2-aminopyridine derivatives, pharmaceutical composition containing the same and method for therapy

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

 

The technical field

The present invention relates to a new connection, 2-aminopyridine, the method of its production and use as a medicine.

Prior art

Adenosine is an important regulatory factor involved in various types of intracellular metabolism, such as regulation of energy levels and camp levels in the body, the opening and closing of calcium channels, influx of calcium ions into cells, and can exhibit its physiological activity when interacting with conjugated with G-protein receptors on the cell surface. Adenosine receptors are primarily divided into 2 classes, i.e. A1-a receptor and a2-receptor, on the basis of their participation in the functioning of adenylate cyclase (J. Neurochem., 33, 999-1003 (1997)), and then A2the receptor is divided into two subtypes, i.e. A2Aand a2Bon the basis of their affinity against NECA and CGS-21680 (Mol. Pharmacol., 29, 331-346 (1986); J. Neurochem., 55, 1763-1771 (1990)), which are agonists of adenosine A2-receptor. Thus, to date, identified 4 receptor subtypes A1, A2(A2AAnd2Band a3. And2a receptor is a protein which is conjugated with family protein Gi/o. Upon binding with the ligands it inhibits adenylate cyclase with a decrease in camp levels aktiveret the phospholipase C (PLC) with increased production of Inositol-1,4,5-triphosphate (IP 3and release of intracellular calcium ions. It is known that similar to A1-receptor, And3the receptor is a receptor that reduces camp levels and activates PLC with increased production IP3and release of intracellular calcium ions. On the other hand, A2Aand And2Breceptors are activating adenylate cyclase and increases the production of camp levels. It was also reported that A2Banywhereman with PLC via protein Gq/G11and increases the production level IP3and the influx of calcium ions into cells (Clin. Invest., 96, 1979-1986 (1995)). These subtypes differ from each other in their tissue distribution, i.e. A1the receptor is in a fairly large number in the heart, aorta, bladder, etc. And2receptor-in the eyeball, skeletal muscle, etc. And3-receptor - spleen, uterus, prostate, etc., while A2Bthe receptor is in a fairly large number proximally to a thick intestine and in the eyeball, lung, uterus, and urinary bladder (Br. J. Pharmacol., 188, 1461-1468 (1996)). The reason that the subtypes of adenosine receptors can exhibit their inherent functions, is the difference in their tissue distribution, the difference in local levels of adenosine and the difference in affinity of each subtype in respect of the ligands. Adenosine is involved in different is cnyh physiological functions, such as agglutination of platelets, heart beats, smooth muscle contraction, inflammatory response, release of neurotransmitters, the transmission of nerve excitation, the release of hormones, cell death, DNA biosynthesis, etc. on the basis of which we can assume the existence of a relationship of adenosine with diseases in neutral nerves, cardiovascular diseases, inflammatory diseases, diseases of the respiratory organs, immune diseases and so on, thus, expected utility agonists/antagonists of adenosine receptors in the treatment of these diseases. On the one hand, in recent years we have made important messages about the relationship between adenosine A2receptor and intestinal tract. For example, it was reported that relaxing effect on the longitudinal muscle of the colon is mediated And2receptor (Naunyn-Schmiedeberg''s Arch. Pharmacol., 359, 140-146 (1999)), and that the relaxing effect of adenosine on the reduction of the far longitudinal muscles of the colon in Guinea pigs is mediated by A1receptor and A2Breceptor in the longitudinal muscle (Br. J. Phannacol., 129, 871-876 (2000)). In addition, it was noted that antagonists of adenosine receptors, particularly adenosine A2-receptor, suitable as a means for the treatment or prevention of diabetes complications on the Abete, diabetic retinopathy, obesity or asthma, and it is assumed that they are useful as hypoglycemic agents, means of improving impaired glucose tolerance, means that increase sensitivity to insulin, antihypertensives, diuretics, medicines for treatment of osteoporosis, anti-Parkinson, anti-Alzheimer's disease, a treatment for inflammatory bowel disease or for the treatment of Crohn's disease etc.

For example, there are the following reports of the compounds having antagonistic action, particularly in relation to And2B-receptor.

(1) Compounds represented by the formulas:

(2) Purine derivatives represented by the formula:

(in which R1represents (1) formula:

(in which X represents a hydrogen atom, hydroxyl, optionally substituted lower alkyl; optionally substituted lower alkoxy, etc.; R5and R6are the same or different from each other, and each represents a hydrogen atom, optionally substituted lower lcil, optionally substituted saturated or unsaturated With3-8cycloalkyl etc.) or (2) a 5-6-membered aromatic ring which may have a substituent and heteroatom; W represents the formula-CH2CH2-, -CH=CH - or-C≡ -; R2represents an amino group which may be substituted by an optionally substituted lower alkyl etc, etc.; R3represents optionally substituted C3-8cycloalkyl, optionally substituted aryl, etc.; R4represents optionally substituted lower alkyl etc) or their pharmacologically acceptable salt or hydrate (JP-A-11-263789).

(3) Purine derivatives represented by the formula:

(in which R1represents a hydrogen atom, hydroxyl, halogen atom, optionally substituted C1-8alkyl, etc.; R2represents an amino group which may be substituted With1-8the alkyl etc.; R3is3-8quinil, which may be substituted by halogen atom, hydroxyl or1-4the alkyl etc.; AG represents optionally substituted aryl, optionally substituted heteroaryl etc.; and Q and W are the same or different from each other, and each represents N or CH), their pharmacologically acceptable salt or hydrate.

(4) Antagonists And2Breceptors described in Drug Development Reearch, 48, 95-103 (1999) and J. MecL Chem., 43, 1165-1172 (2000).

On the one hand, in respect to the pyridine compounds, for example, there are reports concerning 5,6-aromatic substituted pyridine compounds in WO 96/24584, application for U.S. patent 5686470 and the application for U.S. patent 5916905. In addition, in DE-A1 4117802 reported 2-amino-3-pyridylcarbonyl and connection, in which the 4-, 5 - and 6-th position of the pyridine ring substituted phenyl groups. However, it is not described or assumed relationship of these compounds with adenosine receptor, and it is quite unknown.

As described above, it is assumed that compounds with antagonism against adenosine receptor, especially the antagonism of adenosine A2the receptor (in particular, a2b-receptor) will show high activity as pharmaceuticals, so it is advisable to get them. However, these compounds with high antagonism against adenosine receptor and is also effective as a medicinal product have not been established. Therefore, the aim of the present invention is the search for and establishment of inhibitory receptor compounds which are suitable as a means for the treatment or prevention of disease, which is the ratio of adenosine receptor (in particular, a2-a receptor, And2b-Rotz is a torus).

Description of the invention

Taking into account the above circumstances, there has been extensive research. The result was first achieved success in the synthesis of compounds represented by the formula:

(in which R1represents cyano, carboxyl or optionally substituted carbarnoyl; R2represents a hydrogen atom, hydroxyl, optionally substituted C1-6alkoxy, optionally substituted C6-14aromatic hydrocarbon cyclic group or optionally substituted 5 to 14-membered aromatic heterocyclic group; and R3and R4are the same or different from each other, and each represents C3-8cycloalkyl,3-8cycloalkenyl,6-14aromatic hydrocarbon cyclic group, a 5 to 14-membered non-aromatic heterocyclic group or a 5 to 14-membered aromatic heterocyclic group which may have a Deputy, respectively, provided that excluded the cases where (1) R1is cyano, R2is 4-bromo-2-thienyl, R3is 3,4-acid and R4is 2-thienyl, (2) R1is cyano, R2represents a hydrogen atom and each of R3and R4represents phenyl, (3) R1is cyano, R2is 4 arvanil, R3represents phenyl and R4is 4-(3,4-dichlorophenyl)-l-oxo-2-(1H)-phthalazine, (4) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 1-piperazinil, (5) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 1-pyridyl, (6) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 4-diphenylmethyl-1-piperazinil, (7) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 4-morpholinyl, (8) R1is cyano, R2is 4-were and each of R3and R4represents phenyl, and (9) R1represents cyano and each of R2, R3and R4is phenyl) or its salt, and unexpectedly it was found that this compound and its salt have high antagonistic effect on adenosine A2-a receptor, in particular, a2Bthe receptor. As a result of further intensive studies, it was found that this compound and its salt is useful not only as a means for the treatment, prevention or relief of disease, which is the ratio of the adenosine receptor, in particular. the 2-a receptor, in particular, a2B-a receptor, for example, constipatio, irritable bowel syndrome, constipatio accompanying irritable bowel syndrome, organic constipatio, constipatio accompanying enteroparasites ileus, constipatio accompanying congenital dysfunction of the digestive tract, constipatio accompanying ileus, diabetes, complications of diabetes, diabetic retinopathy, obesity, asthma, etc. but is also useful as hypoglycemic agents, agents for improving impaired glucose tolerance, means that increase sensitivity to insulin, antihypertensives, diuretics, medicines for treatment of osteoporosis, anti-Parkinson, anti-Alzheimer's disease, means for treatment of inflammatory bowel diseases, for the treatment of Crohn's disease and the like, and thus was accomplished the present invention.

That is, the present invention relates to (1) the compound represented by the above formula (I) or its salts; (2) connection on one of the above p.(1) or salts thereof in which R1represents cyano, (3) connection on one of the above p.(1) or salts thereof in which R1is carbarnoyl represented by the formula:

(in which R5and R6 are the same or different from each other, and each represents a hydrogen atom, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6quinil, optionally substituted C6-14aromatic hydrocarbon cyclic group or optionally substituted 5 to 14-membered aromatic heterocyclic group); (4) the compound according to the above p.(1) or salts thereof in which R2represents C6-14aromatic hydrocarbon cyclic group or a 5-6-membered aromatic heterocyclic group, each of which may have a Deputy; (5) the compound according to the above p.(1) or salts thereof in which R2represents phenyl, naphthyl, pyridyl, thienyl or furyl, each of which may have a Deputy; (6) the compound according to the above p.(1) or salts thereof in which R2represents phenyl which may be substituted by a halogen atom; (7) the compound according to the above p.(1) or salts thereof in which R2represents a hydrogen atom; (8) the compound according to the above p.(1) or salts thereof in which R3and R4are the same or different from each other, and each represents C6-14aromatic hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group, each of which is Oh may have a Deputy; (9) the compound according to the above p.(1) or salts thereof in which R3and R4are the same or different from each other, and each represents phenyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, chinoline, ethenolysis, phthalazine, naphthyridine, indolyl or isoindolyl, each of which may have a Deputy; (10) the compound according to the above p.(1) or its salt, in which each of R3and R4represents phenyl, pyridyl, thienyl or furyl, which respectively may have a Deputy; (11) the compound according to the above p.(1) or salts thereof in which R3and/or R4represents a 5 to 14-membered non-aromatic heterocyclic group, a C6-14aromatic hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group, each of which may be substituted by at least one group selected from the following group of substituents and (as indicated above group of substituents and represents the group consisting of (1) hydroxyl, (2) halogen atom, (3) nitrile, (4) nitro, (5) C1-6of alkyl, C2-6alkenyl or2-6Akinola, each of which may be substituted by at least one group selected from (i) hydroxyl, (ii) nitrile, (iii) halogen atom, (iv) C1-6alkylamino, (v) di (C1-6alkyl) amino, (vi)2-6 alkynylamino, (vii) di (C2-6alkenyl) amino, (viii)2-6alkynylamino, (ix) di (C1-6quinil) amino, (x) N-C1-6alkyl-N-C2-6alkynylamino, (xi) N-C1-6alkyl-N-C2-6alkynylamino, (xii) N-C2-6alkenyl-N-C2-6alkynylamino, (xiii) aralkylated, (xiv) TBDMS, (xv) C1-6alkylsulfonyl, (xvi) C1-6alkylcarboxylic, (xvii)2-6alkenylboronic, (xviii)2-6alkylcarboxylic, (xix) N-C1-6allylcarbamate, (xx) N-C2-6alkenylamine and (xxi) N-C1-6alkynylaryl, (6) C1-6alkoxy, C2-6alkenylacyl or2-6alkyloxy, each of which may be substituted by at least one group selected from (i) C1-6alkylamino, (ii) aralkylated and (iii) hydroxyl, (7) C1-6alkylthio,1-6alkanity or2-6alkylthio, each of which may be substituted by at least one group selected from (i) hydroxyl, (ii) nitrile, (iii) halogen atom, (iv) C1-6alkylamino, (v) aralkylated, (vi) DS, (vii) C1-6alkylsulfonyl, (viii) C1-6alkylcarboxylic and (ix) C1-6allylcarbamate, (8) a carbonyl substituted by a group selected from (i) C1-6alkoxy, (ii) amino, (iii) C1-6alkylamino, (iv) di (C1-6alkyl) amino, (v)2-6alkynylamino, (vi) di (C2-6alkenyl)amino, (vii)2-6alkynylamino, (vii) di (C2-6quinil) amino, (viii) N-C-6 alkyl-N-C2-6alkynylamino, (ix) N-C1-6alkyl-N-C2-6alkynylamino and (x) N-C2-6alkenyl-N-C2-6alkynylamino, (9) amino which may be substituted by one or two groups selected from (i) C1-6of alkyl, (ii)2-6alkenyl, (iii)2-6the quinil, (iv) C1-6alkylsulfonyl, (v)2-6alkanesulfonyl, (vi)2-6alkylsulfonyl, (vii) C1-6alkylsulphonyl, (viii)2-6alkenylboronic and (ix)2-6alkynylaryl, (10) C1-6alkylsulfonyl, (11)2-6alkanesulfonyl, (12) C1-6alkylsulfonyl, (13) C1-6alkylsulfonyl, (14)2-6alkanesulfonyl, (15)2-6alkylsulfonyl, (16) formyl, (17)3-8cycloalkyl or3-8cycloalkenyl, each of which may be substituted by at least one group selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6-alkoxy-C1-6of alkyl and (vii) aralkyl, (18) 5-14-membered non-aromatic heterocyclic group which may be substituted by at least one group selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6alkoxy-C1-6of alkyl and (vii) aralkyl, (19)6-14aromatic hydrocarbon cyclic group which may be substituted by at least one group which, selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6alkoxy-C1-6of alkyl and (vii) aralkyl, and (20) 5-14-membered aromatic heterocyclic group which may be substituted by at least one group selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi) C1-6alkoxy-C1-6of alkyl and (vii) aralkyl); (12) the compound according to the above p.(1) or salts thereof in which R3and/or R4represents phenyl, pyridyl, thienyl or furyl, each of which may be substituted by at least one group selected from hydroxyl, halogen atom, a C1-6the alkyl and C1-6alkoxy; (13) the compound according to the above p.(1) or salts thereof in which R3or R4is 6-oxo-1,6-dihydropyridin, which may have a Deputy; (14) the compound according to the above p.(1)represented by the formula:

(in which R1represents cyano, carboxyl or optionally substituted carbarnoyl; R2represents a hydrogen atom, hydroxyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylthio, optionally substituted C6-14aromatic hydrocarbon cyclic group or optionally substituted 5 to 14-membered aroma is ical heterocyclic group; R7represents a group selected from the following group of substituents b; R8is6-14aromatic hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group which may have a Deputy; and ring a represents a nitrogen-containing 6-membered ring which may be substituted by 1-4 groups selected from the following group of substituents b;

"the group of substituents b"consisting of a hydrogen atom, halogen atom, hydroxyl, nitro, cyano, optionally substituted C1-6the alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxy, optionally substituted C2-6alkenylacyl, optionally substituted C2-6alkyloxy, optionally substituted C1-6alkylthio, optionally substituted C2-6alkanity, optionally substituted C2-6alkylthio,2-7aliphatic acyl group, optionally substituted of carbamoyl, Ariella, heteroaromatic, optionally substituted amino, optionally substituted C1-6alkylsulfonyl, optionally substituted C2-6alkanesulfonyl, optionally substituted C2-6alkylsulfonyl, optionally substituted C1-6alkylsulfonyl, long is correctly replaced With 2-6alkanesulfonyl, optionally substituted C2-6alkylsulfonyl, formyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted 5 to 14-membered non-aromatic heterocyclic group, optionally substituted C6-14aromatic cyclic hydrocarbon group and optionally substituted 5 to 14-membered aromatic heterocyclic group) or its salt; (15) the compound according to the above p.(14) or its salts, in which R1represents cyano; (16) the compound according to the above p.(14) or its salts, in which R1is carboxyl; (17) the compound according to the above p.(14) or its salts, in which R1is carbarnoyl represented by the formula:

in which R5and R6have the meanings defined above; (18) the compound according to the above p.(14) or its salts, in which R2represents a hydrogen atom; (19) the compound according to the above p.(14) or its salts, in which R7and deputies, other than R7in the ring And selected from the above group of substituents and; (20) the compound according to the above p.(14) or its salts, in which R7represents a hydrogen atom, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl yl is optionally substituted C 1-6alkoxy; (21) the compound according to the above p.(14) or its salts, in which R8represents phenyl, pyridyl, furyl or thienyl, each of which may have a Deputy; (22) the compound according to the above p.(14) or its salts, in which R8represents phenyl, pyridyl, furyl or thienyl, each of which may be substituted by a halogen atom; (23) the compound according to the above p.(1), where the compound is selected from

2-amino-6-(2-furyl)-5-(4-pyridyl)-3-pyridylcarbonyl,

2-amino-6-(3-forfinal)-5-(4-pyridyl)-3-pyridylcarbonyl,

2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl,

2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide,

2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinanilide,

2-amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide,

2-amino-6-(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide and

2-amino-6-(3-forfinal)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide or its salts; (24) a pharmaceutical composition comprising the compound represented by the formula:

(in which R1represents cyano, carboxyl or optionally substituted carbarnoyl; R2represents a hydrogen atom, hydroxyl, optionally substituted C1-6alkoxy, optionally substituted C6-14and ematichesky hydrocarbon cyclic group or optionally substituted 5 to 14-membered aromatic heterocyclic group; and R3and R4are the same and differ from each other, and each represents C3-8cycloalkyl,3-8cycloalkenyl,6-14aromatic hydrocarbon cyclic group, a 5 to 14-membered non-aromatic heterocyclic group or a 5 to 14-membered aromatic heterocyclic group which may have a Deputy, respectively, provided that excluded the cases where (1) R1is cyano, R2is 4-bromo-2-thienyl, R3is 3,4-acid and R4is 2-thienyl, (2) R1is cyano, R2represents a hydrogen atom and each of R3and R4represents phenyl, (3) R1is cyano, R2represents 4-chlorophenyl, R3represents phenyl and R4is 4-(3,4-dichlorophenyl)-1-oxo-2-(1H)-phthalazine, (4) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 1-piperazinil, (5) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 1-pyridyl, (6) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 4-diphenylmethyl-1-piperazinil, (7) R1is cyano, R2represents a hydrogen atom, R 3is 4-pyridyl and R4is 4-morpholinyl, (8) R1is cyano, R2is 4-were and each of R3and R4represents phenyl, and (9) R1represents cyano, and each of R2, R3and R4represents phenyl or its salt; (25) the composition according to the above p.(24), which is an agent for the treatment or prevention of disease, which is the ratio of adenosine receptor; (26) the composition according to the above p.(24), which is an agent for the treatment or prevention of disease, which is the ratio of adenosine A2receptor; (27) the composition according to the above p.(24), which is an agent for the treatment or prevention of disease, which is the ratio of adenosine A2Breceptor; (28) the composition of the above p.(24), which is an antagonist of adenosine receptor; (29) the composition according to p.(24), which is an antagonist of adenosine A2receptor; (30) the composition according to the above p.(24), which is an antagonist of adenosine A2Breceptor; (31) the composition of the above p.(24)used for amplification of defecation; (32) the composition of the above p.(24), which is a tool for the treatment, prevention and olabl is of constipatio; (33) the composition of the above p.(24), where the higher is the functional higher; (34) the composition of the above p.(24), which is a treatment for irritable bowel syndrome, constipatio accompanying irritable bowel syndrome, organic constipatio, constipatio accompanying enteroparasites ileus, constipatio accompanying congenital dysfunction of the digestive tract or constipatio accompanying ileus; (35) the composition of the above p.(24)used to delete the contents of the intestinal tract during the examination of the digestive tract or before and after surgery; (36 song at the above p.(24), which is an agent for the treatment or prevention of diabetes, complications of diabetes, diabetic retinopathy, obesity or asthma; (37) the composition of the above p.(24), which is a hypoglycemic agent, a means for improving impaired glucose tolerance and a means of enhancing insulin sensitivity; (38) the composition of the above p.(24), which is an antihypertensive agent, a diuretic, a treatment for osteoporosis, anti-Parkinson, anti-Alzheimer's, tool for the treatment of inflammatory bowel disease, with adsto for the treatment of Crohn's disease etc.

