Cyclic amine compound

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

 

The technical field to which the invention relates.

The present invention relates to a new connection, a cyclic amine, MES, its pharmaceutically acceptable salts and pharmaceutical compositions.

The level of technology

α2-Adrenergic receptors are divided into three subtypes, i.e α2, α2 and α2. Recently been obtained and tested in experimental animals in which there is overproduction or do not have a gene of subtype of α2-adrenergic receptors. Clear antidepressant effect was observed for animals that have no gene α2, and the opposite effect was observed for animals with overproductive specified gene. Thus, it was shown that α2-adrenergic receptors are closely associated with the development of depression (non-patent document 1).

Currently as therapeutic agents against depression is widely used inhibitors capture neurotransmitters, such as serotonin and norepinephrine. For a number of these inhibitors was suggested that their effectiveness is affected by the antagonism of α2-adrenergic receptors (non-patent documents 2 and 3). Blockade of α2-adrenergic receptors increases the release of norepinephrine and serotonin, providing therapeutic effect on depression. It has also been suggested that the effect of α2-adrenergic receptors on cholinergic and dopamine is rychecky nervous system has a beneficial effect on depression.

Among the antagonists, α2-adrenergic receptors, for which a study was conducted on their use as antidepressants, clinical application found mirtazapine, mianserin, etc. But because these drugs exhibit a variety of pharmacological effects, often observed adverse effect. Taking into account these factors suggest that the compounds inhibitors α2-adrenergic receptors may be suitable as a therapeutic agent for stress-induced mental disorders, which is a highly effective and takes less adverse effect.

On the other hand, clozapine, which is atypical medicine to treat schizophrenia, is a therapeutic agent with the highest efficiency compared with conventional therapy. I believe that the clozapine is the result of suppression of the activity of the mesolimbic dopaminergic nervous system by blocking the D2 receptor. I believe that a significant activity of clozapine can be attributed to the blocking of 5-TNA receptor D4 receptor or α2-adrenergic receptors. As for the other atypical drugs for schizophrenia, such as risperidone, it was also reported that the antagonism of α2-adrenergic receptors is involved in the treatment of schizophrenia (non-patent shall document 4).

In addition, based on the results of animal experiments, it was reported that for the D2 antagonist of the receptor was observed a marked release of dopamine from the middle prefrontal cortex; what is selectively observed significant release of dopamine in the middle prefrontal cortex in the case when jointly used antagonist of α2-adrenergic receptors; and that eliminated the undesirable effects on the extrapyramidal system (non-patent document 5). It was also reported that the antagonist of α2-adrenergic receptors is effective in the clinical setting for the treatment of depression and schizophrenia (non-patent documents 6 and 7).

Caused by blockade of D2 receptor stimulation catalepsy is inhibited by compounds having affinity to α2-adrenergic receptors (non-patent document 8). In addition, since clozapine exhibits high affinity to α2 subtype, then I think the connection that selectively blocks α2-adrenergic receptors among α2 subtypes, it may be a new therapeutic tool from schizophrenia, with the effect of remission in relation to negative symptoms and is effective against persistent diseases.

Currently, there are many compounds with cyclic amines (non-patent documents 9, 10, 11, 12 and 13; patent documents 1, 2, 3, 4 and 5). Non-patent documents 9 and 10 describe the hcpa the op perate at the D2 receptor and 5-NTA receptor, and non-patent documents 11 and 12 describe the action against amphetamine, respectively. None of these documents is not marked effect on α2-adrenergic receptors. In non-patent document 13 and patent documents 1, 2, 3, 4 and 5 reported antagonism to α2-adrenergic receptors. For the part of the compounds disclosed in patent documents 1-5, the inhibitory effect on individual subtypes of α2-adrenergic receptors is described in non-patent document 13. However, from these documents it is impossible to establish the selectivity α2/α2.

[Patent document 1] WO 98/45297;

[Patent document 2] WO 00/20421;

[Patent document 3] WO 00/20422;

[Patent document 4] WO 00/20423;

[Patent document 5] WO 00/37466;

[Non-patent document 1] Sallinen et al., Mol. Psychiatry., (1999), 4(5), 443-452;

[Non-patent document 2] Potter and Manji, Clin. Chem., (1994), 40(2), 279-287;

[Non-patent document 3] Sussman and Stahl, Am. J. Med., (1996), 101(6A), 26S-36S;

[Non-patent document 4] Hertel et al., Neuropsychopharmacology., (1997), 17(1), 44-55;

[Non-patent document 5] Hertel et al., Science, (1999), 286(5437), 105-107;

[Non-patent document 5] Van Dorth, Acta. Psychiatr. Scand. Suppl., (1983), 302, 72-80;

[Non-patent document 6] Litman et al., Br. J. Psychiatry., (1996), 168(5), 571-579;

[Non-patent document 8] Kalkman et al., Br. J. Pharmacol., (1998), 124(7), 1550-1556;

[Non-patent document 9] Abou-Gharbia et al., J. Med. Chem., (1987), 30, 1100-1105;

[Non-patent document 10] Abou-Gharbia et al., J. Med. Chem., (1987), 30, 188-1823;

[Non-patent document 11] Harbert et al., J. Med. Chem., (1980), 23, 635-643;

[Non-patent document 12] Harbert et al., Molecular Pharmacol., (1980), 17, 38-42;

[Non-patent document 13] Kennis et al., Bioorg. Med. Chem. Lett., (2000), 10, 71-74.

