Heterocyclic compounds, method of their production, composition and method of combating tachykinin receptors

 

(57) Abstract:

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen. The ring represents a benzene ring which may be substituted by 1 to 3 substituents selected from halogen, halogenated1-C4of alkyl, halogenated1-C4alkoxy; R represents hydrogen or C1-C6alkyl, one of X or Y represents-NR1and the other represents-CO-, or one of them represents - N = and the other denotes = (CR2- where R1is hydrogen, C1-C6alkyl, R2is hydrogen, halogen, C1-C6alkyl, carboxyl or alkoxycarbonyl group, n denotes 1 or 2, or their salts. The compounds of formula I have an excellent antagonistic action to tachykinin receptors and can find application in medicine. The compound of formula I is produced by interaction of the corresponding carboxylic acid with the compound form is containing a series as an active ingredient a compound of formula I in an effective amount. The invention relates to a method of combating tachykinin receptors by introducing an effective amount of the compounds of formula I. 4 C. and 10 C.p. f-crystals, 2 tab.

The invention relates to new heterocyclic lidocaine with excellent antagonistic action to tachykinin receptors, methods for their production and compositions containing these compounds.

Tachykinin is a General term that refers to a group of neuropeptides. In mammals known substance P, neurokinin-A, neurokinin-B. it is Also known that by their binding to specific receptors (neirokinina-1, neirokinina-2, neirokinina-3) present in a living organism, these peptides show diverse biological activity.

Among them substance P is one of neuropeptides known for the longest time and have been studied in more detail. Its presence was confirmed in substance extracted from intestinal neural tube horses in 1931, and the structure of a peptide consisting of 11 amino acids was determined in 1971, it is Known that substance P plays a crucial role as a mediator in peripheral and Central nelena, allergies, frequent urination, urinary disorders respiratory tract diseases, mental disorders, and so on).

As the compounds having antagonistic activity to receptors substance P, are aware of the following:

(1) in JPA HI (1989) - 287095 connection formula:

R1- A - Trp (R2) - Phe - R3,

where R1denotes H or aminoamides group;

R2denotes H, an amino protecting group, carbarnoyl - (lower) alkyl group, carboxyl (lower) alkyl group or a protected carboxy (lower) alkyl group;

R3denotes ar (lower) alkyl group, a group represented by the formula:

< / BR>
(where R4and R5respectively represent H, aryl group, or optionally substituted lower alkyl group, or R4and R5connected to each other to form condensed with benzene lowest alkalinous group) or a group represented by the formula:

-OR6,

(where R6represents H, aryl group, or optionally substituted lower alkyl group);

A denotes a single bond or one or two amino acid residue, provided that, if A stands for one amino acid residue, not only is armoloy:

< / BR>
(3) in EP-A-429366, among others, the compound represented by the formula:

< / BR>
(4) in the Journal of Medicinal Chemistry, 34, p. 1751 (1991), among others, the compound represented by the formula:

< / BR>
(5) in WO 91/09844, among others, the compound represented by the formula:

< / BR>
(6) in EP-A-522808, among others, the compound represented by the formula:

< / BR>
(7) in WO 93/01169, among others, the compound represented by the formula:

< / BR>
(8) in EP-A-522456, among others, the compound represented by the formula:

< / BR>
However, were not disclosed condensed heterocyclic lidocaine having - CON<, associated directly with condensed heterocyclic ring which has an antagonistic activity against tachykinin receptors.

And for use as medicines for the treatment of the above-mentioned various diseases is still not detected these compounds, which are satisfactory from the point of view of strong antagonistic activity to tachykinin receptors, particularly antagonistic activity to the receptor, substance P, and other favorable properties, such as security and sufficiently long duration of action after injection. If CC is Sousa from patterns of known compounds, possessing excellent antagonistic activity to tachykinin receptors, and which are quite satisfactory as therapeutic drugs for these diseases.

These inventors, taking into consideration the above circumstances, spent a lot of painstaking research and as a result was first achieved success in the synthesis, heterocyclic lidocaine with characteristic chemical structure - CON< directly related to the condensed heterocyclic ring, and having a private structure represented by the formula:

< / BR>
where all symbols are the same values that are given here, and found that the connection has unexpectedly very high antagonistic activity to tachykinin receptors, particularly antagonistic activity to the receptor, substance P, and that it fully meets the requirements of the medicinal substance, applicable on the basis of its activity, thus, thus, achieved the perfection of this invention.

Formulating more specifically, this invention concerns:

(1) compounds represented by the formula

< / BR>
where the at least one of them represents optionally substituted heterocyclic ring; ring C represents optionally substituted benzene ring;

R denotes a hydrogen atom or optionally substituted hydrocarbon residue;

one of X and Y represents-NR1- (R1denotes a hydrogen atom or optionally substituted hydrocarbon residue) or-O-and the other represents - CO - or - CS-, or one of them represents - N= and the other represents - CR2-;

(R2denotes a hydrogen atom, halogen atom, optionally substituted hydrocarbon residue, optionally substituted by an amino group or optionally substituted hydroxyl group);

n denotes 1 or 2, or its salt,

(2) compounds, which are described above in (1), in which one of the rings A or B denotes an optionally substituted aromatic ring, and the other denotes an optionally substituted aromatic heterocyclic ring,

(3) the compound described above in (2) where the Deputy or deputies optionally substituted aromatic rings are from 1 to 4 substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl group, optionally halogenated C1-4alkoxygroup, optional is s, mono-C1-4- alkylamino, di-C1-4- alkylamino, carboxyl group and C1-4- alkoxycarbonyl group,

(4) compounds, which are described above in (2), in which the aromatic heterocyclic ring is a 5 - or 6-membered ring containing up to two heteroatoms selected from nitrogen, sulfur or oxygen,

(5) compounds, which are described above in (2) where the Deputy or deputies optionally substituted aromatic heterocyclic ring represented by 1 to 4 substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl group, optionally halogenated C1-4alkoxygroup, optionally halogenated C1-4allylthiourea, C1-3alloctype, hydroxyl group, amino group, mono-C1-4- alkylamino, di-C1-4- alkylamino, carboxyl group and C1-4alkoxycarbonyl group,

(6) the compound described above in (1) through (5), in which ring C may have 1 to 3 substituents each of which is selected from the group consisting of a halogen atom optionally halogenated C1-4alkyl groups and NeoMaster - -Y - represents - NR1a-CO-, -CO-NR1a- -O-CO-, -CO-O - or-N=C(R2a) - (R1aand R2arespectively denote a hydrogen atom or a C1-6alkyl group),

(8) compounds, which are described above with (1) through (5), in which R is C1-6alkyl group,

(9) compounds, which are described above with (1) through (5) in which n is 1,

(10) the compound described above in (1), the Deputy or deputies arbitrarily substituted Homo - or heterocyclic ring which contains from 1 to 4 substituents selected from the group consisting of halogen atom, optionally halogenated alkyl group, optionally halogenated C1-4allylthiourea, C1-3alloctype, hydroxyl group, amino group, mono-C1-4- alkylamino, di-C1-4- alkylamino, a carboxyl group, a C1-4alkoxycarbonyl group and the carbonyl group,

(11) the compound described above in (1), in which the heterocyclic ring is 5 - or 6-membered ring containing up to two heteroatoms selected from nitrogen, sulfur and oxygen,

(12) the compound described above in (1), in which homolliella ring is 5 - or 6-membered cyclic or-N=C(R2a)-(R1aand R2arespectively represent a halogen atom or C1-6alkyl group),

(14) the compound described in (1) above, in which the heterocyclic ring represented by ring A or B is a 5 - or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and sulfur, homolliella ring represented by ring A or B is a 5 - or 6-membered cyclic hydrocarbon group, and homolliella ring represented by ring A or B, respectively, may be substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and an optionally halogenated C1-4alkyl group; ring C may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl groups, and optionally halogenated C1-4alkoxygroup,

R is a hydrogen or C1-4alkyl group; X-Y is - CO-NR1a-, -NR1a-CO-or-N=C (R2a) - (R1aand R2arespectively denote a hydrogen atom or a C1-4alkyl group); and n is 1,

(15) the compound described above in (1), in which collectability, selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl groups, and optionally halogenated C1-4alkoxygroup; ring C may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl groups, and optionally halogenated C1-4alkoxygroup, R is a hydrogen atom or a C1-6alkyl group; X is - CO-; Y is-NR1a- (R1adenotes a hydrogen atom or a C1-6alkyl group); and n is 1,

(16) N-[3,5-bis(trifluoromethyl)benzyl] -7,8-dihydro-N,7-dimethyl - 5-(4-were)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide,

(17) N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-forfinal)- 7,8-dihydro-N,7-dimethyl-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide,

(18) N-[3,5-bis(trifluoromethyl)benzyl] -4-(4-forfinal)-6,7 - dihydro-N, 6-dimethyl-7-oxo-5-thieno[2,3-c]pyridinecarboxamide,

(19) N-[3,5-bis(trifluoromethyl)benzyl]-1,2,5,6,7,8-hexahydro - N,2,7-trimethyl-4-(4-were)-1-oxo-3 - pyrido[3,4-c]pyridinecarboxamide,

(20) the method of obtaining the compounds described in (1), which includes the interaction of the compounds represented by the formula:

< / BR>
where all the characters who eat represented by the formula:

< / BR>
where all symbols have the same values given above in (1) or its salt.

In the above formula, ring A and ring B are optionally substituted Homo - or heterocyclic ring and at least one of them is optionally substituted heterocyclic ring.

"Homo - or heterocyclic ring is (1) an aromatic or non-aromatic heterocyclic ring, which contains, for example, one or two heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, preferably one or two of them in connection with carbon atoms, or (11) cyclic hydrocarbon consisting of carbon atoms.

As the "aromatic heterocyclic ring" is used, for example, 5 - or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in connection with the carbon atoms (for example, pyridine, pyrazinone, pyrimidine, pyridazine, pyrrole, imidazole, pyrazol, triazole, thiophene, furan, thiazole, oxazole and isoxazole ring and so on), predostavljaetsja preferred. Especially commonly used 6-membered heterocyclic ring containing one or two nitrogen atom in connection with carbon atoms, for example, pyridine or pyrazinone ring and so on, or a 5-membered aromatic heterocyclic ring containing one sulfur atom in connection with carbon atoms, for example, thiophene ring, etc.

As a "non-aromatic heterocyclic ring is 5 - or 6-membered non-aromatic heterocyclic ring containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in connection with the carbon atoms. For example, as for A ring, use the ring, tetrahydropyridine, dihydropyridines, tetrahydropyrazino, tetrahydropyrimidine, tetrahydropyridine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazolo, dihydrothiophene, dihydrofuran, dihydrothiazolo, dihydrothiazolo, dihydrooxazolo and dihydroisoxazole among others, and as for ring B, are used, in addition to the above, piperidino, pieperazinove, hexahydropyridine, hexahydropyridine, tetrahydropyrrole, morpholine, pyrolidine, imidazolidinone, pyrazolidinone, tetrahydrocarbazole ring and so on Preferably, as for the ring A, is commonly used 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atom in connection with carbon atoms, for example, tetrahydropyrimidine and tetrahydropyridine ring, etc. Especially typically used, for example, tetrahydropyridine ring.

As for ring B, for example, used a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atom in connection with carbon atoms, particularly typically used pieperazinove ring or the like.

As the "cyclic hydrocarbon" is used, for example, 5 - or 6-membered cyclic hydrocarbon. For example, ring A is benzene, C5-6cycloalken (for example, cyclopentene, cyclohexene and so on) and as ring B is used in addition to the above C5-6cycloalken (for example, cyclohexane, cyclopentane, and so on). As ring A, for example, preferably 6-membered homolliella ring such as benzene ring, cyclohexanone ring or the like, and is particularly usually used benzene ring. As ring B is preferably a 6-membered homolliella also.

Preferably, when one of the rings A or B is substituted by choice aromatic ring, the other is a choice of substituted aromatic heterocyclic ring.

As the "aromatic ring" is used, for example, (1) 5-or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, preferably one or two of them in conjunction with the carbon atoms (for example, pyridine, pyrazinone, pyrimidine, pyridazine, pyrrole, imidazole, pyrazol, triazole, thiophene, furan, thiazole, isothiazol, oxazoline and etoxazole ring and so on), or (11) of the benzene ring.

Substitutes which do not necessarily have the "aromatic ring" include those similar to the substituents that do not have the rings A and B, as described in the following.

As the "aromatic heterocyclic ring "arbitrarily substituted aromatic heterocyclic ring" is used in the above-mentioned "5 - and 6-membered aromatic heterocyclic ring".

As the substituents do not have zames who have entrusted the ring A and ring B, as described in the following.

Ring A and ring B are, preferably, when one of them represents a benzene ring, the other is a 5 - or 6-membered aromatic heterocyclic ring.

As the "aromatic heterocyclic ring" is used, for example, pyridine, pyrazinone, pyrimidine, pyridazine, pyrrole, imidazole, pyrazol, triazole, thiophene, furan, thiazole, isothiazol and isoxazoline ring, preferably pyridine, pyrazinone and thiophene ring, etc. are usually used. And for example, preferred pyrrole and Diatlovo rings. Especially commonly used 6-membered ring containing N-heterocyclic ring comprising one or two nitrogen atom in connection with carbon atoms, for example, pyridine and pyrazinone ring and so on, or a 5-membered aromatic heterocyclic ring containing one sulfur atom in connection with carbon atoms, for example, thiophene ring.

As substituents that can be "Homo - and heterocyclic ring", "aromatic heterocyclic ring", "non-aromatic heterocyclic ring", "cyclic hydrocarbons", "aroma is on, arbitrarily substituted alkyl group, optionally halogenated alkoxygroup optionally halogenated allylthiourea, C1-7alluminare (for example, formamido, acetylamino, propionamido, bucillamine, benzoylamine and so on), C1-3atelocerata (for example, formyloxy, acetoxy, propionyloxy and so on), a hydroxyl group, a nitrogroup, cyano, amino group, mono - or di-C1-4- alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, and so on), a cyclic amino group (for example, 5 - to 9 - membered cyclic amino group, optionally containing, in addition, the nitrogen atom 1-3 heteroatoms, such as oxygen atom, sulfur atom and so on, almost more like pyrrolidino, piperidino, morpholino and so on), C1-4alkylcarboxylic (for example, acetylamino, propionamido, bucillamine and so on), C1-4alkylsulfonamides (for example, methylsulfonylamino, ethylsulfonyl and so on), C1-4alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and so on ), a carboxyl group, a C1-6acylcarnitine group (for example, methylcarbamoyl, ethylcarboxyl, propylmalonic and so on), carnemolla group, mono - or di - C1-4I so on), C1-6alkylsulfonyl group (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl and so on), etc., and also, for example, oxoprop.

The number of substituents is from 1 to 3.

As the "halogen atom", which may have a ring A and ring B, is used, for example, fluorine, chlorine, bromine, iodine, etc. and preferred those that include fluorine, chlorine.

As the "optionally substituted alkyl group" which may have a ring A or ring B, is typically used C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and so on), which may have from 1 to 4 substituents selected from the group consisting of, for example, hydroxyl group, amino group, carboxyl group, nitro, mono - or di-C1-6-alkylamino (for example, methylamino, ethylamino, dimethylamino, diethylamino and so on), C1-6alkylcarboxylic (for example, acetoxy, ethylcarbonate and so on) and halogen atom (e.g. fluorine, chlorine, bromine and so on). Especially preferred choice halogenated alkyl group, and C1-6an alkyl group or these groups substituted by 1-5 of such halogen atoms listed above, the example is, integtrated, propyl, 3,3,3-cryptochromes, isopropyl, 2-trifloromethyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tryptophanyl, 4-trifloromethyl, hexyl, 6,6,6-triptorelin, 5-triptoreline and so on, and preferably, C1-4alkyl group or this group substituted by 1-3 halogen atoms, which are mentioned above, for example, methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, 3,3,3-cryptochromes, isopropyl, 2-trifloromethyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, etc.

As "arbitrary halogenated alkoxygroup", which may have a ring A and ring B, is typically used C1-6alkoxygroup or this group, substituted by 1-5 of such halogen atoms as mentioned above, for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, isopropoxy, butoxy, 4,4,4-triptoreline, isobutoxy, sec-butoxy, pentox, hexyloxy and so on, and preferably, C1-4alkoxygroup or this group, substituted 1-3 of such halogen atoms as mentioned above, for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-cryptonetx isolino halogenated ancilliary", which may have a ring A and ring B, is typically used C1-6allylthiourea or this group, substituted by 1-5 of such halogen atoms as mentioned above, for example, methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia, pentylthio, hexylthio, etc. and preferably, C1-4allylthiourea or this group, substituted 1-3 such halogen atoms as mentioned above, for example, methylthio, deformality, triptoreline, ethylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia etc.

Hereafter the number of halogen atoms in accordance with the term "arbitrarily halogenated" used in the description varies from 1 to 5, preferably from 1 to 3.

Examples of preferred substituents, which may be of ring A and ring B include a halogen atom (e.g. fluorine, chlorine, bromine and so on), optionally halogenated C1-4alkyl group (e.g. methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, 3,3,3-forproper, isopropyl, 2-trifloromethyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, and so on), optionally halogenated C1-what propoxy, butoxy, 4,4,4-triptoreline, isobutoxy, sec-butoxy and so on), optionally halogenated C1-4allylthiourea (for example, methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia and so on), C1-3atelocerata (for example, formyloxy, acetoxy, propionyloxy and so on ), hydroxyl group, amino group, mono - or di - C1-4alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and so on ), a carboxyl group, and C1-4alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and so on), and oxoprop.

As preferred substituents, which may be of ring A and ring B are normally used halogen atom (e.g. fluorine, chlorine, bromine and so on), optionally halogenated C1-4alkyl group (e.g. methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, 3,3,3-cryptochromes, isopropyl, 2-trifloromethyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, and so on), optionally halogenated C1-4alkoxygroup (for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, p the group, mono - or di - C1-4-alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and so on), C1-3atelocerata (for example, formyloxy, acetoxy, propionyloxy and so on), oxoprop etc. Among them, the most commonly used halogen atom (e.g. fluorine, chlorine, bromine and so on), optionally halogenated C1-4alkyl group (e.g. methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, 3,3,3-cryptochromes, isopropyl, 2-permethylated, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, and so on ) and arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, isopropoxy, butoxy, 4,4,4-triptoreline, isobutoxy, sec-butoxy and so on and so on

The substituents in the ring A and the ring B can be placed in any substitutable position of the rings, and when there are two or more substituents, they are the same or different, and their number can vary from 1 to 4. Preferably, the number of substituents is from 1 to 3.

When the ring A and/or ring B are nitrogen atom, they may not necessarily form a Quaternary ammonium SUP>-, Br-I-and so on), sulfate ion, a hydroxyl ion, etc.

As preferred options, when ring A is homolliella ring consisting of carbon atoms (hereafter...... denotes a single or double bond), groups are used, in particular, represented by the formula:

< / BR>
< / BR>
where A1denotes a halogen atom such as fluorine, chlorine, etc. optionally halogenated C1-4alkyl group such as methyl, ethyl, isopropyl, trifluoromethyl, and so on, or arbitrarily halogenated C1-4alkoxygroup, such as methoxy, triptoreline, ethoxy and so on, or formula

< / BR>
where A2and A3independently represent a halogen atom, such as fluorine, chlorine, etc. optionally halogenated C1-4alkyl group such as methyl, ethyl, isopropyl, trifluoromethyl, etc. or any halogenated C1-4alkoxygroup, such as methoxy, triptoreline, ethoxy etc.

In preferred examples, in particular, are benzene ring, represented by formula

< / BR>
or

< / BR>
where A4and A5independently represent a halogen atom, such as fluorine, chlorine, sawdust, etc.

And are usually used as arbitrarily substituted benzene ring, for example, the following

< / BR>
or

< / BR>
especially

< / BR>
or

< / BR>
where each symbol has the same meaning given above.

From these above formulas, especially preferred among the other ones where

(1) AIis a halogen atom (e.g. fluorine, chlorine, and so on) or arbitrarily halogenated C1-4alkyl group (for example, stands, trifluoromethyl, ethyl, isopropyl, and so on),

(2) A2and A3are, independently, optionally halogenated C1-4alkyl group (for example, stands, trifluoromethyl, ethyl, isopropyl, and so on ) or arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy and so on),

(3) A4and A5is, independently, C1-4alkyl group (for example, stands, ethyl, isopropyl, and so on),

(4) A1represents a halogen atom (e.g. fluorine, chlorine, and so on ),

(5) A2and A3are, independently, C1-4alkoxygroup (for example, methoxy, ethoxy and so on).

