets, pellets, shell, coated tablets and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable substances nose, the prevalence for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient in the case of soft gelatin capsules carrier may not be required). Suitable substances-carriers to obtain solutions and syrups are, for example, water, polyols, saccharose, invert sugar and other Suitable carriers for the preparation of solutions for injection are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols. Suitable carrier materials for local products are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose. As pharmaceutically suitable auxiliary medicinal substances should be considered a conventional stabilizers, preservatives, wetting and emulsifying agents, agents for improving the consistency, agents for improving taste and smell, salts for regulating the osmotic pressure, buffer substances, soljubilizatory tinted substance, masking agents and antioxidants.

The dosage of the compounds of the formula I can in order to reroute within wide limits depending on the disease, which is subject to control, age, specific condition of the patient and the route of administration, and should certainly match the individual needs in each individual case. For adult patients a daily dosage of approximately 1 to 1000 mg, especially from approximately 1 to 100 mg depending on the severity of symptoms and specific pharmacokinetic profile connection, you can enter in the form of dosage units of one or several times a day, for example, from 1 to 4 unit dosage forms.

As indicated above, the new compounds according to the present invention, as has been discovered, are antagonists of adenosine AV-receptor. Compounds according to the present invention, thus, can be used for the treatment and/or prevention of diseases which are mediated by antagonism of adenosine AV-receptor, in particular diabetes, diabetic retinopathy, asthma and diarrhoea, in particular diabetes.

The present invention also relates to pharmaceutical compositions comprising a compound as described above, and a pharmaceutically acceptable carrier and/or excipient.

The present invention also includes compounds as described above for use as therapeutically active link is, in particular, for use as therapeutically active compounds for the treatment and/or prevention of diseases which are mediated by antagonism of adenosine AV-receptor, particularly as therapeutically active compounds for the treatment and/or prevention of diabetes, diabetic retinopathy, asthma and diarrhoea, in particular diabetes.

In accordance with another preferred embodiment the present invention relates to a method of therapeutic and/or prophylactic treatment of diseases which are mediated by antagonism of adenosine AV-receptor, particularly for therapeutic and/or prophylactic treatment of diabetes, diabetic retinopathy, asthma and diarrhoea, particularly diabetes, this method includes the introduction of compounds indicated above, human or animal.

The present invention includes the use of compounds listed above for therapeutic and/or prophylactic treatment of diseases which are mediated by antagonism of adenosine AV-receptor, particularly for therapeutic and/or prophylactic treatment of diabetes, diabetic retinopathy, asthma and diarrhoea, in particular diabetes.

The present invention also relates to the use of compounds as defined above, to obtain medicines DL is a therapeutic and/or prophylactic treatment of diseases, which is mediated by antagonism of adenosine AV-receptor, particularly for therapeutic and/or prophylactic treatment of diabetes, diabetic retinopathy, asthma and diarrhoea, particularly diabetes. Such medicines include a compound which is listed above.

Prevention and/or treatment of diabetes is the preferred reading. The following scheme of reactions and the accompanying explanatory notes relate to the General method of synthesis of new compounds according to the present invention.

Scheme 1

Notes to figure 1

The heated mixture of the corresponding ketone with I timesaving and iodine to 90-100°C in the absence of solvent allows to obtain the derivatives of thiazole II. Acylation of compounds II aroyl or heteroaromatic in the presence of a base, such as potassium carbonate or pyridine, which when heated causes acylated products III. Alternatively, the deprotonation of compound II with the use of a strong base, such as sodium hydride, followed by acylation using aroyl or heteroaromatic also allows to obtain the acylated products III.

Compounds of structure III can also be obtained by condensation of amine II with arylcarbamoyl acid using O-(7-azabenzo eazol-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (HATU), or a combination of p-toluensulfonate and N-methylimidazole as condensing agents.

Scheme 2

Explanation of diagram 2

Remove protection compound IV using triperoxonane acid allows to obtain the intermediate compound is a derivative of piperidine V. Compound V can then be subjected to interaction with a suitable arylalkenes, benzoylchloride or arylsulfonamides in the presence of a base, such as triethylamine, to obtain the compounds VI, VII and VIII.

Conditions for the above interactions can to some extent be varied. Ways of carrying out the above reactions and the implementation of such methods known from the prior art or can be similar to the methods described in the examples. Source materials are either commercially available or can be obtained by methods which are similar to the methods described in the examples.

The following examples illustrate preferred embodiments of the present invention but do not limit the scope of the present invention.

Example 1

N-(8H-Indeno[1,2-d]thiazol-2-yl)benzamid

Stage 1: 8H-indeno[1,2-d]thiazol-2-ylamine hydroiodide

A mixture of 1-indanone (6,00 g; to 45.4 mmol), thiourea (6,92 g; 90,8 mmol) and iodine (to 11.52 g; to 45.4 mmol) was heated to 95°C with stirring. After 3 hours the mixture is allowed to cool down to on the th temperature. The crude solid is triturated with absolute ethanol and filtered. The light yellow solid is washed twice with absolute ethanol, then dried in the air, while receiving 9,13 g of 8H-indeno[1,2-d]thiazole-2-ylamine of hydroiodide 1A.

Stage 2: 8H-indeno[1,2-d]thiazol-2-ylamine

Indeno[1,2-d]thiazole-2-ylamine hydroiodide 1A (9,13 g) is stirred with 100 ml of 1 n sodium hydroxide solution for 1 hour at room temperature, then filtered. The solid is washed with water (3×20 ml) and then dried in the air, while receiving 5.30 g of 8H-indeno[1,2-d]thiazole-2-ylamine 1b.