Description of the invention

As stated above, have not been offered new connections cyclic amine, which potentially have an inhibitory effect on the binding α2-adrenergic receptors and are suitable for the prevention and treatment of disorders that can be attributed α2-adrenergic receptors (such as depression, anxiety and schizophrenia). It is necessary to develop such a connection cyclic amine.

As a result of intensive and extensive research aimed at solving the above problems, the authors of the present invention have found that specific compounds of cyclic amine are effective and show subtype-selective activity against α2-adrenergic receptors. Thus was accomplished the present invention. The object of the present invention is the following compound cyclic amine, his MES or its pharmaceutically acceptable salt, inhibitor binding α2-adrenergic receptors and pharmaceutical composition for the prevention and treatment of diseases that can be attributed α2-adrenergic receptors (such as depression, anxiety and schizophrenia).

(1) Obedinenie cyclic amine, represented by the following formula (1), MES or its pharmaceutically acceptable salt:

Formula (1)

where X is O, S, SO, SO2or NR2(where R2represents a hydrogen atom, a C1-C12alkyl group, a C2-C8alkanoyloxy group or2-C13alkoxycarbonyl group);

When X is O, S, SO, SO2, R1represents a hydrogen atom, a cyano, a carboxyl group, a C2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C13cyclic aminocarbonyl group1-C12alkyl group, a C1-C12alkoxygroup,1-C8alkylthio-group

With1-C8alkylsulfonyl group1-C8alkylsulfonyl group2-C8alkanoyloxy group, a nitro-group or a hydroxyl group; and when X is NR2(where a value of R2above), R1represents cyano, carboxyl group, With2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C cyclic aminocarbonyl group1-C12alkyl group, a C1-C12alkoxygroup,1-C8alkylthio-group

With1-C8alkylsulfonyl group1-C8alkylsulfonyl group2-C8alkanoyloxy group, a nitro-group or a hydroxyl group;

Ar1and Ar2the same or different and each represents an aryl or heteroaryl group which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,7-C26Uralkaliy,2-C8alkenylphenol,2-C8alkylamino,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl,1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl,2-C8alkanoyloxy, cyano, nitro, phenyl and fenoxaprop; or Ar1and Ar2 together with the neighboring carbon atoms to which they are attached, form a group represented by one of the following formulas (a) - (e):

(where S cycle and the cycle t of the same or different and each means a benzene, pyrrole cycle, furan cycle, titanovyi cycle, imidazole cycle, pyrazol cycle, oxazolyl cycle, isoxazolyl cycle, thiazole cycle, isothiazol cycle, the pyridine cycle, pyrimidine cycle, pyrazinoic cycle or pyridazinyl cycle, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,7-C26Uralkaliy,2-C8alkenylphenol,2-C8alkylamino,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl,1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl,2-C8alkanoyloxy, tzia is about, nitro, phenyl, phenoxy group; and Y represents O, S, SO, SO2or NR3(where R3represents a hydrogen atom, a C1-C12alkyl group, a C2-C8alkanoyloxy group or2-C13alkoxycarbonyl group);

cycle means benzene, pyrrole cycle, furan cycle, titanovyi cycle, imidazole cycle, pyrazol cycle, oxazolyl cycle, isoxazolyl cycle, thiazole cycle, isothiazol cycle, the pyridine cycle, pyrimidine cycle, pyrazinoic cycle or pyridazinyl cycle, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,7-C26Uralkaliy,2-C8alkenylphenol,2-C8alkylamino,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl,1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbarnoyl the ing, With2-C8alkanoyloxy, cyano, nitro, phenyl and fenoxaprop;

n means an integer from 1 to 10; and

p and q are the same or different and each denotes an integer of 1 or 2.

(2) Connection of a cyclic amine, his MES or its pharmaceutically acceptable salt according to the above item (1),

where X is O, S, SO or SO2;

R1means a hydrogen atom, a cyano, a carboxyl group, a C2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C7cyclic aminocarbonyl group, a nitro-group or a hydroxyl group;

Ar1and Ar2the same or different and each means a phenyl group, naftalina group, follow group, thienyl group, pyridyloxy group or imidazolidinyl group, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl With 2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl, cyano, nitro, phenyl and fenoxaprop; or Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form a group represented by one of the following formulas (f) to (j):

(where R4and R5the same or different and each means a hydrogen atom, a halogen atom, a C1-C12alkyl group, a C1-C8halogenating group1-C12alkoxygroup,1-C8halogenlampe, hydroxyl group, With1-C12alkylamino,2-C24dialkylamino,2-C12the cyclic amino group, the amino group, With2-C13alkoxycarbonyl group, carboxyl group, With2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C13cyclic aminocarbonyl group, karbamoilnuyu group, a cyano, a nitro-group, phenyl group, or fenoxaprop; and Y represents O, S, SO, SO2or NR3(where R3represents a hydrogen atom or a C1-C12alkyl group);

cycle means benzene, furan cycle, titanovyi C is CL, the pyridine cycle or imidazole cycle, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl, cyano, nitro, phenyl and fenoxaprop;

n means an integer from 1 to 5; and

p and q are different and each denotes an integer of 1 or 2.