Examples of preferred options aromatic or neuraminidase ring, such as pyridine, pyrazinone, thiophene, tetrahydropyridine, pyrrole and thiazole ring. As specific examples usually use the following:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and so on.

In addition, among others, preferred are the following:

< / BR>
< / BR>
and so on.

As preferred options arbitrarily substituted aromatic or non-aromatic heterocyclic rings are pyridine, pyrazinone, thiophene, tetrahydropyridine, pyrrole and thiazole rings, etc. who by choice have one or two substituent selected from the carbonyl group optionally substituted alkyl group (having the same meaning given to substituents, possible for ring A and ring B), (C6-10aryl groups (e.g. phenyl and so on ) and halogen atom (e.g. fluorine, chlorine, bromine and so on). More specifically, preferred are those, among others, which have the following formula:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
where D denotes a hydrogen atom, a halogen atom (e.g. fluorine, chlorine, bromine and so on); E represents C1-4alkyl group (e.g. methyl, ethyl, propyl, isopropyl, and so on), see halogen ion (for example, Cl-, Br-I-and so on) , sulfate ion or hydroxyl ion, and so on; G represents preferably a hydrogen atom or a C1-4alkyl group (e.g. methyl, ethyl, propyl, isopropyl, and so on); denotes a hydrogen atom, a C1-4alkyl group (e.g. methyl, ethyl, propyl, isopropyl etc.,) or C6-10aryl group (e.g. phenyl and so on ). Ring A, more preferably, is a pyridine ring.

As the preferred homozygotesare ring, when ring B is composed of carbon atoms (hereafter ... denotes a single or double bond), used by such groups, which are represented, for example, by the formula:

< / BR>
where B1denotes a halogen atom such as fluorine, chlorine, etc. optionally halogenated C1-4alkyl group such as methyl, trifluoromethyl, ethyl, isopropyl, etc. or arbitrarily the halogenated alkoxygroup, such as methoxy, triptoreline, ethoxy and so on, the formula is:

< / BR>
where B2and B3independently represent a halogen atom, such as fluorine, chlorine, etc. optionally halogenated C1-4alkyl group such as methyl, trifluoromethyl, ethyl, isopropyl, etc. or arbitrarily halogenic the B4B5and B6independently represent a halogen atom, such as fluorine, chlorine, etc. optionally halogenated C1-4alkyl group such as methyl, trifluoromethyl, ethyl, isopropyl, etc. or arbitrarily halogenated C1-4alkoxygroup, such as triptoreline, ethoxy etc.

More preferably, a group represented by the formula:

< / BR>
or

< / BR>
where B7B8and B9independently represent halogen, such as fluorine, chlorine, etc. optionally halogenated C1-4alkyl group such as methyl, trifluoromethyl, ethyl, isopropyl, etc., or C1-4alkoxygroup, such as methoxy, triptoreline, ethoxy, and so on, and so on

Especially commonly used group represented by the formula:

< / BR>
or

< / BR>
where B10denotes a halogen atom such as fluorine, chlorine, etc.

C1-4alkyl group such as methyl, trifluoromethyl, ethyl, etc. or C1-4alkoxygroup, such as methoxy, triptoreline, ethoxy etc.

And it is also preferable that when ring B is arbitrarily substituted benzene ring group, for example, represented by the formula:

< / BR>
< / BR>
or< a preferred group, represented by the formula:

< / BR>
or

< / BR>
where all symbols have the same meanings given above.

Among the substituents in the above formulas are particularly preferred include:

(1) B1B2B3B4B5and B6independently represent a halogen atom (e.g. fluorine, chlorine, and so on) or arbitrarily halogenated C1-4alkyl group (e.g. methyl, trifluoromethyl, ethyl, isopropyl, and so on),

(2) B1B2B3B4B5and B6independently represent proizvoditelopredelennogo C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy and so on),

(3) B7B8and B9denote halogen atom (e.g. fluorine, chlorine, and so on ),

(4) B10denotes a fluorine atom, and

(5) B10represents C1-4alkyl group (e.g. methyl etc)

More preferred are those which include

< / BR>
< / BR>
and so on

As the preferred choice of substituted aromatic or non-aromatic heterocyclic ring represented by ring B are, for example, 5 - or 6-membered aromatic and non-aromatic heterocyclic ring. These rings can the>

Especially preferred, for example, those substituents, which is represented by the formula:

< / BR>
or

< / BR>
and they are usually used.

When the ring A and/or ring B are (were) heterocyclic rings, also preferably unsubstituted heterocyclic ring.

In the above formula, the ring C represents an arbitrarily substituted benzene ring. The benzene ring may be the same or different 1 to 5 substituents, preferably 1-3. And these rings have substituents at arbitrary positions. Examples of such substituents include arbitrarily halogenated C1-4alkyl group (e.g. methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, isopropyl, 3,3,3-cryptochromes, butyl, and so on), C1-4alkyl group, a substituted amino group (for example, aminomethyl, 2-amino-ethyl, and so on ), C1-4alkyl group, a substituted mono - or di-C1-4-alkylamino (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminomethyl, 2-dimethylaminoethyl and so on), C1-4alkyl group, substituted carboxyl group (for example, carboxymethyl, carboxyethyl and so on), C1-4alkyl group, Thames
alkyl group substituted with hydroxyl group (for example, hydroxymethyl, hydroxyethyl, and so on), C1-4alkyl group, substituted C1-4alkoxycarbonyl group (for example, methoxymethyl, methoxyethyl, ethoxyethyl and so on), C3-6cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on ), halogen atom (e.g. fluorine, chlorine, bromine, iodine and so on), a nitrogroup, cyano, hydroxyl group, optionally halogenated C1-4alkoxygroup (for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, butoxy, isopropoxy and so on), optionally halogenated C1-4allylthiourea (for example, methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio and so on), amino group, mono - or di-C1-4-alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and so on), the cyclic amino group (for example, from 5 to 9-membered cyclic amino group, optionally containing 1 to 3 heteroatoms, such as oxygen atom and sulfur atom besides the nitrogen atom, specifically, for example, pyrrolidino, piperidino, morpholino and so on), C1-4alkylcarboxylic (for example, acetylamino, is the Rupp (for example, methylaminorex, ethylenedicarboxylic, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and so on), C1-4alkylsulfonamides (for example, methylsulfonylamino, ethylsulfonyl, propylsulfonyl and so on ), C1-4alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isobutoxide and so on ), benzyloxycarbonyloxy group, a carboxyl group, a C1-6alkylcarboxylic group (for example, methylcarbamoyl, ethylcarboxyl, butylcarbamoyl and so on), C3-6cycloalkylcarbonyl group (for example, cyclohexylcarbonyl and so on), karbamoilnuyu group, mono - or di-C1-4-alkylcarboxylic group (for example, methylcarbamoyl, ethylcarbitol, propellerblades, butylcarbamoyl, diethylcarbamoyl, dibutylbarbituric and so on), C1-6alkylsulfonyl group (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl and so on).

In addition, there is also an option when the ring C is substituted, in particular, 5 - or 6-membered aromatic managerialism group (for example, fullam, teinila, oxazolium, isoxazolyl, thiazolyl, isothiazolines, imidazolium, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, forum, pyridium, pyridazinyl, pyrimidinyl, pyrazinium, triazinium and so on), 5 - or 6-membered aromatic mono - heterocyclic group can be substituted, for example, from one to three arbitrarily halogenated C1-4alkyl groups (e.g. methyl, chlormethine, deformationally, trichloroethylene, triptoreline, ethyl, ISO-propyl, and so on).

As the preferred substituents in ring C are arbitrarily halogenated C1-4alkyl group (e.g. methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, isopropyl, 3,3,3-cryptochromes and so on), halogen atom (e.g. fluorine, chlorine, bromine and so on), the nitro-group, hydroxyl group, optionally halogenated C1-4alkoxygroup (for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, and so on), an amino group, a C1-4alkyl group, a substituted mono - or di-C1-4alkylamino (for example, methylaminomethyl, dimethylaminomethyl and so on ), mono - or di-C1-4-alkylamino (for example, methylamino, ethylamino, dimethylamino, diethylamino and so on), C1-4alkoxycarbonyl group (for example, methoxycarbonylamino halogenated C1-4alkyl group (e.g. methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, propyl, isopropyl, and so on), halogen atom (e.g. fluorine, chlorine, bromine and so on) and arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy, propoxy, and so on). The number of these substituents ranges, preferably, from 1 to 3.

As a more preferred ring C is benzene ring arbitrarily substituted from 1 to 3 substituents selected from the group consisting of, for example, halogen atom (e.g. chlorine, fluorine, bromine and so on), optionally halogenated C1-4alkyl groups (e.g. methyl, trifloromethyl, ethyl, isopropyl, and so on), optionally halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy and so on), di-C1-4-alkylamino (for example, dimethylamino, and so on), C1-3alloctype (for example, acetoxy, and so on) and a hydroxyl group. More specifically, it is used arbitrarily substituted benzene ring represented by, for example, by the formula

< / BR>
where C1C2and C3independently represent a hydrogen atom, a halogen atom (e.g. fluorine, chlorine, bromine and so on ), etc and so on), arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy, propoxy, and so on), mono or di (C1-4alkylamino (for example, methylamino, ethylamino, dimethylamino, diethylamino and so on), C1-3alloctype (for example, acetoxy, and so on) or a hydroxyl group, or the formula

< / BR>
where C4and C5independently represent a hydrogen atom, a halogen atom (e.g. fluorine, chlorine, bromine and so on), optionally halogenated C1-4alkyl group (e.g. methyl, trifluoromethyl, ethyl, isopropyl, t-butyl, etc. or arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy, propoxy, and so on). More preferably benzene ring, such as in the aforementioned formula (C-1), (C-2),

(1) C1C2and C3independently represent a halogen atom, optionally halogenated C1-4alkyl group or arbitrarily halogenated C1-4alkoxygroup.

(2) C1C2and C3independently represent a halogen atom or arbitrarily halogenated C1-4alkyl group,

(3) C1C2and C3independently represent a halogen atom,

(4) C11C2and C3independently denote an arbitrarily halogenated C1-4CNS group,

(6) C4and C6independently represent a halogen atom,

(7) C4and C5independently denote an arbitrarily halogenated C1-4alkyl group, or

(8) C4and C5independently denote an arbitrarily halogenated C1-4alkoxygroup.

In (1) to (8), as examples of "arbitrarily halogenated C1-4alkyl groups are methyl, trifluoromethyl, ethyl, propyl, isopropyl, and so on; as examples of "arbitrarily halogenated C1-4alkoxygroup" are methoxy, triptoreline, ethoxy, propoxy, and so on; and as examples of halogen atoms are fluorine, chlorine, bromine, etc.

As a more preferred ring C is benzene ring, for example, such as in the above formula (C-1) and (C-2),

(a) C1C2and C3simultaneously denote fluorine, methyl, isopropyl or methoxy group,

(b) or one of C4and C5denotes the hydrogen atom and the other denotes a methoxy group,

(c) C1C2and C3simultaneously denote fluorine,

(d) C4and C5

As preferred examples of ring A and ring B are those in which one of the rings A or B is a 5 - or 6-membered heterocyclic ring containing one or two heteroatoms selected from nitrogen atom, sulfur atom in connection with the carbon atoms (for example, pyridine, pyrazin, thiophene, tetrahydropyridine, piperidine, piperazine, and so on), which may be substituted C1-4alkyl group (for example, stands, ethyl, isopropyl, and so on), and the other is a benzene ring optionally substituted by from one to three substituents selected from the group consisting of a halogen atom (e.g. fluorine, chlorine, bromine and so on), optionally halogenated C1-4alkyl group (e.g. methyl, trifloromethyl, ethyl, propyl, isopropyl, and so on ) and arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy, propoxy, isopropoxy and so on).

As preferred examples of ring A and ring B are those in which one of the rings A or B is a 5 - or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from a nitrogen atom, or sulfur atom in connection with carbon atoms, and the other is the C halogen atom (for example, chlorine, bromine and so on ), optionally halogenated C1-4alkyl groups (e.g. methyl, trifloromethyl, ethyl, propyl, isopropyl, and so on) and arbitrarily halogenated C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy, propoxy, isopropoxy and so on).

In the above formulas, one of X and Y is-NR1- (R1denotes a hydrogen atom or arbitrarily substituted hydrocarbon residue) or-O-and the other is-CO - or-C-; or one of them is-N= and other =CR2- (R2denotes a hydrogen atom, halogen atom, optionally substituted hydrocarbon residue, optionally substituted by an amino group or arbitrarily substituted hydroxyl group). Preferably, as - X-Y - are - NR1a-CO-, -CO-NR1a- (R1adenotes a hydrogen atom or a C1-6alkyl group such as methyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl etc.,),- O-CO-, -CO-O - or-N=C (R2a) - (R2adenotes a hydrogen atom or a C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and so on), more preferably, -CO-NR1a-, -NR1a- CO - (R1ahas the same meaning given above>- (R1ahas the same meaning given above).

As the above-mentioned "halogen atom" are, for example, fluorine, chlorine, bromine, iodine and so on, preferably, for example, fluorine, chlorine, etc. are usually used.

As above(Oh) "hydrocarbon residue (or group)" used group obtained by removing a hydrogen atom from the carbon atom in the hydrocarbon.

"Hydrocarbon (s) residue (or group)" include an alkyl group, alkenylphenol group, alkylamino group, cycloalkyl group and aryl group, and so on, preferably, an alkyl group, cycloalkyl group and aryl group, especially preferably an alkyl group, are usually used.

As the "alkyl group" used C1-6an alkyl group with straight or branched chain, C1-4an alkyl group with straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

As alkenylphenol group" use C2-6Alchemilla group, such as ethynyl, propenyl, Isopropenyl, butenyl, Isobutanol, sec-butanol and so on , preferably C2-4Alchemilla group, so ininna group, such as ethinyl, PROPYNYL, Isopropenyl, butenyl, Isobutanol, sec-butenyl and so on, preferably C2-4alkyl group, such as ethinyl, PROPYNYL, Isopropenyl etc.

As cycloalkyl group" is C3-8cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on, preferably, C3-6cycloalkyl group, such as cyclopropyl, cyclobutyl etc.

As "cycloalkyl-alkyl group is C3-6cycloalkyl C1-4alkyl group, such as cyclopropylmethyl, cyclopropylethyl etc.

As the "aryl group" is C6-14aryl group such as phenyl, 1-naphthyl, 2-naphthyl, antril, tenantry and so on, preferably, C6-10aryl group such as phenyl, 1-naphthyl, 2-naphthyl and so on, especially commonly used phenyl.

As the substituents, which may have a hydrocarbon residue (or group)" used from one to five, preferably one or more (preferably 1 to 3) substituents selected from the group consisting of, for example, halogen atom (e.g. fluorine, chlorine, bromine, iodine and so on), nitro, ceanography, a hydroxyl group, a C1-41-4alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, triethylamine and so on), a cyclic amino group (for example, from 5 to 9-membered cyclic amino optionally, containing, in addition to the nitrogen atom, 1 to 3 heteroatoms, such as oxygen atom, sulfur atom and so on , practically, for example, pyrrolidino, piperidino, morpholino and so on), C1-4alkylcarboxylic (for example, acetylamino, propionamido, bucillamine and so on), C1-4alkylsulfonamides (for example, methylsulfonylamino, ethylsulfonyl and so on), C1-4alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and so on), a carboxyl group, a C1-6alkylcarboxylic group (for example, methylcarbamoyl, propylmalonic and so on), carbamoyl group, mono - or di-C1-4alkylcarboxylic group (for example, methylcarbamoyl, ethylcarbitol and so on), C1-6alkylsulfonyl group (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl and so on), phenyl group which may be substituted C1-3alkoxygroup (for example, phenyl, methoxyphenyl, ethoxyphenyl and so on), among others.

PAP)", include a hydroxyl group, a C1-4alkoxygroup (for example, methoxy, ethoxy, propoxy, and so on), amino group, mono or di (C1-4alkylamino (for example, methylamino, ethylamino, diethylamino and so on ), C1-4alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and so on), a carboxyl group, karbamoilnuyu group and phenyl group is particularly usually used carboxyl group, carnemolla group, etc.

As mentioned above according to the choice of substituted hydroxyl group" is, for example, a hydroxyl group, a C1-4alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and so on), C6-10alloctype (for example, phenyloxy, naphthyloxy and so on), C1-4alkylcarboxylic (for example, formyloxy, acetoxy, propionyloxy and so on) and C6-10arylcarboxylic (for example, benzyloxy, naphthyloxy and so on ), preferably C1-4alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy and so on) are usually used.

As substituents that may have these groups are those which are essentially the same as the substituents of the above-mentioned (about the volume (for example, fluorine, chlorine, bromine and so on).

As the aforementioned "arbitrarily substituted amino group" are, among others, amino group which may be substituted by one to three substituents selected from the group consisting of (I) C1-4alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, etc.), (II) C1-4alkylcarboxylic group (for example, acetyl, propionyl, butyryl and so on), (III) C1-4alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and so on), (IV) phenyl group, (V) C1-4alkylphenyl group (for example, 4-were, 3-were, 2nd were, and so on), (VI) halogenated phenyl group (for example, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, and so on ) and (VII) C1-4alkoxyphenyl group (for example, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, and so on); and the most commonly used amino group, mono - and di-C1-4alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and so on).

As R1preferred C1-4group (for example, methyl, ethyl, propyl, isopropyl, and so on), especially preferred methyl group.

As R2the preferred hydrogen atom.

In you is>/P>As "arbitrarily substituted (Oh) hydrocarbon (Oh) residue (or group)" represented by R, residuals are similar to those described for R1and R2. As R preferred a hydrogen atom or a C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, etc., especially methyl and so on), especially the commonly used hydrogen atom. In the above formula, n denotes 1 or 2 and, when n = 1, preferred.

As compounds (I) of this invention, preferred are those in which one of the rings A or B is a 5 - or 6-membered heterocyclic ring containing heteroatoms selected from nitrogen atom or sulfur atom, in combination with carbon atoms and the other is a benzene ring, these rings may have one or two substituent selected from the group consisting of a halogen atom and arbitrary halogenated C1-4alkyl group;

ring C is benzene ring that may be substituted from one to three substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl groups and randomly halogenated C1-4alkoxygroup;

R denotes the atom of odor which respectively mean a hydrogen atom or a C1-6alkyl group); and n denotes 1, or preferred their pharmaceutically acceptable salts.

As the "5 - or 6-membered heterocyclic ring are, for example, pyridine, pyrazin, pyrrole, thiophene, thiazole, tetrahydropyran, piperidine, and so on,

and as the rings A are, specifically, those represented by the formula:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and so on.

As ring B are represented by the formula:

< / BR>
and so on.

As the "halogen atom" are, for example, fluorine, chlorine, bromine, etc. as "arbitrary halogenated C1-4alkyl group" is, for example, methyl, chloromethyl, deformity, trifluoromethyl, trichloromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, propyl, 3,3,3-tryptophol, isopropyl, 2-trifloromethyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, etc.

As "arbitrary halogenated C1-4alkoxygroup" is, for example, methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, isopropoxy, butoxy, 4,4,4-triptoreline, isobutoxy, sec-butoxy, etc. as "C1-6alkyl group" is, for example, methyl, ethyl, train those in which ring A is A 5 - or 6-membered heterocyclic ring containing one nitrogen atom or nitrogen atom in connection with the carbon atoms that is represented, for example, by the formula:

< / BR>
Ring B is a benzene ring, optionally having 1 to 3 substituents selected from the group consisting of a halogen atom (e.g. fluorine, chlorine, and so on) and C1-4alkyl groups (e.g. methyl, trifluoromethyl, ethyl, propyl, isopropyl, and so on);

Ring C is a benzene ring, optionally having 1 to 3 substituents selected from the group consisting of halogen atom (having the same meaning as above), optionally halogenated C1-4alkyl group (having the same meaning as above) and C1-4alkoxygroup (for example, methoxy, triptoreline, ethoxy, propoxy, isopropoxy and so on);

R is a hydrogen or C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, and so on);

-X-Y - is-CO-NR1a- (R1adenotes a hydrogen atom or a C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, and so on), and n denotes 1.