Stage 3: N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid

To the mixture indeno[1,2-d]thiazole-2-ylamine of hydroiodide 1A (100 mg; 0.32 mmol) in pyridine (2 ml) is added dropwise a benzoyl chloride (0,12 ml; 0.96 mmol). The resulting mixture was shaken at 80°C in a sealed tube overnight. The obtained mixture is allowed to cool to room temperature and the solvent is removed in vacuum. The resulting residue is transferred into ethyl acetate and the extract is stirred with 2 M sodium carbonate solution for 2 hours at room temperature. The organic layer is then washed with saturated salt solution, dried over sodium sulfate and concentrated in vacuo. The crude product chromatographic on silica gel (eluent: gradient from 10% ethyl acetate/hexane to 40% ethyl acetate) to thereby obtain 53 mg of N-(8H-indeno[1,2-d]thiazol-2-yl)benzamide 2. Mass spectroscopy high resolution (EI), m/e: calculated for C17H12N2OS 292,0670 found 292, 0666.

Example 2

4-Fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid

The acylation of 8H-indeno[1,2-d]thiazole-2-ylamine of hydroiodide 1A (obtained according to example 1, step 1, 100 mg; 0.32 mmol) 4-tormentilla (0,116 ml; 0.96 mmol) is carried out in accordance with the methodology, which is similar to the procedure described in example 1, stage 3, while receiving 35 mg 4-fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamide 3. Mass spectroscopy high resolution (EI), m/e: calculated for C17H11FN2OS 310,0576 found 310,0577.

Example 3

4-cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid

The acylation of 8H-indeno[1,2-d]thiazole-2-ylamine of hydroiodide 1A (obtained according to example 1, step 1, 100 mg; 0.32 mmol) 4-cyanobenzaldehyde (164 mg; 0.96 mmol) is carried out in accordance with the methodology, which is similar to the procedure described in example 1, stage 3, while receiving 26 mg of 4-cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamide 4. Mass spectroscopy high resolution (EI), m/e: calculated for C18H14N2OS (M+) 306,0827 found 306,0827.

Example 4

N-(8H-Indeno[1,2-d]thiazol-2-yl)-4-methylbenzamide

The acylation of 8H-indeno[1,2-d]thiazole-2-ylamine of hydroiodide 1A (obtained according to example 1, step 1, 100 mg; 0.32 mmol) 4-methylbenzylamino (0,130 ml; 0.96 mmol) perform in accordance with the methodology which is similar to the procedure described in example 1, stage 3, while receiving 25 mg of compound 5. Mass spectroscopy high resolution (EI), m/e: calculated for C16H11N3OS (M+) 293,0623 found 293,0621.

Example 5

(8H-Indeno[1,2-d]thiazol-2-yl)amide thiophene-2-carboxylic acid

The acylation of 8H-Indeno[1,2-d]thiazole-2-ylamine of hydroiodide 1A (obtained according to example 1, step 1, 100 mg; 0.32 mmol) 2-thiophenecarbonitrile (0,106 ml; 0.96 mmol) is carried out in accordance with the methodology, which is similar to the procedure described in example 1, stage 3, while receiving 17 mg (8H-indeno[1,2-d]thiazol-2-yl)amide thiophene-2-carboxylic acid 6. Mass spectroscopy high resolution (EI), m/e: calculated for C15H10H2OS2(M+) 298,0235 found 298,0233.

Example 6

N-(8H-Indeno[1,2-d]thiazol-2-yl)nicotinamide

Suspension of hydroiodide 8H-indeno[1,2-d]thiazole-2-ylamine 1A (obtained according to example 1, stage 1, mg; mmol), hydrochloride of nicotinanilide (92 mg; 0.50 mmol) and diisopropylethylamine (0,50 ml, 2.77 mmol) in dichloroethane is heated in a sealed tube to 120°C. in microwave oven for 10 minutes. The obtained mixture is allowed to cool to room temperature and then the solvent is removed in vacuum. The resulting residue is transferred in 2 M sodium carbonate solution, then extracted using ethyl acetate. Received extra what you dried (sodium sulfate), filtered and concentrated in vacuo. The crude product chromatographic on silica gel (eluent: gradient from 50% ethyl acetate/hexane to 100% ethyl acetate/hexane), to thereby obtain 43 mg of N-(8H-indeno[1,2-d]thiazol-2-yl)nicotinamide 7. Mass spectroscopy high resolution (EI), m/e: calculated for C16H11N4OS (M+) 293,0623 found 293,0620.

Example 7

N-(8H-Indeno[1,2-d]thiazol-2-yl)isonicotinamide

To a mixture of 8H-indeno[1,2-d]thiazole-2-ylamine 1b (obtained according to example 1, stage 2, 640 mg; 3.4 mmol) and potassium carbonate (5,40 g; 39,1 mmol) in dry tetrahydrofuran (20 ml) under nitrogen atmosphere add hydrochloride isonicotinohydrazide (959 mg; 5,10 mmol). Then, the resulting suspension is refluxed for 18 hours. At this stage add potassium carbonate (5,40 g; 39,1 mmol) and hydrochloride isonicotinohydrazide (959 mg; 5,10 mmol), boiling under reflux continued for 22 hours, then the reaction mixture is allowed to cool to room temperature. The solvent is removed in vacuum and then the residue was diluted with water and extracted using methylene chloride. The insoluble substance is filtered off and washed with methylene chloride and water, and finally triturated with diethyl simple ether, thus obtaining 253 mg of N-(8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide 8. Mass spectroscopy high resolution (EI), m/e: calc is slena for C 16H11N3OS (M+) 293,0623 found 293,0621.