(3) Connection of a cyclic amine, his MES or its pharmaceutically acceptable salt according to the above item (1),

where X is NR2(where R2represents a hydrogen atom or a C1-C12alkyl group);

R1means cyano, carboxyl group, With2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C7cyclic aminocarbonyl group, nitro group is or hydroxyl group;

Ar1and Ar2the same or different and each means a phenyl group, naftalina group, follow group, thienyl group, pyridyloxy group or imidazolidinyl group, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl, cyano, nitro, phenyl and fenoxaprop; or Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form a group represented by one of the following formulas (f) to (j):

(where R4and R5the same or different and each means a hydrogen atom, a halogen atom, a C1-C12alkyl group, a C1-C8halogenating group1-C12alkoxygroup,1-C8halogenlampe, hydroxyl group, With1-C12alkylamine the group, With2-C24dialkylamino,2-C12the cyclic amino group, the amino group, With2-C13alkoxycarbonyl group, carboxyl group, With2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C13cyclic aminocarbonyl group, karbamoilnuyu group, a cyano, a nitro-group, phenyl group, or fenoxaprop; and Y represents O, S, SO, SO2or NR3(where R3represents a hydrogen atom or a C1-C12alkyl group);

cycle means benzene, furan cycle, titanovyi cycle, the pyridine cycle or imidazole cycle, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl, cyano, nitro, phenyl and fenoxaprop;

n means an integer from 1 d is 5; and

p and q are different and each denotes an integer of 1 or 2.

(4) Connection of the cyclic amine, his MES or its pharmaceutically acceptable salt according to the above item (1),

where X is O or N;

R1means a hydrogen atom, a cyano, a carboxyl group, a C1-C6alkoxycarbonyl group or karbamoilnuyu group;

Ar1and Ar2the same or different and each means a phenyl group which may be substituted atom(s) halogen, C1-C6alkyl(s) group(s), With a1-C6alkoxygroup(AMI), triptorelin(s) group(s) or cryptomaterial(AMI); or Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form N-xanthene-9-ilen group;

cycle means In benzene, in which one of its hydrogen atoms may be substituted by a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, triptorelin group or cryptomaterial;

n means an integer from 2 to 4; and

p and q are different and each denotes an integer of 1 or 2.

(5) Connection of the cyclic amine, his MES or its pharmaceutically acceptable salt according to the above item (1),

where X is NR2(where R2represents the atom in Dorada, methyl group or ethyl group);

R1means cyano, carboxyl group, With1-C6alkoxycarbonyl group or karbamoilnuyu group;

Ar1and Ar2the same or different and each means a phenyl group which may be substituted atom(s) halogen, C1-C6alkyl(s) group(s), With a1-C6alkoxygroup(AMI), triptorelin(s) group(s) or cryptomaterial(AMI);

cycle means In benzene, in which one of its hydrogen atoms may be substituted by a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, triptorelin group or cryptomaterial;

n means an integer from 2 to 4; and

p and q are different and each denotes an integer of 1 or 2.

(6) the Inhibitor binding α2-adrenergic receptors, including the connection of the cyclic amine, his MES or its pharmaceutically acceptable salt according to any of the above(1) - (5).

(7) a Pharmaceutical composition comprising a compound of a cyclic amine, his MES or its pharmaceutically acceptable salt according to any of the above items (1) to (5) and a pharmaceutically acceptable carrier.

(8) the Pharmaceutical composition according to the above item (7), which is used for before the prevention or treatment of depression, anxiety or schizophrenia.

According to the present invention can obtain a new connection cyclic amine, which has an inhibitory effect on the binding α2-adrenergic receptors and effectively from the disorders that can be attributed α2-adrenergic receptors (in particular, depression, anxiety or schizophrenia), MES or pharmaceutically acceptable salt of the compounds of the cyclic amine.

According to a preferred variant implementation of the present invention can obtain a new connection cyclic amine, which shows high selectivity for subtypes α2/α2, his MES or a pharmaceutically acceptable salt.

In addition, according to the present invention can be obtained inhibitor binding α2-adrenergic receptors preventive measure against diseases that can be attributed α2-adrenergic receptors (in particular, depression, anxiety or schizophrenia), and therapeutic cure for these diseases.