That is, the present invention is a pharmaceutical composition comprising the above compound 2-aminopyridine or its pharmacologically acceptable salt and a pharmaceutically acceptable carrier, the use of the above compound or its pharmacologically acceptable salts for obtaining funds for the treatment or prevention of disease, which is the ratio of the adenosine receptor, and a method of treatment or prevention of disease, which is the ratio of the adenosine receptor, the introduction of a pharmacologically effective dose of the above compound or its pharmacologically acceptable salt to a patient.

Detailed description of the invention

In further explains the meaning of symbols, terms, etc. used in the present description, and describes in detail the present invention.

“Antagonist” in this description refers to an agent that has affinity against adenosine receptors, particularly adenosine A2receptor (most preferably As2B-receptor), and inactivating the receptor.

In this description of the disease, which is the ratio of adenosine receptor” means a disease to which is the ratio of adenosine A1-a receptor, And2A-a receptor, And2b-receptor or a3the receptor. For example, it is RA who personal the kinds of constipatio, irritable bowel syndrome, a higher-accompanying irritable bowel syndrome, organic higher, higher, accompanying enteroparasites ileus, a higher-accompanying congenital dysfunction of the digestive tract, the higher accompanying ileus, diabetes, complications of diabetes, diabetic retinopathy, obesity, asthma or a disease against which an effective hypoglycemic agent, agent for improving impaired glucose tolerance, means that increase sensitivity to insulin, antihypertensive agent, a diuretic, a treatment for osteoporosis, anti-Parkinson, anti-Alzheimer's disease, for the treatment of inflammatory bowel disease, treatment for disease Krona.

The term “and/or”used in this description, refers to both “and”and “or”.

Structural formulas of the compounds in this description may be convenient to specify a specific isomer, but the present invention includes all the possible isomers, which may be formed in the structures of the compounds, for example, geometric isomer, optical isomer based on an asymmetric carbon, torque isomer, stereoisomer and tautomer, as well as mixtures of such isomers, so that the connection invented the Yu may be any isomer or mixture without limitation formulas presents for convenience. Therefore, the connection of the present invention may be intramolecular asymmetric carbon with the advent in the form of optically active isomers or racemic modifications, and any of these compounds included in the present invention without limitation. In addition, it may be a polymorphism of crystals without restrictions, and it can be a single crystal or a mixed crystal form. The compound (I) of the present invention or its salt may be anhydrides or hydrates, any of which is subject to the claims in the present description. The metabolites formed during transformation of compound (I) of the present invention in vivo, as well as prodrugs of compound (I) of the present invention or its salt is also subject to the claims in the present description.

“Halogen atom”used in this description, includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom, etc. and preferred are a fluorine atom, a chlorine atom and a bromine atom.

“C1-6alkyl”, as used herein, refers to an alkyl containing 1-6 carbon atoms, and its examples include linear or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl is l, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-ethylpropyl, n-hexyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-properproper, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl or 3-methylpentyl.

“C2-6alkenyl”used in this description refers to alkenyl containing 2-6 carbon atoms. As preferred examples include, for example, vinyl, allyl, 1-propenyl, 2-propenyl, Isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6-hexadienyl etc.

“C2-6quinil”used in this description refers to the quinil containing 2-6 carbon atoms. As preferred examples include, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propinyl, 1-ethinyl-2-PROPYNYL, 2-methyl-3-PROPYNYL, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6-hexadienyl etc.

“C1-6alkoxy”, as used herein, refers to an alkoxy containing 1-6 carbon atoms, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, sec-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, sec-pentyloxy, n-is Exocet, isohexane, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropylene, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 2,2-Dimethylbutane, 2,3-dimethylbutylamino, 1,3-dimethylbutylamino, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylpentane, 3 methylpentane, hexyloxy etc.

“C2-6alkenylacyl”used in this description, refers to alkenylacyl containing 2-6 carbon atoms. As preferred groups include, for example, vinyloxy, allyloxy, 1 propenyloxy, 2-propenyloxy, isopropanolamine, 2-methyl-1-propenyloxy, 3-methyl-1-propenyloxy, 2-methyl-2-propenyloxy, N-methyl-2-propenyloxy, 1 butenyloxy, 2-butenyloxy, 3 butenyloxy, 1 pentyloxy, 1 hexenoate, 1,3-hexadienyl, 1, 6-hexadienoic etc.

“C2-6alkyloxy”used in this description, refers to alkyloxy containing 2-6 carbon atoms. Preferably include, for example, itineracy, 1 propenyloxy, 2-propenyloxy, 1 butenyloxy, 2-butenyloxy, 3 butenyloxy, 3-methyl-1-propenyloxy, 1-ethinyl-2-propenyloxy, 2-methyl-3-propenyloxy, 1 pentyloxy, 1 hexyloxy, 1,3-hexadienyl, 1,6-hexadienoic etc.

“C1-6alkylthio”used in this description, refers to alkylthio containing 1-6 ATO is s carbon. For example, you can call methylthio, ethylthio, n-propylthio, isopropylthio, sec-propylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio, n-pentylthio, isopentyl, sec-pentylthio, n-hexylthio, isohexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylphenylthio, 3 methylphenylthio etc. “C2-6alkanity”used in this description, refers to alkanity containing 2-6 carbon atoms. Its preferred examples include VINITI, allylthio, 1 propylthio, 2-propylthio, isopropylthio, 2-methyl-1-propylthio, 3-methyl-1-propylthio, 2-methyl-2-propylthio, 3-methyl-2-propylthio, 1 butylthio, 2-butylthio, 3 butylthio, 1 pentylthio, 1 hexanite, 1,3-hexadienyl, 1,6-hexadienyl etc. “C2-6alkylthio”used in this description, refers to alkylthio containing 2-6 carbon atoms. Its preferred examples include etenity, 1 propylthio, 2-propylthio, 1 butylthio, 2-butylthio, 3 butylthio, 3-methyl-1-propylthio, 1-ethinyl-2-propylthio, 2-methyl-3-propylthio, 1 pentylthio, 1 hexylthio, 1,3-hexadienyl,1,6-hexadienyl etc.

“C3-8cycloalkyl”used in this description refers to cycloalkyl containing 3-8 carbon atoms, and its examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.

“C3-8cycloalkenyl”used in this description, refers to C3-8cycloalkenyl containing 3-8 carbon atoms. For example, you can call cyclopropene-1-yl, cyclopropene-3-yl, cyclobuta-1-yl, cyclobuta-3-yl, 1,3-cyclobutadiene-1-yl, cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadiene-1-yl, 1,3-cyclopentadiene-2-yl, 1,3-cyclopentadiene-5-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl, 1,3-cyclohexadiene-1-Il,

1,3-cyclohexadiene-2-yl, 1,3-cyclohexadiene-5-yl, 1,4-cyclohexadiene-3-yl, 1,4-cyclohexadiene-1-yl, cyclohepten-1-yl, cyclohepten-3-yl, cyclohepten-4-yl, cyclohepten-5-yl, 1,3-cyclohepten-2-yl, 1,3-cyclohepten-1-yl, 1,3-cycloheptadiene-5-yl, 1,3-cycloheptadiene-6-yl, 1,4-cycloheptadiene-3-yl, 1,4-cycloheptadiene-2-yl, 1,4-cycloheptadiene-1-yl, 1,4-cycloheptadiene-6-yl, 1,3,5-cycloheptatrien-3-yl, 1,3,5-cycloheptatrien-2-yl, 1,3,5-cycloheptatrien-1-yl, 1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl, cycloocta-3-yl, cycloocten-4-yl, cycloocten-5-yl, 1,3-cyclooctadiene-2-yl, 1,3-cyclooctadiene-1-yl, 1,3-cyclooctadiene-5-yl, 1,3-cyclooctadiene-6-yl, 1,4-cyclooctadiene-3-yl, 1,4-cyclooctadiene-2-yl, 1,4-cyclooctadiene-1-yl, 1,4-llook adien-6-yl, 1,4-cyclooctadiene-7-yl, 1, 5cyclooctadiene-3-yl, 1, 5cyclooctadiene-2-yl, 1,3,5-cyclooctadiene-3-yl, 1,3,5-cyclooctadiene-2-yl, 1,3,5-cyclooctadiene-1-yl, 1,3,5-cyclooctadiene-7-yl, 1,3,6-cyclooctadiene-2-yl, 1,3,6-cyclooctadiene-1-yl, 1,3,6-cyclooctadiene-5-yl, 1,3,6-cyclooctadiene-6-yl, etc.

“5 to 14-membered non-aromatic heterocyclic group”used in this description, refers to monocyclic, bicyclic or tricyclic, 5-14-membered non-aromatic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, sulfur atom and oxygen atom. Specific examples of the group include pyrrolidinyl, pyrrolyl, piperidinyl, piperazinil, imidazolyl, pyrazolyl, imidazolyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, dihydrofuran, dihydropyran, imidazolines, oxazolines etc. in Addition, non-aromatic heterocyclic group also includes a group derived Spiridonovka rings or non-aromatic condensed ring (for example, a group derived phthalimide rings, operations of the rings etc).

“C6-14aromatic hydrocarbon cyclic group” and “aryl”, as used herein, refers to an aromatic cyclic hydrocarbon group containing 6-14 carbon atoms, and include monocyclic group and condenser the bath ring, such as bicyclic group, tricyclic group, etc. and Specific examples of this group include phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulene, heptenyl, biphenyl, indanyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrene, anthracene, Cyclopentasiloxane, benzocyclobutene etc.

In this description of the “5 to 14-membered aromatic heterocyclic group” or “heteroaryl” refers to monocyclic, bicyclic or tricyclic, 5-14-membered aromatic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, sulfur atom and oxygen atom. Specific examples of the group include, for example, 1) nitrogen-containing aromatic heterocyclic groups such as pyrrolyl, pyridyl, peritonitis, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, isoindolyl, indolizinyl, purinol, indazoles, hinely, ethanolic, hemolysis, ftalazol, naphthyridine, Minoxidil, hintline, cinnoline, pteridine, imidazolidinyl, pyrazinamidase, acridines, phenanthridines, carbazolyl, carbazolyl, pyrimidinyl, phenanthrolines, pinacidil, imidazopyridines, imidazopyrimidines, pyrazolopyrimidines, pyrazolopyrimidines etc.; 2) sulfur-containing aromatic heterocyclic group such as thienyl, benzothieno and so on; 3) oxygen-containing aromatic heterocyclic groups such as furyl, pyranyl, cyclopentadienyl, benzofuran, isobenzofuran, etc. and 4) an aromatic heterocyclic group containing two or more heteroatoms, such as thiazolyl, isothiazolin, benzothiazolyl, benzotriazolyl, phenothiazinyl, isoxazolyl, furutani, phenoxazines, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, pyrazoloquinoline, imidazothiazoles, thienopyrrole, properly, pyridoxine etc.

“C2-7aliphatic acyl group”used in this description, refers to a group of atoms obtained by removing Oh-group at the carboxyl group With2-7aliphatic carboxylic acids. As her preferred groups include, for example, acetyl, propionyl, butteroil etc.

“Arlacel”, as used herein, refers to a carbonyl, substituted C6-14aromatic hydrocarbon group, and “heteroaromatic” refers to a carbonyl, substituted 5 to 14-membered aromatic heterocyclic group. “C6-14aromatic hydrocarbon cyclic group” and “5 to 14-membered aromatic heterocyclic group” has the meaning as defined above,

Preferred examples of “C1-6alkylsulfonyl”, “C2-6alkanesulfonyl” and “C2-6alkynylaryl the Nile”, used in this description, include methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, tert-butylsulfonyl, vinylsulphonyl, arylsulfonyl, isopropylalcohol, isopentenyladenine, ethniccultural etc. Preferred examples “C1-6alkylsulfonyl”, “C2-6alkanesulfonyl” and “C2-6alkylsulfonyl”used in this description, include methylsulfinyl, ethylsulfinyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, tert-butylsulfonyl, vinylsulphonyl, arylsulfonyl, isopropylaniline, isopentenyladenine, ethniccultural etc.

As the “substituent” in the “optionally substituted amino group”used in this description, may be called, for example, one or two groups selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, C1-6alkylsulfonyl,2-6alkanesulfonyl,2-6alkinyl were radioactive, C1-6alkylcarboxylic,2-6alkenylboronic and C2-6alkynylaryl, each of which may have a Deputy, and the substituents may be linked together with the formation of a 3-8-membered nitrogen-containing ring. Preferred examples of the “substituent” of the above C1-6of alkyl, C2-6alkenyl,2-6the quinil, C1-6alkylsulfonyl,2-6al is fenilsulfonil, With2-6alkylsulfonyl, C1-6alkylcarboxylic,2-6alkenylboronic and C2-6alkynylaryl include hydroxyl, halogen atom, nitrile, C1-6alkoxy, C1-6alkylthio etc. In particular, as particularly preferred examples of the above “amino group which may have a substitute, you can call methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamine, isopentylamine, neopentylene, n-hexylamino, 1 methylpropylamine, 1,2-dimethylpropylene, 2-ethylpropylamine, 1-methyl-2-ethylpropylamine, 1-ethyl-2-methylpropylamine, 1,1,2-trimethylpropyl, 1 methylbutylamine, 2-methylbutylamine, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 2-ethylbutylamine, 1,3-dimethylbutylamino, 2-methylpentylamino, 3 methylpentylamino, N,N-dimethylamino, N,N-diethylamino, N,N-di(n-propyl)amino, N,N-di(isopropyl)amino, N,N-di(n-butyl)amino, N,N-di(isobutyl)amino, N,N-di(tert-butyl)amino, N,N-di(n-pentyl)amino, N,N-di(isopentyl)amino, N,N-di(neopentyl)amino, N,N-di(n-hexyl) amino, N,N-di (1-methylpropyl) amino, N,N-di(1,2-dimethylpropyl)amino, N-methyl-N-ethylamino, N-ethyl-N-(n-propyl)amino, N-methyl-N - (isopropyl)amino, vinylamine, allyamine, (1-propenyl)amino, isopropylamino, (1-butene-1-yl)amino, (1-butene-2-yl)amino, (1-butene-3-yl)amino, (2-butene-1-yl)amino, (2-butene-2-yl)amino, N,N-diphenylamino, N,N-dial is ylamino, N,N-di(1-propenyl)amino, N,N-isopropylamino, N-vinyl-N-allylamino, ethynylene, 1 propylamino, 2-propylamino, butylamino, pentylamine, hexylamine, N,N-diethylamino, N,N-(1-PROPYNYL)amino, N,N-(2-PROPYNYL)amino, N,N-dibutylamino, N,N-diphenhydramine, N,N-digoxigenin, hydroxymethylamino, 1 hydroxyethylamino, 2-hydroxyethylamino, 3-hydroxy-n-propyl, methylsulfonylamino, ethylsulfonyl, n-propylsulfonyl, isopropylaniline, n-butylsulfonyl, tert-butylsulfonyl, vinylsulfonate, arylsulfonamides, isopropylacetanilide, isopentenyladenine,

etenilsililidin, methylcobalamine, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-butylcarbamoyl, tert-butylcarbamoyl, vinylnorbornene, arylcarboxamide, isopropylcarbodiimide, isopentenyladenosine, tinycorelinux etc.