Example 8

(8H-Indeno[1,2-d]thiazol-2-yl)amide 2-methyl-2H-pyrazole-3-carboxylic acid

To a mixture of 8H-indeno[1,2-d]thiazol-2-ylamine 1b (obtained according to example 1, stage 2, 320 mg; 1.70 mmol) and potassium carbonate (3,10 g; of 22.4 mmol) in dry tetrahydrofuran (10 ml) under nitrogen atmosphere is added 2-methyl-2H-pyrazole-3-carbonylchloride (516 mg; 3,57 mmol). Then, the resulting suspension is refluxed for 3 hours. The solvent is removed in vacuo, the resulting residue was diluted with water and extracted using ethyl acetate. The organic layer is washed using 50 ml of 1 n hydrochloric acid and then with saturated salt solution and dried (sodium sulfate), filtered and concentrated in vacuo. The crude product is purified by trituration with diethyl simple ether with getting this 155 mg (8H-indeno[1,2-d]thiazol-2-yl)amide 2-methyl-2H-pyrazole-3-carboxylic acid 9. Mass spectroscopy high resolution (EI), m/e: calculated for

C15H12N4OS(M+) 296,0732 found 296,0731.

Example 9

N-(6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide

Stage 1: 6-chloro-8H-indeno[1,2-d]thiazol-2-ylamine hydroiodide

A mixture of 5-chloro-1-indanone (1,00 g; 6,00 mmol), thiourea (0,917 g; to 12.0 mmol) and iodine (1.55 g; 6,10 mmol) is heated to 100°C. in a sealed samples of the REC. After 1 hour, the obtained mixture is allowed to cool to room temperature. The solid is triturated with water and filtered. Then the solid is triturated with absolute ethanol, filtered and washed several times with absolute ethanol, while receiving 0,60 g hydroiodide 6-chloro-8H-indeno[1,2-d]thiazole-2-ylamine 10.

Stage 2: N-(6-chloro-8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide

A mixture of hydroiodide 6-chloro-8H-indeno[1,2-d]thiazole-2-ylamine 10 (80 mg, 0.23 mmol), potassium carbonate (138 mg, 1.0 mmol) and hydrochloride isonicotinohydrazide (89 mg; 0.5 mmol) in dry tetrahydrofuran heated to 80°C. in a sealed tube. After 20 hours the mixture is allowed to cool down to room temperature and concentrated in vacuo. The obtained residue was diluted using methylene chloride, and washed with water. The organic layer is dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was then purified by reversed-phase GHUR (eluent: acetonitrile/water/0.1% of triperoxonane acid), while receiving 20 mg of N-(6-chloro-8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide 11 in the form of salt - trifenatate. Mass spectroscopy high resolution (EI), m/e: calculated for

C16H10ClN3OS (M+) 327,0233 found 327,0217.

Example 10

(8H-Indeno[1,2-d]thiazol-2-yl)amide 1H-pyrazole-4-carboxylic acid

Stage 1: 4-pyrazolecarboxylate

A mixture of 4-pyrazolylborate the acid (600 mg) in thionyl chloride (5 ml) is heated to 90°C. in a nitrogen atmosphere. After 18 hours the mixture is allowed to cool down to room temperature and then the solvent is removed under vacuum, thus obtaining 579 mg of 4-pyrazolecarboxylate 12, which is used without further purification in the next stage (stage 2). Mass spectroscopy high resolution (EI), m/e: calculated for C16H11N3OS (M+) 293,0623 found 293,0621.

Stage 2: (8H-indeno[1,2-d]thiazol-2-yl)amide 1H-pyrazole-4-carboxylic acid

The acylation of 8H-indeno[1,2-d]thiazole-2-ylamine 1b (obtained according to example 1, stage 2, 377 mg; 2.00 mmol) 4-pyrazolecarboxylate 12 (208 mg; 1.6 mmol) is carried out in accordance with the methodology, which is similar to the method described in example 7, while receiving 190 mg (8H-indeno[1,2-d]thiazol-2-yl)amide 1H-pyrazole-4-carboxylic acid 13 in the form of a dark powder.

Example 11

Triptorelin (8H-indeno[1,2-d]thiazol-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid

To a mixture of 8H-indeno[1,2-d]thiazole-2-ylamine 1b (obtained according to example 1, step 2, 94 mg; 0.50 mmol), 1-methyl-1H-imidazole-5-carboxylic acid (65 mg; 0.50 mmol) and reagent THIEF (443 mg; 1.0 mmol) in dry methylene chloride at room temperature is added dropwise diisopropylethylamine (0,55 ml of 3.13 mmol). After 96 hours the reaction mixture is diluted using methylene chloride, and washed with water and then a saturated solution of salt. The organic layer is dried (sodium sulfate), filtered and concentrated in vacuo. After purification using reversed-phase GHUR (eluent: acetonitrile/water/0.1% of triperoxonane acid), while receiving 70 mg of compound 14. Mass spectroscopy high resolution (EI), m/e: calculated for C15H12N4OS (M+) 296,0732 found 296.0728.