Best mode for carrying out the present invention

Connection cyclic amine according to the present invention

Connection cyclic amine represented by the following formula (1)

Formula (1)

In the above formula (1) X means O, S, SO, SO2or NR2(where R2represents the volume of hydrogen, With1-C12alkyl group, a C2-C8alkanoyloxy group or2-C13alkoxycarbonyl group). Preferably X is O, S, SO, SO2or NR2(where R2represents a hydrogen atom or a C1-C12alkyl group). More preferably X is O, S or NR2(where R2represents a hydrogen atom, methyl group or ethyl group).

When X is O, S, SO, SO2, R1in the above formula (1) means a hydrogen atom, a cyano, a carboxyl group, a C2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C13cyclic aminocarbonyl group1-C12alkyl group, a C1-C12alkoxygroup,1-C8alkylthio-group

With1-C8alkylsulfonyl group1-C8alkylsulfonyl group2-C8alkanoyloxy group, a nitro-group or hydroxyl group. When X is O, S, SO, SO2, R1preferably means hydrogen atom, cyano, carboxyl group, With2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3 -C25dialkylaminoalkyl group or3-C13cyclic aminocarbonyl group.

When X is NR2(where a value of R2above), R1in the above formula (1) denotes a cyano, carboxyl group, With2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C13cyclic aminocarbonyl group1-C12alkyl group, a C1-C12alkoxygroup,1-C8alkylthio-group1-C8alkylsulfonyl group1-C8alkylsulfonyl group2-C8alkanoyloxy group, a nitro-group or hydroxyl group. When X is NR2(where a value of R2above), R1preferably means cyano, carboxyl group, With2-C13alkoxycarbonyl group, carbamoyl group2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group or3-C13cyclic aminocarbonyl group.

Ar1and Ar2in the above formula (1) may be the same or different. Ar1and Ar2each represents an aryl or heteroaryl gr the PPU, which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,7-C26Uralkaliy,2-C8alkenylphenol,2-C8alkylamino,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl,1-C12alkylamino,2-C24dialkylamino,2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl,2-C8alkanoyloxy, cyano, nitro, phenyl and fenoxaprop. The number of substituents in the aryl or heteroaryl group in Ar1and Ar2is preferably 1 or 0.

Preferred substituents in the aryl or heteroaryl group in Ar1and Ar2are the atoms of halogen, C1-C12alkyl, C1-C8halogenation,7-C26kalkilya,2-C8Alchemilla,2-C8Alchemilla,1-C12alkoxy, C1-C8halogen is coxi, amino, carboxyl, carnemolla, cyano, nitro, phenyl and fenoxaprop.

Otherwise, Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form a group represented by one of the following formulas (a) - (e). Among the groups represented by the formulas (a) - (e), preferred is a group represented by the formula (b)

In the above formulas (a) - (e) S cycle and the cycle T may be the same or different. In the above formulas (a) - (e) S cycle and the cycle T every means benzene, pyrrole cycle, furan cycle, titanovyi cycle, imidazole cycle, pyrazol cycle, oxazolyl cycle, isoxazolyl cycle, thiazole cycle, isothiazol cycle, the pyridine cycle, pyrimidine cycle, pyrazinoic cycle or pyridazinyl cycle, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,7-C26Uralkaliy,2-C8alkenylphenol,2-C8alkylamino,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl,1-C12alkylamino,2-C24dia is calamine, With2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl,2-C8alkanoyloxy, cyano, nitro, phenyl and fenoxaprop. The S cycle and the cycle T in the above formulas (a) - (e) each preferably represents a monosubstituted cycle or unsubstituted cycle.

More preferably the S cycle and the cycle T in the above formulas (a) - (e) each means monosubstituted benzene or unsubstituted benzene. In this case, the group represented by the above formulas (a) - (e)are the same as the groups represented by the formulas (f) to (j), respectively, which are described later.

Preferred substituents in the cycle S cycle and T are the atoms of halogen, C1-C12alkyl, C1-C8halogenation, amino, carboxyl, cyano, nitro, phenyl or fenoxaprop.

Y in formulas (b) and (C) means O, S, SO, SO2or NR3(where R3represents a hydrogen atom, a C1-C12alkyl group, a C2-C8alkanoyloxy group or2-C13alkoxycarbonyl group). In formulas (b) and (C) Y preferably denotes O, S, SO, SO2or NR3(the de R 3represents a hydrogen atom or a C1-C12alkyl group).

As indicated above, the groups represented by formulas (a) - (e)are preferably groups represented by the formulas (f) to (j), respectively. Thus, Ar1and Ar2in the formula (1) together with the neighboring carbon atoms to which they are attached, may form a group represented by any of formulas (f) to (j). Among the groups represented by the formulas (f) to (j), preferred is a group represented by the formula (g).