As the “substituent” in the expression “which may have a substitute, used in this description include halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom etc), hydroxyl, nitro, cyano, C1-6alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-ethylpropyl, n-hexyl, 1-methyl-ethylpropyl etc), With2-6alkenyl (for example, vinyl, allyl, 1-propenyl, 2-propenyl, Isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6-hexadienyl etc.)2-6quinil (for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-PROPYNYL, 1-ethinyl-2-PROPYNYL, 2-methyl-3-PROPYNYL, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6-hexadienyl etc.), C1-6alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, sec-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, sec-pentyloxy, n-hexose etc.)2-6alkenylamine (for example, vinyloxy, allyloxy, 1 propenyloxy, 2-propenyloxy, isopropanolate etc.)2-6alkyloxy (for example, itineracy, 1 propenyloxy, 2-propenyloxy etc.), C1-6alkylthio (for example, methylthio, ethylthio, n-propylthio, isopropylthio, sec-propylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio etc.)2-6alkanity (for example, VINITI, allylthio, 1 propylthio, 2-propylthio etc.)2-6alkylthio (for example, etenity, 1 propylthio, 2-propylthio etc.)2-7aliphatic acyl (e.g. acetyl, propionyl, butteroil etc), carbarnoyl, arylaryl, heteroaryl, amino, C1-6alkylsulfonyl, C2-6alkanesulfonyl is l, With2-6alkylsulfonyl, C1-6alkylsulfonyl,2-6alkanesulfonyl,2-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, tert-butylsulfonyl, vinylsulphonyl, arylsulfonyl, isopropylalcohol, isopentenyladenine, ethnicolor, methylsulfinyl, ethylsulfinyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, tert-butylsulfonyl, vinylsulphonyl, arylsulfonyl, isopropylaniline, isopentenyladenine, ethniccultural etc), formyl, C3-8cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.)3-8cycloalkenyl (for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl etc), 5-14-membered non-aromatic heterocyclic group (for example, pyrrolidinyl, pyrrolyl, piperidinyl, piperazinil, imidazolyl, pyrazolyl, imidazolyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, dihydrofuran, dihydropyran, imidazolines, oxazolines, the group obtained from Spiridonovka ring group derived from phthalimide rings or operations of the rings, etc.)6-14aromatic hydrocarbon cyclic group (for example, phenyl, indenyl, 1-naphthyl, 2-naphthyl, biphenyl, indanyl etc), 5-14-membered aromatic GE is eroticlinks ring (for example, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, isoindolyl, indolizinyl, purinol, indazoles, hinely, ethanolic, hemolysis, ftalazol, naphthylidine, Minoxidil, hintline, cinnoline, pteridine, imidazolidinyl, pyrazinamidase, acridines, phenanthridines, carbazolyl, carbazolyl, pyrimidinyl, phenanthrolines, pencil, imidazopyridines, imidazopyrimidines, pyrazolopyrimidines, pyrazolopyrimidines, thienyl, benzothiazyl, furyl, pyranyl, cyclopentadienyl, benzofuran, isobenzofuran, thiazolyl, isothiazolin, benzothiazolyl, benzotriazolyl, phenothiazinyl, isoxazolyl, furutani, phenoxazines, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, pyrazoloquinoline, imidazothiazoles, thienopyrrole, properly, pyridoxamine etc), and these substituents may further have substituents.

In the formula (I) above, R1represents cyano, carboxyl or carbarnoyl, which may have a Deputy, and the most preferred group is not specifically limited. As preferable examples of the “substituent” in the “carbamoyl, which may have a substitute can be called a group selected from C1-6of alkyl, which may have a Deputy, With2-6alkenyl, which may have to cover the spruce, With2-6the quinil, which may have a Deputy, With3-8cycloalkyl, which may have a Deputy, With3-8cycloalkenyl, which may have a Deputy, With6-14aromatic hydrocarbon cyclic group which may have a Deputy, 5-14-membered aromatic heterocyclic group which may have a Deputy, etc. the nitrogen Atom in carbamoyl may be substituted by one or two groups selected from the substituents described above. In addition, the above substituents may be linked together with education 3-14-membered nitrogen-containing ring (for example, pyrrolidine, pyrroline, piperidine, piperazinil, imidazolyl, pyrazolyl, imidazolidine, morpholine, tetrahydropyranyl, aziridinyl, oxiranyl, oxathiolane, phthalimide, succinimide, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl etc), and nitrogen-containing ring may optionally have substituents.

Preferred groups R2in the formula (I) are not specifically limited, but preferred groups include a hydrogen atom, a C1-6alkoxy, phenyl, naphthyl, pyridyl, pyridil, pyrimidyl, Persil, thienyl, furyl and imidazolyl, each of which may have a Deputy, and more preferably a hydrogen atom.

In the formula (I) above, R3and R4not counting the one from the other, and each represents C3-8cycloalkyl,3-8cycloalkenyl,6-14aromatic hydrocarbon cyclic group, a 5 to 14-membered non-aromatic heterocyclic group or a 5 to 14-membered aromatic heterocyclic group, each of which may have a Deputy, and preferred groups include6-14aromatic hydrocarbon cyclic group (for example, phenyl, naphthyl and so on), 5-14-membered non-aromatic heterocyclic group (for example, pyrrolidinyl, pyrrolyl, piperidinyl, piperazinil, imidazolines, pyrazolidine, imidazolidine, morpholine, tetrahydropyranyl, aziridinyl, oxiranyl, oxathiolane, 6-oxo-1,6-dihydropyridin, in which the nitrogen atom may be substituted and so on) or 5 to 14-membered aromatic heterocyclic group (for example, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, indolyl, isoindolyl, indolizinyl, chinoline, ethenolysis, finalizing phthalazine, naphthyridin, Minoxidil, chinadoll, imidazolidinyl, pyrazinamidase, thienyl, benzothiazyl, furyl, pyranyl, cyclopentadienyl, benzofuran, isobenzofuran, thiazolyl, isothiazolin, benzothiazolyl, benzotriazolyl, phenothiazin, isoxazolyl, pyrazoloquinoline, imidazothiazoles, cyanophoric, properly, pyridoxine etc), and these substituents may have replace the I. Examples of more preferred values of R3and R4for example, are groups represented by the formulas:

which may be respectively substituted. When the above 6-oxo-1,6-dihydropyridin has a Deputy, is also included a case where the Deputy is linked to the nitrogen atom.

In relation to the “substituent” in the “C3-8cycloalkyl, which may have a Deputy”, “C3-8cycloalkenyl, which may have a Deputy”, “C6-14aromatic hydrocarbon cyclic group which may have a Deputy”, “5 to 14-membered non-aromatic heterocyclic group which may have a Deputy” and “5 to 14-membered aromatic heterocyclic group which may have a substitute, presents R3and R4, (1) preferred are one or more groups selected from hydroxyl, halogen atom, cyano, nitro, C1-6of alkyl, which may have a Deputy, With2-6alkenyl, which may have a Deputy, With2-6the quinil, which may have a Deputy, C1-6alkoxy which may have a Deputy, With2-6alkenylacyl, which may have a Deputy, C1-6alkylthio, which may have a Deputy, With2-6-alkanity, which may have a Deputy, With2-6alkylthio, who may have a Deputy, substituted carbonyl, amino, which may have a Deputy, C1-6alkylsulfonyl, which may have a2-6alkanesulfonyl, Deputy, Deputy, Deputy, Deputy, Deputy, which which can can C1-6alkylsulfanyl, which can2-6alkanesulfonyl, which can2-6alkylsulfanyl, which may have a Deputy, formyl, C3-8cycloalkyl, which may have a Deputy, With3-8cycloalkenyl, which may have a Deputy, 5-14-membered non-aromatic heterocyclic group which may have a Deputy, C6-14aromatic hydrocarbon group which may have a Deputy, and a 5-14-membered aromatic heterocyclic group which may have a Deputy; (2) is more preferred are one or more groups selected from 1) hydroxyl, 2) halogen atom, (3) cyano, (4) nitro, 5) C1-6of alkyl, C2-6alkenyl or2-6the quinil, each of which may be substituted by at least one group selected from (i) hydroxyl, (ii) cyano, (iii) halogen atom, (iv) C1-6alkylamino, (v) di (C1-6alkyl) amino, (vi)2-6alkynylamino, (vii) di (C2-6alkenyl) amino, (viii)2-6alkynylamino, (ix) di (C1-6alkynylamino, (x) N-C1-6alkyl-N-C2-6alkynylamino, (xi) N-C1-6alkyl-N-C2-6and is cinelatino, (xii) N-C2-6alkenyl-N-C2-6alkynylamino, (xiii) aralkylated, (xiv) DS, (xv) C1-6alkylsulfonyl, (xvi) C1-6alkylcarboxylic, (xvii)2-6alkenylboronic, (xviii)2-6alkylcarboxylic, (xix) N-C1-6allylcarbamate, (xx) N-C2-6alkenylamine and (xxi) N-C1-6alkynylaryl, 6) C1-6alkoxy, C2-6alkenylacyl or2-6alkyloxy, each of which may be substituted by at least one group selected from (i) C1-6alkylamino, (ii) aralkylated and (iii) hydroxyl, 7) C1-6alkylthio,2-6alkanity or2-6alkylthio, each of which may be substituted by at least one group selected from (i) hydroxyl, (ii) nitrile, (iii) halogen atom, (iv) C1-6alkylamino, (v) aralkylated, (vi) DS, (vii) C1-6alkylsulfonyl, (viii) C1-6alkylcarboxylic and (ix) C1-6allylcarbamate, 8) carbonyl substituted by a group selected from (i) C1-6alkoxy, (ii) amino, (iii) C1-6alkylamino, (iv) di (C1-6alkyl) amino, (v)2-6alkynylamino, (vi) di(C2-6alkenyl) amino, (vii)2-6alkynylamino, (vii) di(C2-6quinil)amino, (viii) N-C1-6alkyl-N-C2-6alkynylamino, (ix) N-C1-6alkyl-N-C2-6alkynylamino and (x) N-C2-6alkenyl-N-C2-6alkynylamino, 9) amino which may be substituted by one or two groups, select nimi of (i) C 1-6of alkyl, (ii)2-6alkenyl, (iii)2-6the quinil, (iv) C1-6alkylsulfonyl, (v)2-6alkanesulfonyl, (vi)2-6alkylsulfonyl, (vii) C1-6alkylsulphonyl, (viii)2-6alkenylboronic and (ix)2-6alkynylaryl, 10) C1-6alkylsulfonyl, 11)2-6alkanesulfonyl, 12)2-6alkylsulfonyl, 13) C1-6alkylsulfonyl, 14)2-6alkanesulfonyl, 15)2-6alkylsulfonyl, 16) formyl, 17)3-8cycloalkyl or3-8cycloalkenyl, each of which may be substituted by at least one group selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6alkoxy-C1-6of alkyl and (vii) aralkyl, 18) 5-14-membered non-aromatic heterocyclic group which may be substituted by at least one group selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6alkoxy-C1-6of alkyl and (vii) aralkyl, 19)6-14aromatic hydrocarbon cyclic group which may be substituted by at least one group selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6alkoxy-C1-6of alkyl and (vii) aralkyl, 20) 5-14-membered aromatic heterocyclic group, which the traveler may be substituted by at least one group, selected from (i) hydroxyl, (ii) halogen atom, (iii) nitrile, (iv) C1-6of alkyl, (v) C1-6alkoxy, (vi)1-6alkoxy-C1-6of alkyl and (vii) aralkyl; and (3) the most preferred are one or more groups selected from hydroxyl, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom etc), cyano, nitro, C1-6the alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile, isopentyl, neopentyl, n-hexyl etc.)2-6alkenyl (for example, vinyl, allyl, 1-propenyl, Isopropenyl etc.)2-6the quinil (for example, ethinyl, 1-propinyl, 2-propinyl, butinyl, pentenyl, hexenyl etc.), C1-6alkoxy (methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy etc.) and (C2-6alkenylamine (vinyloxy, allyloxy, 1 propenyloxy, isopropanolate etc).

Preferred compounds represented by formula (I) above according to the present invention or its salt is not specifically limited, among which preferred is a compound or its salt, in which R3is a group represented by the formula:

(in which R7represents a group selected from the above group of substituents b; and ring a represents a nitrogen-containing 6-membered ring, which may be C maseno 1-4 groups selected from the above group of substituents (b), and even more preferred is a compound represented by the formula:

(in which R1represents cyano, carboxyl or optionally substituted carbarnoyl; R2represents a hydrogen atom, hydroxyl, C1-6alkoxy which may have a Deputy, C1-6alkylthio, which may have a Deputy, With6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; R7represents a group selected from the above group of substituents b; R8is6-14aromatic hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group, each of which may have a Deputy; the ring a represents a nitrogen-containing 6-membered ring which may be substituted by 1-4 groups selected from the above group of substituents (b), or its salt. Preferred types of each of R1, R7and R8have the meanings given above.

In this description of “salt” are not specifically limited provided that forms a salt with the compound of the present invention, and it is pharmacologically acceptable. Pre is respectfully can be called the hydrogen halides) (for example, hydroptere, hydrochloride, hydrobromide and hydroiodide), salts of inorganic acids (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate), salt of organic carboxylic acids (e.g. acetate, triptorelin, oxalate, maleate, tartrate, fumarate and citrate), salt of organic sulfonic acid (e.g., methanesulfonate, triftorbyenzola, aconsultant, bansilalpet, toluensulfonate and camphorsulfonate), salt, amino acids (for example, aspartate and glutamate), salt, Quaternary amine, an alkali metal salt (e.g. sodium salt and potassium salt), salts of alkaline-land of metal (such as magnesium salt, calcium salt) and so on, and the hydrochloride, oxalate are the most preferred as a pharmacological acceptable salts”.

The way to obtain

A typical way to obtain the compounds of the present invention represented by the above formula (I), will be presented below. In this case, the “room temperature”, below, refers to a temperature in the range from 0 to about 40°C.

The method of obtaining 1

In the formula, R3a'represents a 5 to 14-membered aromatic heterocyclic group which has a nitrogen atom in position 4 and may have a substituent (for example, 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl etc.); R4abefore the hat With 6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; and R9represents C1-8alkyl. 1,2-biaryl-1 Etalon (ii)' as a starting compound for the compounds represented by the above formula (I) according to the present invention can be obtained by interaction of aromatic carboxylate (i) with 4-

metroroommates.com heterocyclic compound represented by the formula, R3a'-CH3in the presence of a base in a solvent, followed by condensation with elimination of alcohol. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called the salt of the secondary amine and the metal represented bis(trimethylsilyl)amidon lithium and diisopropylamide lithium. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycol the ü. The reaction temperature is usually the range from -78°C to room temperature, preferably about 0°C.

The method of obtaining 2

In the formula, R3arepresents C6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; R4ahas the values defined above; and X1represents a halogen atom, alkylsulfonate or arylsulfonate. Derived 1,2-biaryl-1 ethanone (ii)as starting compound to obtain a compound represented by the above formula (I) according to the present invention can be obtained by way of getting 2 instead of the above method of obtaining 1. That is, his get in. condensation of aromatic triallylisocyanurate derived from aromatic aldehyde (iii)with the compound represented by the formula, R3a-CH2X1in the presence of a base; and then by the interaction of the fluorine-containing compounds with subsequent trialkylsilanes by designerware. As a reagent for obtaining aromatic triallylisocyanurate from (iii) it is preferable to use trialkylsilanes submitted by trimethylsilylcyanation. In this the beam is also the preferred simultaneous use of metal salt, such as iodide, zinc (II)as a catalyst that makes it possible to achieve a high response speed. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called the salt of the secondary amine and the metal represented bis(trimethylsilyl)amidon lithium and diisopropylamide lithium, etc. Used fluoride compound varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called hydrofluoric acid, hydrofloric amine and more preferably tetrabutylammonium fluoride. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol. The reaction temperature is usually the range from -78°C to room temperature.

The method of obtaining 3

In the formula, R 3aand R4aare6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a substituent. The derived 3-(dimethylamino)-2-propen-1-she (iv) is the reference compound to obtain the compound (I) of the present invention. The compound (iv) can be obtained by the interaction of dimethylacetal N,N-dimethylformamide with an active methylene (ii)obtained in the above production method of 1 or 2. This reaction is most preferably carried out in the absence of solvent, but preferred results can be achieved even if it is carried out at a dilution solvent, which is inert to the reaction and dissolves to a certain extent the original connection (for example, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-organic, benzene, toluene, etc. and so on, the reaction Temperature is usually the interval from room temperature to 120°C, more preferably about 100°C.

Using the compounds obtained in the above methods of obtaining 1-3, it is possible to obtain the compound (vii) according to the present invention as follows.

The method of obtaining 4

In the formula, R3Aand R4Ahave the meanings defined above; and X2p is ecstasy halogen atom. The compound (vii) can be obtained via the intermediate compound (v) and (vi) in this order from the compound (iv)obtained in the above method of obtaining 3 (stage 4-(1)-4-(3) in the diagram). The derived 2-oxo-1,2-dihydro-3-pyridylacetonitrile (v) can be obtained by the interaction of (iv) with 2-cyanoacetamide in the presence of a base (stage 4-(1)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call the alcoholate of an alkali metal such as sodium methylate, sodium ethylate or tert-butyl potassium. In addition, a preferable result can be obtained also with the use of alkali metal carbonates, such as potassium carbonate or sodium carbonate. Solvent used varies depending on the starting compounds, reagents etc., and not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called N,N-dimethylformamide, N-organic, dimethylsulfoxide, methanol, ethanol, etc. the reaction Temperature is usually the interval from room temperature to 120°C, more preferably about 80°C. the Derived 2-halogen-3-pyridylcarbonyl the sludge (vi) can be obtained by conversion of the carbonyl group in (v) halogen atom (stage 4-(2)). The reaction is preferably carried out in the absence of solvent. In addition, a preferred result can also be obtained when it is carried out at suspendirovanie in a solvent which is inert to the reaction and dissolves the original connection to a certain degree (for example, acetonitrile, dioxane, tetrahydrofuran, etc.). Halogenation agent used for the conversion of carbonyl group into a halogen atom, varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably include phosphorus oxychloride, oxybromide phosphorus, etc. Preferably the reaction of the effects of halogenation agents carried out at the reaction temperature 70-120°C. in Addition, when in this reaction system is added a tertiary amine, such as Tripropylamine, salt, Quaternary amine, such as chloride of tetraethylammonium, or N,N-dimethylformamide, etc., the addition reaction is accelerated, and you can get a good result. Derivative 2-amino-3-pyridylacetonitrile (vii) of the present invention can be obtained by the interaction of X2(halogen atom) in (vi) with ammonia (stage 4-(3)). This reaction is usually carried out at a temperature of 0-150°S, more preferably in an autoclave (50 to 100°). COI is Leshey solvent varies depending on the starting compound, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, 1-methylpyrrolidine etc.