Example 12

N-(4,5-Dihydronaphtho[1,2-d]thiazol-2-yl)isonicotinamide

Stage 1: 4,5-dihydronaphtho[1,2-d]thiazol-2-ylamine hydroiodide

A mixture of 1-tetralone (5,00 ml of 37.6 mmol), thiourea (5,72 g, 75.2 mmol) and iodine (9,54 g of 37.6 mmol) was heated to 95°C with stirring. After 4 hours the mixture begins to harden and she is allowed to cool to room temperature. The mixture is diluted using 200 ml of water, after which the solid is filtered off and triturated with absolute ethanol. The solid is washed several times with absolute ethanol, while receiving of 4.00 g of 4,5-dihydronaphtho[1,2-d]thiazole-2-ylamine of hydroiodide 15 in the form of not quite white powder.

Stage 2: N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)isonicotinamide

Add sodium hydride (26 mg; 1.1 mmol) to a stirred suspension of 4,5-dihydronaphtho[1,2-d]thiazole-2-ylamine of hydroiodide 15 in dry tetrahydrofuran under nitrogen atmosphere at room temperature. After 15 minutes add isonicotinohydrazide hydrochloride (107 mg; a 0.60 mmol), the mixture is stirred t is the treatment for 2 hours at room temperature and then concentrated in vacuo. The obtained residue was diluted with water, the obtained solid is filtered off. After purification using reversed-phase GHUR (eluent: acetonitrile/water/0.1% of triperoxonane acid) receive 20 mg of N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)isonicotinamide 16 in the form of salt - trifenatate. Mass high resolution spectroscopy (ES), m/e: calculated for

C17H13N3OS (M+H) 308,0852 found 308,0851.

Example 13

N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)isonicotinamide

Step 1: 5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-ylamine hydroiodide

A mixture of 1-benzocoumarin (1,00 ml, 6.7 mmol), thiourea (1,02 g; a 13.4 mmol) and iodine (1.70 g; 6.7 mmol) is heated to 95°C with stirring. After 20 hours the mixture is allowed to cool down to room temperature, diluted using 200 ml of water, the obtained solid is filtered off, washed twice using 25 ml of water and then diethyl simple ether (3×20 ml), while receiving 1.50 g of hydroiodide 5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-ylamine 17 in the form of not quite white powder.

Stage 2: N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)isonicotinamide

Added at room temperature sodium hydride (17 mg; 0.7 mmol) to a stirred suspension of hydroiodide 5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-ylamine 17 (80 mg, 0.23 mmol) in dry tetrahydrofuran in a nitrogen atmosphere. 15 the minutes add hydrochloride isonicotinohydrazide (62 mg; 0.35 mmol) and the resulting mixture is stirred for 1 hour at room temperature, then concentrated in vacuo. The resulting residue is triturated with water, the obtained solid is filtered off. After purification using reversed-phase GHUR (eluent:acetonitrile/water/0.1% of triperoxonane acid) receive 20 mg of N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)isonicotinamide 18 in the form of salt - trifenatate. Mass spectroscopy high resolution (EI), m/e: calculated for

C18H15N3OS (M+) 321,0936 found 321,0935.

Example 14

N-(4H-Chromeno[4,3-d]thiazol-2-yl)isonicotinamide

Stage 1: 4N-chromeno[4,3-d]thiazole-2-ylamine hydroiodide

A mixture of 4-chromanone (2.00 g; 13.5 mmol), thiourea (of 2.06 g; of 27.0 mmol) and iodine (3,43 g; 13.5 mmol) was heated to 95°C with stirring. After 4.5 hours the mixture is allowed to cool down to room temperature, triturated with methylene chloride, the obtained solid is filtered off. Then the solid is triturated with ethyl acetate, filtered and washed with ethyl acetate, thus obtaining 3.00 g 4H-chromeno[4,3-d]thiazole-2-ylamine of hydroiodide 19 in the form of not quite white powder.

Stage 2: N-(4H-chromeno[4,3-d]thiazol-2-yl)isonicotinamide

Add sodium hydride (19 mg; 0.8 mmol) to a stirred suspension of 4H-chromeno[4,3-d]thiazole-2-ylamine of hydroiodide 19 (90 mg; 0.27 mmol) in dry tetrahydrofuran, atmosphere nitrogen at room temperature. After 15 minutes add the hydrochloride isonicotinohydrazide (62 mg; 0.35 mmol) and then the resulting mixture is stirred for 3 hours at room temperature, then concentrated in vacuo. The obtained residue was diluted with water and then extracted using ethyl acetate. The extract is dried (sodium sulfate), filtered and concentrated in vacuo. After purification using reversed-phase GHUR (eluent: acetonitrile/water/0.1% of triperoxonane acid) to obtain 12 mg of N-(4H-chromeno[4,3-d]thiazol-2-yl)isonicotinamide 20 in the form of salt - trifenatate. Mass high resolution spectroscopy (ES), m/e: calculated for C16H11N3OS (M+H) 310,0645 found 310,0646.

Example 15

N-Oil[1,2-d]thiazole-2-isonicotinamide

Stage 1: the oil[1,2-d]thiazole-2-ylamine hydrobromide

Bromine (0.26 per ml; 5,14 mmol) is added dropwise to a stirred mixture of 2-naphthaleneamine (800 mg; of 3.96 mmol) in dry methylene chloride (10 ml) at room temperature. Then the mixture is refluxed. After 2 hours, the obtained mixture is allowed to cool to room temperature. The solid is filtered off and washed several times with methylene chloride, while receiving 1.12 g of the hydrobromide of oil[1,2-d]thiazole-2-ylamine 21.