In formulas (f) - (j) R4and R5may be the same or different. In formulas (f) - (j) R4and R5each means a hydrogen atom, a halogen atom, a C1-C12alkyl group, a C1-C8halogenating group1-C12alkoxygroup,1-C8halogenlampe, hydroxyl group, With1-C12alkylamino,2-C24dialkylamino,

With2-C12the cyclic amino group, the amino group, With2-C13alkoxycarbonyl group, carboxyl group, With2-C13alkylaminocarbonyl group3-C25dialkylaminoalkyl group3-C13cyclic aminocarbonyl group, karbamoilnuyu group, a cyano, a nitro-group, fenil the second group or fenoxaprop. In formulas (f) - (j) R4and R5each preferably denotes a hydrogen atom, a halogen atom, a C1-C12alkyl group or a C1-C8halogenating group, and most preferably a hydrogen atom or a halogen atom.

Y in formulas (f) - (j) means O, S, SO, SO2or NR3(where R3represents a hydrogen atom or a C1-C12alkyl group). Y preferably denotes O, S, SO or NH, and most preferably means Acting

Cycle In the formula (1)

Cycle In the formula (1) means benzene, pyrrole cycle, furan cycle, titanovyi cycle, imidazole cycle, pyrazol cycle, oxazolyl cycle, isoxazolyl cycle, thiazole cycle, isothiazol cycle, the pyridine cycle, pyrimidine cycle, pyrazinoic cycle or pyridazinyl cycle, each of which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, With1-C12alkyl, C1-C8halogenation,7-C26Uralkaliy,2-C8alkenylphenol,2-C8alkylamino,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl,1-C12alkylamino,2-C24dialkylamino, 2-C12cyclic amino, amino, C2-C13alkoxycarbonyl, carboxyl, C2-C13alkylaminocarbonyl,3-C25dialkylaminoalkyl,3-C13cyclic aminocarbonyl, carbamoyl,2-C8alkanoyloxy, cyano, nitro, phenyl and fenoxaprop.

The number of substituents in the loop In the formula (1) preferably is 1 or 0. Cycle In the formula (1) preferably means benzene, pyrrole cycle, furan cycle, the pyridine cycle, pyrimidine cycle or pyrazinoic cycle.

Preferred substituents in the loop In the formula (1) are the atoms of halogen, C1-C12alkyl, C1-C8halogenation,1-C12alkoxy, C1-C8halogenoalkane, hydroxyl, amino, carboxyl, carnemolla, cyano, nitro, phenyl and fenoxaprop. More preferred substituents in the loop In the formula (1) are the atoms of halogen, C1-C12alkyl, C1-C8halogenation,1-C12alkoxy, C1-C8halogenlampe.

n in the formula (1) means an integer from 1 to 10. Preferably n means an integer from 1 to 5; and more preferably n means an integer from 2 to 4.

p and q in the formula (1) may be the same or different and each Osnach is no integer 1 or 2. Preferably p is 1 and q is 2; or p is 2 and q is 1.

(The description of the substituents and the like)

The following explains the various substituents and the like, which are used in the present invention.

The term “C1-C12alkyl group” in this description means an alkyl group with straight or branched chain or cyclic alkyl group containing from 1 to 12 carbon atoms, and examples include methyl, ethyl, sawn, ISO-propyl, cyclopropyl, boutelou, tert-boutelou, pentelow, neopentylene, hexeline, tsiklogeksilnogo, heptylene, octillo, decile and dodecyloxy group. Preferred among them are1-C6alkyl group (particularly, methyl, ethyl and various groups).

The term “C2-C8alcoolica group” in this description means alkanoyloxy group with a straight or branched chain or cyclic alkanoyloxy group containing 2 to 8 carbon atoms, and its examples include acetyl, propionyl, cyclopropanecarbonyl, butyryloxy, isobutyryloxy, pencilling, isopentanol, capolino, annantalo, octillo and cyclohexanecarbonyl group. Preferred among them are2-C4alcoholnye group (in particular, acetyl and propylaniline group).

The term “C2-sub> 13alkoxycarbonyl group” in this description means a carbonyl group substituted by alkoxygroup straight or branched chain or cyclic alkoxygroup containing from 1 to 12 carbon atoms, and its examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, ventilatsioonile, hexyloxyphenol, octyloxybiphenyl, dezintoksikatsionnye and dodecyloxybenzoyl group. Preferred among them are2-C7alkoxycarbonyl group (in particular, methoxycarbonyl and ethoxycarbonyl group).

The term “C2-C13alkylaminocarbonyl group” in this description means aminocarbonyl group, substituted alkyl group with straight or branched chain or cyclic alkyl group containing from 1 to 12 carbon atoms, and its examples include methylaminoethanol, ethylaminoethanol, propylenecarbonate, isopropylaminocarbonyl, cyclopropanecarbonyl, butylaminoethyl, tert-butylaminoethyl, intramyocardially, neopentylglycol, hexylaniline, cyclohexyloxycarbonyloxy, octylaniline, decriminalising and dodecyldimethyl group. Preferred is considerable among them are 2-C7alkylaminocarbonyl group.