The method of obtaining 5

In the formula, R3brepresents C6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; X3represents a halogen atom; and Y represents C1-6alkyl. Allalove (ix)used in stage 6-(4))in the method of obtaining a 6, you can get metilirovaniem of helgaleena (viii) and subsequent interaction with galahitiyawa. In response siciliani is preferable to use alkylate, such as n-utility, second-utility, tert-utility etc. Used halogenalkyls varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call chloride trimethylamine, chlorine is ID or anti-bromide teatralova. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called a simple ether, such as tetrahydrofuran, diethyl ether, etc. the reaction Temperature is preferably the interval from -100°C to room temperature.

When the derived 3-(dimethylamino)-2-propen-1-it is obtained by the interaction of the compounds (acetylated aryl or acetylated heteroaryl represented by the formula, R4aThe PINES3), where R3ain (ii) is replaced by a hydrogen atom in the reaction method of producing 3, optionally subjected to a "stage 4-(1)in the method of obtaining 4, get the compound (x)in which R3ain (v) is replaced by a hydrogen atom. The method of obtaining the compound (xiv) according to the present invention from compound (x) is presented below.

The method of obtaining 6

In the formula, R3band R4ahave the meanings defined above; and X4represents a halogen atom. The compound (xiv) according to the present invention can be obtained from (x) through the stages 6-(1)-6-(4) (intermediate compound (xi)to(xiii). The compound (xi) can be obtained by alkylation of the oxygen atom is position 2 in (x) using 2-halogenated in the presence of a base (stage 6-(1)). Used 2-halogenated varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. The reaction is conducted using 2-chloracetamide is preferred and is carried out when adding additional sodium iodide is particularly preferred. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called ketones, such as acetone or methyl ethyl ketone, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. the reaction Temperature is usually 0 to 100°C. the Compound (xii) can be obtained is by transaminasemia derived 2-aminocarbonylmethyl-3-cyanopyridine (xi) in the presence of a base in a solvent (stage 6-(2)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called ketones, such as acetone or methyl ethyl ketone, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from room temperature to 150°C. the Compound (xiii) can be obtained by halogenoalkanes position 5 of the pyridine ring in the derived 2-aminonicotinamide (xii) gelatinosum agent in a solvent (stage 6-(3)). As the halogenation agent, preferred are N-bromosuccinimide, bromine, etc. solvent Used varies depending on the starting compounds, reagents, etc. and special about what Asom not limited to, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from -20°C to room temperature. The compound (xiv) according to the present invention can be obtained by the interaction alloleva obtained in the production method of 5, with a derivative of 2-amino-5-halogennitromethyl (xiii) in the presence of palladium catalyst in a solvent with the introduction of an aromatic group in position 5 of the pyridine ring in (xiii) (stage 6-(4)). Used palladium catalyst varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call dichlorobis(triphenylphosphine)palladium (II), palladium (II)acetate, tetrakis(triphenylphosphine)palladium (0), Tris(dibenzylideneacetone)dipalladium (0), etc. solvent Used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to determine elenai much of the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, toluene, xylene, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from room temperature to 150°C.

Of the compounds represented by the above formula (I) according to the present invention, compounds in which R2, R3and/or R4represent α-hydroxy-nitrogen-containing aromatic heterocyclic group having hydroxyl in α-position of the nitrogen atom, can be obtained as follows.

For example, the compound (xvi)with α-hydroxy-nitrogen-containing aromatic heterocyclic group in position 5 of the pyridine ring, can be obtained by hydrolysis α-alkoxy-nitrogen-containing aromatic compound (xv).

The method of obtaining 7

In the formula, R4ashall have the meaning given above; R10represents C1-6alkyl, C2-6alkenyl,2-6quinil etc.; ring And1is pyridinyl, pyrimidyl and pyrazinyl; and the ring And2is dihydroxypyridine, dihydroxypyrimidine, dihydropyrazine or tetrahydropyranyl. The reaction is preferably carried out in an aqueous solution of a mineral to the slots, such as, for example, hydrochloric acid, Hydrobromic acid or sulfuric acid, or a mixed solvent of the above solution of mineral acid and acetic acid. The reaction temperature is typically between room temperature to 100°C.

In addition, you can enter a Deputy in α-hydroxy-nitrogen-containing aromatic heterocyclic ring in the compound (xvi) according to the present invention, obtained by the above method of obtaining 7, the following method.

The way to obtain 8

In the formula, R4aand the ring And2have the meanings defined above; R11represents C1-6alkyl, C2-6alkenyl,2-6quinil etc.; and X5represents a halogen atom. On this way (xvi) is subjected to interaction with alkylhalogenide, etc. in the presence of a base in a solvent, whereby it is possible to obtain the compound (xvii)with the Deputy, introduced into the nitrogen atom in the ring And2. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and carbon is potassium. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. the reaction Temperature is usually 0 to 100°C.

The method of obtaining 9

In the formula, R3a, R4aand X4have the meanings defined above; and R2ais6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a substituent. The compound (xxv) according to the present invention can be obtained from (xviii) and (xix) through stage 9-(1)-9-(6) (intermediate compound (XX)to(xxiv)). The compound (XX) can be obtained by condensation with elimination of water (xviii) and (xix) in the presence of a base (stage 9-(1)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, if uslovii that it is inert to the reaction. Before occhialino can be called inorganic bases, such as potassium hydroxide or sodium hydroxide. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called a mixed solvent of alcohol, such as ethanol, and water. The derived 2-oxo-1,2-dihydro-3-pyridylacetonitrile (xxi) can be obtained by the interaction of (XX) with 2 cyanoacetamide in the presence of a base (stage 9-(2)). The reaction can be accelerated in an atmosphere of oxygen. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call the alcoholate of an alkali metal such as sodium methylate, sodium ethylate or tert-butyl potassium. Or when using alkali metal carbonates such as potassium carbonate or sodium carbonate, can also achieve the preferred result. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you shall aswat N,N-dimethylformamide, N-organic, dimethylsulfoxide, methanol, ethanol, etc. the reaction Temperature is usually preferably from room temperature to 120°C, more preferably about room temperature. The compound (xxii) can be obtained by alkylation of the oxygen atom in position 2 in (xxi) using 2-halogenated in the presence of a base (stage 9-(3)). Used 2-halogenated varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. It is preferable, when the reaction is carried out using 2-chloracetamide, and more preferably when the reaction is carried out followed by the addition of sodium iodide. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Before occhialino can be called ketones, such as acetone or methyl ethyl ketone, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. the reaction Temperature is usually 0 to 100°C. the Compound (xxiii) can be obtained by transaminasemia derived 2-aminocarbonylmethyl-3-cyanopyridine (xxii) in the presence of a base in a solvent (stage 9-(4)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate, etc. solvent Used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. can be called other solvents, for example ketones, such as acetone or methyl ethyl ketone, alcohols, such as methanol, ethanol, propanol or butanol, ethers, such as tetrahydro the uranium, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol. The reaction temperature is usually the interval from room temperature to 150°C. the Compound (xxiv) can be obtained by halogenoalkanes 5th position of the pyridine ring in the derived 2-aminonicotinamide (xxiii} halogenation agent in the solvent (stage 9-(5)). Used halogenation agent varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called N-bromosuccinimide, bromine, etc. in Addition, the solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from -20°C to room temperature. The compound (xxv) according to the present invention can be obtained by the interaction of the derivative 2-amino-5-halogennitromethyl (xxiv) with a reagent alloleva obtained in SP is the way to get 5, in the presence of palladium catalyst in a solvent, for the introduction of an aromatic group in position 5 of the pyridine ring in (xxiv) (stage 9-(6)). Used palladium catalyst varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call dichlorobis(triphenylphosphine)palladium (II)acetate, palladium (II)

tetrakis(triphenylphosphine)palladium (0),

Tris(dibenzylideneacetone)dipalladium (0),

dichlorobis(acetonitrile)palladium (II), etc. in Addition, the solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol, ethanol, propanol, butanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, toluene, xylene, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from room temperature to 150°C.

The method of obtaining 10

In the formula, R3a, R4aand X4have the meanings defined above; R2bp is ecstasy optionally substituted alkyl; and Y is lower alkyl. The compound (xxxiii) according to the present invention can be obtained from (xxvi) and (xix) through stage 10-(1)-10-(7) (intermediate compound (xxvii)to(xxxii). The compound (xxvii) can be obtained by condensation of (xxvi) (xix) (stage 10-(1)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called tert-butyl potassium. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferred is tert-butanol. The reaction temperature is usually the interval from room temperature to 120°C, more preferably about room temperature. Compound (xxxviii) can be obtained by alkylation of (xxvii) with methylchloride in the presence of a base (stage 10-(2)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called inorganic base such as potassium carbonate, etc. Predpochtitel is the principal example of methylchloride is methyliodide. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called a ketone, such as acetone or methyl ethyl ketone. The reaction temperature is preferably the range from room temperature to 120°C, more preferably about room temperature.

The derived 2-oxo-1,2-dihydro-3-pyridylacetonitrile (xxix) can be obtained by the interaction of (xxviii) with 2 cyanoacetamide in the presence of a base (stage 10-(3)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call the alcoholate of an alkali metal such as sodium methylate, sodium ethylate, isoproponal sodium tert-butyl potassium, etc. solvent Used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferred are N,N-dimethylformamide, N-organic, dimethylsulfoxide, isopropanol, etc. Those which the reaction temperature is preferably 0° S-120°C. the Compound (xxx) can be obtained by alkylation of the oxygen atom in position 2 (xxix) using 2-halogenated in the presence of a base (stage 10-(4)). As 2-halogenated preferred is 2-chloracetamide, and more preferably when the reaction is carried out followed by the addition of sodium iodide. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called ketones, such as acetone or methyl ethyl ketone, alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. the reaction Temperature is usually 0 to 100°C. the Compound (xxxi) can be obtained by transaminasemia derived 2-aminocarbonylmethyl and-3-cyanopyridine (xxx) in the presence of a base in a solvent (stage 10-(5)). Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate, etc. solvent Used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called ketones, such as acetone or methyl ethyl ketone, alcohols, such as methanol, ethanol, propanol or butanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, N,N-dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from room temperature to 150°C. the Compound (xxii) can be obtained by halogenoalkanes position 5 of the pyrimidine ring in the derived 2-aminonicotinamide (xxxi) using a halogenation agent in the solvent (stage 10-(6)). Used halogenation agent varies depending on the starting compounds used solvent, etc. and is not specifically limited, priruslovye, it is inert to the reaction. Preferably can be called N-bromosuccinimide, bromine, etc. solvent Used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, and so on, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, etc., N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from -20°C to room temperature. The compound (xxxiii) according to the present invention can be obtained by the interaction of the reagent alloleva obtained in the production method of 5, with a derivative of 2-amino-5-halogennitromethyl (xxxii) in the presence of palladium catalyst in a solvent, for the introduction of an aromatic group in position 5 of the pyridine ring in (xxxii) (stage 10-(7)). As used palladium catalyst are preferred, for example, dichlorobis(triphenylphosphine)palladium (II)acetate, palladium (II)

tetrakis(triphenylphosphine}palladium (0),

Tris(dibenzylideneacetone)dipalladium (0),

dichlorobis(acetonitrile)palladium (II), etc. solvent Used varies dependent on the capabilities of the original connection, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, toluene, xylene, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from room temperature to 150°C.

The method of obtaining 11

In the formula, R2aand R4ahave the meanings defined above; R10represents C1-6alkyl, C2-6alkenyl,2-6quinil; ring And1is pyridinyl, pyrimidyl or pyrazinyl; and the ring And2is dihydroxypyridine, dihydroxypyrimidine, dihydropyrazine or tetrahydropyranyl. Compound (xxxv), containing α-hydroxy-nitrogen-containing aromatic heterocyclic group in position 5 of the pyridine ring, can be obtained by hydrolysis α-alkoxy-nitrogen-containing aromatic heterocyclic compounds (xxxiv). Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves up is definitely much of the original connection. Preferably can be called an aqueous solution of mineral acid such as hydrochloric acid, Hydrobromic acid or sulfuric acid, or a mixed solvent of the above aqueous solution of mineral acid and acetic acid. The reaction temperature is typically between room temperature to 100°C.

The method of obtaining 12

In the formula, R2b, R4aring And1and the ring And2have the meanings defined above; and R10represents C1-6alkyl, C2-6alkenyl,2-6quinil etc. Compound (xxxvii), containing α-hydroxy-nitrogen-containing aromatic heterocyclic group in position 5 of the pyridine ring, can be obtained by hydrolysis α-alkoxy-nitrogen-containing aromatic heterocyclic compounds (xxxvi). Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called an aqueous solution of mineral acid such as hydrochloric acid, Hydrobromic acid or sulfuric acid, or a mixed solvent of the above aqueous solution of mineral acid is acetic acid. The reaction temperature is typically between room temperature to 100°C.

The method of obtaining 13

In the formula, R2crepresents a hydrogen atom, hydroxyl, C1-6alkoxy which may have a Deputy, C1-6alkyl which may have a Deputy, With6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; R3cis6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; and R4aand X4have the meanings given above. The compound (xxviii) of the present invention can be obtained by the interaction of the derivative 2-amino-5-halogennitromethyl (xxxix) with a reagent arivera or alloleva in the presence of a palladium catalyst and a base in a solvent, for the introduction of an aromatic group in position 5 of the pyridine ring in (xxxix). Used palladium catalyst varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call dig the Orbis(triphenylphosphine)palladium (II), the palladium (II)acetate,

tetrakis(triphenylphosphine}palladium (0),

Tris(dibenzylideneacetone)dipalladium (0),

dichlorobis(acetonitrile)palladium (II), etc. Used by the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called inorganic base such as potassium carbonate or calcium phosphate, or an organic amine, such as ethyldiethanolamine. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call alcohols, such as methanol or ethanol, ethers, such as tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, toluene, xylene, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually the interval from room temperature to 150°C.

The method of obtaining 14

In the formula, R3dis6-14aromatic hydrocarbon cyclic group which may have a Deputy, 5-14-membered aromatic heterocyclic group, a cat heaven may have a Deputy, or 5 to 14-membered non-aromatic heterocyclic group which may have a Deputy; and R2cand R4ahave the meanings given above. Connection (x1i) of the present invention can be obtained by hydrolysis of ceanography connection (x1) in the presence of a base in a solvent. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called inorganic base such as sodium hydroxide or potassium hydroxide. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferred are alcohols, such as methanol or ethanol, or a mixture of such alcohols and water. The reaction temperature is usually the interval from room temperature to 150°C.

The method of obtaining 15

In the formula, R1bis carbarnoyl, which may have a Deputy; and R2c, R3dand R4ahave the meanings given above. Carbamoyl derivative (xlii) of the present invention can be obtained by the condensation of OTS the warming water carboxylic acid (xli) with an amine in the presence of a condensing agent in a solvent. As used condensing agent, preferred is 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide etc. Reaction is accelerated by the addition of 1-hydroxybenzotriazole, etc. When the amine, which is condensed with carboxylic acid forms a salt with hydrogen chloride etc., add appropriate amount of a tertiary amine such as triethylamine. As used solvent are preferred, for example, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol, N,N-dimethylformamide, 1-methylpyrrolidine etc. the reaction Temperature is usually 0-50°and more preferably about room temperature.

The method of obtaining 16

In the formula, R2drepresents a hydrogen atom, a C1-6alcokey, which may have a Deputy, C1-6alkyl which may have a Deputy, C6-14aromatic hydrocarbon cyclic group which may have a Deputy, or a 5-14-membered aromatic heterocyclic group which may have a Deputy; ring And3is pyridinyl, pyrimidyl or pyrazinyl; R11represents C1-6alkyl which may have a Deputy, With2-6alkenyl, which may have a Deputy, or With2-6quinil, which can metsamastina; X5represents a leaving group such as halogen atom or sulfonate, which may have a Deputy, and R4aand the ring And2are, respectively, the values defined above. The compound (xliv) and (xlv) of the present invention can be obtained by the interaction of the compound (xliii) with R9-X5in the presence of a base in a solvent.

Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called inorganic bases, represented by potassium carbonate, potassium bicarbonate and potassium carbonate. Usually the solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably, you can call amide, such as N,N-dimethylformamide. The reaction temperature is typically between room temperature to 100°and more preferably about 65°C.

The method of obtaining 17

In the formula, R12represents C6-14aromatic hydrocarbon cyclic group which may have a Deputy who, or 5 to 14-membered aromatic heterocyclic group which may have a Deputy; and R2c, R4aand the ring And2are, respectively, the values defined above. The compound (xlvii) of the present invention can be obtained by the interaction of the compound (xlvi) with reagent arivera in the presence of a base and a copper catalyst in a solvent. Used the base varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably can be called a tertiary amine, such as pyridine, diisopropylethylamine, triethylamine, etc. Used copper catalyst varies depending on the starting compounds used solvent, etc. and is not specifically limited, provided that it is inert to the reaction. Preferably, you can call divalent copper such as copper acetate, copper bromide, copper sulfate, etc., and copper acetate is more preferred. Solvent used varies depending on the starting compounds, reagents, etc. and is not specifically limited, provided that it is inert to the reaction and dissolves to a certain extent the original connection. Preferably can be called N,N-dimethylformamide, those whom rehydrator, the ethyl acetate etc. the reaction Temperature is preferably about room temperature.

Above is a typical example of the production method of compound (I) of the present invention, and the original connection when the connection of the present invention may form a salt or hydrate, and is not specifically limited provided that they are inert to the reaction. In addition, when compound (I) of the present invention receive a free form, it can be converted into a salt, which can form the above compound (I) in the usual way. In addition, you can clean up and allocate the different obtained isomers of the compound (I) of the present invention (for example, geometric isomer, optical isomer based on an asymmetric carbon, torque isomer, stereoisomer and tautomer) using conventional means of separation, for example, by recrystallization, by the way diastereoisomeric salts, method of enzymatic fractionation and various kinds of chromatography (e.g., thin-layer chromatography, column chromatography and gas chromatography).