Stage 2: N-oil[1,2-d]thiazole-2-isonicotinamide

Add sodium hydride (73 mg, 2.89 mmol) to paramashiva is my suspension of compound 21 (90 mg; 0.27 mmol) in dry tetrahydrofuran under nitrogen atmosphere at room temperature. After 30 minutes add the hydrochloride isonicotinohydrazide (150 mg; 0.84 mmol) and the resulting mixture is stirred for 72 hours at room temperature. The resulting mixture was concentrated in vacuo, the obtained residue is transferred into ethyl acetate and washed with a saturated solution of ammonium chloride. The organic layer is dried (sodium sulfate), filtered and concentrated in vacuo. After purification using reversed-phase GHUR (eluent: acetonitrile/water/0.1% of triperoxonane acid) to obtain 26 mg of N-oil[1,2-d]thiazole-2-isonicotinamide 22. Mass high resolution spectroscopy (ES), m/e: calculated for C17H11N3OS (M+H) 306,0696 found 306,0691.

Example 16

tert-Butyl ester 4-(8H-indenol[1,2-d]thiazole-2-ylcarbonyl)piperidine-1-carboxylic acid

To stir with a magnetic stirrer mixture of mono-tert-butyl ether piperidine-1,4-dicarboxylic acid (195 mg, 0,848 mmol) in CH3CN (10 ml) at room temperature was added 1-Mei (200 ml, 2,52 mmol, firm "Aldrich"). The reaction mixture is cooled in a bath with ice and then add p-toluensulfonate (192 mg, 1.01 mmol, firm "Aldrich"). After stirring in a bath with ice for 30 minutes add 8H-indeno[1,2-d]thiazol-2-ylamine (160 mg, 0.84 mmol). Bath ice is removed and then the reaction mixture was stirred at room temperature for 2 hours. LC/MS analysis indicates total expenditure original substances. The reaction mixture was filtered and the obtained solid is washed with acetonitrile, thus obtaining tert-butyl ester 4-(8H-indenol[1,2-d]thiazole-2-ylcarbonyl)piperidine-1-carboxylic acid (330 mg, yield 99%) as not quite white solid. Mass spectroscopy high resolution: calculated for C21H25N3O3S (M+H)+400,169 found 400,169.

Example 17

(8H-Indeno[1,2-d]thiazol-2-yl)amide 3-(trifloromethyl)piperidine-4-carboxylic acid (44 mg, yield 55.2 per cent)

Stage 1

Removing the protective groups of the tert-butyl ester 4-(8H-indenol[1,2-d]thiazole-2-ylcarbonyl)piperidine-1-carboxylic acid (350 mg, 0,876 mmol) under the action of TFU carried out in accordance with known methods, while receiving (8H-indeno[1,2-d]thiazol-2-yl)amide piperidine-4-carboxylic acid - TFU salt as a white powder (306 mg, yield of 84.5%); mass spectroscopy, high-resolution16H17N3OS (M+H)+m/z: 300,12.

Stage 2

To the mixture (8H-indeno[1,2-d]thiazol-2-yl)amide piperidine-4-carboxylic acid (70 mg; 0,169 mmol) and triethylamine (59 ml; 0.42 mmol) in 10 ml of methylene chloride at room temperature is added dropwise 3-(trifluoromethyl)benzoyl chloride (25 ml; 0,169 mmol). After 24 hours at room temperature the reaction mixture is diluted with, is using ethyl acetate and then washed with 1 N. HCl solution, saturated aqueous NaHCO3, water and saturated salt solution. The organic layer is dried (sodium sulfate), filtered and concentrated in vacuo. The crude product is purified by chromatography (gradient elution, a mixture of 75% ethyl acetate/hexane to 100% ethyl acetate), choosing (8H-indeno[1,2-d]thiazol-2-yl)amide 3-(trifloromethyl)piperidine-4-carboxylic acid (44 mg, yield of 55.2%); mass spectroscopy high resolution: calculated for C24H20N3O3F3S (M+N)+472,1301 found 472,1301.

Example 18

(8H-Indeno[1,2-d]thiazole-2-alamid 1-(3-cryptomaterial-sulfonyl)piperidine-4-carboxylic acid

Similarly receive (8H-indeno[1,2-d]thiazole-2-alamid 1-(3-trifloromethyl)piperidine-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)amide piperidine-4-carboxylic acid (obtained according to example 17, step 1) (60 mg, 0,145 mmol), 3-(trifluoromethyl)benzosulfimide (of 42.6 mg, 0,174 mmol) and triethylamine in the form of a white solid (58 mg, yield 78,9%); mass-high resolution spectroscopy, calculated for C23H20N3O3F3S2(M+N)+508,0971 found 508,0971.

Example 19

1-(3-Trifloromethyl)piperidine-4-carboxylic acid (N-indeno[1,2-d]thiazol-2-yl)amide

To stir magnetic stirrer (Mus) and (8H-indeno[1,2-d]thiazol-2-yl)amide piperidine-4-carboxylic acid (obtained according to example 17, stage 1) (70 mg, 0,169 mmol) in DMF (15 ml, the firm "Aldrich") at room temperature add cesium carbonate (0.5 g, 0,0153 mmol)and then 3-(trifluoromethyl)benzylchloride (26 ml, 0,169 mmol, firm "Aldrich"). The reaction mixture was stirred at room temperature for 3 hours. The crude reaction mixture was filtered and concentrated. After purification using reversed-phase GHUR (eluent: acetonitrile/water/0.1% of triperoxonane acid) receive (N-indeno[1,2-d]thiazol-2-yl)amide 1-(3-trifloromethyl)piperidine-4-carboxylic acid, salt with TFU (33 mg, yield 34,1%) as a white solid; mass spectroscopy high resolution: calculated for C24H22N3OF3S (M+N)+458,1509 found 458,1506.