The compound (I) of this invention has, theoretically, the isomers on the basis of steric conamara can depending on the species to be separated, they are included in this invention.

When the compound (I) forms a salt, and it is used as a pharmaceutical product, preferably the salt is pharmaceutically acceptable.

Examples of such pharmaceutically acceptable salts include such as salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or salts with organic acids such as acetate, malate, maleate, fumarate, tatrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, palmitate, salicylate and stearate, but are not limited to these salts.

The compound (I) or its salt of the present invention can be obtained, for example, when given the opportunity carboxylic acid represented by the compound (II) or its salt or its reactive derivative to react with compound (III) or its salt (reaction formation nedovazeni). For example, in the case where the compound (III) or its salt (for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, etc. or salts with organic acids, such as methanesulfonate acid, benzolsulfonat acid, toluensulfonyl (II) or its salt (for example, salts with alkali or alkaline earth metals such as sodium, potassium, magnesium and so on, mainly, it is preferable to use a suitable condensing agent, or the compound (II) or its salt is first converted into their reactive derivative, which is then allowed to react with compound (III) or its salt. As the condensing means is used, for example, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diethylthiophosphate, diphenylphosphoryl, etc. In the case of these condensing means is particularly preferable to conduct the reaction in a solvent (e.g. ethers, esters, complex, halogenated hydrocarbons, hydrocarbons, Amidah, sulfoxidov and so on, such as tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, dichloromethane, 1,2-dichloroethane, benzene, toluene, N,N-dimethylformamide, dimethyl sulfoxide and so on). This reaction can be carried out in the presence of a base to accelerate the reaction at temperatures in the range of about -10oC to 100oC, preferably from about 0oC to 60oC. the reaction Time ranges usually from 1 to 96 hours, preferably from 1 to 72 hours. The number of Saedinenie, preferably from 1 to 3 molar equivalents, per 1 mol of compound (II) or its salt. As the base used, for example, bonds alkylamines, such as triethylamine, etc., cyclic amines, such as N-methylmorpholine, pyridine, etc. and the number that you want to apply, varies from 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, per 1 mol of compound (II) or its salt.

As reactive derivatives of the compounds (II) are used, for example, halides (e.g. chloride, bromide, and so on), anhydrides of carboxylic acids, mixed anhydrides of carboxylic acids (e.g., anhydride with methylcarbonate, anhydride with ethylcarbonate, anhydride with isobutylketone), active esters (complex) (for example, ester with imide hydroxyethanoic acid, ester with 1-hydroxybenzotriazole, ester with N-hydroxy-5-norbornene-2,3-dicarboximido, ester with p-NITROPHENOL, ether with 8-oksihinolina and so on). The reaction of the compound (III) or its salt with a compound (II) or its reactive derivative is carried out usually in a solvent (e.g. halogenated hydrocarbons, ethers, esters, hydrocarbons, Amidah and so on, such as chloroform, dechlorinated and so on). This reaction can be accelerated in the presence of a base. The reaction time ranges usually from 1 to 48 hours, preferably from 1 to 24 hours. The amount of compound (III) or its salt is in the range from 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, per one mol of the reactive derivative of compound (II). As bases are used, for example, bonds alkylamines, such as triethylamine, etc., cyclic amines, such as N-methylmorpholine, pyridine, etc., aromatic amines such as N,N-dimethylaniline, N,N-diethylaniline and so on; carbonates of alkali metals such as sodium carbonate, potassium carbonate and so on, the bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and so on, and the number of such bases, which must be used ranges from 1 to 5 molar equivalents, preferably, from 1 to 3 molar equivalents, per 1 mol of compound (II) or its reactive derivative. And when this reaction, when used immiscible with water, the solvent, the reaction can be carried out by adding water to the reaction system, i.e., in the biphasic solvent system.

The compound (I) or its salt Mogi, and Z and W denotes R or a group with the formula:

< / BR>
where the symbols in the formula have the same meaning given above, provided that at least one of Z and W denotes a group represented by chemical formula (VI).

As the deleted group L of the compound (V) are halogen atoms (e.g. chlorine, bromine, iodine and so on) or substituted sulfonyloxy (for example, methanesulfonate, p-toluensulfonate and so on).

When the compound (IV) can be used in its free state, it may undergo reactions in the form of salts, for example, salts of alkaline metal such as lithium, sodium, potassium, etc., To one mol of compound (IV) or its salt compound W-L is introduced into the reaction in an amount of from 1 to 10 moles, preferably 1 to 5 moles. Usually, the reaction is carried out in a solvent. As the solvent used, for example, halogenated hydrocarbons such as dichloromethane, chloroform, etc., NITRILES, such as acetonitrile and so on, ethers such as dimethoxyethane, tetrahydrofuran, etc., dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and so on, Adding the Foundation serves to enable a favorable reaction. Site is potassium, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, diisopropylethylamine, pyridine, etc., and in this reaction, instead of applying the base, the compound (IV) is converted, for example, in such salt is an alkali metal or alkaline earth salt of a metal, etc. that are mentioned above and which can then be brought into reaction with the compound W-L. Since the amount of base that should be used varies depending on the kind of the compound (IV), W-L and the solvent and other reaction conditions, it usually ranges from 1 to 10 moles, preferably 1 to 5 moles per 1 mol of compound (IV). The reaction temperature ranges from -50oC to 200oC, preferably from -20oC to 150oC. Because the reaction time varies depending on kinds of the compound (IV), connection type W-L or their salts or reaction temperature, it ranges from 1 to 72 hours, preferably from 1 to 24 hours.

Among compounds (I) of this invention, the compound in which ring A is tetrahydropyridinium ring, can be obtained by the recovery of compounds in which ring A is A pyridine ring. Since this reaction can be conducted by various methods, is whom recovery. Examples of catalysts to be used for this catalytic reduction include platinum catalysts such as platinum black, platinum oxide, platinum carbon and so on , palladium oxide, palladium barium sulfate, palladium charcoal, etc., Nickel catalysts, such as reducing Nickel, Raney Nickel (Raney), etc. are Preferable examples of the solvents include alcohols such as methanol, ethanol, propanol, isopropanol and so on, ethers such as tetrahydrofuran, dioxane and so on, esters such as ethyl acetate, among others. The reaction temperature ranges from 0o200oC, preferably from 20oC to 110oC. the reaction Time usually ranges from 0.5 to 48 hours, preferably from 1 to 16 hours. Although the reaction is usually conducted at normal atmospheric pressure, when necessary, it is performed at high pressure (from 3 to 10 atmospheres). At the same time, the amount of the catalyst varies depending on its type, and it usually ranges from 0.1 to 10% (weight) on the amount of compound (I). By using essentially the same method above any other aromatic heterocyclic ring can be turned tetrahydropyridine ring, can also be obtained by reaction of compounds in which ring A is A pyridine ring with an alkylating agent represented by Q-L', where Q denotes arbitrarily substituted alkyl group, and L' denotes a group to delete (as L' is the same groups as for L), to obtain a Quaternary salt, and subsequent recovery of the Quaternary salt. As alkylating funds Q-L' applied to the transformation into a Quaternary salt, used the alkane halide (e.g. chloride, bromide, iodide, and so on), esters of sulfuric acid or ester sulfonic acid (for example, methanesulfonate, p-toluensulfonate, bansilalpet and so on), is particularly preferably used alkylhalogenide. The amount of alkylating agent that should be used ranges from 1 to 100 equivalents per one mole of substrate, preferably from 1 to 30 equivalents. This reaction is usually conducted in a solvent. As the solvent are alcohols such as methanol, ethanol, propanol, isopropanol and so on, ethers such as tetrahydrofuran, dioxane and so on, esters such as ethyl acetate and so on, halogenated hydrocarbons such as dichloromethane, 1,El. The reaction temperature ranges from 10oC to 200oC, preferably from 20oC to 110oC. the reaction Time ranges from 0.5 hours to 24 hours, preferably from 1 to 16 hours.

The reduction in the ratio thus obtained "tetrahydropyridine ring Quaternary salt can be carried out in an inert solvent using a metal hydride, for example, borohydride sodium, borohydride lithium, borohydride zinc, cyanoborohydride sodium, cyanoborohydride lithium aluminum hydride-lithium, etc. are Preferably used borohydride sodium. As solvent for the reaction are lower alcohols, such as methanol, ethanol and so on, ethers such as dioxane, tetrahydrofuran, etc. or a hydrocarbon, such as benzene, toluene and so on, separately or in a mixture. The reaction temperature ranges from -100oC to 40oC, preferably from approximately -80oC to 25oC. the reaction Time ranges usually from 5 minutes to 10 hours, preferably from 10 minutes to 5 hours. The amount of reducing agent is typically in the range from 1 to 10 equivalents in respect of the Quaternary salt, preferably 1-2 equivalents.

And by oxidation of compounds in which ring A is A Quaternary salt of a pyridine ring, can also be obtained compound in which ring A is A pyridine ring. The oxidation reaction can be carried out by a known method, "E. A. Prill et al., Organic Syntheses, Combined Book Vol. 2, p. 419 (1957)", or alternatively, a similar method.

When ring B is a heterocyclic ring, by carrying with him a similar response recovery can be obtained its prevous is ineni, in which one of X or Y is-CS-, can be obtained by reaction of compounds in which the respective Deputy is-CO-, with a suitable sulfide. As sulfide used for this reaction, is used, for example, phosphorus pentasulfide, the reagent Lawesson (Lowesson), and so on, This reaction is usually carried out in anhydrous conditions in a solvent such as dichloromethane, chloroform, dioxane, tetrahydrofuran, benzene, toluene and so on, the Amount of sulfide that you want to apply equimolar or more, preferably equal to 2-5 the moles, and the reaction temperature is in the range from 10oC to 120oC. Although the reaction time varies depending on the starting compounds or sulfide, the reaction temperature and the like, it usually ranges from 1 to 8 hours.

When the compound (I) or its salt obtained by the method described above, contain lower alkoxygroup (C1-6in the benzene rings in the ring A, B and C, this alkoxygroup can be converted, when necessary, a hydroxyl group by reaction alkoxygroup, for example, tribromide boron. This reaction is conducted usually in a solvent (e.g. halogenated hydrocarbons, hydrocarbons, etc. such as dichlooC to 80oC, preferably from about 0oC to 30oC. the Number of tribromide boron ranges from about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents per lowest alkoxygroup. The reaction time ranges usually from 15 minutes to 24 hours, preferably from 30 minutes to 12 hours. And when the compound (I) or its salt obtained by the method described above, contains a hydroxyl group in the benzene ring in the group represented by ring A, ring B and ring C, it can be converted into alkoxy - or alloctype, respectively, by alkylation, acylation, depending on the need. The alkylation reaction is conducted by reaction of an alkylating agent, for example, halide arbitrarily substituted alkane (e.g., chloride, bromide, iodide, and so on), a complex ester of sulfuric acid or of ester sulfonic acid (for example, methanesulfonate, p-toluensulfonate, bansilalpet and so on) with this group in a solvent (e.g. alcohols such as methanol, ethanol, propanol and so on, ethers such as dimethoxyethane, dioxane, tetrahydrofuran, etc., ketones, such as acetone, etc., amides such as N,N-e who, N-methylmorpholine, pyridine, picoline, N,N-dimethylaniline etc., or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide etc., the reaction Temperature ranges usually from -10oC to 100oC, preferably from about 0oC to 80oC. the Number of these alkylating funds varies from about 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents per one mole of original phenol derivative. The reaction time ranges usually from 15 minutes to 24 hours, preferably from 30 minutes to 12 hours.

The acylation reaction can be carried out by reaction with the desired carboxylic acid or its reactive derivative. This reaction is carried out for different variations of the species alleluya means and the source of phenolic derivatives usually in a solvent (for example, hydrocarbons, ethers, esters, halogenated hydrocarbons, amides, aromatic amines, and so on, such as benzene, toluene, ethyl ether, ethyl acetate, chloroform, dichloromethane, dioxane, tetrahydrofuran, N,N-dimethylformamide, pyridine, and so on ), and to accelerate the reaction can be added to the appropriate base like sodium carbonate, potassium carbonate and so on, acetates such as sodium acetate, tertiary amines such as triethylamine, etc. , aromatic amines such as pyridine, etc. to the reaction system. As reactive derivatives of carboxylic acids are the acid anhydrides, mixed acid anhydrides, halides (e.g. chloride, bromide), among others. The number of these alleluya agents ranges from 1 to 5 molar equivalents per one mole of original phenol derivative, preferably from 1 to 3 molar equivalents. The reaction temperature is in the range usually from 0oC to 150oC, preferably from about 10oC to 100oC. the reaction Time usually varies from 15 minutes to 12 hours, preferably from 30 minutes to 6 hours.

When the compound (I) thus obtained, is a free compound, it can be converted into a salt in accordance with standard procedure with an inorganic acid (e.g. hydrochloric acid, sulfuric acid, Hydrobromic acid, etc. ) organic acid (for example, methanesulfonic acid, benzosulfimide acid, toluensulfonate acid, oxalic acid, fumaric acid, militry, potassium, alkaline earth metal such as calcium, magnesium, etc., aluminum or ammonium, and so on) or organic base (e.g. triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N,N'-dibenziletilendiaminom and so on), and when the connection is obtained in the form of a salt, it can be turned in accordance with generally accepted methodology in the free compound or another salt.

The compound (I) or its salt obtained as described above can be purified and extracted using already known methods for separation and purification (e.g., concentration, solvent extraction, column chromatography, recrystallization and so on)

Methods of obtaining starting compound (II) or its salt that should be used to obtain the compound (I) or its salts of the present invention described below. For example, a compound in which ring A is A thiophene ring, can be obtained by the method described in European openly published patent application N 472116 (open publication from February 26, 1992), or, in addition, similar methods. Basically, the method of synthesis of the compound represented the General formula (II-1), in which ring A, and Solenoe ring (the same value that that and "optional substituted benzene ring" represented by ring a and ring B), can be used for the synthesis of compound (II) in which ring A and ring B containing heterocyclic ring. As methods of synthesis of compounds such as (II-I), above, are, for example, published in EP 421456 (publication dated April 11, 1991) EP 354994 (publication (21 February 1990) EP 481383 (publication, 22 April 1992) and PCT international N WO 9112249 (published August 22, 1991)

The compound (II) may in some cases to form a salt. As these salts are used, for example, salts with inorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromide acid, sulfuric acid, etc. or salts with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonate acid, benzolsulfonat acid and so on). In addition, when the compounds have an acidic group such as - COOH, they can form salts with inorganic bases (e.g. alkali metal ilycheskie bases (for example, three-C1-3alkylamine such as triethylamine).

In each of the above reactions in the case when the original connection is amino, carboxyl or hydroxyl group as substituent, can be used by these groups as a pre-protected with an appropriate protecting groups which are commonly used, for example, in peptide chemistry and, if necessary, the target compound can be obtained by removing the protective group after the reaction.

Examples of protecting groups for such amino groups include arbitrarily substituted C1-6alkylsulphonyl (for example, formyl, methylcarbamyl, ethylcarboxyl and so on ), phenylcarbinol, C1-6allyloxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and so on), vinyloxycarbonyl (for example, menthoxycarbonyl and so on), 7-10C aralkylamines (for example, benzyloxycarbonyl and so on), trityl, phthaloyl, etc. as these substituents are halogen atoms (e.g. fluorine, chlorine, bromine, iodine and so on), C1-6alkylsulphonyl (for example, methylcarbamoyl, ethylcarboxyl, butylcarbamoyl and so on), and the number of substituents ranges from 1 to 3.

Examples of protective groups for the carboxyl group include arbitrarily substituted Cthe number of these substituents are halogen atoms (for example, fluorine, chlorine, bromine, iodine and so on), C1-6alkylsulphonyl (for example, formyl, methylcarbamyl, ethylcarboxyl, butylcarbamoyl and so on), the nitro-group or the like, and the number of these substituents ranges from 1 to 3.

As protective groups for hydroxyl groups are used, for example, optionally substituted C1-6alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and so on), phenyl, C7-10aralkyl (e.g., benzyl etc.,), C1-6alkylsulphonyl (for example, formyl, methylcarbamyl, ethylcarboxyl and so on ), vinyloxycarbonyl (for example, menthoxycarbonyl and so on), C7-10aralkyl-carbonyl (for example, benzyloxy boil and so on), pyranyl, furanyl, silyl etc. as substituents are halogen atoms (e.g. fluorine, chlorine, bromine, iodine and so on), C1-6alkyl, phenyl, C7-10aralkyl, the nitro-group, and so on, and the number of substituents is from 1 to about 4.

And as a means for the removal of such protective groups are already known means, and also similar to them. For example, used the treatment with an acid or base, restoration, irradiation with ultraviolet light, treatment with hydrazine, phenylhydrazine, N-methyldithiocarbamate, is received by the methods described above can be isolated and purified by using common methods such as recrystallization, distillation, chromatography. When the compound (I) thus obtained is in a free form, it can be converted into a salt using known techniques, as well as similar methods (for example, neutralization, and so on) and Vice versa, when the product is a salt, it can turn into a free form or another salt.

The compound (I) or its salt obtained in accordance with this invention, has an excellent antagonistic activity to tachykinin receptors, particularly strong antagonistic activity against substance P (hereafter in some cases, denoted for brevity CP) and have low toxicity, being thus useful for medicine and safe substances.

The compound (I) or salts thereof have an inhibitory effect on tracheal transudate plasma, caused for example by capsaicin. Capsaicin is known as the substance that is the main component that causes burning taste red pepper, and stimulates selectively among primary sensory nerves containing C-valoo neuropeptide of them. This action of compound (I) or salts on the inhibitory action on the vascular transudate, considered to be based on antagonistic activity to tachykinin receptors.

CF is widely distributed in the Central and peripheral nervous system and, in addition, is the primary neurotransmitter sensitive nerves, has various physiological activities such as vasodilator activity, effects on the vascular transudation, the contractile activity of smooth muscles, stimulating the neurons activity, stimulating salivation activity, diuretic activity, immunological activity, and so on, it Was known that in particular, CF emitted pain pulse at the end of the posterior roots of the spinal cord that transmit information about pain secondary neurons, and that CF released from peripheral nerve endings, causes an inflammatory reaction in the area of pain receptor. Furthermore, CF is assumed to be involved in the mechanism of dementia type Alzheimer's disease. (Review article: "Physiological Reviews 73, p. 229 - 308, 1993". "Journal of Autonomic Pharmacology, 13, p. 23 - 93, 1993). Therefore, the compound (I) or salts thereof of this invention, having a strong antagonistically drugs for inflammatory or allergic diseases (for example, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, wet cough, rhinitis, rheumatoid arthritis, deforming arthritis, osteoporosis, multiple sclerosis, endemite, cystitis, and so on), bole, migraine, neuralgia, diseases with itching, cough and, in addition, diseases of the Central nervous system, such as schizophrenia, Parkinson's disease, psychosomatic disease, dementia (such as Alzheimer's disease), diseases of the digestive tract (for example, when the syndrome of inflammation of the bowel, ulcerative colitis, Crohn's disease (9), and so on), vomiting, urination disorders (for example, pollakiuriya, urinary incontinence, and so on), circulatory disorders (e.g., angina, hypertension, heart failure, thrombosis, and so on ) and immunopathy, etc. in mammals (e.g. mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, people, and so on).

When the compound (I) or salts thereof of this invention are used as the above-mentioned medical products, they are produced in the form of a dosage form using suitable pharmaceutically acceptable carriers, fillers (e.g. starch, lactose, sucrose, calcium carbonate, a phosphate to tilcelulozei, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, and so on ), moving substances (for example, stearic acid, magnesium stearate, calcium stearate, talc and so on), disintegrators (e.g., calcium carboxymethylcellulose, talc and so on ), solvents (for example, saline etc) and so on, which can be administered orally or otherwise in such dosage forms as powders, fine granules, granules, tablets, capsules, injectables or the like, using conventional procedures. As the dosage depends on the kind of compound (I) or pharmaceutically acceptable salts, way (way) of the introduction, the symptoms of the disease, patient's age and other determining conditions for oral administration is assigned to adult patients with dysuria, for example, a daily dose of about 0.005 to 50 mg, per compound (I) or its salt per kg of weight per day, preferably from about 0.05 to 10 mg, more preferably from about 0.2 to 4 mg divided into 1-3 doses.