The connection represented by the above formula (I) according to the present invention, its salt or hydrate can be included in pharmaceutical drug a little bit about the usual as the preferred dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, lozenges, inhalation drugs, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices, lotions, etc. Upon receipt of a pharmaceutical product can be used commonly used excipients, binders, disintegrating agents, lubricants, colorants, flavoring substances and, if necessary, stabilizers, emulsifiers, substances that contribute to the absorption, surface-active substances, substances to bring the pH, preservatives and antioxidants, and it can make in the usual way by mixing the ingredients normally used as starting compounds for pharmaceutical preparations. As such ingredients include, for example, 1) animal and vegetable oils such as soybean oil, solid fat or synthetic glycerides; 2) hydrocarbons such as liquid paraffin, salanova or solid paraffin; 3) essential oils, such as octyldodecanol or isopropylmyristate; 4) higher alcohols such as cetosteatil alcohol or buchenavia alcohol; 5) a silicone resin; 6) silicone oil; 7) surfactants such as esters of polyoxyethylene and fatty acids, ester sorbitan and fatty acid ester glycerol and fatty acids, ester of polyoxyethylene-sorbitan and fatty acids, polyoxyethylene gidrirovannoe castor oil or block copolymers of polyoxyethylene-polyoxypropylene; 8) water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone or methylcellulose; 9) lower alcohols, such as ethanol or isopropanol; 10) polyhydric alcohols, such as glycerin, propylene glycol, dipropyleneglycol or sorbitol; 11) sugars such as glucose or sucrose; 12) inorganic powder such as silicic anhydride, aluminum silicate magnesium or aluminum silicate, and 13) of pure water. You can use 1 respectively) as fillers, e.g. lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and so on; 2) as binders, for example polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum Arabic, tragakant, gelatin, shellac, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, block copolymers of polypropylenglycol-polyoxyethylene, meglumine, calcium citrate, dextrin, pectin and so on; 3) as leavening agents, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, CIT is at calcium, dextrin, pectin, calcium carboxymethyl cellulose; 4) as lubricants, for example magnesium stearate, talc, polyethylene glycol, silicon dioxide, utverjdenie vegetable oil and so on; 5) as coloring substances, any permitted for addition to pharmaceuticals; 6) as flavouring substances, cocoa powder, menthol, aromatic powder, oil of peppermint, borneol, cinnamon powder, etc. and 7), as antioxidants, you can use antioxidants permitted for addition to pharmaceuticals, such as ascorbic acid, α-tocopherol, etc., respectively.

1) Preparation for oral administration obtained by mixing the compounds of the present invention or its salts, fillers and, if necessary, binder, baking powder, lubricant, coloring agent, flavoring agent and so on, and then transform in the usual way into powders, fine granules, granules, tablets, coated tablets, capsules, etc. 2) Tablets and granules may be coated sugar or gelatin shell and, if necessary, other appropriate wrapper. 3) Liquid preparations such as syrups, injections and eye drops are prepared by mixing the active agent with the agent for bringing the pH, solubilizer and stonerosetta etc. and, with auxiliary solubilizers substance, stabilizer, buffer, suspenders agent, an antioxidant, etc. if necessary, with subsequent conversion to the product in the usual way. The liquid preparation can be turned into dried by freezing the product, and the injection can be done intravenously, subcutaneously or intramuscularly. Preferred examples of the suspending agent include methylcellulose, Polysorbate-80, hydroxyethyl cellulose, gum Arabic, tragakant, sodium carboxymethyl cellulose, monolaurin of polyoxyethylene-sorbitan etc.; preferred examples solubilizing excipients include utverjdenie a polyoxyethylene castor oil, Polysorbate-80, nicotinamide, monolaurin of polyoxyethylene-sorbitan etc.; preferable examples of the stabilizer include sodium sulfite, metasulfite sodium, ether and so on; preferred examples of the preservative include methyl p-oxybenzoic, ethyl-p-oxybenzoic, sorbic acid, phenol, cresol, chlorocresol etc. 4) it is Possible to prepare the agent for external use any normal way. That is, the initial primary connection can be used with a variety of original substances, commonly used in pharmaceutical preparations, intermediate, cosmetics, etc. for Example, the substance includes animals and raises the global oil, mineral oil, essential oil, waxes, higher alcohols, fatty acids, silicone oil, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, clean water, etc. If you want additionally you can add substance to bring the pH, antioxidant, helatoobrazovatel, preservative, coloring agent, flavoring, etc. in Addition, if necessary, you can also include ingredients having activity to induce differentiation, the agent that promotes penetration into the bloodstream, a sterilizer, an anti-inflammatory agent, an activator of cells, vitamins, amino acids, humidifier, keratin the solubilizer etc.

Although the dose of the drug according to the present invention varies depending on the severity of symptoms, age, sex, body weight, dosage form, type of salt, sensitivity to chemical compounds, the type of disease and so on, it is administered daily in one dose or divided doses adult usually in a dose of from about 30 μg to 10 g, preferably from 100 μg to 5 g, more preferably from 100 μg to 100 mg, by oral administration, or from about 30 μg to 1 g, preferably 100 μg to 500 mg, more preferably from 100 μg to 30 mg intravenous.

Really and what gain can be obtained a new connection 2-aminopyridine. Compounds of the present invention or their salts have high antagonistic effect on adenosine receptor (adenosine A1-And2A-And2bor As3-receptor) and are excellent as an antagonist of adenosine A2receptors, particularly adenosine A2b-receptor. Compounds of the present invention or their salts are suitable as a means for the treatment or prevention of disease, which is the ratio of adenosine receptor (adenosine A1-, A2a-And2bor As3-receptor), and diseases against which effective receptor antagonist. The compound of the present invention or its salt is suitable not only as a means for the treatment, prevention or relief of constipatio, irritable bowel syndrome, constipatio accompanying irritable bowel syndrome, organic constipatio, constipatio accompanying enteroparasites ileus, constipatio accompanying congenital dysfunction of the digestive tract, constipatio accompanying ileus, diabetes, complications of diabetes, diabetic retinopathy, obesity, asthma and the like, but also suitable as hypoglycemic agents, agents for improving impaired glucose tolerance, tools that enhance the sensibility is to insulin, antihypertensives, diuretics, medicines for treatment of osteoporosis, anti-Parkinson, anti-Alzheimer's disease, a treatment for inflammatory bowel diseases, for the treatment of Crohn's disease etc.

EXAMPLES

Referential examples, examples and sample tests presented below are for illustrative purposes only, and in any case, the compounds according to the invention is not limited to the following specific examples. The present invention can be implemented in the maximum volume of the experts in this field, making various modifications, not only in respect of the following examples, but also the claims in the present description, and data modifications fall within the scope of the claims of this application.

Reference example 1

1-(2-Furyl)-2-(4-pyridyl)-1-alanon

In the atmosphere of nitrogen bis(trimethylsilyl)amide lithium (100 ml, 100 mmol) was added dropwise to a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylic (7.7 g, 54,9 mmol) in tetrahydrofuran (40 ml) at 0°C for 1 h followed by stirring for 2 hours To the reaction solution was added hexane (140 ml) and the resulting crystals were filtered off. The obtained crystals were dissolved in ethyl acetate and aqueous saturated solution of ammonium chloride. The body is ical layer washed with aqueous saturated solution of ammonium chloride (x2) and a saturated solution of salt, was dried over anhydrous sodium sulfate and concentrated. To the residue was added hexane, and the precipitate was filtered and washed with hexane to obtain specified in the title compound (6.5 g, 70%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4.26 deaths (2H, s), 6,77 (1H, DD, J=2,0, 3.6 Hz), 7,31 (2H, DD, J=1,6, 4,4 Hz), the 7.65 (1H, DD, J=0,8, 3.6 Hz), with 8.05 (1H, DD, J=0,8, 2.0 Hz), 8,51 (2H, DD, J=1,6, 4,4 Hz).

Reference example 2

3-(Dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propen-1-he

Dimethylacetal N,N-dimethylformamide (5 ml) was added to 1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, is 10.7 mmol) followed by stirring at 100°C for 2 hours After cooling, the reaction solution was diluted with ethyl acetate and aqueous saturated solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate (X6). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain specified in the title compound (2.5 g, 97%) as a reddish brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,80 (6N, Sirs), 6,53 (1H, W), 6,60 (1H, W), 7,10 (2H, d, J=4.0 Hz), the 7.65 (1H, W), of 7.75 (1H, s), 8,44 (2H, d, J=4.0 Hz).

Reference example 3

6-(2-Furyl)-2-oxo-5-(4-pyridyl)-1,2-dihydro-3-pyridylcarbonyl

The sodium methylate (1.20 g, of 22.2 mmol) was added to the Astaro 3-(dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propen-1-it (2,27 g, 9,37 mmol) and 2-cyanoacetamide (950 mg, 11.3 mmol) in N,N-dimethylformamide, followed by stirring at 80°C for 2 h in nitrogen atmosphere. After cooling on standing, the reaction solution was concentrated and diluted with water. After neutralization with 6N hydrochloric acid, the resulting solid substance was filtered and washed with water to obtain specified in the title compound (1.78 g, 72%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; only 6.64 (1H, DD, J=1,6, 4.0 Hz), 6,92 (1H, d, J=4.0 Hz), 7,24 (2H, DD, J=1,6, 4,4 Hz), 7, 75 (1H, DD, J=0,8 and 1,6 Hz), 8,21 (1H, s), to 8.57 (2H, DD, J=1,6, 4,4 Hz).

Reference example 4

2-Chloro-6-(2-furyl)-5-(4-pyridyl)-3-pyridylcarbonyl

A suspension of 6-(2-furyl)-2-oxo-5-(4-pyridyl)-1,2-dihydro-3-pyridinecarboxamide (21,0 g of 79.8 mmol) in phosphorus oxychloride (90 g) was stirred in nitrogen atmosphere at 110°C. After 4 h was added phosphorus oxychloride (50 g), followed by heating under stirring for 5 hours After cooling on standing, the reaction solution was concentrated. To the residue was added ice, neutralized with saturated sodium bicarbonate solution. After extraction with a mixture of ethyl acetate (2 l)-tetrahydrofuran (1 l), the organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. After to the Alenia to the residue diethyl ether obtained solid was filtered and washed with diethyl ether to obtain specified in the connection header (13,6 g, 61%) as a dark yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,62 (1H, DD, J=1,6, 3.6 Hz), 6,78 (1H, DD, J=0,8, 3.6 Hz), 7,42 (2H, DD, J=1,6, 4,4 Hz), 7,76 (1H, DD, J=0,8 and 1,6 Hz), 8,48 (1H, s), 8,69 (2H, DD, J=1,6, 4,4 Hz).

Reference example 5

3-(Dimethylamino)-1-(2-furyl)-2-propen-1-he

A mixture of 2-acetylfuran (25,0 g, 0,227 mmol) and dimethylacetal N,N-dimethylformamide (40 ml) was stirred at 100°C for 9 hours After cooling, the reaction solution was concentrated. To the residue was added diethyl ether and hexane, and the obtained solid was filtered and washed with hexane to obtain specified in the title compound (36.5 g, 97%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,88 (3H, Sirs), 3,14 (3H, Sirs), the 5.65 (1H, d, J=12,6 Hz), 6,60 (1H, DD, J=2.0 a, 3,4 Hz), 7,10 (1H, DD, J=0,8, 3,4 Hz), to 7.68 (1H, d, J=12,6 Hz), 7,79 (1H, DD, J=0,8, 2.0 Hz).

Reference example 6

6-(2-Furyl)-2-oxo-1,2-dihydro-3-pyridylcarbonyl

A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-it (15.0 g, 90,9 mmol), 2-cyanoacetamide (8.5 g, 101 mmol) and potassium carbonate (38.0 g, 275 mmol) in dimethyl sulfoxide (80 ml) was stirred at 120-140°C for 21 hours After cooling on standing, the reaction mixture was diluted with water. After adjusting the pH to 3 with concentrated hydrochloric acid poluchennogo substance was filtered and washed with water to obtain specified in the connection header (13,0 g, 77%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 6.75 (1H, d, J=8.0 Hz), 6,78 (1H, DD, J=1,6, 3.6 Hz), to 7.61 (1H, d, J=3, 6 Hz), 8,02 (1H, d, J=1.6 Hz), 8,15 (1H, d, J=8.0 Hz).

Reference example 7

2-[[3-Cyano-6-(2-furyl)-2-pyridyl]oxy]ndimethylacetamide

A suspension of 6-(2-furyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide (6.0 g, and 32.3 mmol), 2-chloracetamide (3.0 g, of 37.7 mmol), sodium iodide (5.7 g, 38,0 mmol) and potassium carbonate (9.0 g, 56.2 mmol) in acetone (100 ml) was stirred at 60°C for 6 hours After cooling on standing, the reaction solution was diluted with ethyl acetate and water. The organic layer is washed with aqueous saturated sodium bicarbonate solution (x2) and aqueous saturated solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether, the precipitate was filtered and washed with diethyl ether to obtain specified in the connection header (4,2 g, 54%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 4.87 (2H, s), of 6.75 (1H, DD, J=2.0 a, 3,4 Hz), 7,26 (1H, W), 7,26 (1H, DD, J=0,8, 3,4 Hz), was 7.45 (1H, d, J=8.0 Hz), to 7.61 (1H, W), of 7.96 (1H, DD, J=0,8, 2.0 Hz), 8,29 (1H, d, J=8.0 Hz).

Reference example 8

2-Amino-6-(2-furyl)nicotinamide

A suspension of 2-[[3-cyano-6-(2-furyl)-2-pyridyl]oxy]ndimethylacetamide (8.0 g, from 32.9 mmol) and CT is onata potassium (9,1 g, 65,9 mmol) in N,N-dimethylformamide (80 ml) was stirred at 120°within 1.5 hours After cooling on standing, the reaction solution was diluted with water and ethyl acetate and insoluble substance was separated by filtration. The water layer in the filtrate was extracted with ethyl acetate. The combined organic layer washed with aqueous saturated solution of ammonium chloride (x2), dried over anhydrous sodium sulfate and concentrated. The residue is suspended in methanol, the obtained solid was filtered and washed with methanol to obtain specified in the connection header (3,81 g, 63%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 6.68 (1H, DD, J=1,6, 3.6 Hz), of 6.96 (2H, Sirs), 7,02 (1H, d, J=8,2 Hz), 7,13 (1H, DD, J=0,8, 3.6 Hz), 7,89 (1H, DD, J=0,8 and 1,6 Hz), to $ 7.91 (1H, d, J=8,2 Hz).

Reference example 9

2 Amino-5-bromo-6-(2-furyl)nicotinamide

N-Bromosuccinimide (3.5 g, of 19.7 mmol) was added to a solution (60 ml) of 2-amino-6-(2-furyl)nicotinanilide (4.0 g, 21.6 mmol) in N,N-dimethylformamide in a nitrogen atmosphere at 1-2°C, followed by stirring. After 30 min the reaction solution was diluted with ethyl acetate and aqueous saturated potassium carbonate solution. The organic layer is washed with aqueous saturated potassium carbonate solution and aqueous saturated solution of ammonium chloride, then dried over anhydrous is a Ulfat sodium and concentrated. To the residue was added methanol, and the obtained solid was filtered and washed with methanol to obtain specified in the connection header (3,02 g, 53%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,72 (1H, DD, J=1,8, 3.6 Hz), 7,19 (2H, Sirs), 7,44 (1H, DD, J=0,8, 3.6 Hz), of 7.96 (1H, DD, J=0,8, 1.8 Hz), compared to 8.26 (1H, s).

Reference example 10

5-Bromo-2-methoxypyridine

After dissolution of the sodium (10 g, 0,435 mol) in methanol (500 ml) was added 2,5-dibromopyridine (50 g, 0,211 mol) and the mixture is boiled for 2 hours under reflux. The reaction solution was cooled when standing and then concentrated. Then the residue was diluted with ethyl acetate and aqueous saturated solution of ammonium chloride. The organic layer is washed with aqueous saturated solution of ammonium chloride and a saturated salt solution, then dried over anhydrous sodium sulfate and concentrated to obtain specified in the title compound (33 g, 83%) as a pale brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,84 (ZN, C), 6,72 (1H, DD, J=0,8, 8,8 Hz), 7,89 (1H, DD, J=2,4, 8,8 Hz), 8,29 (1H, DD, J=0.8, the 2,4 Hz).

Reference example 11

2-Methoxy-5-(1,1,1-tributylstannyl)pyridine

2.5m solution of n-utility in hexane (12.0 ml, 30.0 mmol) was added dropwise to a solution of 5-bromo-2-methoxypyridine (50 g, to 26.6 mmol) in tetrahydrofuran (100 ml) for 30 min at -70°C in nitrogen atmosphere. Then was added dropwise a solution of the presence of TBT chloride (10.4 ml, of 32.0 mmol) in tetrahydrofuran (20 ml) for 1 h Then the reaction solution was heated to room temperature and stirred. After 30 min the reaction solution was diluted with aqueous saturated solution of ammonium chloride and ethyl acetate. The organic layer is washed with aqueous saturated solution of ammonium chloride and a saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (eluent: hexane to hexane:ethyl acetate = 40:1) to obtain the specified title compound (7.9 g, 75%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,82-0,90 (N, m), 1,02-1,08 (6N, m), 1,22-1,35 (6N, m), 1,46-1,54 (6N, m), 3,82 (3H, s), to 6.80 (1H, DD, J=0,8, 8.0 Hz), 7,69 (1H, DD, J=1,6, 8.0 Hz), 8,10 (1H, DD, J=0,8 and 1,6 Hz).

Reference example 12

(E)-1,3-Di(3-forfinal)-2-propen-1-he

A mixture of 3-forventelige (7,63 ml, to 72.4 mmol), 3-fortetienne (10 g, to 72.4 mmol), potassium hydroxide (5,18 g of 92.6 mmol), ethanol (23 ml) and water (47 ml) was stirred overnight at room temperature. After diluting the reaction solution with water, the solid was filtered and washed with ethanol and diethyl ether to receipt of the m specified in the title compound (16.4 g, 93%).