Example 20

Products - amides 1-19 receive in accordance with the above scheme 1 and described below method in a parallel format.

A mixture of N-methylpyrrolidine-2-about (NMP) solution of carboxylic acid (0.3 M, 1 ml, 0.3 mmol), O-(7-asobancaria-1-yl)-N,N,N, N'-tetramethylurea hexaflurophosphate, HATU (0.3 M, 1 ml, 0.3 mmol) and net diisopropylethylamine (0.05 ml, 0.3 mmol) in vitro with a capacity of 12 ml shaken for 20 minutes at room temperature. Then add aminothiazole in N-MP (0.2 M, 1 ml, 0.2 mmol). The test tube is closed with a stopper and shaken at 90°C for 12 hours. After cooling to room temperature according to the scientists, the reaction mixture is diluted, using ethyl acetate (2 ml) and sodium hydroxide solution (0.5 M, 2 ml). The tubes are shaken for carrying out the extraction and centrifuged to separate the layers. The organic layers are transferred into scintillation vials 20 ml of Water layers again extracted with ethyl acetate thus, as described above. Scintillation vials containing combined an ethyl acetate extracts are then placed in the Genevac evaporator in order to remove all organic solvents. The crude products analyze method GHUR to assess purity and then clean GHUR, while receiving pure amides.

Product 1: N-(8H-indeno[1,2-d]thiazol-2-yl)-3-perbenzoic, 37 mg (yield 60%), purity 100% (LC-MS (LR)calculated 311,06 found 311,03).

Product 2: N-(8H-indeno[1,2-d]thiazol-2-yl)-3-hydroxybenzamide, 2 mg (yield 3%), purity 100% (LC-MS (LR)calculated 309,07 found 309,05).

Product 3: N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylpent-5-unoiled, 31 mg (yield 55%), purity 100% (LC-MS (LR)calculated 285,1 found 285.08).

Product 4: N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylbutanoate, 28 mg (51%yield), purity 100% (LC-MS (LR)calculated 273,1 found 273,09).

Product 5: N-(8H-indeno[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid, 63 mg (yield 84%), purity 100% (LC-MS (LR)calculated 377,01 found 377,03).

Product 6: N-(8H-indeno[1,2-d]thiazol-2-yl)-2-furosemid, 53 mg (yield 95%), purity 100% (LC-MS (LR), wycislo,05, found 283,04).

Product 7: N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-4-hydroxynicotinate, 2 mg (yield 3%), purity 100% (LC-MS (LR)calculated 328,05 found 328,06).

Product 8: N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl) (4-aminosulfonyl)benzamid, 7 mg (yield 9%), purity 100% (LC-MS (LR)calculated 390,03 found 390,03).

Product 9: N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl) (4-tert-butoxycarbonylmethyl)benzamid, 14 mg (yield 16%), purity 100% (LC-MS (LR)calculated 440,14 found 440,19).

Product 10: N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)thiophene-3-carboxamide, 10 mg (yield 16%), purity 100% (LC-MS (LR)calculated 317,08 found 317,07).

Product 11: N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4-hydroxynicotinate, 4 mg (yield 6%), purity 100% (LC-MS (LR)calculated 234,08 found 324,08).

The product is 12: N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)thiophene-3-carboxamide, 10 mg (yield 16%), purity 100% (LC-MS (LR)calculated 213,04 found 313,03).

Product 13: N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl) 4-hydroxynicotinate, 2 mg (yield 3%), purity 100% (LC-MS (LR)calculated 354,09 found 354,09).

Product 14: N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid, 15 mg (yield 18%), purity 100% (LC-MS (LR)calculated 421,03 found 421,02).

Product 16: N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)-4-hydroxynicotinate, 10 mg (yield 15%), purity 100%, (LC-MS (LR)calculated 338,09 found 338,19).

Product 17: N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene--yl) thiophene-3-carboxamide, 22 mg (yield 34%), purity 100%, (LC-MS (LR)calculated 327,06 found 327,12).

Product 18: N-(8H-indeno[1,2-d]thiazol-2-yl)-3-chloro-4-hydroxybenzamide, GHSD 16 mg (yield 23%), purity 100% (LC-MS (LR)calculated 343,03 found 343,07).

Product 19: N-(8H-indeno[1,2-d]thiazol-2-yl) (4-aminosulfonyl)benzamid, 10 mg (yield 13%), purity 100% (LC-MS (LR)calculated 372,04 found 373,06).

Example 21

Inhibitory activity against NECA-induced production of cyclic AMP in cells SNACK expressing adenosine AV-receptor human.