The following represents the experimental data, demonstrating the pharmacological efficacy of the compound (I) or its salts of the present invention.

Inhibitory activity of spezialformate human cells (IM-9)

Was modified and used method of Margaret A. "Molecular Pharmacology, 42, p. 458 (1992)". The receptors were obtained from human lymphoblast cells (IM-9), IM-9 cells (2 of 105cells per ml) were seeded and incubated for 3 days (one liter), which was then subjected to centrifugation for 5 minutes at 500 g for obtaining sediment cells. The precipitate once were washed in phosphate buffer (Flow Laboratories, CAT. N 28-103-05), after which the precipitate was destroyed using a homogenizer transmitter station "Kinematika Germany in 30 ml of 50 mm Tris-HCl buffer (pH of 7.4) containing 120 mm sodium chloride, 5 mm potassium chloride, 2 μg/ml of hemostatis, 40 μg/ml bacitracin, 5 μg/ml of phosphoramidon, 0.5 mm phenylmethylsulfonyl, 1 mm ethylenediaminetetraacetic acid, and then subjected to centrifugation at 40,000 g for 20 minutes. The precipitate was twice washed with 30 ml of the above buffer, which is then frozen to be stored (-80oC) as the sample receptor.

The sample suspended in reaction buffer (50 mm Tris-HCl buffer (pH of 7.4), 0.02% of bovine serum albumin, 1 mm phenylmethylsulfonyl, 2 μg/ml of hemostatis, 40 μg/ml bacitracin, 3 mm manganese chloride) and 100 μl portion of the suspension used for the reaction. After addition of the sample, and125citiescape binding was determined by adding the substance P to a final concentration equal to 2 10-6M. After the reaction, using the device to collect cells (290 PHD Cambridge Technology, Inc. U. S. A. conducted rapid filtration through a glass filter (GF/B Whatman, USA.) to stop the reaction. After triple washing with 250 μl of 50 mm Tris HCl buffer (pH of 7.4) containing 0.02% of bovine serum albumin, remaining on the filter radioactivity was determined using a gamma counter. Before use, the filter was immersed in 0.1% polyethylenimine for 24 hours and dried in air. Antagonistic activity of each tested drug in the form of concentration required to cause 50% inhibition (IC50) under the above described conditions, expressed in nm (table. 1 and 2, see the end of the description). (Radioligand means a substance P labeled125I.) the Number of these experiments is 1.

From table 1 it is evident that the compound (I) or salts thereof of this invention have excellent antagonistic activity to the receptor substance P.

The vast effect on transudate plasma induced by capsaicin in the trachea of Guinea pigs

Guinea pigs (Hartley type, white males Guinea pigs), (n = 6) were anestesiologi 35 mg/kg of phenobarbital, which was administered intraperitoneally (I/b), then intravenous (IV) was administered istitutioni, to cause a reaction. After ten minutes of the test animals was scored by cutting the aorta, then perfesional through the pulmonary artery 50 ml of physiological sodium chloride solution. The trachea was dissected and defined its raw weight. The trachea were incubated at room temperature in 1 ml of acetone and 0.3% of sodium sulfate (7:3) during the night, and the blue dye Evans was extracted from the trachea. The extract solution was centrifuged at 2800 rpm for 5 minutes. The amount of blue dye Evans in the supernatant was determined by measuring the absorption at 620 nm.

Transudate plasma was expressed by the amount of blue dye Evans (g) in relation to the weight of the trachea (g). The efficiency of a drug was evaluated by calculating the % suppression by the following formula.

< / BR>
A: the amount of blue dye Evans (µg/g) in each of the test animal

B: the average number of blue dye Evans (µg/g) groups, which did not enter capsaicin.

C: the average number of blue dye Evans (µg/g) in the control group.

Table 2 shows that the compound (I) or its salt of the present invention have an excellent suppressive effect on transudate plasma visocnik examples and examples, but these examples are merely examples and are not limiting of the present invention, and they may be modified within the limits which do not go beyond the scope of this invention.

Elution in column chromatography in the reference examples and examples was carried out under the control by TLC (thin layer chromatography). When tracking (control) using TLC was used 60F254produced Megs in the form of plates for TLC, the solvent used for column chromatography as manifesting eluent and a UV detector at detection, respectively.

As silica gel for column chromatography was used silica gel 60 (grain size 70-230) produced by Merck. "Room temperature" usually means temperatures in the range from about 10oC to 35oC.

For drying the extract solution was used sodium sulfate or magnesium sulfate.

In the examples and reference examples, the abbreviations mean the following.

NMR (NMR) Spectrum, nuclear magnetic resonance

E1-MS: Mass spectrum when bombarded by electrons SI-MS: Secondary electron ion mass spectrum

DMF DMF: dimethylformamide, THF (THF: tetrahydrofuran, D is t s: singlet, b: broad, like: approximate

Example 1

N-[3,5-bis (trifluoromethyl)benzyl] -5-(4-forfinal)-7,8-dihydro-N, 7-dimethyl-8-oxo-6-pyrido [3,4-b]pyridinecarboxamide

To a suspension of 5-(4-forfinal)-7,8-dihydro-7-methyl-8-oxo-6-pyrido [3,4-b] -pyridineboronic acid (reference example 1) (1.50 g) in benzene (70 ml) was added tinyload (3.0 ml) and DMF (one drop). The mixture was heated for two hours in a flask with reflux condenser. The solvent is kept off and the residue was washed with hexane and then suspended in THF (40 ml). This suspension was added to a solution of N-3,5-bis (trifluoromethyl) benzyl of methylamine (1.80 g) and triethylamine (1,40 ml) in THF (40 ml). The mixture was stirred for 5 hours under heating in a flask with reflux condenser. The solvent drove away. To the residue was added ethyl acetate, and the mixture was washed with water, aqueous sodium hydrogen carbonate solution and water, successively, then dried and the solvent drove away with getting named in the title substance as a colorless crystals (0,80 g) so pl. 211-212oC (recrystallized from ethyl acetate - ethyl ether).

NMR (200 Hz, CDCl3) memorial plaques: and 2.83 (3H, s), to 3.67 (3H, s), 4,25 (1H, d, J = 14.4 Hz), is 4.85 (1H, d, J = 14.4 Hz), 6,99 (2H, t-like, J = 8 Hz), 7,13 (1H, m), 7,37 (1H, m), 7,50 - rate of 7.54 (2H, m), 7,55 (2H, s), 7.8-e: C, 58,11; H, 3,38; N 7,82

Found: C, 58,03; H 3,34; N 7,72

The compounds of examples 2 and 3 were obtained by using 5-(4-forfinal)-7,8-dihydro-7-methyl-8-oxo-6-pyrido[3,4-b] pyridylcarbinol acids and amines having the necessary provisions of the respective deputies, which gives the opportunity to undergo reaction, and processing the reaction mixture in essentially the same manner as in example 1.

Example 2

N-[3,5-bis(trifluoromethyl)benzyl] -5-(4-forfinal)-7,8-dihydro-7-methyl-8 - oxo-6-pyrido [3,4-b]pyridinecarboxamide

So pl. 210 - 212oC (recrystallized from metrologically-ethyl acetate)

NMR (200 MHz, CDCl3) memorial plaques: is 3.21 (3H, s), 4,55 (2H, d, J = 6.2 Hz), 6,98 (2H, t-like, J = 8.6 Hz), 7,25 was 7.45 (4H, m), 7,76 (2H, s), to 7.84 (1H, s), charged 8.52 (1H, t-like, J = 5.8 Hz), 8,63 (1H, dd, J=2,0, 4,0 Hz)

Example 3

5-(4-forfinal)-7,8-dihydro-N-(2-methoxybenzyl)-7-methyl-8-oxo - 6-pyrido[3,4-b]pyridinecarboxamide

So pl. 254-256oC (recrystallized from methanol - dichlorodimethylsilane)

NMR (200 MHz, CDCl3), M. D.: 3,54, (3H, s), of 3.77 (3H, s), 4,34 (2H, d, J = 6.0 Hz), to 6.80 (2H, t-like, J=7,6 Hz), 6,86 - to 7.00 (4H, m), 7,20 - to 7.32 (3H, m), 7,37 (1H, dd, J = 4.2, and an 8.4 Hz), to 7.50 (1H, dd, J = 1,6, and 8.4 Hz), 8,77 (1H, dd, J = 1,6, 4,2 Hz).

Elemental analysis for C24H20N3O3F 1/4H2O:

Calculated: C 68,32; H 4,90; N 9,96

The mixture of compounds obtained in example 3 (1.20 g) of sodium hydride (60% oil) (150 mg) and DMF (50 ml) was stirred for 30 minutes at room temperature, then added methyliodide (5.0 ml) followed by stirring for 4 hours at room temperature. The solvent drove away. To the residue was added ethyl acetate. This mixture was washed with water and dried, then the solvent is kept off so that it was not named in the title substance as a colorless crystals (1.10 g).

So pl. 159 - 150oC (paracrystalline of melanomacrophage simple ether)

NMR (200 MHz, CDCl3) memorial plaques: is 2.74 (3H, s); to 3.67 (3H, s); of 3.77 (3H, s); of 4.38 (1H, d, J = 1,8 Hz), and 4.68 (1H, d, J = 14,8 Hz), 6,46 (1H, dd, J = 1,6, 7,4 Hz), 6,78 (1H, dt, Jd= 1.2 Hz, Jt= 7,4 Hz), PC 6.82 (1H, d, J = 8,2 Hz),? 7.04 baby mortality - 7,30 (4H, m), 7,42 - 7,56 (2H, m), to 7.59 (1H, dd, J 1,8, 8,4 = Hz) of 8.92 (1H, dd, J = 1,6, 4,2 Hz)

Elemental analysis for C25H22N3O3F:

Calculated: C 65,59; H 5,14; N 9,74

Found: C 69,23; H 5,12; N 9,75

Example 5

N, N-bis[3,5-bis(trifluoromethyl)benzyl]-5-(4-forfinal)-7,8-dihydro-7 - methyl-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

5-(4-(forfinal)-7,8-dihydro-7-methyl-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide (reference example 1 - method 2, process 3) was allowed to react and undergo treatment with 3,5-bis and substance in the form of colorless crystals, so pl. 252 - 254oC (recrystallized from ethyl acetate-ethyl ether).

NMR (200 MHz, CDCl3), M. D.: to 3.67 (3H, s), 4,32 (1H, J = 14.6 Hz), 4,37 (1H, d, J = 15,4 Hz), of 4.67 (1H, d, J = 15,4 Hz), and 4.75 (1H, d, J = 14.6 Hz), 7.03 is - 7,28 (5H, m), 7,34 (2H, s), 7,41 - to 7.67 (3H, m), of 7.75 (2H, s), to $ 7.91 (1H, dd, J = 1,8, 4,2 Hz)

Elemental analysis for C34H20N3O2F13:

Calculated: C 54,48; H 2,69; N 5,61

Found: C 54,67; H 2,59; N 5,78

Example 6

N-[3,5-bis(trifluoromethyl)benzyl] -3-chloro-5-(4-forfinal)-7,8-dihydro - N, 7-dimetil-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Uterine fluid after collecting the compound from example 1 was combined with the washing and then subjected to chromatography on a column of silica gel (hexane: ethyl acetate (1:2) ethyl acetate - ethyl acetate: methanol (95:5)) for separation and purification. From the first fraction was obtained is indicated in the name of the substance in the form of colorless crystals (0.16 g), so pl. 114 - 115oC (recrystallized from ethyl acetate - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: and 2.83 (3H, s), the 3.65 (3H, s), 4,25 (1H, d, J = 14.4 Hz), 4,84 (1H, d, J = 14.4 Hz), 7,01 (2H, t-like, J = 8,4 Hz), 7,12 (1H, m), 7,34 (1H, m), 7,47 (1H, d, J = 2.2 Hz), 7,55 (2H, s), a 7.85 (1H, s), 8,82 (1H, d, J = 2.2 Hz)

Elemental analysis for C26H17N3O2ClF71/8 H2O :

Calculated : C 63,95; H to 3.73; N To 9.32

NMR (200 MHz, CDCl3) memorial plaques: 3,16 (NH/3, s), 3,21 (NH 2/3, s ), of 4.44 (NH/3, s), 4,55 (NH,3 s), 7,17 (2H, t, J = 8,4 Hz) to 7.50 (1H, m), a 7.85 (3H, m), is 8.75 (1H, dd, J = 1,6, 4,8 Hz)

Stage 2

The mixture of compounds obtained in stage (1) (22,8 g), toluene (300 ml) and 1,8-diazabicyclo 5,4,0-7-undecene (13,2 ml) was stirred for 16 hours in a flask with reflux condenser. The solvent drove away. To the solution was added water, then the resulting crystalline precipitate was collected by filtration. The crystals were washed with water, methanol and ethyl ether to obtain 5-(4-forfinal)-7,8-dihydro-7-methyl-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide in the form of colorless Cree is a).

NMR (200 MHz, CDCl3) memorial plaques: to 3.92 (3H, s), 7,29 (2H, t - like, J = 8,8 Hz), of 7.36 - of 7.48 (2H, m), 7,60 (1H, dd, J = 4.2, and an 8.4 Hz), 7,71 (1H, dd, J = 1,8, and 8.4 Hz), 9,04 (1H, dd, J = 8,4, 4,2 Hz)

Stage 3

The mixture of compounds (14,37 g) obtained in stage 2, ethanol (100 ml) and 1N NaOH (100 ml) was stirred for 3 hours in a flask with reflux condenser. The reaction mixture was concentrated, added 1N HCl to bring the pH to 5, then the resulting crystalline precipitate was collected by filtration, washed with water, methanol and ethyl ether to obtain 5-(4-fluoro-phenyl)-7,8-dihydro-7-methyl-8-oxo-6-[3, 4 - b]pyridinecarboxamide in the form of colorless crystals (14,85 g).

So pl. 329 - 330oC (recrystallized from methanol - dichloromethane-ethyl ether)

NMR (200 MHz, DMSO-b6) memorial plaques: to 3.56 (3H, s), 7,25 - of 7.55 (5H, m), 7,66 (1H, dd, J = 4.2, and an 8.4 Hz), 7,86 (1H, bs), 8,11 (1H, bs), 8,83 (1H,dd, J = 1,6, 4,2 Hz)

Stage 4

To a mixture of compound (2,36 g), obtained in stage 3, and conc. HCl (30 ml) parts add sodium nitrite (15.0 g) and was stirred for 60 hours. To the reaction mixture was added water, the pH was brought to 3.0 with aqueous potassium carbonate solution. The solvent drove away. The residue was suirable water: ethanol (1:0 to 0:4) when using Amberlite XAD-2 to obtain vyshenazvany the-6-methyl-5-oxo-7-pyrido[3,4-b] pyrazinecarboxamide acid

Stage 1

To a suspension of magnesium (4,2 g) in THF (20 ml) was added iodine (catalytic amount) under stirring at room temperature in argon atmosphere. To the mixture then was added dropwise a solution of 1-bromo-4-fervently (22,8 g) in THF (60 ml) and the mixture was stirred for 30 minutes. The mixture dropwise with stirring at room temperature was added to a solution of 2,3-pyrazinecarboxamide anhydride (20,0 g) in THF (100 ml), followed by stirring for one hour. The reaction mixture was poured into diluted HCl (bringing the pH to 4 to 5) followed by extraction with ethyl acetate. The extraction solution was washed with water and dried, then the solvent drove with 3-(4-perbenzoic)-2-pyrazinecarboxamide acid in the form of a colorless oily product (25,8 g).

NMR (200 MHz, DMSO-d6) memorial plaques: 7,31 (2H, t - like, J = 8,8 Hz), 7,60 to 7.75 (2H, m), 8,84 (1H, d, J = 2.5 Hz), 8,88 (1H, d, J = 2.5 Hz)

This compound was used for next reaction without purification.

Stage 2

To a suspension of compound (15,8 g) obtained in stage 1, in benzene (200 ml) was added thionyl chloride (35 ml) and DMF (one drop). The mixture was stirred for 2 hours in a flask with reflux condenser. The solvent is kept off and the residue was dissolved in THF (50 ml) ml), which was stirred for 16 hours at room temperature. The solvent drove away. To the residue was added water and was extracted with ethyl acetate. The extraction solution was washed with diluted hydrochloric acid and water successively, dried and the solvent is then drove away. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1:2) to give N-ethoxycarbonylmethyl-3-(4-perbenzoic) -N-methyl-2-pyrazinecarboxamide in the form of an oily product (5,07 g).

NMR (200 MHz, CDCl3): M. D. of 1.31 (3H, t, J = 7.2 Hz), 3,19 (3H, s), up 3.22 (3H, s ), 4,18 - to 4.33 (4H, m), 7,16 (2H, t - like, J = 8.7 Hz), 7.95 is - 8,10 (2H, m), 8,59 (2H, m)

Stage 3

The mixture of compounds (5,07 g) obtained in stage 2, toluene (150 ml) and 1,8-diazabicyclo [5,4,0]-7-undecene (2.5 ml) was stirred for 16 hours in a flask with reflux condenser. The reaction mixture was added diluted hydrochloric acid (brought to pH 4-5) and extracted with ethyl acetate - THF. The extraction solution was washed with a saturated aqueous solution of salt, dried and the solvent is then drove away. The residue was purified by column chromatography on silica gel (chloroform: acetone = 10:1) to obtain-8-(4-forfinal)-5,6-dihydro-6-methyl-5-oxo-7-pyrido[3,4-b] pyrazines risovanny of ethyl acetate THF-ethyl ester)

NMR (200 MHz, CDCl3) memorial plaques:the 1.04 (3H, t, J = 7.2 Hz), 3,70 (3H, s), is 4.15 (2H, q, J = 7.2 Hz), 7,16 (2H, t - like, J = 8.7 Hz), 7,27 - 7,40 (2H, m), 8,87 (2H, s)

Stage 4

A mixture of compound (1.10 g) obtained in stage 3, ethanol (25 ml), THF (25 ml) and 1 N NaOH (15 ml) was stirred for one hour in a flask with reflux condenser. The reaction mixture was cooled and diluted HCl was added to bring the pH to 3 to 4. The mixture was saturated with NaCl, followed by extraction with ethyl acetate. The extraction solution was dried, the solvent is then drove away, so what we had mentioned in the title substance as a colorless crystals (0,93 g).

So pl. 247 - 249oC (recrystallized from THF - ethyl ester)

NMR (200 MHz, CDCl3) memorial plaques : a 3.75 (3H, s), of 4.95 (1H, bs), 7,14 (2H, t - like, J = 8,8 Hz), 7,34 - of 7.48 (2H, m), 8,83 (1H, d, J = 2.0 Hz), cent to 8.85 (1H, d, J = 2.0 Hz)

Elemental analysis for C15H10N3O3F 0,2 H2O :

Calculated: C 59,49; H of 3.46 ; N 13,87

Found: C 59,59; H 3,71; N 13,72

Reference example 3

4-(4-forfinal)-1,2-dihydro-2-methyl-1-oxo-3-pyrido[3,4-c] piridinkarbonovaya acid

Stage 1

To a mixture of 3,4-pyridylcarbinol anhydride (8,50 g) and fervently (170 ml) was added under stirring at room temperature, anhydrous aluminium chloride (12.0 g). was poured into a mixture of hydrochloric acid and ice water. This mixture was brought to pH 4 aqueous solution of sodium bicarbonate. The resulting crystalline precipitate was collected by filtration to obtain 3-(4-perbenzoic)-4-pyridineboronic acid as colorless crystals (1.51 g).

So pl. 305 - 310oC (decomposition) (recrystallized from methanol - ethyl acetate)

NMR (200 MHz, DMSO-d6) memorial plaques: of 7.36 (2H, d, J = 8,8 Hz), 7,76 (2H, t - like, J = 8.0 Hz), 7,88 (1H, d, J = 5,2 Hz), 8,73 (1H, s), to 8.94 (1H, d, J = 2.5 Hz)

Uterine fluid and filtrate were combined and then extracted. The extraction solution was washed with saturated aqueous salt solution and dried, the solvent is then drove to obtain 4-(4-perbenzoic)-3-pyridineboronic acid in the form of colorless crystals of 2.27 g).