The term “C3-C25dialkylaminoalkyl group” in this description means aminocarbonyl group substituted by two identical or different alkyl groups with straight or branched chain or cyclic alkyl groups, each of which contains from 1 to 12 carbon atoms, and its examples include dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, dipropylenetriamine, diisopropylaminoethanol, dicyclopentadienyl, buyprednisoneonline, heptamethylnonane, dictionaryonline and didodecyldimethylammonium group. Preferred among them are3-C13dialkylaminoalkyl group.

The term “C3-C13cyclic aminocarbonyl group” in this description means a carbonyl group to which is attached a cyclic amino group containing from 2 to 12 carbon atoms, and its examples include 1-aziridinyl, 1-azetilirovanny, 1-pyrrolidinylcarbonyl, piperidinylcarbonyl, 1-perhydroanthracene, 1-perhydroanthracene, 1-perhydroanthracene, 1-imidazolidinecarboxamide, 1-pyrazolidinone, 1-piperazinylcarbonyl, 3-oxazolidinecarboxylate and morpholinoethyl the Yu group. Preferred among them are3-C7cyclic aminocarbonyl group.

The term “C1-C12alkoxygroup” in this description means alkoxygroup straight or branched chain or cyclic alkoxygroup containing from 1 to 12 carbon atoms, and examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropane, butoxy, tert-butoxy, pentyloxy, neopentylene, hexyloxy, cyclohexyloxy, heptyloxy, octyloxy, decyloxy and dodecyloxy. Preferred among them are1-C6alkoxygroup.

The term “C1-C8alkylthio group” in this description means alkylthio group with a straight or branched chain or cyclic alkylthio-group containing from 1 to 8 carbon atoms, and its examples include methylthio, ethylthio, propylthio, isopropylthio, cyclopropylethyl, butylthio, tert-butylthio, pentylthio, neopentyl, hexylthio, cyclohexylthio, octylthio group. Preferred among them are1-C4alkylthio group.

The term “C1-C8alkylsulfonyl group” in this description means sulfonyloxy group, substituted alkyl group with straight or branched chain or cyclic alkyl group containing from 1 to 8 carbon atoms, and its examples include methanesulfonyl, Athens shinelnuyu, propanesulfonyl, isopropylaniline, cyclopropanesulfonyl, butanesulfonyl, tert-butanesulfinamide, pentanesulfonic, neopentadactyla, hexanesulfonic, cyclohexanesulfonyl and octanesulfonyl group. Preferred among them are1-C4alkylsulfonyl group.

The term “C1-C8alkylsulfonyl group” in this description means sulfonyloxy group, substituted alkyl group with straight or branched chain or cyclic alkyl group containing from 1 to 8 carbon atoms, and its examples include methanesulfonyl, ethanolgasoline, propanesulfonyl, isopropylaniline, cyclopropanesulfonyl, butanesulfonyl, tert-butanesulfonyl, pentanesulfonic, neopentadactyla, hexanesulfonic, cyclohexanesulfonyl and octanesulfonyl group. Preferred among them are1-C4alkylsulfonyl group.

The term “halogen atom” in the present description means a fluorine atom, chlorine, bromine or iodine. Among them, preferred are a fluorine atom, chlorine or bromine.

The term “C1-C8halogenation group” in this description means an alkyl group with straight or branched chain or cyclic alkyl group containing from 1 is about 8 carbon atoms, which is substituted by 1 to 3 halogen atoms, and its examples include triptoreline, trichlorethylene, 2,2,2-triptoreline, 4,4,4-triptoreline, 3-chloropropylene and 4-bromatology group. Preferred among them are1-C4halogenoalkane group.

The term “C7-C26kalkilya group” in this description means an alkyl group with straight or branched chain or cyclic alkyl group containing from 1 to 8 carbon atoms, which is substituted by 1-3 phenyl groups or peredelnyj groups (these substituents may be the same or different), and its examples include benzyl, fenetylline, 4,4-diphenylbutane, 2-picollo, 3-picollo, 4-picollo or trityloxy group. Preferred among them are7-C13kalkilya group.

The term “C2-C8Alchemilla group” in this description means alkenylphenol group with a straight or branched chain or cyclic alkenylphenol group containing from 2 to 8 carbon atoms, and examples include the vinyl, allyl, propenyloxy, Isopropenyl, butenyloxy, cyclobutenyl, hexadienyl and octenidine group. Preferred among them are2-C4alkeneamine group.

The term “C2-C8Alchemilla group” in this description means the AET alkylamino group with a straight or branched chain or cyclic alkylamino group, containing from 2 to 8 carbon atoms, and its examples include etinilnoy, propenyloxy, pentangelo, hexanediol and activelow group. Preferred among them are2-C4alkyline group.

The term “C1-C8halogenoalkane group” in this description means alkoxygroup straight or branched chain or cyclic alkoxygroup containing from 1 to 8 carbon atoms, which is substituted, for example, 1 to 3 halogen atoms, and its examples include triptoreline, trichlormethane, 2,2,2-triptoreline, 4,4,4-triptoreline, 3 chloropropoxy and 4-bromobutoxy. Preferred among them are1-C4halogenlampe.