1H NMR (400 MHz, DMSO-d6) δ ppm; 7,10-7,16 (1H, m), 7,27-7,37 (2H, m), 7,39-7,42 (2H, m), 7,46 (1H, d, J=15 Hz), to 7.50 (1H, DD, J=5,4, 7,7 Hz), 7.68 per-7,73 (1H, m), to 7.77 (1H, d, J=15 Hz), 7,78-of 7.82 (1H, m).

Reference example 13

4,6-Di(3-forfinal)-2-oxo-1,2-dihydro-3-pyridylcarbonyl

(E)-1,3-Di(3-forfinal)-2-propen-1-he (16.4 g, and 67.2 mmol), 2-cyanoacetamide (6,21 g, 73,9 mmol) and a solution of potassium tert-butylate (30,2 g, 269 mmol) in dimethyl sulfoxide (131 ml) was stirred overnight at room temperature under oxygen atmosphere. To the reaction solution were added water (300 ml) and 6N hydrochloric acid (390 ml). The solid was filtered and washed with water to obtain specified in the connection header (17,4 g, 84%).

1H NMR (400 MHz, DMSO-d6) δ ppm; for 6.81 (1H, s), 7,28 and 7.36 (1H, m), 7,50-7,58 (1H, m), 7.68 per-7,88 (2H, m).

Reference example 14

Isopropyl 3-(2-furyl)-3-oxopropanoic

A mixture of isopropyl(methylsulfanyl)methanoate (7.0 g, to 46.7 mmol), 2-acetylfuran (5,14 g, to 46.7 mmol), of potassium tert-butylate (10,5 g of 93.5 mmol) and tert-butanol (35 ml) was stirred overnight at room temperature. To the reaction

to the solution was added ice and subsequent acidification of 5N hydrochloric acid. The solid was filtered and washed with water to obtain specified in the connection header (,7 g, 37%).

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,38 (6N, d, J=8,8 Hz), 5,58-5,69 (1H, m), 6,27 (1H, s), 6,53 (1H, DD, J=2.0 a, and 3.3 Hz), 7,05 (1H, DD, J=0,4, and 3.3 Hz), 7,52 (1H, DD, J=0,4, 2.0 Hz).

Reference example 15

(Z)-1-(2-Furyl)-3-isopropoxy-3-(methylsulfanyl)-2-propen-1-he

A mixture of isopropyl 3-(2-furyl)-3-oxopropionate (3.7 g, 17.5 mmol), potassium carbonate (7,3 g, a 52.4 mmol) and acetone (15 ml) was boiled under reflux for 1 h After cooling the mixture to 0°With added methyliodide (2,17 ml, is 34.9 mmol), followed by stirring at room temperature for 2 hours After diluting the reaction solution with ethyl acetate, the insoluble substance was separated by filtration. The filtrate was concentrated and then the residue was purified column chromatography on silica gel (eluent: a mixture of ethyl acetate/hexane = 1:1) to obtain the specified title compound (3.2 g, 81%).

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,42 (6N, d, J=6.0 Hz), 2,28 (3H, s), 4.72 in-4,82 (1H, m), 6.35mm (1H, s), of 6.49 (1H, DD, J=1.5 and 3.6 Hz), 7,10 (1H, DD, J=1,0, 3.6 Hz), 7,47 (1H, DD, J=1,0, 1.5 Hz).

Reference example 16

6-(2-Furyl)-4-isopropoxy-2-oxo-1,2-dihydro-3-pyridylcarbonyl

Sodium (309 mg, of 13.4 mmol) was dissolved in isopropanol (46 ml). Then was added (Z)-1-(2-furyl)-3-isopropoxy-3-(methylsulfanyl)-2-propen-1-he (3.03 g, a 13.4 mmol) and 2-cyanoacetamide (1.13 g, a 13.4 mmol)followed by stirring overnight at room temperature. To the reaction solution was added ice-water, then the solid was filtered and washed with water and diethyl ether to obtain specified in the title compound (2.3 g, 70%).

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,35 (6N, d, J=6.0 Hz), 4,98-5,08 (1H, m), 6,60 of 6.66 (1H, m), 6,77-for 6.81 (1H, m), 7,60-to 7.67 (1H, m), 8,00-with 8.05 (1H, m).

Example 1

2-Amino-6-(2-furyl)-5-(4-pyridyl)-3-pyridylcarbonyl

A solution of ammonia in ethanol, 30 ml (ethanol, saturated at 0°With gaseous ammonia) was added to 2-chloro-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarboxamide (200 mg, 0,710 mmol). Then was sealed in a stainless steel autoclave and heated with stirring at 100°C. After 24 h the reaction solution was cooled when standing and concentrated. The residue was subjected to column chromatography on silica gel (eluent: hexane to hexane:ethyl acetate= 2:1, 1:1, 1:2) and then suspended in diethyl ether. The precipitate was filtered and washed with diethyl ether to obtain specified in the title compound (50 mg, 27%) as a pale orange solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; is 6.54 (1H, DD, J=1,6, 3.6 Hz), to 6.57 (1H, DD, J=0,8, 3.6 Hz), 7,20 (2H, Sirs), from 7.24 (2H, DD, J=1,6, 4,4 Hz), to 7.64 (1H, DD, J=0,8 and 1,6 Hz), 7,92 (1H, s), 8,55 (2H, DD, J=1,6, 4,4 Hz).

MC m/e (ESI) 263 (MN+).

Example 2

2-Amino-6-(forfinal)-5-(4-pyridyl)-3-pyridylcarbonyl

Specified in zag is lowke compound was synthesized in the same way, as in examples 18-20, described below, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,99-7,03 (1H, m), 7,09-7,14 (3H, m), 7,16-7,22 (1H, m), 7,28-to 7.35 (3H, m), of 8.09 (1H, s), 8,43 (2H, DD, J 1.6, the 4,4 Hz).

MC m/e (ESI) 291 (MN+).

Example 3

2-Amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl

A solution of 2-amino-5-bromo-6-(2-furyl)nicotinanilide (1.80 g, PC 6.82 mmol), 2-methoxy-5-(1,1,1-tributylstannyl)pyridine (5.20 g, 13,1 mmol) and dichlorobis(triphenylphosphine)palladium (II) (480 mg, 0,634 mmol) in N,N-dimethylformamid de (18 ml) was stirred at 80°C for 2 h in nitrogen atmosphere. After cooling on standing, the reaction solution was diluted with ethyl acetate and aqueous saturated solution of ammonium chloride.

The organic layer is washed with aqueous saturated solution of ammonium chloride (x2), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (eluent: hexane to hexane:ethyl acetate = 8:1, 4:1) and then suspended in diethyl ether. The obtained solid was filtered and washed with diethyl ether to obtain specified in the title compound (1.12 g, 56%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,88 (3H, s)6,38 (1H, DD, J=0,8, 3.6 Hz), 6,51 (1H, DD, J=1,6, 3.6 Hz), 6,83 (1H, d, J=4.6 Hz), was 7.08 (2H, Sirs), 7,54 (1H, DD, J=2,4, 4.6 Hz), to 7.67 (1H, DD, J=0,8 and 1,6 Hz), to 7.84 (1H, s), of 8.04(1H, d, J=2,4 Hz).

Example 4

2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

A solution of 2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl (1.0 g, of 3.42 mmol) in a mixture ukusna acid (6 ml)-concentrated Hydrobromic acid (10 ml) was stirred at 100°within 1.5 hours After cooling when standing pH of the reaction solution was brought up to 12-13 5N sodium hydroxide and washed with ethyl acetate. The organic layer was extracted 1H sodium hydroxide (x2) and then the combined aqueous layer was neutralized 5N hydrochloric acid. The obtained solid was filtered to obtain specified in the title compound (760 mg) as a yellow crude crystals. After suspension of the product in methanol was added a mixture of 4N HCl/ethyl acetate to dissolve and subjected to column chromatography on silica gel (eluent: dichloromethane, a mixture of dichloromethane:methanol= 40:1, 20:1, 10:1). The crude target compound suspended in water and then neutralized 5N sodium hydroxide. The solid was filtered and washed with water to obtain specified in the title compound (486 mg, 51%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,30 (1H, d, J=9.6 Hz), to 6.57 (1H, DD, J=1,8, 3,4 Hz), 6,59 (1H, DD, J=0,6, 3,4 Hz), 7,02 (2H, Sirs), 7,20 (1H, DD, 7=is 2.8, 9.6 Hz), 7,33 (1H, d, J=2,8 Hz), 7,75 (1, DD, J=0,6, 1.8 Hz), 7,82 (1H, s).

MC m/e (ESI) 279 (MN+).

Example 5

2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

The sodium methylate (155 mg, 2,87 mmol) was added to a suspension of 2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide (400 mg, 1.44 mmol) in methanol (8 ml) at room temperature in a nitrogen atmosphere, followed by stirring. After 15 min was added Iodate (0,35 ml of 4.38 mmol), followed by stirring. After 15 h added another Iodate (0,35 ml of 4.38 mmol) and the mixture was still stirred. After 24 h the reaction solution was concentrated. The residue was subjected to column chromatography on silica gel (eluent: hexane to hexane:ethyl acetate= 2:1, 1:2, 1:5). The crude target compound suspended in diethyl ether, then the solid was filtered and washed with diethyl ether to obtain specified in the title compound (149 mg, 34%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.23 (3H, t, J=7.2 Hz), 3,91 (2H, KB, J=7,2 Hz), 6,34 (1H, d, J=9,2 Hz), to 6.57 (1H, DD, J=2.0 a, and 3.2 Hz), 6, 62 (1H, DD, J=0,8, a 3.2 Hz), 7,06 (2H, Sirs), 7,19 (1H, DD, J=2,8, 9,2 Hz), 7,71 (1H, d, J=2,8 Hz), of 7.75(1H, DD, J=0,8, 2,0 Hz), 7,88 (1H, s).

MS m/e (ESI) 307 (MN+).

Example 6

2-Amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Specified in the title compound was synthesized in the same manner as the example 30.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.45 (3H, s), 6.35mm (1H, d, J=9,2 Hz), to 6.57 (1H, DD, J=1,6, 3.6 Hz), of 6.65 (1H, DD, J=0,8, 3.6 Hz), 7,06 (2H, Sirs), 7,17 (1H, DD, J=2,8, 9,2 Hz), of 7.75 (1H, d, J=2,8 Hz), 7,76 (1H, DD, J=0,8 and 1,6 Hz), to 7.84 (1H, s).

MS m/e (ESI) 293 (MN+).

Example 7

2-Amino-6-(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Specified in the title compound was synthesized in the same manner as in examples 21-29.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 6.19 (1H, d, J=9, 6 Hz), 6,86 (2H, Sirs), 7,00 (1H, DD, J=2,8, 9.6 Hz), 7,17-7,28 (4H,

m), 7,37 was 7.45 (1H, m), compared to 8.26 (1H, s).

MC m/e (ESI) 307 (MN+).

Example 8

2-Amino-6- (3-forfinal)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Using 2-amino-6-(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide specified in the title compound was synthesized in the same manner as in example 30.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,40 (3H, s), 6,17 (1H, d, J=9.6 Hz), 6,85 (1H, DD, J=2,4, and 9.6 Hz), 7,12 (2H, Sirs), 7,14-7,26 (3H, m), 7,34-7,42 (1H, m), 7,74 (1H, d, J=2.4 Hz), 7,98 (1H, s).

MC m/e (ESI) 321 (MH+).

Example 9

2-Amino-5-(4-cyanophenyl)-6-(2-furyl)nicotinamide

2-Amino-5-bromo-6-(2-furyl)nicotinamide (20 mg, to 75.7 mmol), 4-cyanoaniline acid (30 mg, 204 μmol), dichlorobis(acetonitrile) palladium (II) (2 mg, 7,71 mmol) and 2M aqueous potassium carbonate solution (150 μl, 300 μmol) in N,N-dimethylformamide is (0.6 ml) was stirred at 80° With over 14 hours After cooling, the reaction solution was diluted with ethyl acetate and water. After separation of the insoluble matter by filtration of the organic layer in the filtrate was concentrated. Half of the residue was purified HPLC on a column of reversed phase and was used as an eluent system of water-acetonitrile-triperoxonane acid with obtaining specified in the connection header of 3.33 mg).

MS m/e (ESI) 401 (MN+)

Specified in the headers of the compounds of the following examples 10-76 synthesized in the same manner as in example 3, or 9, or a similar method.

Example 10

2-Amino-5,6-di(2-furyl)nicotinamide

Example 11

2-Amino-5-(4-cyanophenyl)-6-(2-furyl)nicotinamide

Example 12

2-Amino-6-(2-furyl)-5-familycommunity

Example 13

2-Amino-6-(2-furyl)-5-(4-were)nicotinamide

Example 14

2-Amino-6-(2-furyl)-5-(3-were)nicotinamide

Example 15

2-Amino-6-(2-furyl)-5-(2-were)nicotinamide

Example 16

2-Amino-6-(2-furyl)-5-(4-methoxyphenyl)nicotinamide

Example 17

2-Amino-6-(2-furyl)-5-(3-methoxyphenyl)nicotinamide

Example 18

2-Amino-5-(2,4-acid)-6-(2-furyl)nicotinamide

Example 19

2-Amino-5-(3,4-acid)-6-(2-furyl)nicotinamide

Example 20

2-Amino-6-(2-furyl)-5-(3,4,5-trimethoxyphenyl)nicotinamide

Example 21

2-Amino-5-(1,3-benzodioxol-yl)-6-(2-furyl)nicotinamide

Example 22

2-Amino-5-[4-(benarasi)phenyl]-6-(2-furyl)nicotinamide

Example 23

2-Amino-5-[3-(benzyloxy)phenyl]-6-(2-furyl)nicotinamide

Example 24

2-Amino-6-(2-furyl)-5-(4-phenoxyphenyl)nicotinamide

Example 25

2-Amino-5-(3-ethoxyphenyl)-6-(2-furyl)nicotinamide

Example 26

2-Amino-6-(2-furyl)-5-[4-(triptoreline)phenyl]nicotinamide

Example 27

2-Amino-6-(2-furyl)-5-[3-(triptoreline)phenyl]nicotinamide

Example 28

2-Amino-5-(4-dimethylaminophenyl)-6-(2-furyl)nicotinamide

Example 29

2-Amino-6-(2-furyl)-5-[4-(methylsulfanyl)phenyl]nicotinamide

Example 30

2-Amino-5-(4-forfinal)-6-(2-furyl)nicotinamide

Example 31

2-Amino-5-(3-forfinal)-6-(2-furyl)nicotinamide

Example 32

2-Amino-5-(2-forfinal)-6-(2-furyl)nicotinamide

Example 33

2-Amino-5-(2,4-differenl)-6-(2-furyl)nicotinamide

Example 34

2-Amino-6-(2-furyl)-5-(2,3,4,5,6-pentafluorophenyl)nicotinamide

Example 35

2-Amino-6-(2-furyl)-5-[4-(trifluoromethyl)phenyl]nicotinamide

Example 36

2-Amino-6-(2-furyl)-5-[3-(trifluoromethyl)phenyl]nicotinamide

Example 37

2-Amino-6-(2-furyl)-5-[2-(trifluoromethyl)phenyl]nicotinamide

Example 38

2-Amino-5-[3,5-di(trifluoromethyl)phenyl]-6-(2-furyl)nicotinamide

Example 39

2-Amino-6-(2-furyl)-5-(4-nitrophenyl)nicotinamide

Example 40

2-Amino-6-(2-furyl)-5-(3-nitrophenyl)nicotinee the Rhyl

Example 41

2-Amino-6-(2-furyl)-5-(4-methyl-3-nitrophenyl)nicotinamide

Example 42

2-Amino-5-(2-fluoro-4-biphenylyl)-6-(2-furyl)nicotinamide

Example 43

2-Amino-6-(2-furyl)-5-(4-methylsulfinylphenyl)nicotinamide

Example 44

2-Amino-6-(2-furyl)-5-(4-methylsulfinylphenyl)nicotinamide

Example 45

2-Amino-5-(4-biphenylyl)-6-(2-furyl)nicotinamide

Example 46

2-Amino-5-(3-biphenylyl)-6-(2-furyl)nicotinamide

Example 47

2-Amino-5-(3-cyanophenyl)-6-(2-furyl)nicotinamide

Example 48

5-(4-Acetylphenyl)-2-amino-6-(2-furyl)nicotinamide

Example 49

5-(3-Acetylphenyl)-2-amino-6-(2-furyl)nicotinamide

Example 50

5-(2-Acetylphenyl)-2-amino-6-(2-furyl)nicotinamide

Example 51

2-Amino-5-(3-formylphenyl)-6-(2-furyl)nicotinamide

Example 52

2-Amino-5-(2-formylphenyl)-6-(2-furyl)nicotinamide

Example 53

2-Amino-5-(3-chlorophenyl)-6-(2-furyl)nicotinamide

Example 54

2-Amino-5-(2-chlorophenyl)-6-(2-furyl)nicotinamide

Example 55

2-Amino-5-(2,4-dichlorophenyl)-6-(2-furyl)nicotinamide

Example 56

2-Amino-5-(3,4-dichlorophenyl)-6-(2-furyl)nicotinamide

Example 57

2-Amino-5-(2,5-dichlorophenyl)-6-(2-furyl)nicotinamide

Example 58

2-Amino-5-(4-tert-butylphenyl)-6-(2-furyl)nicotinamide

Example 59

2-Amino-6-(2-furyl)-5-(1-naphthyl)nicotinamide

Example 60

2-Amino-6-(2-furyl)-5-(2-naphthyl)nicotinamide the

Example 61

2-Amino-5-benzo[b]furan-2-yl-6-(2-furyl)nicotinamide

Example 62

2-Amino-5-dibenzo[b,d]furan-4-yl-6-(2-furyl)nicotinamide

Example 63

2-Amino-6-(2-furyl)-5-(3-furyl)nicotinamide

Example 64

2-Amino-6-(2-furyl)-5-(2-thienyl)nicotinamide

Example 65

2-Amino-6-(2-furyl)-5-(3-thienyl)nicotinamide

Example 66

2-Amino-6-(2-furyl)-5-(5-methyl-2-thienyl)nicotinamide

Example 67

2-Amino-6-(2-furyl)-5-(4-methyl-2-thienyl)nicotinamide

Example 68

5-(5-Acetyl-2-thienyl)-2-amino-6-(2-furyl)nicotinamide

Example 69

2-Amino-5-(2-formyl-3-thienyl)-6-(2-furyl)nicotinamide

Example 70

2-Amino-5-(3-formyl-2-thienyl)-6-(2-furyl)nicotinamide

Example 71

2-Amino-5-(5-chloro-2-thienyl)-6-(2-furyl)nicotinamide

Example 72

2-Amino-5-benzo[b]thiophene-2-yl-6-(2-furyl)nicotinamide

Example 73

2-Amino-5-benzo[b]thiophene-3-yl-6-(2-furyl)nicotinamide

Example 74

2-Amino-6-(2-furyl)-5-(3-pyridyl)nicotinamide

Example 75

2-Amino-6-(2-furyl)-5-(2-pyridyl)nicotinamide

Example 76

2-Amino-6-(2-furyl)-5-(4-vinylphenol)nicotinamide

Example 77

2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinic acid

Ethanol (5 ml) and 5N aqueous sodium hydroxide (10 ml) was added to 2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinanilide (308 mg, 1.01 mmol) with sleduyushim boiling under reflux for 4 hours After cooling on standing, the reaction solution was neutralized 5N hydrochloric acid. The obtained solid was filtered and then washed with water to obtain specified in the title compound (320 mg, 98%) as a yellow solid

matter.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,22 (3H, t, J=7.2 Hz), 3,92 (2H, q, J=7.2 Hz), 6.35mm (1H, d, J=9,2 Hz), 6,54 return of 6.58 (1H, m), 6,60 (1H, DD, J=0,8, 3.6 Hz), 7,21 (1H, DD, J=2,4, 9,2 Hz), 7,31 (2N, W), 7,71 (1H, d, J=2.4 Hz), 7,73 (1H, DD, J=0,8, 3.6 Hz), to 7.93 (1H, s).