So pl. 217-219oC (recrystallized from methanol-ethyl ether)

NMR (200 MHz, DMSO-d6) memorial plaques: to 7.35 (2H, t - like, J = 8.5 Hz), 7,53 (1H, d, J= 5.0 Hz), of 7.75 (2H, m), of 8.92 (1H, d, J = 5.0 Hz), 9,17 (1H, s)

Stage 2

Using 4-(4-torbenson)-3-pyridylcarbonyl acid, obtained in stage 1 and N-methylphenethylamino ester hydrochloride, were essentially the same reaction and process as in example for reference 2, stage 2, to obtain N-methyl-3-ethoxycarbonylmethyl-4-(4-perbenzoic)-N-pyridine (3H, s) to 4.16 (2H, s), 4,22 (2H, q, J = 7.0 Hz), 7,16 (2H, t - like, J = 8.0 Hz), 7,27 - 7,37 (1H, m), 7,81 - 7,87 (2H, m), 8,75 - 8,82 (2H, m)

Stage 3

Using the compound obtained in stage 2 and 1,8 - diazabicyclo [5,4,0]-7-undecene conducted essentially the same reaction and process as in example for reference 2, stage 3, with polecenie 4-(4-forfinal)-1,2-dihydro-2-methyl-1-oxo-3-pyrido[3,4-c] pyridineboronic acid ethyl ester as colorless crystals.

So pl. 158 - 160oC (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: a 1.01 (3H, t, J = 7.0 Hz), 3,61 (3H, s), 4,10 (2H, q, J = 7.0 Hz), 7,03 (1H, d, J = 5.6 Hz), 7,13 - 7,34 (4H, m), 8,69 (1H, d, J = 5.6 Hz), RS 9.69 (1H, s)

Stage 4

Using the compound obtained in stage 3, and an aqueous solution of sodium hydroxide, were essentially the same reaction and process as in reference example 2, stage 4, obtaining mentioned in the title compounds as colorless crystals.

So pl. 246-247oC (decomposition) recrystallized from THF - methanol)

NMR (200 MHz, DMSO-d6) memorial plaques: 3,54 (3H, s), 7,00 (1H, d, J = 5.6 Hz), 7,33 - 7,38 (4H, m), 8,69 (1H, d, J = 5.6 Hz), 9,46 (1H, s)

Elemental analysis for C18H11N2O3F 1/4H2O:

Calculated: C, 63.47 per; H 3,83; N 9,25

Found: C 63,37; H 3,80; OTA

Stage 1

Using 3-(4-perbenzoic)-4-pyridylcarbonyl acid obtained by the method of reference example 3, stage 1, and N-methylphenethylamino ester hydrochloride, were essentially the same reaction and process as in reference example 2, step 2, to obtain the N-ethoxycarbonylmethyl-3-(4-perbenzoic)-N-methyl-4-pyridinecarboxamide in the form of a colorless oily product.

NMR (200 MHz, CDCl3) memorial plaques : is 1.31 (3H, t, J = 7,0 Hz) of 3.00 (3H, s), 4,20 (2H, s), are 4.24 (2H, q, J = 7.0 Hz), 7,18 (2H, t - like, J = 8.0 Hz), 7,40 - of 7.48 (1H, m), a 7.85 - a 7.92 (2H, m), 8,77 - 8,86 (2H, m)

Stage 2

Using the compound obtained in stage 1, and 1,8 - diazabicyclo [5,4, 0] -7-undecene, were essentially the same reaction and process as in reference example 4-(4-fluoro-phenyl)-1,2-dihydro-2-methyl-1-oxo-3-pyrido [4,3-c] pyridineboronic acid ethyl ester as colorless crystals, so pl. 181 - 183oC (recrystallized from ethyl acetate - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques : a 1.01 (3H, t, J = 7.0 Hz), 3,63 (3H, s), 4.09 to (2H, q, J = 7.0 Hz), 7,14 - 7,38 (4H, m), compared to 8.26 (1H, d, J = 5.4 Hz), 8,63 (1H, s), is 8.75 (2H, J = 5.4 Hz)

Stage 3

Using the compound obtained in stage 2, and an aqueous solution of sodium hydroxide, were essentially the same reaction s) (recrystallized from THF-methanol).

NMR (200 MHz, CDCl3) memorial plaques : 3,55 (3H, s), 7,31 was 7.45 (4H, m), 8,13 (1H, d, J = 5,2 Hz), of 8.47 (1H, s), 8,73 (1H, d, J = 5,2 Hz)

Elemental analysis for C16H11N2O3F 1/4 H2O:

Calculated: C, 63.47 per; H 3,83; N 9,25

Found: C 63,48; H 3,82; N 9,35

Reference example 5

5,6-dihydro-6-methyl-8-(2-were)-5-oxo-7-pyrido[4,3-b] piridinkarbonovaya acid

Stage 1

Using 2,3-pyridinedicarboxylic anhydride (5,96 g) and 2-bromthymol (8,2 g) was subjected to essentially the same reaction and process as in reference example 2, stage 1 (Grignard reaction) to obtain 2-(2-methylbenzoyl)-3-pyridineboronic acid and 3-(2-methylbenzoyl)-2-pyridineboronic acid as an oily product ( 6,45 g). (This connection was used for subsequent reactions without purification).

Stage 2

Using the connection (6,45 g) obtained in stage 1, and N-methylaminoethanol hydrochloride (3.7 g) was subjected to essentially the same reaction and process as in reference example 1, process 2, stage 1 (amidation), to obtain a mixture of N-cyanomethyl-N-methyl-2-(2-methylbenzoyl)-3-pyridinecarboxamide and N-cyanomethyl-N-methyl-3-(2-methylbenzoyl)-2-pyridinecarboxamide in the form of an oily product (7.5 g). (This connection was used for subsequent the bicyclo [5,4, O]-7-undecene (4,0 ml), were essentially the same reaction as in reference example 1, process 2, step 2 (reaction cyclodehydration) (heated in a flask under reflux for 4 hours in toluene) and the reaction mixture was purified using column chromatography on silica gel (hexane : ethyl acetate (2:1 --->1:1) - acetone). From the first fraction was obtained 5,6-dihydro-6-methyl-8-(2-were)-5-oxo-7-pyrido [4,3-b] pyridinecarboxylic in the form of colorless crystals (3.5 g), so pl. 216 - 218oC (recrystallized from ethyl acetate - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques, a 2.12 (3H, s) : a 3.87 (3H, s) 7,26 - 7,44 (4H, m), 7,54 (1H, dd, J = 4,6, 8.1 Hz), 8,78 (1H, dd, J = 1,8, 8.1 Hz), 8,97 (1H, dd, J = 1,8, 4.6 Hz)

The following fractions were obtained 7,8-dihydro-7-methyl-5-(2-were)-8-oxo-6-pyrido [3,4-b] pyridinecarboxylic in the form of colorless crystals (2.4 g), so pl. 238 - 240oC (recrystallized from ethyl acetate).

NMR (200 MHz, CDCl3) memorial plaques : to 2.15 (3H, s) to 3.92 (3H, s), 7,34 - to 7.59 (6H, m), of 9.02 (1H, dd, J = 1,8, 4,4 Hz)

Stage 4

Using 5,6-dihydro-6-methyl-8-(2-were)-5-oxo-7-pyrido [4,3-b] pyridinecarboxylic (3.5 g) obtained in stage 3, and IN NaOH, were essentially the same reaction as in reference example 1, process 2, stage 3 (hydrolysis) (heating in the co-7-pyrido-[4,3-b] pyridinecarboxamide in the form of colorless crystals (2.2 g).

So pl. 315 - 320oC (recrystallized from methanol)

NMR (200 MHz, DMSO - d6) memorial plaques: to 1.98 (3H, s), of 3.56 (3H, s), 7,17 - 7,26 (4H, m), 7,54 (1H, dd, J = 4,4 8,0 Hz), 7,80 (1H, bs), of 8.04 (1H, bs), to 8.62 (1H, dd, J = 1,8, 8.0 Hz), 8,82 (1H, dd, J = 1,8, 4,4 Hz)

Stage 5

To a mixture of compound (2.2 g) obtained in stage 4, and hydrochloric acid (30 ml) was added in limited amounts of sodium nitrite (5,2 g) under stirring at 0oC. This mixture was stirred for 3 hours at room temperature and the pH was brought to the interval from 5 to 6 using sodium carbonate. The resulting precipitate was filtered and the filtrate was allowed to adsorb on Amberlite XAD-2 and suirable methanol to obtain the above-mentioned substances in the form of colorless crystals (0,83 g), so pl. 268 - 273oC (decomposes) (recrystallized from methanol - THF).

NMR (200 MHz, DMSO-d6) memorial plaques : a 1.96 (3H, s), 3,53 (3H, s), 7,08 - 7,14 (4H, m), 7,34 (1H, dd, J = 4,4 8,0 Hz) and 8.50 (1H, dd, J = 1,2, 8.0 Hz), 8,69 (1H, dd, J = 1,2, 4,4 Hz)

SI - MS m/z : 295 (M+1)+< / BR>
Reference example 6

5-(chloro-2-were)-7,8-dihydro-7-methyl-8-oxo-6-pyrido [3,4-b]piridinkarbonovaya acid and its isomer

Stage 1

Using 7,8-dihydro-7-methyl-5-(2-were)-8-oxo-6-pyrido [3,4-b] pyridinecarboxylic (reference example 5, step 3) (2,40 g)dildocam for 16 hours) and the process as in reference example 1, process 2, step 3, to obtain 7,8-dihydro-7-methyl-5-(2-were)-8-oxo-6-pyrido-[4,3-b] pyridinecarboxamide in the form of colorless crystals (1,57 g), so pl. 305 - 307oC (recrystallized from methanol - THF).

NMR (200 MHz, DMSO-d6) memorial plaques : a 2.01 (3H, s), of 3.57 (3H, s), 7,20 (1H, dd, J = 1,6, 8,2 Hz), 7,26 and 7.36 (4H, m), 7,63 (1H, dd, J = 4,4, 8,2 Hz), 7,78 (1H, bs), of 8.04 (1H, bs), 8,82 (1H, dd, J = 1,6, 4,4 Hz)

Stage 2

To a mixture of compound (1.5 g) obtained in stage 1, and hydrochloric acid (30 ml) portions was added sodium nitrite (7.0 g), at 0oC and stirring. This mixture was which for 20 hours at room temperature and the pH was brought to the interval from 5 to 6 with sodium carbonate. The resulting precipitate was filtered and the filtrate was adsorbing on Amberlite XAD - 2 and suirable methanol to obtain the above-mentioned substance (mixture) as colorless crystals (0.9 g), so pl. 290 - 295oC (decomposition) (recrystallized from methanol - THF).

NMR (200 MHz, DMSO-d6) memorial plaques : 1,97 (3Hx2/5, S) 2,03 (3Hx3/5, s), of 3.56 (3H, s), 7,11 - 7,47 (4H, m), 7,54 (1H, dd, J = 4,2, 8,2 Hz), 8,68 (1H, dd, J = 1,6, 4,2 Hz)

SI-MS m/z: 329, 331 (M+1)+< / BR>
Reference example 7

N-methyl-4-(2-pyridyl)-3-chinainternational

Stage 1

A mixture of 2-(2-aminobenzoyl) PI is the first in the crystalline residue (3.0 g) was collected by filtration. The mixture of the crystalline product, lithium chloride (1.8 g) and DMSO (30 ml) was stirred for 2 hours at temperatures in the range from 180 to 190oC. the Reaction mixture was cooled and poured into water followed by extraction with chloroform. The extract was washed with water and dried, the solvent is then drove away. The residue was subjected to column chromatography on silica gel (hexane : ethyl acetate =1 : 2) to give the ethyl ester of 4-(2-pyridyl)-3 - quinoline-carboxylic acid as colorless crystals (1.28 g).

So pl. 70oC (recrystallized from ethyl ether - hexane)

NMR (200 MHz, CDCl3) memorial plaques with 1.07 (3H, t, J = 7.2 Hz), of 4.16 (2H, q, J = 7.2 Hz), 7,35 - of 7.55 (4H, m), 7,70 - of 7.95 (2H, m), 8,21 (1H, d, J = 8,4 Hz), 8,79 (1H, d, J = 4.4 Hz), 9,46 (1H, s)

Stage 2

A mixture of compound (1.19 g), obtained in stage 1, and 40% solution of methylamine in methanol (30 ml) was stirred for 3 days at room temperature. The solvent drove, so what remained of the above compound in the form of colorless crystals (666 mg), so pl. 171 - 172oC (recrystallized from ethyl acetate - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: 2,72 (3H, d, J = 5.0 Hz), 6,33 (1H, m), 7,40 - of 7.55 (4H, m), 7,70 - of 7.95 (2H, m), 8,17 (1H, d, J = 8,4 Hz), 8,79 (1H, m), 9,17 (1H, s)

Elemental analysis for C16H
-(4-forfinal)-6,7-dihydro-6-methyl-7-oxo-5-thieno[2,3-c] piridinkarbonovaya acid

Stage 1

To a mixture of 2,3-typediabetes anhydride (1.98 g) and fervently (30 ml) was added under stirring at room temperature, anhydrous aluminium chloride (2.7 g). The reaction mixture was stirred for 3.5 hours under heating in a flask with reflux condenser, cooled and poured into a mixture of hydrochloric acid - ice water. This mixture was subjected to extraction with ethyl acetate. The extraction solution was washed with saturated aqueous sodium chloride solution and dried, then the solvent drove, as remained 3-(4-perbenzoic)-2-thiencarbazone acid as colorless crystals (3,21 g), so pl. 152oC (recrystallized from ethyl ether - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: 7,10 - 7,30 (3H, m), 7,66 (1H, d, J = 5,2 Hz), 7,80 - of 7.95 (2H, m)

Stage 2

To a solution of compound (3,21 g) obtained in stage 1, in THF (60 ml) was added oxalicacid (1.7 ml) and DMF (5 drops) and the mixture was stirred for 30 minutes at room temperature. The solvent is kept off and the residue was dissolved in THF (20 ml). This solution was added to a mixture of N-methylglycine ethyl ester hydrochloride (2.5 g), triethylammonium bicarbonate and water and then dried. The solvent is kept off and the residue was subjected to column chromatography on silica gel (hexane : ethyl acetate = 1 : 1) to obtain N-ethoxycarbonylmethyl-3-(4-perbenzoic)-N-methyl-2 - thiophencarboxylic in the form of an oily product (0,38 g).

NMR (200 MHz, CDCl3) memorial plaques: of 1.27 (3H, t, J = 7,1 Hz), 2,99 (3H, bs), of 4.05 (2H, s), 4,19 (2H, q, J = 7,1 Hz), 7,05 - 7,30 (3H, m), 7,45 (1H, m), 7,80 - of 7.95 (2H, m).

Stage 3

The mixture of compounds (0,98 g), obtained at the stage, toluene (50 ml) and 1,8-diazabicyclo[5,4,0]-7-undecene (1.5 ml) was stirred for 3 hours in a flask with reflux condenser. The reaction mixture was cooled and poured in 2NHCl. This mixture was subjected to extraction with ethyl acetate. The extraction solution was washed with water and dried, the solvent is then drove away. The residue was subjected to column chromatography on silica gel (hexane : ethyl acetate = 1 : 1) to obtain 4-(4-forfinal)-6,7-dihydro-6-methyl-7-oxo-5 - thieno[2,3-c]pyridineboronic acid ethyl ester, so pl. 145 - 147o(recrystallized from ethyl acetate-hexane).

NMR (200 MHz, CDCl3) memorial plaques: a 1.01 (3H, t, J = 7.2 Hz), the 3.65 (3H, s), 4,10 (2H, q, J = 7.2 Hz), 6,92 (1H, d, J = 5,1 Hz), 7,13 (2H, t - like, J = 8.6 Hz), 7,25 - 7,40 (2H, m), to 7.67 (1H, d, J = 5,1 Hz).

Stage 4

Using the compound (304 mg), obtained in stage 3, was performed according to su the aqueous compound as colorless crystals (240 mg), so pl. 205oC (recrystallized from ethyl acetate - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: 3,70 (3H, s), 6,93 (1H, d, J = 5.3 Hz), 7,14 (2H, t - like, J = 8.6 Hz), 7,37 - 7,49 (2H, m), of 7.70 (1H, d, J = 5.3 Hz)

Elemental analysis for C15H10NO3SF:

Calculated: C 59,40; H 3,32; N 4,62

Found: C 59,24; H 3,42; N 4,55

Reference example 9

7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thieno[3,2-c] piridinkarbonovaya acid

Using the filtrate after collecting the crystals obtained in reference example 8, step 1, were essentially the same reaction and process as in reference example 8, step 2, to obtain the N-ethoxycarbonylmethyl-2-(4-perbenzoic)-N-methyl - 3-thiophencarboxylic in the form of a pale yellow oily substance. This oily substance (1.4 g) were essentially the same reaction and process as in example for reference 8, stage 3, to obtain the ethyl ester of 7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thieno[3,2-c] pyridineboronic acid as colorless crystals (1.27 g). So pl. 127 - 129oC (recrystallized from ethyl acetate - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: a 1.01 (3H, t, J = 7.2 Hz), 3,63 (3H, s), 4,10 (2H, q, J = 7.2 Hz), 7,14 (2H, t - like, J = 8.7 Hz), 7,35 is 7.50 (2H, m), of 7.36 (1H, d, J = 5 and reference example 8, stage 4, to obtain the above compound as colorless crystals (0.65 g). So pl. 233oC (recrystallized from ethyl acetate - THF - isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: of 3.69 (3H, s), to 5.08 (1H, bs), 7,14 (2H, t - like, J = 8,8 Hz), 7,33 (1H, d, J = 5.4 Hz), 7,43 - of 7.55 (2H, m), of 7.70 (1H, d, J = 5.4 Hz)

Reference example 10

7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thieno[3,4-c] piridinkarbonovaya acid

Using 3,4-typediabetes anhydride as a starting material, were essentially the same reaction and treatment as on stages 1 through 4, reference example 8, to obtain the above-mentioned substances. Compounds derived from each stage, and the relevant physico-chemical constants are as follows:

Stage 1

4-(4-perbenzoic)-3-thiencarbazone acid

So pl. 161 - 162oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 7,18 (2H, t - like, J = 8.6 Hz), 7,76 (1H, d, J = 3.3 Hz), 7,80 - of 7.95 (2H, m), 8,39 (1H, d, J = 3.3 Hz), for 9.90 (1H, bs)

Stage 2

N-Ethoxycarbonylmethyl-4-(4-perbenzoic)-N-methyl-3 - thiophencarboxylic

Pale yellow oily substance (used for the subsequent reaction without purification)

Stage 3

7-(4-forfinal)-4,5-is risovanny from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: a 1.00 (3H, t, J = 7.2 Hz), 3,52 (3H, s), 4,07 (2H, q, J = 7.2 Hz), 7,05 - 7,20 (3H, m), 7,30 was 7.45 (2H, m), 8,42 (1H, d, J = 2,6 Hz)

Stage 4

7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-triene[3,4-c] piridinkarbonovaya acid (the above-mentioned substance)

So pl. 217 - 218oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: to 3.58 (3H, s), 7,06 (1H, d, J = 3.3 Hz), 7,12 (2H, t-like, J = 8,8 Hz), 7,40 -7,50 (2H, m), 8,40 (1H, d, J = 3.3 Hz)

Reference example 11

8-(4-forfinal)-5,6-dihydro-6-methyl-5-oxo-7-pyrido-[4,3-b] -piridinkarbonovaya acid

Stage 1

To a solution of 2,3-pyridylcarbinol anhydride (18.6 g) in THF (150 ml) was added under stirring at room temperature a solution of p-forfinal-magnesium-bromide [derived from p-bromptonville (13,6 ml) and magnesium (to 13.6 ml) and magnesium (3,91 g)] in THF (100 ml). The reaction mixture was stirred for one hour at room temperature, then poured into HCl-ice water, the pH of which was brought to values in the range of 2-3 using IN an aqueous solution of sodium hydroxide, followed by extraction with ethyl acetate. The extraction solution was washed with water and dried, then the solvent is kept off, so that was a mixture of 3-(4-perbenzoic)-2-pyridinylamino oily substance (10.5 g). This oily substance was subjected to column chromatography on silica gel to separate these compounds from one another. Physico-chemical constants of the latter compound are as follows.