The term “C1-C12alkylamino” in this description means an amino group, a substituted alkyl group with straight or branched chain or cyclic alkyl group containing from 1 to 12 carbon atoms, and its examples include methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, tert-butylamino, pentylamine, neopentylene, hexylamino, cyclohexylamino, heptylamine, octylamine, decylamine, dodecylamine group. Preferred among them are1-C6alkylamino.

The term “C2-C24dialkylamino” in this description means an amino group, amestoy two alkyl groups are straight or branched chain or cyclic alkyl groups (which are the same or different), each of which contains from 1 to 12 carbon atoms, and its examples include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dicyclopropyl, butylparaben, heptylamine, dioctylamine and deadeningly. Preferred among them are2-C12dialkylamino.

The term “C2-C12cyclic amino group” herein means a cyclic amino group containing from 2 to 12 carbon atoms, and its examples include 1-aziridinyl, 1-azetidinone, 1-pyrrolidino, piperidino, 1-perhydroanthracene, 1-peligrosisimo, 1-perhydroanthracene, 1-imidazolidinyl, 1-pyrazolidinone, 1-piperazinilnom, 3-oxazolidinyl and morpholinopropan. Preferred among them are2-C6cyclic amino group.

The term “aryl group” in this specification means a group derived from aromatic hydrocarbon cycle by removing one hydrogen atom attached to the cycle, and its examples include phenyl, taillow or naftalina group. Preferred among them are phenyl and naftalina group.

The term “heteroaryl group” in this description means a monocyclic or condensed aromatic cycle, containing in the ring 1 to 4 atoms independently chosen from oxygen atoms, is a career or nitrogen, and its examples include pirollo, follow, thienyl, imidazolidinyl, pyrazolidine, oxazolidine, isooxazolyl, thiazolidine, isothiazolinone, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, pyridyloxy, pyrimidinyl, personilnya, pyridazinyl, indazolinone, benzofuranyl, benzothiazoline, benzoimidazolyl, benzoxazolyl, benzothiazolyl, pinolillo, izohinolinove, khinoksalinona, chinazolinei, talinolol and naphthyridinone group.

(Specific examples of compounds of cyclic amine of the present invention)

Specific examples of the compounds of cyclic amine of the present invention include, but are not limited to, the following connections.

Connection 1:

methyl-5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanoate;

Connection 2:

5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentane acid;

3 connection:

amide 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanol acids;

Compound 4:

5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentenenitrile;

Connection 5:

5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

Compound 6:

5-(3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

Soy is inania 7:

5-(3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

Compound 8:

2,2-diphenyl-5-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pentenenitrile;

Compound 9:

5-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2,2-diphenylpentane;

The connection 10:

5-(8-fluoro-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

The connection 11:

5-(8-chloro-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

The connection 12:

5-(8-methyl-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

The connection 13:

5-(8-methoxy-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

The connection 14:

2,2-diphenyl-5-(8-triptoreline-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)pentenenitrile;

The connection 15:

2-(4,4-diphenylbuta)-1,2,3,4-tetrahydro-[1]-benzofuro[3,2-c]pyridine;

The connection 16:

9-[3-(3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)propyl]-N-cantankerously;

The connection 17:

4-(3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylbutane;

The connection 18:

6-(3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylhexane.

Connection cyclic amine according to the present invention can provide a MES or its pharmaceutically acceptable salt. Hereinafter in this description, the term “connection on the present and the gain” includes connecting a cyclic amine of the present invention, his solvate or pharmaceutically acceptable salt.

In this specification, examples of MES include pharmaceutically acceptable solvate such as a hydrate. Upon contact with air or in the process of recrystallization of the compound cyclic amine of the present invention can absorb moisture. As a result, the connection can be covered with the absorbed water or can turn into a hydrate. MES-derived compounds of cyclic amine of the present invention also includes such a hydrate.

In this specification, examples of pharmaceutically acceptable salts may include acid additive salts such as inorganic salts (in particular, hydrochloride, hydrobromide, hydroiodide, sulfates, phosphates or nitrates), salts of sulfonic acids (in particular, methansulfonate, econsultancy, bansilalpet or p-toluensulfonate) and organic acid salts (in particular, oxalates, tartratami, citrates, maleate, succinate, acetates, benzoate, mandelate, ascorbate, lactate, gluconate or maleate); salts of amino acids such as salts of glycine, lysine salt, arginine salt, salt of ornithine, glutamate or aspartate; inorganic salts (in particular, lithium salt, sodium salt, potassium salts, calcium salts or magnesium salts) or ammonium salts; and salts with organic bases, such as salts of triethylamine, Sol is Diisopropylamine or salts cyclohexylamine. Among them are suitable hydrochloride, hydrobromide, phosphates, methanesulfonate, p-toluensulfonate, oxalates, tartratami, citrates, acetates, lactates, glutamate, aspartate, sodium salt, potassium salt, ammonium salt or salt of triethylamine. Preferably used salts of sodium, hydrochloride or sulfates; more preferably used hydrochloride. It should be noted that the compounds of the present invention include such compounds, which in the body during metabolism into other compounds of the present invention, i.e. the so-called prodrugs.