Specified in the headers of the compounds of the following examples 78 and 79 was synthesized in the same manner as in the example above 77, or a similar method.

Example 78

2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinic acid

Example 79

2-Amino-6-(3-forfinal)-5-(4-pyridyl)nicotinamide

Example 80

2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl) nicotinic acid (20 mg, is 61.5 mmol), 1-hydroxybenzotriazole (28 mg, 183 μmol), 3-(3'-dimethylaminopropyl)-1-ethylcarbodiimide (29 mg, 187 mmol), ammonium chloride (16 mg, 299 μmol) and the suspension of triethylamine (43 μl, 309 μmol) in N,N-dimethylformamide (1.0 ml) was stirred at room temperature for 18 hours After diluting the reaction solution with water obtained solid substance on filytrovali and washed with water to obtain specified in the title compound (9 mg, 45%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.24 (3H, t, J=7.2 Hz), 3,92 (2H, KB, J=7,2 Hz), 6,37 (1H, d, J=9,2 Hz), 6,53-6,56 (1H, m), to 6.58 (1H, DD, J=0,8, a 3.2 Hz), 7.23 percent (1H, DD, J=2,8, 9,2 Hz), 7,37 (3H, W), to 7.67 (1H, d, J=2,8 Hz), of 7.70 (1H, DD, 7=to 0.8, 3.2 Hz), to 7.93 (1H, s), to 7.99 (1H, Shir.).

Specified in the headers of the compounds of the following examples 81-102 was obtained in the same manner as in the example above 80, or a similar method.

Example 81

2-Amino-6-(3-forfinal)-5-(4-pyridyl)nicotinamide

Example 82

N-(2-Hydroxyethyl)-2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 83

N-Cyclopropyl-2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 84

N,N-Dimethyl-2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 85

N-Cyclopropylmethyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 86

N-(2-Foradil)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 87

N-Cyclopropyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)6-(2-furyl)nicotinamide

Example 88

N-(3-Diethylamino)propyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 89

N-Methyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 90

N-Phenyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

<> Example 91

N-Allyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 92

N-(2-Amino-2-oxoethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 93

N-Isobutyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 94

N-(5-Cyanophenyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 95

N-[3-(2-Octatetraene-1H-1-pyrrolyl)propyl]-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 96

N-(2-Pyridylmethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 97

N-(3-Pyridylmethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 98

N-[2-(4-Pyridyl)ethyl]-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 99

N-[2-(2-Pyridyl)ethyl]-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 100

N-(2-PROPYNYL)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 101

N-(3-Hydroxypropyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 102

N-Ethyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 103

103-(a):2-Amino-6-(2-furyl)-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)nicotinamide

103-(b):

2-Amino-6-(2-furyl)-5-(4-propyl-3-pyridyl)-3-pyridylcarbonyl

2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide (20 mg, 0,071 mmol) and potassium carbonate (30 mg, 0.22 mmol)dissolved in N,N-dimethylformamide (1 ml)were loaded into the reaction vessel. Added propyliodide (52 mg, 0.31 mmol) followed by stirring at 70°C for 18 hours After the reaction was added water and was extracted with ethyl acetate. After removing the aqueous layer, the organic layer was concentrated and purified by high-performance liquid chromatography with obtaining specified in the title compound as a yellow solid (2.6 mg, 11%; 1.8 mg, 7.8 per cent).

103-(a): 2-Amino-6-(2-furyl)-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)nicotinamide

1H NMR (400 MHz, CDCl3) δ ppm; and 0.98 (3H, t, J=7,4 Hz)and 1.83 (2H, q, J=7,4 Hz)to 3.99 (2H, t, J=7.4 Hz), 5,50 (2H, Sirs), 6,47 (1H, DD, J=3,6, 1.8 Hz), was 6.73 (1H, DD, J=3,6, and 0.8 Hz), for 6.81 (1H, d, J=9,2 Hz), 7,26 (1H, m), 7,30 (1H, DD, J=9,2, 2.4 Hz), 7,46 (1H, DD, J=1,8, 0.8 Hz), 7,58 (1H, s).

MC (ESI) m/e 321 (MH+).

103-(b): 2-Amino-6-(2-furyl)-5-(4-propyl-3-pyridyl)-3-pyridylcarbonyl

1H NMR (400 MHz, CDCl3) δ ppm; of 1.07 (3H, t, J=7.4 Hz), of 1.85 (2H, m), 4,30 (2H, t, J=6.6 Hz), 6,38-6,41 (2H, m), for 6.81 (1H, DD, 7=8,8, 0.8 Hz), 7,46-of 7.48 (2H, m), a 7.62 (1H, s), of 8.06 (1H, d, J=0.8 Hz).

MC (ESI) m/e 321 (MN+).

Example 104

2-Amino-5-[1-(4-cyanophenyl)-6-oxo-1,6-dihydro-3-pyridinyl-6-(2-furyl)nicotinamide

2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide (20 mg, 0,071 mmol), 4-cyanoaniline acid (35 mg, 0.24 mmol), monohydrate copper acetate (3.0 mg, 0.015 mmol), pyridine (0.015 g ml to 0.19 mmol) and N,N-dimethylformamide (1.0 ml) were loaded into a reaction vessel and stirred at room temperature for 20 hours To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was dried, then dissolved in dimethyl sulfoxide (1.0 ml) and purified by high-performance liquid chromatography with obtaining specified in the title compound as a yellow solid (8,32 mg, 62%).

1H NMR (400 MHz, DMSO-d6) δ ppm; of 6.49 (1H, d, J=9, 6 Hz), is 6.61 (1H, DD, J=1,6, and 3.2 Hz), 6,79 (1H, d, J=3.2 Hz), 7,07 (2H, Sirs), 7,30 (1H, DD, J=2,6, 9.6 Hz), 7,74 (1H, d, J=2.6 Hz), 7,76 (2H, d, J=8.6 Hz), 7,82 (1H, d, J=1,6 Hz), 7,98 (1H, s), 8,02 (2H, d, J=8.6 Hz).

MS (ESI) m/e 380 (MH+).

Specified in the headers of the compounds of the following examples 105-146 was obtained in the same manner as in the above example 5, 105 or 104, or similar methods.

Example 105

2-Amino-6-(2-furyl)-5-[6-oxo-1-(3-phenylpropyl)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 106

Ethyl 4-to 5 - [6-amino-5-cyano-2-(2-furyl)-3-pyridyl]-2-oxo-1,2-dihydro-1-pyridineboronic

Example 107

2-Amino-5-[1-(3-cyanopropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl) - nicotine is nitrile

Example 108

2 Amino-5-[1-(3-cyanobacterial)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl) nicotinamide

Example 109

2-Amino-6-(2-furyl)-5-[6-oxo-1-(4,4,4-trifloromethyl)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 110

2-Amino-6-(2-furyl)-6-[5-oxo-1-(3,4,4-Cryptor-3-butenyl)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 111

2-Amino-6-(2-furyl)-5-[6-oxo-1-(3,3,3-cryptochromes)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 112

2-Amino-5-(1-butyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 113

2-Amino-6-(2-furyl)-5-(1-heptyl-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 114

2-Amino-6-(2-furyl)-5-(1-isopentyl-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 115

5-(1-Allyl-6-oxo-1,6-dihydro-3-pyridinyl)-2-amino-6-(2-furyl)nicotinamide

Example 116

2-Amino-5-[1-(3-butenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 117

2-Amino-6-(2-furyl)-5-[6-oxo-1-(4-pentenyl)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 118

2-Amino-6-(2-furyl)-5-[1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 119

2-Amino-5-[1-(2,3-dihydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 120

2-Amino-5-[1-(3-forproper)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 121

2-Amino-5-[1-(3-chloro propyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-Furi is)nicotinamide

Example 122

2-Amino-5-[1-(4-chlorobutyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 123

2-Amino-5-[1-(5-chloropentyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-{2-furyl)nicotinamide

Example 124

2-Amino-5-[1-(cyclohexylmethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 125

2-Amino-6-(2-furyl)-5-[6-oxo-1-(tetrahydro-2H-2-pyranometer)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 126

2-Amino-5-(1-benzyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 127

2-Amino-5-[1-(2-cyanoethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 128

2-Amino-6-(2-furyl)-5-[6-oxo-1-(2-PROPYNYL)-1,6-dihydro-3-pyridinyl]nicotinamide

Example 129

2-Amino-5-[1-(2-butynyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 130

2-Amino-6-(2-furyl)-5-(6-oxo-1-[3-(1,1,1-gramaticales)-2-PROPYNYL]-1,6-dihydro-3-pyridinyl}nicotinamide

Example 131

2-Amino-5-(1-[(6,7-dimethoxy-2-oxo-2H-4-chromanol)methyl]-6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 132

2-Amino-5-(1-[4-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)butyl]-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 133

2-Amino-6-(2-furyl)-5-{1-[2-(1H-3-indolyl)ethyl]-6-oxo-1,6-dihydro-3-pyridinyl}nicotinamide

Example 134

2-Amino-6-(2-furyl)-5-[6-oxo-1-(2-oxopropyl)-1,6-dihydro-3-pyridinyl] nicotinamide

When the EP 135

2-Amino-6-(2-furyl)-5-{6-oxo-1-2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl-1,6-dihydro-3-pyridinyl}nicotinamide

Example 136

2-Amino-6-(2-furyl}-5-(6-oxo-1-phenyl-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 137

2-Amino-5-[1-(4-cyanophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 138

2-Amino-6-(2-furyl)-5-[6-oxo-1-(4-vinylphenol)-1,6-dihydro-3-pyridinyl)nicotinamide

Example 139

2-Amino-6-(2-furyl)-5-[1-(4-were)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 140

2-Amino-6-(2-furyl)-5-[1-(2-were)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 141

2-Amino-6-(2-furyl)-5-[1-(4-methoxyphenyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 142

2-Amino-6-(2-furyl)-5-[1-(3-methoxyphenyl)-6-oxo-1,6-dihydro-3-pyridinyl] nicotinamide

Example 143

2-Amino-6-(2-furyl)-5-[1-(2-methoxyphenyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinamide

Example 144

2-Amino-5-[1-(4-forfinal)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 145

2-Amino-5-[1-(3-forfinal)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Example 146

2-Amino-5-[1-(2-forfinal)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinamide

Specified in the headers of the compounds of the following examples 147-175 was obtained in the same manner as in the example above 103, or equivalent means.

Example 147

6-Amino-2-(2-furyl)-6'-(3-phenylpropoxy)-[3,3']bipyridinyl-5-carbonitrile

Example 148

Ethyl 4-(6'-amino-5'-cyano-2'-(2-furyl)-[3,3']bipyridinyl-6-yloxy)butyrate

Example 149

6-Amino-6'-(3-cyanopropyl)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 150

6-Amino-6'-cyclobutylmethyl-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 151

6-Amino-2-(2-furyl)-6'-(4,4,4-triptoreline)-[3,3']bipyridinyl-5-carbonitrile

Example 152

6-Amino-2-(2-furyl)-6'-(3,4,4-Cryptor-3-butenyloxy)-[3,3']bipyridinyl-5-carbonitrile

Example 153

6-Amino-2-(2-furyl)-6'-(3,3,3-cryptocracy)-[3,3']bipyridinyl-5-carbonitrile

Example 154

6-Amino-6'-butoxy-2-(2-furyl)-[3,3']]bipyridinyl-5-carbonitrile

Example 155

6-Amino-2-(2-furyl)-b'-heptyloxy-[3,3']bipyridinyl-5-carbonitrile

Example 156

6-Amino-2-(2-furyl)-6'-(3-methylbutoxy)-[3,3']bipyridinyl-5-carbonitrile

Example 157

6'-Allyloxy-6-amino-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 158

6-Amino-6'-(3-butenyloxy)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 159

6-Amino-2-(2-furyl)-6'-(4-pentyloxy)-[3,3']bipyridinyl-5-carbonitrile

Example 160

6-Amino-2-(2-furyl)-6'-(3-hydroxypropoxy)-[3,3']bipyridinyl-5-carbonitrile

Example 161

6-Amino-6'-(2,3-dihydroxypropane)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 162

6-Amino-6'-(3-forproperty)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

P the emer 163

6-Amino-6'-(3-chloropropoxy)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 164

6-Amino-6'-(4-chloroethoxy)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 165

6-Amino-6'-(5-chloropentane)-2-(2-furyl}-[3,3']bipyridinyl-5-carbonitrile

Example 166

6-Amino-6'-cyclohexyloxy-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 167

6-Amino-2-(2-furyl)-6'-(2-tetrahydropyranyloxy)-[3,3']bipyridinyl-5-carbonitrile

Example 168

6-Amino-2-(2-furyl}-6'-(2-propenyloxy)-[3,3']bipyridinyl-5-carbonitrile

Example 169

6-Amino-6'-(2-butenyloxy)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 170

6-Amino-2-(2-furyl)-6'-(3-trimethylsilyl-2-propenyloxy)-[3,3'] bipyridinyl-5-carbonitrile

Example 171

6-Amino-6'-(6,7-dimethoxy-2-oxo-2H-chromen-4-ylethoxy)-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 172

6-Amino-6'-[4-(1,3-dioxo-1,3-dihydro-2-isoindolyl)butoxy]-2-(2-furyl)-[3,3']bipyridinyl-5-carbonitrile

Example 173

6-Amino-2-(2-furyl)-6'-[2-(1H-3-indolyl)ethoxy]-[3,3']bipyridinyl-5-carbonitrile

Example 174

6-Amino-2-(2-furyl)-6'-(2-oxopropyl)-[3,3']bipyridinyl-5-carbonitrile

Example 175

6-Amino-2-(2-furyl)-6'-[2-[4-(trifluoromethyl)phenyl]ethoxy]-[3,3']bipyridinyl-5-carbonitrile

Example 176

2-Amino-4,6-di(3-forfinal)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl

Specified in the title compound was obtained t is Kim the same way, as in the reference examples 6-9 and example 3, or similar methods.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,81 (3H, s), 5,43 (2H, Sirs), 6,41-6,46 (1H, m), 6,79-6,83 (1H, m), 6,88? 7.04 baby mortality (6N, m), 7,17 (1H, dt, J=2,4, 5,9 Hz), 7,29 (1H, dt, J=2,4, 5,9 Hz), 7,53-EUR 7.57 (1H, m).

Example 177

The hydrobromide of 2-amino-4,6-di(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridyl)nicotinanilide

Specified in the title compound was obtained in the same manner as in example 4, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,01 (1H, d, J=9, 4 Hz), 6,86 (1H, d, J=2.4 Hz), 6,93 (1H, DD, J=2,4, and 9.4 Hz),? 7.04 baby mortality-7,24 (6N, m), 7,32-7,39 (1H, m), 7,40-7,47 (1H, m).

Example 178

2-Amino-6-(2-furyl)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl

Using 6-(2-furyl)-4-isopropoxy-2-oxo-1,2-dihydro-3-pyridylcarbonyl specified in the title compound was obtained in the same manner as in reference examples 7 to 9 and example 3, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,12 (6N, d, J=8.1 Hz), 3,98 (3H, s), 4,58 with 4.65 (1H, m), 5,44 (2H, Sirs), 5,97 (1H, d, J=3.3 Hz), of 6.29 (1H, DD, J=1,8, and 3.3 Hz), for 6.81 (1H, d, J=8,4 Hz), 7,37-the 7.43 (2H, m), of 7.96 (1H, d, J=1,8 Hz).

Example 179

The hydrobromide of 2-amino-6-(2-furyl)-4-hydroxy-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide

Using 2-amino-6-(2-furyl)-4-isopropoxy-5-(4-methox the-3-pyridyl)-3-pyridylcarbonyl specified in the title compound was obtained in the same way, as in example 4, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 6.20 (1H, d, J=3,7 Hz), of 6.31 (1H, d, J=9.3 Hz), is 6.61 (1H, DD, J=1,5, and 3.7 Hz), 7,01 (2H, Sirs), was 7.08 (1H, DD, J=2,4, and 9.3 Hz), 7,12 (1H, d, J=2.4 Hz), 7,92 (1H, d, J=1.5 Hz), 10,79 (1H, Sirs).