So pl. 179-181oC (recrystallized from methanol - ethyl ether)

NMR (200 MHz, CDCl3) memorial plaques: for 7.12 (2H, t-like), of 7.55 (1H, dd, J = 4,8, and 8.2 Hz), 7,81 (2H, dd-like), 8,39 (1H, dd, J = 1,6, 8,2 Hz), 8,84 (1H, dd, J = 1,6, 5.0 Hz)

Stage 2

C 2-(4-perbenzoic)-3-pyridineboronic acid (1.50 g) obtained in stage 1, were essentially the same reaction and process as in reference example 1, process 2, step 1, to obtain N-cyanomethyl-1-methyl-2-(4-perbenzoic)-3-pyridinecarboxamide in the form of an oily product (1.8 g).

NMR (200 MHz, CDCl3) memorial plaques: to 3.02 (3H, s) to 4.52 (2H, s), 7,15 (t-like), 7,55 (1H, m), 7,81 (1H, d, J = to 7.61 Hz), 8,08 (2H, m), 8,73 (1H, dd, J = 1,6, 4,8 Hz)

Stage 3

Connection (2,04 g) obtained in stage 2, were essentially the same reaction and process as in reference example 1, process 2, step 2, to obtain 8-(4-forfinal)-5,6-dihydro-6-methyl-5-oxo-7-pyrido[4,3-b] pyridinecarboxylic in the form of colorless crystals (1.55 g)

So pl. 258-259oC (recrystallized from dichloromethane - ethyl acetate)

NMR (200 MHz, CDCl

So pl. 300-301oC (recrystallized from methanol - ethyl ether)

NMR (200 MHz, CDCl3) memorial plaques: (3H, s), 5,42 - 5,67 (2H, b), 7,16 (2H, t-like), was 7.45 (3H, m), is 8.75 (1H, dd, J = 1,8, 8.0 Hz), of 8.90 (1H, dd, J = 1,8, 4,4 Hz)

Stage 5

With compound (900 mg) obtained in stage 4, were essentially the same reaction and process as in reference example 1, process 2, step 4, to obtain the above compound as colorless crystals (561 mg).

So pl. 237oC (decomposition) (recrystallized from methanol - ethyl ether)

NMR (200 MHz, DMCO - d6) memorial plaques: 3,54 (3H, s), 7,25 (2H, t - like), 7,37 (2H, m), 7,58 (1H, dd, J = 4,4, 8,2 Hz), to 8.62 (1H, dd, J = 1,8, 8,2 Hz), 8,88 (1H, dd, J = 1,8, 4,4 Hz)

Reference example 12

1,2 - Dihydro-2-methyl-1-oxo-4-(2-thienyl)-3-izohinolinove acid

Stage 1

To a mixture of phthalic anhydride (2,96 g) in dichloromethane (10 ml) and aluminum chloride by 5.87 g) was added to a solution of thiophene (1.6 g) in dichloromethane in limited quantities under stirring at room temp the offer was poured into HCl - ice-cold water followed by extraction with ethyl acetate. The extraction solution was washed with water and dried, then the solvent is kept off, so that left 2-(2-thienylboronic) benzoic acid as colourless crystals (2,72 g).

So pl. 142-143oC (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 7,06 (1H, dd, J = 3,6, and 4.8 Hz), 7,25 (1H, dd, J = 1,2, 3.8 Hz), 7,46 (1H, dd, J = 1,6, 7,2 Hz), 7,52 - 7,74 (3H, m), of 8.09 (1H, dd, J = 1,2, 7,8 Hz)

Connection from stage 2 to stage 4 were obtained by using the compound obtained in stage 1, as source material and conducting essentially the same reaction and process as in reference example 8, stages 2 through 4. The compounds obtained in the respective stages and their physico-chemical constants are as follows.

Stage 2

N-Ethoxycarbonylmethyl-N-methyl-2-(2-thienylboronic)-benzoperoxide

Pale yellow oily product

NMR (200 MHz, CDCl2) memorial plaques: 1,19 - of 1.37 (3H, m), 2,99 (3 Hx3/5, s) 3,09 (3Hx2/5, s), 4.00 points (2Hx2/5, s), 4.09 to 4,30 (2H + 2Hx3/5, m), 7,13 (1H, t - like), 7,40 - 7,66 (4H, m), 7,66 - to 7.77 (2H, m)

Stage 3

1,2-Dihydro-2-methyl-1-oxo-4-(2-thienyl)-3-ethinlestradiol acid ethyl ester

So pl. 137-138oC (recrystallized is 3 - to 7.15 (2H, m), 7,40 - to 7.68 (4H, m), 8,49 (1H, m)

Stage 4

1,2-Dihydro-2-methyl-1-oxo-4-(2-thienyl)-3-izohinolinove acid (the above link)

So pl. 259=260oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: the 3.65 (3H, s), 7,12 (2H, m), 7,39 - of 7.70 (4H, m), 8,46 (1H, m)

Reference material 13

4-(4-forfinal)-N-methyl-5-thieno[2,3-b]pyridinecarboxamide

Stage 1

A mixture of 4-fermentoimalla (2,84 g), 2,5-dihydroxy-1,4-dithiane (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50oC. the Reaction mixture was cooled to obtain 2-(amino-3-(4-perbenzoic)of thiophene in the form of yellow crystals (2,22 g).

So pl. 178oC (recrystallized from ethyl ether-hexane)

NMR (200 MHz, CDCl3) : 6,15 (1H, d, J = 5.8 Hz), 6,85 (1H, d, J = 5.8 Hz), 6,94 (2H, bs), 7,00 - 7,20 (2H, m), 7,60 - 7,80 (2H, m)

Stage 2

Connection (872 mg) obtained in stage 1, were essentially the same reaction and process as in reference example 7, step 1, to obtain the ethyl ester of 4-(4-forfinal)-5-thieno[2,3-b] pyridineboronic acid in the form of a pale yellow oily product (576 mg).

NMR (200 MHz, CDCl3): of 1.10 (3H, t, j = 7,1 Hz) to 4.17 (2H, q, J = 7,1 Hz), 7,03 (1H, d, J = 6.0 Hz), 7,10 - 7,40 (two the same reaction and process as in reference example 7, step 2, to obtain the above compound as colorless crystals (297 mg).

So pl. 188-189oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) : 2,77 (3H, d, J = 5.0 Hz), 5,43 (1H, bs), 7,10 (1H, d, J = 6,1 Hz), 7,15 - 7,30 (2H, m), 7,40 - to 7.50 (2H, m), 7,56 (1H, d, J = 6,1 Hz), 8,82 (1H, s)

Reference example 14

1,2-Dihydro-N,I-dimethyl-2-oxo-4-(2-pyridyl)-3-chinainternational

Stage 1

A mixture of 2-(2-aminobenzoyl) pyridine (4,36 g), diethylmalonate (3,92 ml) and 1,9-diazabicyclo[5,4,0] -7-undecene (0.5 ml) was heated for 3 hours at 180oC. the Reaction mixture was cooled to obtain ethyl ester 1,2-dihydro-2-oxo-4-(2-pyridyl)-3-quinoline-carboxylic acid as crystals (6,1 g: untreated). The crystalline product was dissolved in DMF (100 ml) to which was added sodium hydride (60% in oil) (1.5 g) and the mixture was stirred for one hour at room temperature. The mixture was cooled to 0oC, then under stirring was added itmean (10 ml). The mixture was stirred for one hour at room temperature and then concentrated. To the concentrate was added ethyl acetate. The mixture was washed with water and dried. The solvent is then drove away. The residue was purified by colonic - 3-quinoline-carboxylic acid as pale yellow crystals (2.6 g).

So pl. 145-146oC (recrystallized from ethyl acetate - ethyl ether).

NMR (200 MHz, CDCl3): of 1.03 (3H, t, J = 7,1 Hz), 3,81 (3H, s), of 4.12 (2H, q, J = 7,1 Hz), 7,18 (1H, m), 7,30 - 7,52 (4H, m), a 7.62 (1H, m), 7,83 (1H, m), 8,77 (1H, m).

Stage 2

A mixture of the compound (1.0 g) obtained in stage 1, and 40% methylamine-methanol (30 ml) was heated for 16 hours in a sealed tube at 140oC. the Solvent drove away. To the residue was added ethyl acetate and the solution washed with saturated aqueous salt solution and dried. The solvent is then drove away with obtaining the above-mentioned substances in the form of colorless crystals (0,60 g).

So pl. 239 - 240oC (recrystallized from THF - ethyl acetate)

NMR (200 MHz, CDCl3): of 2.81 (3H, d, J=4,8 Hz), of 3.84 (3H, s), 7,02 - 7,20 (2H, m), 7,30 is 7.50 (3H, m), of 7.64 (1H, m), 7,81 (1H, m), 8,73 (1H, m), 8,81 (1H, m)

Reference example 15

7,8-Dihydro-7-methyl-8-oxo-5-phenyl-6-pyrido[3,4-b] piridinkarbonovaya acid.

Stage 1

To a mixture of 2,3-pyridinedicarboxylic anhydride (21,0 g) and benzene (210 ml) was added anhydrous aluminium chloride (30.0 g) and was stirred for 4 hours under heating in a flask with reflux condenser. The reaction mixture was cooled and poured into ice-cold water with hydrochloric acid. The resulting cristiam 3-benzoyl-2-pyridineboronic acid hydrochloride as pale yellow crystals (23.7 g).

So pl. 149 - 153oC (decomposition) (recrystallized from methanol - ethyl ether)

NMR (200 MHz, CDCl3) Ppm: 7,44 (2H, t-like, J=7.9 Hz), to 7.59 (1H, m), 7,78 (3H, m), 7,88 (1H, dd, J=1.5 and 7.7 Hz), 8,78 (1H, dd, J=1,5, 4,7 Hz)

At stages 2 through 4, using the compound obtained in stage 1, were essentially the same reaction and process as in reference example 1, process 1, stage 2 and 4 to obtain the corresponding substances. Compounds and their physico-chemical constants with the corresponding stages are described below.

Stage 2

3-benzoyl-N-benzyloxycarbonylamino-N-methyl-2-pyridinecarboxamide

Colorless oily product

NMR (200 MHz, CDCl2) memorial plaques: 3,12 (3Hx4/9, s), 3,18 (3Hx5/9, s), 4,24 (2Hx5/9, s), 4.26 deaths (2Hx4/9H, s), 5,15 (2Hx5/9, s), 5,18 (2Hx4/5, s), 7.23 percent - a 7.85 (7H, m), 8,40 (1Hx4/9, dd, J=1,4, 4.8 Hz), a total of 8.74 (1Hx5/9, dd, J=1,4, 4.8 Hz)< / BR>
Stage 3

7,8-Dihydro-7-methyl-8-oxo-5-phenyl-6-pyrido[3,5-b] pyridineboronic acid benzyl ester

So pl. 127 - 128oC (recrystallized from dichloromethane - ethyl acetate)

NMR (200 MHz, CDCl3) memorial plaques: 3,63 (3H, s), 4,99 (2H, s), 7.03 is - was 7.08 (2H, m), 7.23 percent - of 7.55 (9H, m), a 7.62 (1H, dd, J=1,4, 8,3 Hz), of 8.92 (1H, dd, J=1,4, 4,2 Hz)

Stage 4

7,8-Dihydro-7-methyl-8-oxo-5-phenyl-6-pyrido[3,4-b] piridinkarbonovaya acid (the above link)

So pl. 230 - 233oC (RA is (7H, m), 8,82 (1H, m)

Reference example 16

1,2-Dihydro-2-methyl-1-oxo-4-phenyl-3-pyrido[3,4-c] piridinkarbonovaya acid

Stage 1

To a suspension of 3,4-pyridinedicarboxylic anhydride (to 8.94 g) in THF (100 ml) was added dropwise a solution of phenyl-magnesium bromide, obtained from magnesium (2,02 g) and bromine benzol (11,30 g) in THF (45 ml) with stirring at room temperature. The reaction mixture was stirred for one hour at room temperature and then was poured into diluted hydrochloric acid while cooling. To this mixture was added an aqueous solution of sodium carbonate to bring the pH to 2, followed by extraction with ethyl acetate. The extraction solution was washed with water, then dried and the solvent drove to obtain 4-benzoyl-3-pyridineboronic acid in the form of a colorless crystalline product (5,80 g).

So pl. 240 - 241oC (recrystallized from acetone)

NMR (200 MHz, CDCl3+DMSO-d6) memorial plaques: 7,27 - 7,74 (6H, m), 8,86 (1H, d, J= 4.0 Hz), of 9.30 (1H, s)

In the mother liquor and the wash liquids were present additional 4-benzoyl-3-piridinkarbonovaya acid and its isomer, 3-benzoyl-4-piridinkarbonovaya acid.

At stages 2 through 4, using the compound obtained in stage 1, were p is connections. The compounds obtained in the respective stages, and their physico-chemical constants described below.

Stage 2

4-Benzoyl-N-ethoxycarbonylmethyl-N-methyl-3-pyridinecarboxamide

Pale yellow oily product

NMR (200 MHz, CDCl3) memorial plaques: of 1.29 (3H, t, J=7.2 Hz), 3,05 (3Hx1/4, s), 3,06 (3Hx3/4, s), was 4.02 (3Hx1/4, s), 4,14 (3Hx3/4, s), is 4.21 (2H, q, J=7.2 Hz), 7,27 - 7,80 (4H, m), 7,81 (2H, d, J=7,0 Hz), 8,78 (2H, m)

Stage 3

1,2-Dihydro-2-methyl-1-oxo-4-phenyl-3-pyrido[3,4-c] pyridineboronic acid ethyl ester

So pl. 128 - 130oC (recrystallized from ethyl acetate-ethyl ether)

NMR (200 MHz, CDCl3) memorial plaques: to 0.94 (3H, t, J = 7.0 Hz), 3,61 (3H, s), 4,06 (2H, q, J=7.0 Hz), 7,07 (1H, d, J=5.6 Hz), 7,28 - of 7.48 (5H, m), 8,67 (1H, d, J=5.6 Hz), 9,68 (1H, s)

Stage 4

1,2-Dihydro-2-methyl-1-oxo-4-phenyl-3-pyrido[3,4-c] piridinkarbonovaya acid (the above link)

So pl. 255 - 257oC (decomposition) (recrystallized from THF - methanol)

NMR (200 MHz, CDCl3+DMSO-d6) memorial plaques: to 3.67 (3H, s), 7,05 (1H, d, J=5.6 Hz), 7,35 - 7,49 (5H, m) 8,64 (1H, d, J=5.6 Hz), 9,62 (1H, s)

Reference example 17

5,6-Dihydro-6-methyl-5-oxo-8-phenyl-7-pyrido[4,3-b] piridinkarbonovaya acid

This compound was obtained by using instead of the p-forfinal-magnesium bromide in reference example 11, step 1, vinylmania bromine is confident 11. The compounds obtained in the respective stages, and their physico-chemical constants described below.

Stage 1

2-Benzoyl-3-piridinkarbonovaya acid

So pl. 190 - 193oC (recrystallized from methanol-ethyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 7,28 - 7,63 (4H, m), 7,76 (2H, d-like, J= 7 Hz), of 8.37 (1H, dd, J=1,6, 8.0 Hz), 8,83 (1H, dd, J=1,6, 4,9 Hz)

Stage 2

2-Benzoyl-N-cyanomethyl-N-methyl-3-pyridinecarboxamide

Pale yellow oily product

NMR (200 MHz, CDCl3) memorial plaques: 3,02 (3Hx3/4, s), 3,21 (3Hx1/4, s), 4,18 (2Hx1/4, s), 4,50 (2Hx3/4, s), 7,35 - of 7.70 (4H, m), 7,79 (1H, d-like, J= 7,4 Hz), to 7.99 (2H, m), 8,73 (1H, dd, J=1,6, 4,8 Hz)

Stage 3

5,6-Dihydro-6-methyl-5-oxo-8-phenyl-7-pyrido[4,3-b]pyridinecarboxylic

So pl. 256 - 258oC (recrystallized from methanol-ethyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 3,88 (3H, s), 7,45 - of 7.60 (6H, m), 8,79 (1H, dd, J=1,9, 8.1 Hz), 8,99 (1H, dd, J=1,9, and 9.4 Hz)

Stage 4

5,6-Dihydro-6-methyl-5-oxo-8-phenyl-7-pyrido[4,8-b]pyridinecarboxamide

So pl. 280 - 282oC (recrystallized from methanol-ethyl ether)

NMR (200 MHz, CDCl3) memorial plaques: and 3.72 (3H, s), 5,46 (1H, b), of 5.55 (1H, b), 7,46 (6H, m), 8,76 (1H, dd, J=1,9, 8.1 Hz), 8,91 (1H, dd, J=1,9, and 4.5 Hz)

Stage 5

5,6-Dihydro-6-methyl-5-oxo-8-phenyl-7-pyrido[4,3-b] piridinkarbonovaya acid (above wishes is C, DMSO-d6memorial plaques: 3,55 (3H, s), 7,28 - to 7.50 (5H, bs), 7,87 (1H, d, J=4,8, 8.0 Hz), 8,63 (1H, dd, J=1,8, 8,2 Hz), 8,88 (1H, dd, J=2.0 a, 4,4 Hz)

Reference example 18

4-(4-Forfinal)-6,7-dihydro-1,6-dimethyl-7-oxo-5-pyrrolo[2,3 - c] piridinkarbonovaya acid

Stage 1

1-Methyl-2,3-pyrrolocarbazols anhydride and Formentera conducted essentially the same reaction and process as in reference example 1, process 1, in the presence of aluminium chloride with 3-(4-perbenzoic)-1-methyl-2-terracarbon acid in the form of colorless crystals

NMR (200 MHz, CDCl3) ppm: 4,11 (3H, s), 6,51 (1H, d, J=2,9 Hz), 6,85 (1H, d, J=2,9 Hz), 7,20 (2H, t-like, J=8.6 Hz), 7,80 - of 7.90 (2H, m)

At stages 2 through 4, using the compound obtained in stage 1, were essentially the same reactions and processes, and stages 2 through 4 of reference example 2, to obtain the desired substance. The compounds obtained in the respective stages and their physico-chemical constants described below.

Stage 2

N-ethoxycarbonylmethyl-3-(4-perbenzoic)-N,1-dimethyl-2 - errorcorrected

Pale yellow oily product

NMR (200 MHz, CDCl3) memorial plaques: 1,22 (0,9 H, t, J = 7,3 Hz), 1,31 (2,1 H, t, J = 7,1 Hz), 2,93 (2, 1H, s), is 3.08 (0,9 H, s), 3,30 - are 3.90 (1H, m), 3,74 (2,1 H, s), 4,00 - 4,50 (1H, m), 4,12 (0,6 H, q, J = 7,3 Hz), 4,23 (1,4 H, q, J = 7,1 Hz), 6,40 (0,3 H, d, J = 2.6 Hz), 6 is terphenyl)-6,7-dihydro-1,6-dimethyl-7-oxo-5-pyrrol[2,3-c] - pyridineboronic acid ethyl ester.

Pale yellow oily product

NMR (200 MHz, CDCl3) memorial plaques: 0,99 (3H, t, J = 7.2 Hz), of 3.60 (3H, s), 4,07 (2H, q, J = 7.2 Hz), 4,20 (3H, s), 6,03 (1H, d, J = 2,9 Hz), 6,98 (1H, d, J = 2,9 Hz), 7,00 - 7,40 (4H, m)

Stage 4

4-(4-forfinal)-6,7-dihydro-1,6-dimethyl-7-oxo-5-pyrrol[2,3-c] - pyridineboronic acid (the above-mentioned substance)

Colourless crystals

NMR (200 MHz, CDCl3) memorial plaques: the 3.65 (3H, s), 4,20 (3H, s), of 6.02 (1H, d, J = 2,8 Hz), 6,98 (1H, d, J = 2,8 Hz), to 7.09 (2H, t, J = 8,8 Hz), 7,38 - to 7.50 (2H, m)

Reference example 19

7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thiazolo[5,4-c] - piridinkarbonovaya acid

Stage 1

With a 4.5 - thiazolecarboxamide anhydride and florasulam conducted essentially the same reaction and process as in reference example 1, process 1, step 1, in the presence of aluminium chloride to obtain a mixture of 5-(4-perbenzoic)-4-thiazolecarboxamide acid and 4-(4-perbenzoic)-5-thiazolecarboxamide acid. This mixture is used at a later stage 2.