The ovarian cells of Chinese hamsters (SNOC stable transfection with adenosine AV-receptor human studies using cDNA-4b. Cells are grown in an atmosphere of 5% CO2/ 95% O2at 37°C in DMEM and D-MEM/F-12 (mixture in ratio 1:1) (firm Invitrogen, Grand island, new York (U.S. state)) with 10% fetal calf serum (firm Invitrogen, Grand island, new York (U.S. state)), 100 U/ml penicillin (firm Invitrogen, Grand island, new York (U.S. state)), 100 U/ml streptomycin (firm "Invitrogen", Grand island, new York (U.S. state)), 1 mg/ml G418 (firm Invitrogen, Grand island, NY) and 0.2 mg/ml hygromycin (firm Invitrogen, carlsbad, California (US state)). Experimental culture grown over night in the form of a monolayer in 384-well tablets for tissue culture (0.06 ml/well - 7500 cells/well). Each well was washed with the once using 0.1 ml of Krebs buffer. To each well add 50 ál of Krebs buffer containing 100 μm inhibitor of phosphodiesterase Ro20-1724 (firm Roche), 100 nm NECA (company "Sigma-Aldrich, St. Louis, MO), 0.02% BSA, fraction V, Roche Biochemicals"), test the connection (the corresponding concentration). The final concentration of DMSO is 1.1%. After incubation for 30-45 min hole free and get wet a paper towel to remove residual solvent. For lizirovania cells and measuring the concentration camp uses a set of "HitHunter™ cAMP Assay Kit" company "DiscoverX for adhesive cells (Fremont, California (US state)). Compounds according to examples 1-20 are characterized by values of the IC50the components of <5 μm. The following table shows the values of the IC50obtained for the compounds according to some examples.

ExampleAV camp IC50[mm]
20,41
50,14
120,55

Example

Tablets with the shell containing the following ingredients can be obtained in the conventional way.

1.6 mg
IngredientsPills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Lactose water60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Sodium salt of starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)120,0 mg350,0 mg
Film coating:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient is sifted and mixed with microcrystalline cellulose, and then the resulting mixture granularit using a solution of polyvinylpyrrolidone in water. The obtained granules are mixed with the sodium salt starch glycolate and magnesium stearate, and then pressed while receiving core tablets weighing 120 or 350 mg, respectively. The core tablets are coated using an aqueous solution/suspension of the above components to obtain a film coating.

Example B

Capsules containing the following ingredients can be obtained in the conventional way:

IngredientsOn capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Ingredients sifted, mixed and placed into capsules of size 2.

The example In

Prepare injectable solutions of the following composition:

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidIn the quantity required to reach pH 5.0
Water for the preparation of solutions for injectionIn an amount necessary to bring the volume to 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and part of the specified quantity of water for injection. The pH value is brought to a magnitude of 5.0 by addition of acetic acid. The volume was adjusted to 1.0 ml by adding the rest of the water. The solution is filtered, filled them vials of appropriate volume and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained in the conventional way:

The contents of the capsules
Connect four is ula (I) 5.0 mg
Yellow wax8.0 mg
Hydrogenated soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide yellow1.1 mg

The active ingredient is dissolved in warm softened mass, including the other ingredients, then the mixture is filled soft gelatin capsules of appropriate size. Filled gelatin capsules are used for treatment in accordance with conventional methods.

Example F

The bags containing the e following ingredients, can be obtained in the conventional way:

The compound of formula (I)50.0 mg
Lactose, fine powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
Sodium salt of carboxymethylcellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Stirrat magnesium10.0 mg
Flavouring agents1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose, sodium salt of carboxymethyl cellulose and subjected to granulation with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavouring additives and fill the mixture sachets.

1. The compound of formula (I)

or its pharmaceutically acceptable salt,
where X represents-CH2-, -CH2CH2-, -(CH2)3and O(CH2)-;
R represents a 5-or 6-membered saturated or unsaturated of carbon Klionsky or heterocyclic ring system, which optionally may contain one or more heteroatoms selected from N, O and S, and the specified ring system optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsulfonyl, benzyl, benzoyl, phenylsulfonyl, and the specified benzyl, benzoyl or phenylsulfonyl optionally substituted with halogen, a group trichloranisole alkyl;
R1selected from the group consisting of hydrogen, halogen or lower alkoxygroup.

2. Compounds according to claim 1, which correspond to the formula (IA)

or their pharmaceutically acceptable salts,
where X represents-CH2-, -CH2CH2-, -(CH2)3and O(CH2)-;
R represents a 5 - or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms selected from N, O and S, and the specified ring system optionally substituted by one or more substituents, selected from the group consisting of halogen, lower alkyl, nitrile group and a lower alkylsulfonyl.

3. Compounds according to claim 1, where R represents a 5 - or 6-membered ring on sennou or unsaturated carbocyclic or heterocyclic ring system, which optionally may contain one or more heteroatoms selected from N, O and S, and the specified ring system optionally substituted by one or more substituents, selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxycarbonyl, nitrile groups, sulfonamide, lower alkylsulfonyl, benzyl, benzoyl, phenylsulfonyl and acyl specified benzyl, benzoyl or phenylsulfonyl optionally substituted with halogen or a group trichloranisole alkyl.

4. Compounds according to any one of claims 1 to 3, where X represents-CH2-.

5. Compounds according to any one of claims 1 to 4, where R is a phenyl or heterocyclic ring system selected from the group which consists of tanila, pyridinyl, pyrazolyl, imidazolyl, Shrila or piperidinyl specified phenyl or heterocyclic ring system optionally substituted with substituents in an amount of from 1 to 3, selected from the group consisting of halogen, hydroxy, nitrile, lower alkyl, sulfonamide, lower alkylsulfonyl, lower alkoxycarbonyl, benzyl, which is optionally substituted radical CF3, benzoyl, which is optionally substituted radical CF3or phenylsulfonyl, which is optionally substituted radical CF3.

6. Compounds according to any one of claims 1 to 5, where R pre which is a heterocyclic ring system, selected from the group which consists of tanila, pyridinyl, pyrazolyl, imidazolyl, Shrila or piperidinyl specified heterocyclic ring system optionally substituted with substituents in an amount of from 1 to 3, selected from the group consisting of halogen, hydroxy, nitrile, lower alkyl, sulfonamide, lower alkylsulfonyl, lower alkoxycarbonyl, benzyl, which is optionally substituted radical CF3, benzoyl, which is optionally substituted radical CF3or phenylsulfonyl, which is optionally substituted radical CF3.