Example 180

2-Amino-6-(3-forfinal)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl

Specified in the title compound was obtained in the same manner as in examples 14-16, reference examples 7 to 9 and example 3, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,13 (6N, d, 7=8.1 Hz), of 3.95 (3H, s), of 4.44-4,58 (1H, m), 5,28 (2H, Sirs), of 6.66 (1H, d, J=8.6 Hz), 6.89 in-7,01 (3H, m), 7,16 (1H, dt, J=5,9, 8.0 Hz), 7,28 (1H, DD, J=1,6, 8.6 Hz), 7,79-7,81 (1H, m).

Example 181

The hydrobromide of 2-amino-6-(3-forfinal)-4-hydroxy-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide

Using 2-amino-6-(3-forfinal)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl specified in the title compound was obtained in the same manner as in example 4, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,10 (1H, d, J=9.6 Hz), 6.75 in-to 6.80 (1H, m), 6.89 in-6,93 (1H, m), of 6.99 (1H, DD, J=2.7, and 9.6 Hz), 7,12 (1H, d, J=7,4 Hz), 7,22-7,29 (2H, m), 7,41-of 7.48 (1H, m), 10,95 (1H, s).

Example 182

2-Amino-6-(3-forfinal)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl

Specified in the header is VCE compound was obtained in the same way, as in reference examples 7 to 9 or example 3, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,82 (3H, s)of 6.71 (1H, d, J=8,4 Hz), 6,99? 7.04 baby mortality (1H, m), 7,08-7,20 (4H, m), 7,28-to 7.35 (1H, m), of 7.36 (1H, DD, J=2,5, and 8.4 Hz), 7,95 (1H, d, J=2.5 Hz), 8,01 (1H, s).

MS m/e (ESI) 321 (MN+).

Example 183

2-Amino-6-(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Using 2-amino-6-(3-forfinal)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl specified in the title compound was obtained in the same manner as in example 4, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; x 6.15 (1H, d, J=8,2 Hz), 6,94-7,02 (1H, m),? 7.04 baby mortality-7,28 (6N, m), 7,34-7,44 (1H, m), of 7.97 (1H, s).

MS m/e (ESI) 307 (MN+).

Example 184

2-Amino-6-(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Specified in the title compound was obtained in the same manner as in reference examples 1 to 4 and example 1, or a similar method.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,30 (6N, (C), 6,78 (2H, s), 7,01 (1H, d, J=8.0 Hz), 7,10-7,16 (1H, m), 7,17-of 7.23 (1H, m), 7,26 (2H, s), 7,29-to 7.35 (1H, m), 8,03 (1H, s).

MS m/e (ESI) 319 (MN+),

Structural formulas specified in the headers of the compounds of the above examples 1-8, 10-76, 78, 79, 81-102, 105-175 below.

The compound of the present invention represented by the above formula (I), useful as an antagonist of adenosine receptor (A1-, A2a-And2bor As3-receptor), in particular, antagonist And2b-receptor. Examples of tests that show the usefulness of the compounds of the present invention as a drug, is presented below.

The test example 1

Determination of binding capacity with adenosine A1receptor

cDNA adenosine A1receptor human expressed in abundance in cells SNACK, this membrane sample was added at a concentration of protein of 66.7 µg/MP to and suspended in 20 mm HEPES buffer, pH 7.4 (10 mm MgCl2, 100 mm NaCl). To 0.45 ml of a suspension of this membrane sample was added to 0.025 ml of 60 nm of tritium-labeled chlorocyclopentane (3H-SSRA from NEN Ltd.) and 0.025 ml of test compounds. This mixture was stirred at 30°C for 120 min, were rapidly filtered under vacuum through glass fiber filter (GF/B Whatman) and immediately washed twice with 5 ml of 50 mm chilled water Tris-Hcl buffer. Then, the glass fiber filter transfer is in the bottle, added to scintillation fluid and radioactivity was determined on the filter in a liquid scintillation counter. Inhibition of binding3H-SSRA with A1receptor under the influence of the test compounds was determined using the following equation, and this inhibition was calculated concentration that causes 50% inhibition (IC50):

inhibition (%) = [1-{binding in the presence of the test compound - disparitions binding)/(total binding - nonspecific binding}]×100

In the above equation the total binding means3H-SSRI-bound radioactivity in the absence of the test compound; the nonspecific binding means3H-SSRI-associated radioactivity in the presence of 100 μm RPIA ([R]-[1-methyl-2-phenylethyl]adenosine); and linking in the presence of the test compound indicates3H-SSRI-associated radioactivity in the presence of the test compound at a predetermined concentration. The inhibition constant (Ki value) in the table was determined by the formula Gene Prusova.

The test example 2

Determination of binding capacity with adenosine A2Areceptor

Experience in inhibition of the binding of adenosine A2Areceptor was performed using a membrane sample (Receptor Biology inc.), where DVS is adenosine A 2Areceptor expressed in excess. This membrane sample was added at a concentration of protein of 22.2 μg/ml and suspended in 20 mm HEPES buffer, pH 7.4 (10 mm MgCl2, 100 mm NaCl). To 0.45 suspension of this membrane sample was added to 0.025 ml of 500 nm tritium-labeled 2-p-[2-carboxyethyl]phenethylamine-5'-N-ethylcarbodiimide adenosine (3H-CGS21680 from NEN) and 0.025 ml of test compounds. This mixture was stirred at 25°C for 90 min, were rapidly filtered under vacuum through glass fiber filter (GF/B Whatman) and immediately washed twice with 5 ml of 50 mm chilled water Tris-Hcl buffer. Then, the glass fiber filter was transferred into a vial, was added to scintillation fluid and radioactivity was determined on the filter in a liquid scintillation counter. Inhibition of binding3H-CGS21680 with a2Areceptor under the influence of the test compounds was determined using the following equation, and this inhibition was calculated concentration that causes 50% inhibition (IC50):

inhibition (%)=[1-{binding in the presence of the test compound - disparitions binding)/(total binding - nonspecific binding}]×100

In the above equation the total binding means3H-G321680-bound radioactivity in the absence of the test compound; nonspecific tie the means of 3H-CGS21680-associated radioactivity in the presence of 100 μm RPIA; and linking in the presence of the test compound indicates3H-CGS21680-bound radioactivity in the absence of the test compound at a predetermined concentration. The inhibition constant (Ki value) in the table was determined by the formula Gene Prusova.

The test example 3

Experience in inhibition of NECA-stimulated production of camp in cells expressing the adenosine A2breceptor

Cells SNACK, in which in excess is expressed adenosine A2breceptor human, were sown in a 24-well plate at a density of 1.5×105cells/ml, were cultured overnight and used in the experiment. The degree of inhibitory effect of the test compound on the amount of camp produced upon stimulation with 30 nm 5'-N-ethylcarbodiimide adenosine (NECA from Sigma), was evaluated by the affinity of a2b-receptor. That is, the fused cells were twice washed with buffer solution, Krebs-ringer at the rate of 2 ml/well (containing 0.1% BSA; pH 7.4) and pre-incubated for 30 min in a volume of 0.5 ml/well. Then was added a mixed solution containing NECA and the test compound, in the amount of 0.1 ml/well in the presence of the phosphodiesterase inhibitor Ro-20-1724 (product RBI). After pre-incubation for 15 min reacts what Yu were stopped by adding 0.1 n Hcl in a volume of 300 µl/well. Determination of intracellular camp was performed using a kit for immunoassay analysis of production Amersham. Inhibition of NECA-stimulated production of CMAP under the influence of the test compounds was determined using the following equation:

inhibition (%)=[1-{(the amount of camp in the presence of NECA and test connections - the number of camp only in a buffer solution of Krebs-ringer)/(number of camp upon stimulation only NECA ~ number of camp only in a buffer solution of Krebs-ringer)}]×100

The ability of the compounds of the present invention to contact or the ability to inhibit adenosine receptor is the following.

Table 1
Test connectionKi (nm) A1Ki(HM) A2aIC50(nm) A2b
Example 1990232,1
Example 266223,7
Example 540076,5

The compound of the present invention or its salt showed a high inhibitory activity on adenomyoma the receptor.

The test example 4

Assessment actions that stimulate bowel movement

Stimulating the defecation action connection inhibition of adenosine A2b-a receptor, which is established by the determination of its binding activity and inhibitory capacity against adenosine receptor in test example 1, its salt, hydrate, or containing pharmaceutical compositions can be estimated in the following way. Rats SD IGS (at the age of 6 weeks from Charles River) were placed in cages (3 animals/cage) and pre no restrictions were given food and water, and kept for 1 week. Then under each cage was placed weighted water-absorbing litter and animal kept hungry, but no restrictions were given water during the experiment. After 1.5 h of each cell extracted fecal pellets and examined for irregularities before experience. The compound suspended or dissolved in 0.5% (wt./about.) the methylcellulose (MC), administered orally at a dose of 5 ml/kg With one hand/ control group was administered orally with only 0.5% (wt./about.) MS. After entering the connection rats were placed back in the cage provided by the new water-absorbing litter, at 90 min after administration of each of the cells were extracted with a water-absorbing litter fecal pellets and investigated their appearance, and then counted and weighed. The number of fecal pellets was expressed on every cell. After removal of fecal pellets weighed water-absorbing litter and wt is, certain subtracting the initial mass of the water-absorbing litter from the mass after the experience, attributed to the volume of urine.

Table 2
ExampleThe number of fecal pellets
Control-0,50±0,29
11 mg/kg

3 mg/kg

10 mg/kg
1,75±1,03

7,25±1,65

22,25±2,93
21 mg/kg

10 mg/kg
7,80±1,30

18,00±1,30
51 mg/kg

3 mg/kg
7,00±1,23

of 14.25±3,38

The compound of the present invention or its salt has been highly active in stimulating a bowel action.

1. The derived 2-aminopyridine, represented by the formula

in which R1represents cyano, carboxyl or optionally substituted carbarnoyl; R2represents a hydrogen atom, hydroxyl, optionally substituted C1-6alkoxy, optionally substituted phenyl; R3and R4are the same or different from each other, and each represents an aromatic hydrocarbon group such as phenyl or naphthyl; a 5 to 14-membered non-aromatic heterocyclic or a 5 to 14-members of the ing aromatic heterocyclic group, selected from the hydrogenated pyridyl, pyridyl, Shrila or tanila, which may have substituents selected from the group consisting of (1) hydroxyl, (2) halogen, (3) cyano, (4) nitro, (5) C1-6of alkyl, C2-6alkenyl or2-6the quinil, each of which may be substituted by at least one group selected from hydroxyl, cycloalkyl, phenyl, cyano, halogen, C1-6alkylamino, di(C1-6) alkylamino, carbonyl, -S=O, -SO2, alkoxycarbonyl, benzoyl, hydrogenated of pyranyl, 5-membered nitrogen-containing heterocycle, which may be precondensation to a benzene ring, (6) C1-6alkoxy, (7) C1-6alkylthio, (8) phenyl, (9) phenyloxy, (10) phenylthio respectively, provided that excluded the cases where (1) R1is cyano, R2represents a hydrogen atom and each of R3and R4represents phenyl, (2) R1is cyano, R2represents a hydrogen atom, R3is 4-pyridyl and R4is 1-pyridyl, (3) R1is cyano, R2is 4-were and each of R3and R4represents phenyl, and (4) R1represents cyano and each of R2, R3and R4represents phenyl or its salt.

2. The compound according to claim 1 or its salt, in which R1represents cyano.

3. The compound according to claim 1 or with the l, in which R1is carbamoyl represented by the formula

in which R5and R6are the same or different from each other, and each represents a hydrogen atom, a C1-6alkyl, optionally substituted by hydroxyl, amino, alkyl - or dialkylamino, C(O)NH2, cyano, 5-6-membered nitrogen-containing heterocycle; cycloalkyl,2-6alkenyl,2-6quinil or phenyl.

4. The compound according to claim 1 or its salt, in which R2represents phenyl which may have a Deputy.

5. The compound according to claim 1 or its salt, in which R2represents phenyl which may be substituted by a halogen atom.

6. The compound according to claim 1 or its salt, in which R2represents a hydrogen atom.

7. The compound according to claim 1 or its salt, in which R3and R4are the same or different from each other, and each represents an aromatic hydrocarbon group or a 5-14-membered aromatic heterocyclic group, each of which may have a Deputy.

8. The compound according to claim 1 or its salt, in which R3and R4are the same or different from each other, and each represents phenyl, pyridyl, thienyl, furyl or naphthyl, each of which may have a Deputy.

9. The compound according to claim 1 or its salt, in which each of R3The R 4represents phenyl, pyridyl, thienyl or furyl, which may have a Deputy.

10. The compound according to claim 1 or its salt, in which R3and/or R4represent a 5 to 14-membered non-aromatic heterocyclic group, aromatic hydrocarbon group or a 5-14-membered aromatic heterocyclic group, each of which may be substituted by at least one group selected from the following group of substituents consisting of (1) hydroxyl, (2) halogen, (3) cyano, (4) nitro, (5) C1-6of alkyl, C2-6alkenyl or C2-6the quinil, each of which may be substituted by at least one group selected from hydroxyl, cyano, halogen, C1-6alkylamino, di(C1-6alkyl)amino and benzoyl, (6) C1-6alkoxy and (7) phenyl.

11. The compound according to claim 1 or its salt, in which R3and/or R4represent phenyl, pyridyl, thienyl or furyl, each of which may be substituted by at least one group selected from hydroxyl, halogen atom, a C1-6the alkyl and C1-6alkoxy.

12. The compound according to claim 1 or its salt, in which R3or R4are 6-oxo-1,6-dihydropyridin, which may have a Deputy.

13. The compound according to claim 1 represented by the formula

in which R1represents cyano, carboxyl and is not necessarily replaced carbarnoyl; R2represents a hydrogen atom, hydroxyl, optionally substituted C1-6alkoxy, optionally substituted phenyl; R7represents a group selected from the following group of substituents b; R8is6-14aromatic hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group which may have a Deputy; and ring a represents a nitrogen-containing 6-membered ring which may be substituted by 1-4 groups selected from the following group of substituents b;

the group of substituents b consisting of hydrogen atom, halogen atom, hydroxyl, nitro, cyano, optionally substituted C1-6the alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxy, and optionally substituted C1-6alkylthio or its salt.

14. The connection 13 or its salt, in which R1represents cyano.

15. The connection 13 or its salt, in which R1is carboxyl.

16. The connection 13 or its salt, in which R1is carbamoyl represented by the formula

in which R5and R6are the same or different from each other, and each represents a hydrogen atom, a C-6 alkyl, optionally substituted by hydroxyl, amino, alkyl - or dialkylamino, C(O)NH2, cyano, 5-6-membered nitrogen-containing heterocycle; cycloalkyl,2-6alkenyl,2-6quinil or phenyl.

17. The connection 13 or its salt, in which R2represents a hydrogen atom.

18. The connection 13 or its salt, in which R7in the ring And selected from the following group of substituents consisting of (1) hydroxyl, (2) halogen, (3) cyano, (4) nitro, (5) C1-6of alkyl, C2-6alkenyl or2-6the quinil, each of which may be substituted by at least one group selected from hydroxyl, cyano, halogen, C1-6alkylamino, di(C1-6alkyl) amino and benzoyl, (6) C1-6alkoxy and (7) phenyl.

19. The connection 13 or its salt, in which R7represents a hydrogen atom, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl or optionally substituted C1-6alkoxy.

20. The connection 13 or its salt, in which R8represents phenyl, pyridyl, furyl or thienyl, each of which may have a Deputy.

21. The connection 13 or its salt, in which R8represents phenyl, pyridyl, furyl or thienyl, each of which may be substituted by a halogen atom.

22. The compound according to claim 1, where the compound is any one selected from the

2-amino-6(2-furyl)-5-(4-pyridyl)-3-pyridylcarbonyl,

2-amino-6-(3-forfinal)-5-(4-pyridyl)-3-pyridylcarbonyl,

2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridylcarbonyl,

2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide,

2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinanilide,

2-amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinanilide,

2-amino-6-(3-forfinal)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide and

2-amino-6-(3-forfinal)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinanilide, or its salt.

23. Pharmaceutical composition having antagonistic activity against adenosine receptors and including a compound of formula (I) according to claim 1 or its pharmacologically acceptable salt and a pharmaceutically acceptable carrier.

24. The composition according to item 23, which is an antagonist of adenosine receptors.

25. The composition according to item 23, which is an antagonist of adenosine A2-receptor.

26. The composition according to item 23, which is an antagonist of adenosine A2B-receptor.

27. The composition according to item 23, used to stimulate bowel movements.

28. The composition according to item 23, which is a tool for the treatment, prevention and relief of constipatio.

29. The composition according to item 23, where the higher is the functionality of the higher-tion.

30. The composition according to item 23, which is a treatment for irritable bowel syndrome, constipatio accompanying irritable bowel syndrome, organic constipatio, constipatio accompanying enteroparasites ileus, constipatio accompanying congenital dysfunction of the digestive tract, or constipatio accompanying ileus.

31. The composition according to item 23, used to delete the contents of the intestinal tract during the examination of the digestive tract or before and after the operation.

32. The composition according to item 23, which represents an antihypertensive agent, a diuretic, a treatment for osteoporosis, anti-Parkinson, anti-Alzheimer's disease, for the treatment of inflammatory bowel disease or for the treatment of Crohn's disease.

33. The compound according to claim 1 or its pharmacologically acceptable salts for obtaining funds for the treatment or prevention of disease, which is the ratio of the adenosine receptor.

34. The method of stimulation of defecation by introducing a pharmacologically effective dose of a compound according to claim 1 or its pharmacologically acceptable salt, patient.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to organic chemistry and pharmacology, namely a mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic acid in a molar ratio of 1:3, manifesting cardiotonic activity

The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, showing inflammatory and bronchodilatory activity

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new compounds of the mixture of isomers of 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole of the formula I

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of formula (I)

where a represents a 5 - or 6-membered monocyclic aromatic ring containing in the ring 1 or 2 nitrogen atom and unsubstituted or substituted by 1-3 substituents, A represents N; D represents a 2-indolyl, 2-benzimidazolyl or 2-benzo[b]furanyl and is unsubstituted or substituted by 1-3 halogen atoms, except 1-(5-chlorobenzophenone-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and its pharmaceutically acceptable salts

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

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