Stage 2

Using the mixture obtained in stage 1, were essentially the same reaction and process as in reference example 2, step 2, to obtain a mixture of N-ethoxycarbonylmethyl-5-(4-perbenzoic)-N - methyl-4-thiazolecarboxamide and N-ethoxycarbonyl (200 MHz, CDCl3) memorial plaques: 1,20 - 1,40 (3H, m), 3,00, 3,04, 3,15, 3,23 (total 3H, each), 4,0 - and 4.40 (4H, m), 7,16 (2H, t-like, J = 8.6 Hz), 7,84 - 7,95 (1,2 H, m), 8,24 - to 8.34 (0,8 H, m), 8,86, 8,90, 8,94, 8,96 (total 1H, each)

This mixture was used in the next stage 3.

Stage 3

Using the mixture obtained in stage 2, were essentially the same reaction and process as in reference example 2, stage 3, then the reaction mixture was heated in a flask under reflux in toluene in the presence of p-toluensulfonate acid to obtain a mixture of 7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thiazolo- [5,4-c] pyridineboronic acid ethyl ester and 7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thiazolo[4,5-c] - pyridineboronic acid ethyl ester. This mixture was subjected to column chromatography on silica gel (hexane-ethyl acetate = 1:2). From the first fraction of the first of the two was obtained as colorless crystals.

So pl. 129 - 130oC (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: the 1.04 (3H, t, J = 7,1 Hz), 3,68 (3H, s), is 4.15 (2H, q, J = 7,1 Hz), 7,16 (1H, t-like, J = 8.7 Hz), 7,38 - of 7.48 (2H, m), 9,12 (1H, s)

The following fractions were obtained last two in the form of colorless crystals.

So pl. 209-212oC (recrystallized from e is t-like, J = 8.6 Hz), 7,35 - 7,45 (2H, m), of 8.90 (1H, s)

Stage 4

7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thiazolo[5,4-c] - pyridineboronic acid ethyl ester obtained in stage 3, was subjected to hydrolysis at 70% H2SO4at temperatures in the range from 120 to 130oC, to obtain the above compound as colorless crystals.

So pl. 214 - 217oC (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, DMSO-d6) memorial plaques: to 3.58 (3H, s), 7,28 (2H, t-like, J = 9.0 Hz), 7,40 - 7,52 (2H, m), at 9.53 (1H, s)

Reference example 20

7-(4-forfinal)-4,5-dihydro-5-methyl-4-oxo-6-thiazolo[4,5-c] - piridinkarbonovaya acid

Using 7-(4,5-dihydro-5-methyl-4-oxo-6-thiazolo[4,5-c] - pyridineboronic acid ethyl ester obtained in reference example 19, stage 3, were essentially the same reaction (acid hydrolysis), as in reference example 19, step 4, to obtain the above compound as colorless crystals.

So pl. 192-194oC (recrystallized from ethyl acetate - THF - isopropyl ether)

NMR (200 Hz, DMSO-d6): M. D.: of 3.57 (3H, s), 7,34 (2H, t-like, J = 8,8 Hz), 7,46 - EUR 7.57 (2H, m), 9,23 (1H, s)

Reference example 21

4,5-Dihydro-5-methyl-4-oxo-7-phenyl-6-thiazolo[5,4-c] is estu the same reaction and process as in the reference example, process 1, step 1, in the presence of aluminium chloride to obtain a mixture of 4-benzoyl-5-thiazolecarboxamide acid and 5-benzoyl-4-thiazolecarboxamide acid. This mixture was used in the next stage 2.

Stage 2

Using the mixture obtained in stage 1, were essentially the same reaction and process as in reference example 2, step 2, to obtain a mixture of 4-benzoyl-1-ethoxycarbonylmethyl-N-methyl-5 - thiazolecarboxamide and 5-benzoyl-N-ethoxycarbonylmethyl-N-methyl-4 - thiazolecarboxamide in the form of a pale yellow oily product. This mixture is used at a subsequent stage 3.

Stage 3

Using the compound obtained in stage 2, were essentially the same reaction and process as in reference example 19, step 3, to obtain a mixture of 4,5-dihydro-5-methyl-4-oxo-7 - phenyl-6-thiazolo[5,4-c]pyridineboronic acid ethyl ester and 4,5-dihydro-5-methyl-4-oxo-7-phenyl-6-thiazolo[4,5-c] pyridineboronic acid ethyl ester. This mixture was subjected to column chromatography on silica gel (hexane - ethyl acetate = 1:2). From the first fraction was obtained the first of the named substance in the form of colorless crystals.

So pl. 121 - 122oC (recrystallized Hz), 7,44 (5H, s), 9,11 (1H, s)

The following fractions were obtained the last of the above mentioned compounds in the form of colorless crystals.

So pl. 186-188oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: to 0.97 (3H, t, J=7,1 Hz), 3,71 (3H, s), 4,11 (2H, g, J=7,1 Hz), 7,40-to 7.50 (5H, m), 8,89 (1H,s)

Stage 4

Using 4,5-dihydro-5-methyl-4-oxo-7-phenyl-6-thiazolo [5,4-c]pyridineboronic acid ethyl ester, were essentially the same reaction (acid hydrolysis) and process as in reference example 19, step 4, to obtain the above compound as colorless crystals.

So pl. 155-157oC (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, DMCO-d6)memorial plaques: 3,59 (3H, s), the 7.43 (5H, s), at 9.53 (1H, s)

Reference example 22

4,5-Dihydro-5-methyl-4-oxo-7-phenyl-6-thiazolo[4,5-c] piridinkarbonovaya acid

With the ethyl ester of 4,5-dihydro-5-methyl-4-oxo-7-phenyl-6-thiazole [4,5-c] pyridineboronic acid obtained in reference example 21, step 3, was performed essentially the same reaction and process as in reference example 19, step 4, to obtain the above compound as colorless crystals.

So pl. 228-230oC (recrystallized what>/BR>6,7-dihydro-6-methyl-7-oxo-4-phenyl-5-thieno-[2,3-c] piridinkarbonovaya acid

Stage 1

Using 2,3-thiencarbazone anhydride and benzene was performed essentially the same reaction and process as in reference example 8, step 1, in the presence of aluminium chloride to obtain 3-benzoyl-2-thiophencarboxylic acid as colorless crystals.

So pl. 141-143oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 7,33 (1H, d, J=5.4 Hz), and 7.5 and 7.6 (2H, m), the 7.65 (1H, d, J=5.4 Hz), 7,68 (1H, m), 7,8-7,9 (2H, m)

At stages 2 through 4, using the compound obtained in stage 1, were essentially the same reaction and process as in stages 2 through 4 of reference example 8, to obtain the desired substance. The compounds obtained in the respective stages, and their physico-chemical constants described below.

Stage 2

3-Benzoyl-N-ethoxycarbonylmethyl-N-methyl-2-thiophencarboxylic.

Pale yellow oily product

NMR (200 MHz, CDCl3) memorial plaques : of 1.27 (3H, t, J=7.2 Hz), 2,96 (3H, bs), of 4.00 (2H, s), 4,19 (2H, q, J=7.2 Hz), 7,27 (1H, m), 7,4-7,6 (4H, m), 7,83 (2H, m)

Stage 3

6,7-dihydro-6-methyl-7-oxo-4-phenyl-5-thieno[2,3-c] pyridineboronic acid ethyl ester

So pl. 92-94oC (paracrystal,3-7,5 (5H, m), 7,66 (1H, d, J= 5,2 Hz)

Stage 4

6,7-dihydro-6-methyl-7-oxo-4-phenyl-5-thieno[2,3-c] piridinkarbonovaya acid (the above link)

So pl. 185-186oC (recrystallized from ethyl acetate)

NMR (200 MHz, CDCl3) memorial plaques: the 3.65 (3H, s), to 6.95 (1H, d, J=5,2 Hz), 7,40 (5H, s), the 7.65 (1H, d, J=5,2 Hz)

Reference example 24

6,7-dihydro-6-methyl-4-(2-were)-7-oxo-5-thieno[2,3-c] piridinkarbonovaya acid

Stage 1

2,3-tibenderana anhydride was allowed to react with 2-were-magnesium bromide in THF and the reaction mixture was treated with 3-(2-methylbenzoyl)-2-thiophencarboxylic acid as colorless crystals.

So pl. 115-117oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: to 2.42 (3H, s), 7,17 (1H, d, J=5,2 Hz), 7,3-7,5 (4H, m), 7,56 (1H, d, J=5.4 Hz)

At stages 2 through 4 with the compound obtained in stage 1, were essentially the same reaction and process as in reference example 8 to obtain the desired compounds. The compounds obtained in the respective stages, and their physico-chemical constants are presented.

Stage 2

N-ethoxycarbonylmethyl-N-methyl-3-(2-methylbenzoyl)-2 - thiophencarboxylic

Pale yellow oily compound

Stage 3

6,7-dihydro-6-methyl-4-(2-were)-7-oxo-5-thieno[2,3-c] pyridineboronic acid ethyl ester

Pale-yellow oily substance

NMR (200 MHz, CDCl3) memorial plaques: to 0.88 (3H, t, 7.4 Hz), 2,12 (3H, s), to 3.67 (2H, s) to 4.01 (2H, g, J=7,4 Hz), of 6.71 (1H, d, J= 5.4 Hz), 7,2-7,3 (4H, m), 7,63 (1H, d, J=5.4 Hz)

Stage 4

6,7-dihydro-6-methyl-4-(2-were)-7-oxo-5-thieno[2,3-c] piridinkarbonovaya acid (the above link)

So pl. 124 to 128oC (recrystallized from ethyl acetate)

NMR (200 MHz, CDCl3) memorial plaques: 2,11 (3H, s), 3,66 (3H, s), 6,70 (1H, d, J= 5,2 Hz), 7,2-7,3 (4H, m), of 7.64 (1H, d, J=5,2 Hz)

Reference example 25

7,9-Dihydro-7-methyl-5-(4-were)-8-oxo-6-pyrido[3,4-bn] pyridineboronic acid hydrochloride

Stage 1

Using 2,3-pyridylcarbonyl anhydride (10.0 g), toluene (125 ml) and aluminum chloride (15.0 g) was subjected to essentially the same reaction and process as in reference example 1, process 1 and stage 1 pick-3-(4-methylbenzoyl)-2-pyridineboronic acid as colorless crystals (7,8 g).

So pl. 168-170oC (recrystallized from dichloromethane-ethyl acetate)

NMR (200 MHz, CDCl3) memorial plaques: is 2.41 (3H, s), from 7.24 (2H, d, J=8,4 Hz), a 7.62 (2H, d, J=8,4 Hz), of 7.70 (1H, dd, J=8, 4.8 Hz), the 7.85 (1H, dd, J=8, 1.5 Hz), 8,77 (1H, dd, J=4,8, 1.5 Hz)

Stage 2

Using audinprogress 2, stage 1, to obtain N-cyanomethyl-N-methyl-3-(4 - methylbenzoyl)-2-pyridinecarboxamide in the form of a pale brown oily substance.

NMR (200 MHz, CDCl3) memorial plaques: 2,43 (3H, s), 3,13 (3Hx 1/3, s) 3,18 (3Hx 2/3, s), 4,42 (2Hx 2/3, s), 4,49 (2Hx 1/3, s), 7,28 (2H, d, J=8,4 Hz), 7,42-7,52 (1H, m), 7,63-7,73 (2H, m), 7,81-7,94 (1H, m), 8,70 is 8.75 (1H, m).

Stage 3

Using the compound obtained in stage 2, were essentially the same reaction and process as in reference example 1, process 1 and stage 2, with the receipt of 7,8-dihydro-7-methyl-5-(4-were) -8-oxo-6-pyrido[3,4-b] pyridinecarboxamide in the form of colorless crystals.

So pl. 268-270oC (recrystallized from ethyl acetate - ethyl ether.

NMR (200 MHz, CDCl3) memorial plaques: 2,47 (3H, s) to 3.92 (3H, s), 7,28 (2H, d, J=8 Hz), 7,38 (2H, d, J=8 Hz), 7,56 (1H, dd, J=8,4 Hz), of 7.75 (1H, dd, J=8,2 Hz), 9,01 (1H, dd, J=4,2 Hz)

Stage 4

Using the compound obtained in stage 3, were essentially the same reaction and process as in reference example 1, process 2, stage 3, with the receipt of 7,8-dihydro-7-methyl-5-(4 - were)-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide in the form of colorless crystals

So pl. > 310o(recrystallized from methanol).

NMR (200 MHz, CDCl3+DMCO-d6) memorial plaques: 2,43 (3H, s), 3,66 (3H, s), between 6.08 (1H, b), 6,92 (1H, b), 7,2-7,3 (studii 4, acetic acid (150 ml), hydrochloric acid (300 ml) and sodium nitrite (73 g) was stirred for 15 hours at room temperature. The resulting crystalline precipitate (inorganic salt) was separated by filtration and washed with hydrochloric acid. The filtrate and wash liquid were combined and concentrated. This procedure was repeated three times to remove inorganic salts. The residue was treated with THF to obtain the above compound as yellow crystals (5.9 g).

So pl. 178-183oC (after softening hardened in the form of white matter), 249 - 151oC (decomposition) (recrystallized from methanol - THF)

NMR (200 MHz, CDCl3+ DMCO - d6) memorial plaques: 2,43 (3H, s), of 3.77 (3H, s), 7,29 (4H, s), 7,88 (1H, dd, J = 8,5, 4,8 Hz), 8,02 (1H, dd, J = 8,5, and 1.4 Hz), 9,04 (1H, dd, J = 4,8, 1,4 Hz)

Reference example 26

7,8-Dihydro-5-(4-methoxyphenyl)-7-methyl-8-oxo-6-pyrido[3,4-b] piridinkarbonovaya acid

Stage 1

Using 2,3-pyridylcarbonyl anhydride and 4-methoxy-phenyl magnesium bromide, were essentially the same reaction and process as in reference example 5, step 1, to obtain a mixture of 3-(4-methoxybenzoyl)-2-pyridineboronic acid and 2-(4-methoxybenzoyl)-3-pyridineboronic acid. This mixture was subjected races the e pale yellow powdery product.

NMR (200 MHz, CDCl3+DMCO-d6) memorial plaques: a 3.87 (3H, s), 6,91 (2H, d, J = 8.6 Hz), and 7.6 (1H, m), to 7.67 (2H, d, J = 8.6 Hz), 7,79 (1H, d, J = 9 Hz), the rate of 8.75 (1H, b)

Stage 2

Using the compound obtained in stage 1, were essentially the same reaction and process as in reference example 1, process 2, step 1, to obtain N-cyanomethyl-3-(4-methoxybenzoyl)-N-methyl-2-pyridinecarboxamide in the form of a pale brown oily substance.

NMR (200 MHz, CDCl3) memorial plaques: 3,17 (3Hx1/4, s), 3,19 (3Hx3/4, s), 3,88 (3H, s), of 4.44 (2Hx3/4, s), 4,48 (2Hx1/4, s) of 6.96 (2H, d, J = 8 Hz), 7,43 - 7,52 (1H, m), 7,76 - to $ 7.91 (3H, m), 8,73 (1H, dd, J = 5,1, 1,6 Hz)

Stage 3

Using the compound obtained in stage 2, were essentially the same reaction and process as in reference example 1, process 2, step 2, obtaining 7,8-dihydro-5-(4-methoxyphenyl)-7-methyl-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide in the form of colorless crystals.

So pl. 248 - 150oC (recrystallized from ethanol)

NMR (200 MHz, CDCl3) memorial plaques: 3,90 (3H, s), 3,91 (3H, s), was 7.08 (2H, d, J = 8,8 Hz), 7,33 (2H, d, J = 8,8 Hz), EUR 7.57 (1H, dd, J = 8,2, 4,4 Hz), to 7.77 (1H, dd, J = 8,2, 1.8 Hz), 9,01 (1H, dd, J = 4,4, 1.8 Hz)

Stage 4

Using the compound obtained in stage 3, were essentially the same reaction and process as in reference example 1, process 2, stage 3, receiving 7,8x2">

So pl. > 310oC (recrystallized from methanol - THF)

NMR (200 MHz, CDCl3+DMCO-d6) memorial plaques: to 3.73 (3H, s), a 3.87 (3H, s), only 6.64 (1H, b), 6,98 (2H, d, J = 8,8 Hz), 7,25 (1H, b), 7,32 (2H, d, J = 8,8 Hz), of 7.48 (1H, dd, J = 8,4, 4,2 Hz), 7,63 (1H, d, J = 8,4, and 1.6 Hz), 8,86 (1H, dd, J = 4,1, 1,6 Hz)< / BR>
Stage 5

Using the compound obtained in stage 4, were essentially the same reaction and process as in reference example 25, step 5, to obtain the above compound as a yellow powdery substance.

NMR (200 MHz, CDCl3+ DMCO - d6) memorial plaques: a 3.75 (3H, s), a 3.87 (3H, s), of 6.99 (2H, d, J = 8 Hz), 7,31 (2H, d, J = 8 Hz), 7,6 - 7,8 (2H, m), of 8.95 (1H, b)

Reference example 27

1,2-Dihydro-2-methyl-4-(4-were)-1-oxo-3-pyrido[3,4-c] pyridineboronic acid hydrochloride

Process 1:

Stage 1

Using 3,4-pyridylcarbonyl anhydride (10.0 g) and 4-were-magnesium bromide, were essentially the same reaction and process as in reference example 2, step 1, to obtain 4-(4-methylbenzoyl)-3-pyridineboronic acid as colorless crystals.

So pl. 230 - 231oC (recrystallized from methanol)

NMR (200 MHz, CDCl3) memorial plaques: is 2.41 (3H, s), from 7.24 (2H, d, J = 8.0 Hz), 7,28 (1H, d, J = 5.0 Hz), 7,63 (2H, d, J = 8.0 Hz), 8,84 (1H, d, J = 5.0 Hz), of 9.30 (1H, s)

Stage 2

Using the connection,e 2, stage 2, to obtain the N-etoxycarbonyl-methyl-N-methyl-4-(4-methylbenzoyl)-3-pyridinecarboxamide in the form of a pale brown oily substance.

NMR (200 MHz, CDCl2) memorial plaques: of 1.29 (3H, t, J=7,1), 2,43 (3H, s), 3,05 (3H, s), 4,00 - 4,20 (2H, m), 4,22 (2H, q, J = 7,1 Hz), 7,25 - 7,40 (1H, m), 7,28 (2H, d, J = 8,2 Hz), 7,71 (2H, d, J = 8,2 Hz), 8,71 - 8,83 (2H, m)

Stage 3

Using the compound obtained in stage 2, were essentially the same reaction and process as in reference example 2, stage 3, to obtain 1,2-dihydro-2-methyl-4-(4-were)-1-oxo-3-pyrido[3,4-c] pyridineboronic acid ethyl ester as colorless crystals.

So pl. 134 - 136oC (recrystallized from ethyl acetate-isopropyl ether).

NMR (200 MHz, CDCl3) memorial plaques: 0,99 (3H, t, J = 7,1 Hz), 2,43 (3H, s), 3.61 (3H, s), 4.09 to (2H, q, J = 7,1 Hz), to 7.09 (1H, q, J = 5.4 Hz), 7,18 (2H, d, J = 8,2 Hz), 7,27 (2H, d, J = 8,2 Hz), 8,66 (1H, d, J = 5.4 Hz), 9,68 (1H, s)

Stage 4

Using the compound obtained in stage 3, were essentially the same reaction and treatment was added HCl treatment as in reference example 2, step 4, to obtain the above-mentioned substances in the form of yellow crystals.

So pl. 240 - 242oC (hardened again decomposed, about 280oC) (recrystallized from methanol - THF)

, )

Process 2:

Stage 1

Using the compound obtained in stage 1, were essentially the same reaction and process as in reference example 1, process 2, step 1, to obtain N-cyanomethyl-N-methyl-4-(4-methylbenzoyl)-3-pyridinecarboxamide in the form of a pale brown oily product.