7. Compounds selected from the group consisting of the following compounds:
N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,
4-fluoro-N-(8H-indeno [1,2-d]thiazol-2-yl)benzamid,
4-cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)benzamid,
N-(8H-indeno [1,2-d]thiazol-2-yl)-4-methylbenzamide,
thiophene-2-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)amide,
N-(8H-indeno[1,2-d]thiazol-2-yl)nicotinamide,
N-(8H-indeno [1,2-d]thiazol-2-yl)isonicotinamide,
(8H-indeno[1,2-d]thiazol-2-yl)amid-methyl-2H-pyrazole-3-carboxylic acid,
N-(6-chloro-8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide,
(8H-indeno[1,2-d]thiazol-2-yl)amide 1H-pyrazole-4-carboxylic acid,
N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)isonicotinamide,
N-(4H-chromeno[4,3-d]thiazol-2-yl)isonicotinamide,
N-oil [1,2-d]thiazole-2-isonicotinamide, and
triptorelin (8H-indeno[1,2-a]thiazol-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid.

8. Compounds selected from the group consisting of the following compounds:
tert-butyl ester 4-(8H-indenol [1,2-d]thiazole-2-ylcarbonyl)piperidine-1-carboxylic acid,
(8H-indeno[1,2-d]thiazol-2-yl)amide 3-(trifloromethyl)piperidine-4-carboxylic acid,
(N-indeno[1,2-d]thiazol-2-yl)amide 1-(3-trifloromethyl)piperidine-4-carboxylic acid,
(8H-indeno[1,2-d]thiazole-2-alamid 1-(3-trifloromethyl)piperidine-4-carboxylic acid,
N-(8H-indeno[1,2-d]thiazol-2-yl)-3-perbenzoic,
N-(8H-indeno[1,2-d]thiazol-2-yl)-3-hydroxybenzamide,
N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylpent-5-unoiled,
N-(8H-indeno[1,2-d]thiazol-2-yl)-2-methylbutanoate,
N-(8H-indeno[1,2-d]thiazol-2-yl)-5-methylsulfonylmethane-2-carboxamid,
N-(8H-indeno [1,2-d]thiazol-2-yl)-2-furosemid, and
N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)4-hydroxynicotinic.

9. Compounds selected from the group consisting of the following compounds:
N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-(4-aminosulfonyl)benzamid,
N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-(4-tert-butoxycarbonyl-methyl)benzamide,
N-(6-fluoro-8H-indeno[1,2-d]thiazol-2-yl)-thiophene-3-carboxamide,
N-(4,5-dihydronaphtho[1,2-d]]thiazol-2-yl)-4-hydroxynicotinate,
N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-thiophene-3-carboxamide,
N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-4-hydroxynicotinate,
N-(4,5-dihydro-7-myoxidae[1,2-d]thiazol-2-yl)-5-methylsulphonyl-thiophene-2-carboxyamide,
N-(5,6-dihydro-4H-3-thia-azabenzo[e]azulene-2-yl)-4-hydroxynicotinate,
N-(5,6-dihydro-4H-3-thia-1-azabenzo[e]azulene-2-yl)-thiophene-3-carboxamide,
N-(8H-indeno[1,2-d]thiazol-2-yl)-3-chloro-4-hydroxybenzamide, and
N-(8H-indeno[1,2-d]thiazol-2-yl)-(4-aminosulfonyl)benzamide.

10. Pharmaceutical composition having the properties of an antagonist of adenosine AV receptor comprising an effective amount of a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier and/or excipient.

11. The compounds of formula (I)as defined in any one of claims 1 to 9, for use as therapeutically active compounds with the properties of the antagonist of adenosine AV receptor.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to mono-sodium salt 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazole[4,5-d]pyrimidine-2(3H)-on as a modulator of the activeness of chemokine receptors, method of obtaining it and pharmaceutical composition on its basis, and also its application in production of medicinal agents.

EFFECT: obtaining compounds, which can find application in treatment of diseases mediated by chemokine receptors, such as asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), inflammatory bowel disease, osteoarthritis, and rheumatoid arthritis.

10 cl, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention was targeted at obtaining crystals of acetonitrile solvate of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (compound B), which is an intermediate compound in obtaining crystals of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of III type (compound A). Compound B crystals are mostly precipitated by regulation of super-saturation during crystallisation involving acetonitrile as a solvent. Then compound A crystals of III type are obtained crystal desolvation.

EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to cyclic sulphonamide derivatives of general formula I where bonds indicated with wavy lines represent mutually cis- in relation to cyclohexane ring; R3 represents H or hydrocarbon group having up to 10 carbon atoms; Ar1 and Ar2 independently represent phenyl which carries 0-3 substitutes independently selected from halogen, CF3, CHF2; or its pharmaceutically acceptable salt. Besides, invention refers to technology of compounds of general formula I and to pharmaceutical composition based on compounds of general formula I and applied as gamma-secretase inhibitor.

EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

The invention relates to the use as a medicinal substance medications for the treatment of diseases associated with impaired venous function and/or inflammatory edema tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and its new compounds of General formula I, where a is either a sulfur atom, oxygen or the radical R3N, where R3is a hydrogen atom, a C1-C5-alkyl; R1is either1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted group selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, methyl, phenyl; R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, and methoxy; and pharmaceutically acceptable salts

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

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, 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

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2
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