NMR (200 MHz, CDCl3) memorial plaques: is 2.44 (3H, s), 3,10 (3H, s), to 4.38 (2H, bs), 7,30 (2H, d, J = 8,2 Hz), the 7.43 (1H, d, J = 5.0 Hz), of 7.70 (2H, d, J = 8,2 Hz), the rate of 8.75 (1H, s), 8,88 (1H, d, J = 5.0 Hz)

Stage 2

Using the compound obtained in stage 1, were essentially the same reaction and process as in reference example 1, process 2, step 2, to obtain 1,2-dihydro-2-methyl-4-(4-were)-1-oxo-3-pyrido[3,4-c] pyridylcarbonyl in the form of colorless crystals.

So pl. 201-202oC (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 2,47 (3H, s), 3,86 (3H, s, 7,20 (1H, d, J = 5,9 Hz), 7,29 (2H, d, J = 8,2 Hz), 7,38 (2H, d, J = 8,2 Hz), 8,79 (1H, d, J = 8,9 Hz), 9,73 (1H, s)

Stage 3

Using the compound obtained in stage 2, were essentially the same reaction and process as in reference example 1, process 2, step 2, to obtain 1,2-dihydro-2-methyl-4-(4-were)-1-oxo-3-pyrido[3,4-c] pyridinecarboxamide in the form of colorless crystals.) memorial plaques: of 2.38 (3H, s), of 3.54 (3H, s), 6,97 (1H, d, J = 5.4 Hz), 7.23 percent (2H, d, J = 8.6 Hz), 7,29 (2H, d, J = 8.6 Hz), the 7.85 (1H, bs), 8,11 (1H, bs), 8,66 (1H, d, J = 5.4 Hz), 9,44 (1H, s)

Stage 4

Using the compound obtained in stage 3, were essentially the same reaction and process as in reference example 25, step 5, to obtain the above-mentioned substances in the form of yellow crystals. Physico-chemical constants of this compound are in good agreement with the constants of the compound obtained in process 1 to stage 4.

Reference example 28

7,8-dihydro-7-methyl-5-(3-were)-8-oxo-6-pyrido [3,4-b] pyridineboronic acid hydrochloride

Stage 1

Using 2,3-pyridylcarbinol anhydride and 3-were-magnesium bromide, were essentially the same reaction and process as in reference example 6, step 1, to obtain a mixture of 3-(3-methylbenzoyl)-2-pyridineboronic acid and 2-(3-methylbenzoyl)-3-pyridineboronic acid.

Stage 2

Using the mixture obtained in stage 1, were essentially the same reaction and process as in reference example 1, process 2, step 1, to obtain a mixture of N-cyanomethyl-N-methyl-3-(3-methylbenzoyl)-2-pyridinecarboxamide and N-cyanomethyl-2-(3-methylbenzoyl)-3-pyridinecarboxamide.

Stadion example 1 process 2, step 2. The reaction mixture was subjected to column chromatography on silica gel (acetone : hexane 1:1 - acetone) for the separation into fractions. From the first fraction was obtained 5,6-dihydro-6-methyl-8-(3-were)-5-oxo-7-pyrido [4,3-b] pyridinecarboxylic (so pl. : 234 - 236oC (recrystallized from acetone).

NMR (200 MHz, CDCl3) memorial plaques : is 2.44 (3H, s), a 3.87 (3H, s), 7,26 - 7,47 (4H, m), 7,54 (1H, dd, J = 8.5 Hz), 8,78 (1H, dd, J = 8,2 Hz), 8,99 (1H, dd, J = 5,2 Hz), and the following fractions were obtained 7,8 - dihydro-7-methyl-5-(3-methyl-phenyl)-8-oxo-6-pyrido [3,4-b] pyridylcarbonyl (So pl.: 253 - 255oC (recrystallized from acetone),

NMR (200 MHz, CDCl3) memorial plaques : a 2.45 (3H, s) of 7.2 and 7.5 (4H, m), EUR 7.57 (1H, dd, J = 8,4 Hz), 7,73 (1H, d, J = 8 Hz), of 9.02 (1H, d, J = 4 Hz), respectively, in the form of colorless crystals.

Stage 4

Using 7,8-dihydro-7-methyl-5-(3-were)-8-oxo-6-pyrido [3,4-b} pyridylcarbonyl, obtained in stage 3, were essentially the same reaction and process as in reference example 1, process 2, stage 3, with the receipt of 7,8-dihydro-7-methyl-5-(3-were)-8-oxo-6-pyrido [3,4-b] pyridinecarboxamide in the form of colorless crystals.

So pl. > 310oC (recrystallized from methanol)

NMR (200 MHz, CDCl3) memorial plaques : to 2.42 (3H, s), of 3.57 (3H, s), 5,70 (1H, bs) is 6.78 (1H, bs), 7.23 percent - 7,41 (5H, is essentially the same reaction and process as in reference example 25, step 5, to obtain the above-mentioned compounds in the form of a pale yellow-orange crystals.

So about 220 squareoC (decomposition) (recrystallized from methanol - THF)

NMR (200 MHz, CDCl3+ DMSO - d6) memorial plaques : is 2.41 (3H, s), of 3.78 (3H, s), 7,22 - 7,42 (4H, m), 7,95 (1H, dd, J = 8,4 Hz), 8,07 (1H, d, J = 8 Hz), which is 9.09 (1H, d, J = 4 Hz)

Reference example 29

5-(4-Carboxyphenyl)-7,8-dihydro-7-methyl-8-oxo-6-pyrido [3,4-b] piridinkarbonovaya acid

Stage 1

To a mixture of 3-(4-methylbenzoyl)-2-pyridineboronic acid (6.0 g) and 0.1 N NaOH (340 ml) portions was added KMPO4(8.0 g) under stirring at room temperature. After that, the mixture was heated at 90-100oC for 1.5 hours, to the mixture was added isopropanol and the resulting precipitate was filtered. To the filtrate was added conc. HCl to bring to pH 2. The solution was saturated with NaCl and extracted with ethyl acetate - THF (approximately 3:1). The extract was washed with an aqueous solution of NaCl, dried and the solvent evaporated to obtain 3-(4-carboxybenzoyl)-2-pyridineboronic acid as colorless crystals (1.50 g).

So pl. 210 - 213oC (decomposition) (recrystallized from THF - isopropyl ether)

NMR (200 MHz, CDCl3+ DMSO - d6) memorial plaques : to 7.64 the Zuya connection, obtained in stage 1 (1,46 g) and N-methylglycine ethyl ester (3.0 g) was subjected to essentially the same reaction and process as in reference example 2, step 2, to obtain the N-ethoxycarbonylmethyl-3-[4-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)benzoyl] - N-methyl-2-pyridinecarboxamide in the form of a colorless oil (2.5 g).

NMR (200 MHz, CDCl3) memorial plaques : 1,20 - 1,40 (6H, m), 3,02, 3,13, 3,21 (total 6H, each s), 3.96 points, 4,10-4,40 (total 8H, m), 7,40 - of 7.60 (3H, m), 7,70 - of 7.90 (3H, m), 8,63 (1Hx 2/5, d - like), 8,75 (1Hx 2/5, d - like), 8,75 (1Hx3/5, d - like)

Stage 3

Using the compound obtained in stage 2 (2.2 g) and 1,8 - diazabicyclo [5,4, 0] undec-7-ene (2 ml) was subjected to essentially the same reaction and process as in reference example 2, stage 3, to obtain 5-(4-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)phenyl)-7,8-dihydro-7-methyl-8-oxo-6-pyrido [3,4-b] pyridineboronic acid ethyl ester as colorless crystals (0,82 g).

So pl. 195 - 197oC (recrystallized from ethyl acetate - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques : a 1.01 (3H, t, J = 7,1 Hz) of 1.30 (1H, t, J = 7.2 Hz), of 1.34 (2H, t, J = 6.8 Hz), 3,12 (2H, s), 3,17 (1H, s), 3,68 (3H, s), 4.09 to (2H, q, J = 7,1 Hz), 4,15 - of 4.35 (4H, m), 7,10 - the 7.65 (6H, m), to 8.94 (1H, dd, J = 4,0, 1.2 Hz)

Stage 4

Using the compound obtained in stage 3 (0,77 g), conducted soedineniya in the form of a pale yellow oil, which is used for the reaction of example 73.

Reference example 30

5-Cyclohexyl-7,8-dihydro-7-methyl-8-oxo-6-pyrido [3,4-b] piridinkarbonovaya acid

Using as starting materials 3-cyclohexylcarbonyl-2-pyridylcarbonyl acid, which was obtained from 2,3-pyridinedicarboxylic anhydride, and cyclohexylamine chloride, were essentially the same reaction and treatment as in example 1, process 2, stages 1 through 4, to obtain the substances named in the title, in the form of a pale yellow oil, which was used for the reaction of example 76.

Reference example 31

7,8-Dihydro-7-methyl-5-(4-were)-8-oxo-6-pyrido [3,4-b] pyridineboronic acid hydrochloride

Stage 1

To a mixture of 2,3-pyridinedicarboxylic anhydride (1.50 g) and THF (25 ml) was added dropwise under stirring at room temperature, dimethylacetal of methylaminoacetaldehyde (2,90 ml). The mixture was stirred for 3 hours at room temperature and then concentrated. To the concentrate was added dichlormethane the hydrosulfate (2.7 g) and water. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with aqueous NaCl solution, dried and viparis the crystals (2.10 g).

So pl. 128 - 130oC (decomposition) (recrystallized from acetone - ethyl ether).

Stage 2

To a stirred solution of this compound (1.35 g) obtained in stage 1, potassium carbonate (0,42 g) and acetone (30 ml), was added logmean (10 ml). The mixture was stirred for 14 hours at room temperature and concentrated. To the concentrate was added dichloromethane. The mixture was washed with water and dried, and the solvent evaporated to obtain 2-[N-(2,2-dimethoxymethyl)-N-methyl] carbarnoyl-3-pyridineboronic acid methyl ester as a pale yellow oil (0,90 g).

NMR (200 MHz, CDCl3) memorial plaques: 2,90 (3X2/3, s), 3,23 (3H, x 1/3, s), 3,23 (2Hx1/3, d, J = 5 Hz), 3,29 (3Hx2/3, s), 3,51 (3Hx2/3 + 3Hx1/3x2, s), 3,68 (2Hx2/3, d, J = 5 Hz), 3,92 (3Hx1/3, s), 3,93 (3Hx2/3, s), 4,54 (1Hx1/3, t, J = 5 Hz), 4,77 (1Hx2/3, t, J = 5 Hz), 7,42 (1H, dd, J = 5.8 Hz), 8,31 (1Hx1/3, dd, J = 2,8 Hz), 8,32 (1Hx2/3, dd, J = 2,8 Hz), 8,73 (1Hx1/3, dd, J = 2.5 Hz), 8,76 (1Hx2/3, dd, J = 2.5 Hz)

Stage 3

To a mixture of magnesium (2.0 g), iodine (catalytic amount) in THF (20 ml) under stirring at room temperature was added dropwise a solution of 4 - bromthymol (12 g) in THF (30 ml) and the mixture was stirred for 30 minutes. The mixture dropwise with stirring at -78oC was added to solution of compound (5.8 g) obtained by the method described in stage 2, in THF, with the village is listed with ethyl acetate. The extract was washed with water, dried and the solvent evaporated to obtain N -(2,2-dimethoxymethyl)-N-methyl-3-(4-methylbenzoyl)-2-pyridinecarboxamide in the form of a pale brown oil, which carried out the reaction with stage 4 without purification.

NMR (200 MHz, CDCl3) memorial plaques : 2,43 (3H, s), to 3.09 (3H x 1/3, s), 3,11 (3Hx2/3, s), 3,37 (6H x 1/3, s), 3,44 (6Hx2/3, s), 3,50 (2Hx2/3, d, J = 5.6 Hz), 3,52 (2Hx1/3, d, J = 5.4 Hz), 4,51 (1Hx2/3, t, J = 5.6 Hz), 4,77 (1Hx1/3, t, J = 5.4 Hz), 7,27 (2H, d, J = 8.0 Hz), 7,40 (1H, dd, J = 7,8, and 4.8 Hz), 7,71 (2H, d, J = 8.0 Hz), 8,76 -8,87 (1H, m), 8,65 is 8.75 (1H, m).

Physico-chemical constants of this compound were identical to the connection constants obtained by amidation of 3-(4-methylbenzoyl)-2-pyridineboronic acid via the acid chloride) with the help of dimethylacetal of methylaminoacetaldehyde.

Stage 4

A mixture of compound (crude) obtained in stage 3, THF (30 ml), H2O (30 ml) and conc. HCl (20 ml) was stirred for 1 hour at room temperature. After washing with ethyl acetate, the mixture was treated with aqueous solution of K2CO3to bring to pH 9-10 and then was extracted with ethyl acetate. The extract was washed with water, dried and the solvent evaporated to obtain N-formylmethyl-N-methyl-3-(4-methylbenzoyl)-2-pyridinecarboxamide in the form of a pale brown mass,70 (2H, d, J = 8.0 Hz), 7,79 (1Hx2/5, dd, J = 7,8, and 1.6 Hz), 7,88 (1Hx3/5, dd, J = 7,8, and 1.6 Hz), 8,61 (1Hx2/5, dd, J = 5.0 and 1.6 Hz), 8,75 (1Hx3/5, dd, J = 5.0 and 1.6 Hz), 9,52 (1Hx3/5, m), 9,88 (1Hx2/5, m)

Stage 5

The mixture of compounds obtained in stage 4 (30 g), toluene (60 ml) and 1,8-diazabicyclo[5,4,0] undec-7-ene (0.3 ml) was stirred for 30 minutes when heated in a flask with reflux condenser. The mixture was cooled and the crystals formed were collected by filtration, washed with ethyl ether to obtain 7,8-dihydro-7-methyl-5-(4-methyl-phenyl)-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide in the form of pale yellow crystals (1.98 g).

So pl. 282-284oC (recrystallized from THF - isopropyl ether)

NMR (200 MHz, CDCl3) memorial plaques: 2,48 (3H, s), of 3.95 (3H, s), from 7.24 (2H, d, J = 8.0 Hz), was 7.36 (2H, d, J = 8.0 Hz), 7,53 (1H, dd, J = 8,2, 4,4 Hz), to 7.68 (1H, dd, J=8,2, 1,6 Hz), 9,01 (1H, dd, J = 4,4, 1,6 Hz), being 9.61 (1H, s)

Stage 6

To a mixture of compound obtained in stage 5 (1.0 g), of 0.25 N NaOH (20 ml) and 2-methyl-2-propanol (20 ml) was added potassium permanganate (0.6 g) under stirring at 0oC and to the mixture was added EtOH (5 ml) followed by stirring for 10 minutes After filtering off the resulting precipitate, the filtrate was treated with conc. HCl to bring to pH 2 and then the solvent is evaporated to obtain the above compound as a yellow Arochnom example 25.

Example of formulation 1

Coated tablets (1000 tablets)

Connection example 1 - 10.0 g

Lactose - 60,0

Corn starch - 35,0 g

Gelatin - 3.0 g

Magnesium stearate - 2.0 grams

The mixture of compounds obtained in example 1, lactose and corn starch was granulated using 10% aqueous solution of gelatin through a sieve with openings of 1 mm and the granules were dried at 40oC and again sieved. Thus obtained granules were mixed with magnesium stearate and the mixture is extruded. Thus obtained core tablets were coated by the sugar-coated using aqueous suspension of sucrose, titanium dioxide, talc and water solution Arabian gum. Covered so the tablets are polished with wax.

Example of formulation 2

Tablets (1000 tablets)

Connection example 1 - 10.0 g

Lactose - 70,0

Corn starch - 50.0 g

Soluble starch - 7.0 g

The compound obtained in example 1 and magnesium stearate were granulated using an aqueous solution of soluble starch and dried. The granules were mixed with lactose and corn starch. The mixture was pressed into tablets.

Efficiency is chichinonova receptors and activity suppression of the yield of plasma from blood vessels into the tissue, caused by capsaicin, and, thus, are widely used as medicines, such as tools for healing or reduce disturbance of urination.

1. Heterocyclic compounds of General formula

< / BR>
where ring A and ring B respectively denote an optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen atom, sulfur and oxygen;

ring C represents a benzene ring which may be substituted by 1 to 3 substituents selected from halogen, optionally halogenated C1-C4the alkyl, optionally halogenated C1-C4alkoxy;

R denotes a hydrogen atom or a C1-C6alkyl;

one of X or Y represents-NR1- and the other represents-CO - or one of them represents N and the other represents =CR2- where R1denotes a hydrogen atom or a C1-C6alkyl;

R2denotes a hydrogen atom, a halogen atom, a C1-C6alkyl, carboxyl or alkoxycarbonyl group;

n denotes 1 or 2,

or its salt.

2. Sooo ring, and the other denotes arbitrarily substituted 5 - or 6-membered aromatic heterocyclic ring.

3. Connection on p. 2, characterized in that the Deputy or deputies arbitrarily substituted benzene ring represent from 1 to 4 substituents selected from the group consisting of halogen atom, optionally halogenated C1-C4alkyl group, optionally halogenated C1-C4alkoxygroup, optionally halogenated C1-C4allylthiourea, C1-3alloctype, hydroxyl group, amino group, mono-C1-4alkylamino, di-C1-4-alkylamino, carboxyl group and C1-4-alkoxycarbonyl group.

4. Connection PP.1 to 3, characterized in that X - Y is-NR1a-CO-, -CO-NR1a- or-N=C(R2a)-(R1aand R2arespectively denote a hydrogen atom or a C1-C6alkyl group).

5. Connection PP.1 to 3, characterized in that R is C1-4alkyl group.

6. Connection PP.1 to 3, characterized in that n is 1.

7. Connection on p. 1, characterized in that the Deputy or deputies arbitrarily substituted cycloalkanones or s group, consisting of halogen atom, optionally halogenated C1-C4alkyl group, optionally halogenated C1-4allylthiourea, C1-3alloctype, hydroxyl group, amino group, mono - C1-4alkylamino, di-C1-4alkylamino, a carboxyl group, a C1-4alkoxycarbonyl group and the carbonyl group.

8. Connection on p. 1, wherein introducing the ring A or B, 5 - or 6-membered aromatic heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and sulfur, and represented by ring A or B is a benzene ring can be substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and arbitrary halogenated C1-4alkyl group; ring C may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl groups and randomly halogenated C1-4alkoxygroup; R is a hydrogen or C1-4alkyl group; X-Y is - CO-NR1a-, -NR1a-CO-or-N = (R2a)-(R1aand R2arespectively denote a hydrogen atom or a C1-4alkyl group); n is 1.

1-4alkyl groups and randomly halogenated C1-4alkoxygroup; ring C may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, optionally halogenated C1-4alkyl groups and randomly halogenated C1-4alkoxygroup; R is a hydrogen or C1-6alkyl group; X is-CO-; Y is-NR1a- (R1adenotes a hydrogen atom or a C1-6alkyl group); n is 1.

10. Connection on p. 1, selected from the group including:

N-[3,5-bis(trifluoromethyl)benzyl]-4-(4-terphenyl)-6,7-dihydro-N, 6-dimethyl-7-oxo-5-thieno[2,3-c]pyridinecarboxamide,

N-[3,5-bis(trifluoromethyl)benzyl] -1,2,5,6,7,8-hexahydro-N,2,7-trimethyl-4-(4-were)-1-oxo-3-pyrido[3,4-c] pyridinecarboxamide,

N-[3,5-bis(trifluoromethyl)benzyl] -7,8-dihydro-N, 7-dimethyl-5-(4-were)-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide,

N-[3,5-bis(trifluoromethyl)benzyl] -5-(4-forfinal)-7,8-dihydro-N, 7-dimethyl-8-oxo-6-pyrido[3,4-b] pyridinecarboxamide.

11. A method of obtaining a connection on p. 1, characterized in that carried the s given in paragraph 1

or its salt or reactive derivative with the compound of the formula

< / BR>
where all symbols have the same meanings given in paragraph 1

or its salt.

12. Composition active receptor antagonist tachykinin containing the active ingredient and a carrier, wherein the active component contains an effective amount of the compounds under item 1.

13. The way to counter (antagonism) tachykinin receptors, characterized in that it is administered to a subject in need, an effective amount of the compounds under item 1.

14. Connection on p. 1 active antagonists tachykinin receptors.

Priority points:

10.11.93. on PP.1, 2, 3, 6, 10, 11, 12, 13 and 14;

28.12.93 - PP.4, 5 and 7, the variation of the radicals;

03.03.94 - p. 8, the variation of the radicals;

21.06.94 - p. 9, the variation of the radicals.

 

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< / BR>
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