Connection cyclic amine of the present invention may have isomers such as CIS - and TRANS-isomers. Connection cyclic amine of the present invention includes these isomers as well as mixtures, in which the connection of the cyclic amine and such isomers are contained in any ratio. The connection of the cyclic amine may include asymmetric center. In this case, there can be various optical isomers or different configurations. Thus, the connection of the present invention may exist in different optically active substances, (+) and (-), as well as racemic modifications, or (±) mixtures. In that case, if the connection of the present invention includes two or more Asim is etnicheskih centers, it may also be the diastereomers obtained from the individual optical isomers. Connection cyclic amine of the present invention includes all of these types in any ratio. The diastereomers can be separated by methods well known to experts in the art, such as fractional crystallization; and optically active substances can be obtained using methods of organic chemistry, the use of which is well known for achieving these objectives.

Methods for obtaining compounds of the present invention

The compound of the present invention can be obtained using a known organic chemistry methods. For example, the compound of the present invention can be obtained by any of the means described in the following schemes reactions.

On the schemes of reactions 1 through 5 below, the values of Ar1, Ar2, n, X, p, q, and the cycle described above; R6means1-C12alkyl group, a C1-C12alkoxygroup, the amino group, With1-C12alkylamino,2-C24dialkylamino or1-C12the cyclic amino group; R7means ordinary protective group for alcohols; and Z means a halogen atom (such as chlorine atom, bromine or iodine) or a leaving group (such as methanesulfonate, b is solarforce or triftormetilfullerenov).

The scheme of reactions 1

The following describes the method of obtaining the compounds of the present invention for example, the following scheme of reactions 1. This method is a method of producing compound (8) according to the present invention from the compound (2).

Stage 1

In stage 1 carry out the substitution of the hydroxyl group of the compound (2) a carboxyl group, and the result is the compound (3). The compound (2) can be converted into compound (3), for example, by the way, opened in Takahashi Y. et al. Chemistry letters, 1985, 1733-1734. The compound (2) is a known compound or compound, which can easily be synthesized from known compounds.

Stage 2

In stage 2 conduct the esterification or amidation of the compound (3) and the result is a connection (4). As for the method of esterification in stage 2, it can be applied to terms that are used in conventional esterification of carboxylic acids. For example, the esterification can be carried out according to the method described in T.W.Greene and P.G..Wuts, Protective Groups in Organic Synthesis. As for the method of amidation in stage 2, it can be applied to terms that are used in conventional amidation of carboxylic acid. Can be used, for example, a method in which the carboxylic acid is converted into gelegenheid carboxylic acid, the th as the acid chloride of carboxylic acid or bromohydrin carboxylic acid, and then interact with the amine; the way in which a mixed acid anhydride derived from a carboxylic acid and chlorocarbonate etc. interacts with the amine; the way in which the carboxylic acid is converted into an active ester such as 1-benzotriazolyl ether or Succinimidyl ether, and then injected into interaction with the amine; or a method in which a carboxylic acid reacts with an amine in the presence of a dehydrating condensing agent. All of these reactions may be conducted in an inert solvent in the presence or in the absence of base.

In the case when stage 2 use a dehydrating condensing agent, its examples include the hydrochloride of 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide, dicyclohexylcarbodiimide, diphenylphosphoryl and carbonyldiimidazole. If necessary, can be added to the activator, such as 1-hydroxybenzotriazole or hydroxysuccinimide.

In the case when stage 2 use basis, its examples include organic amines such as pyridine, triethylamine or diisopropylethylamine; and inorganic bases such as potassium carbonate, sodium bicarbonate and sodium hydroxide.

Examples of the inert solvent used in stage 2 include alcohols such as methanol, ethanol or isopropanol; simple is e esters, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

Stage 3

Stage 3 is a stage on which interact compound (4) with compound (5) in an inert solvent in the presence of a base, and then removing the protective group R7and thus obtained compound (6). The compound (5) is a known compound or compound, which can easily be synthesized from known compounds. R7in the compound (5) is a conventional protecting group for alcohols, and its examples include tetrahydropyranyloxy, methoxymethyl, benzyl, p-methoxybenzyloxy, trailing, trimethylsilyloxy, tert-butyldimethylsilyloxy, acetyl and benzoyloxy group.

Examples of the substrate that is used in stage 3 include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydride or potassium hydride; amides of metals, such as sodium amide, bis(trimethylsilyl) lithium or diisopropylamide lithium; an alcoholate such as sodium methoxide or tert-piperonyl potassium; and organic bases such as triethylamine Il is pyridine.

Examples of the inert solvent used in stage 3 include alcohols such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

Removing the protective group at the stage 3 can be made by methods well known from the field of synthetic organic chemistry. For example, it is possible to apply the method described in T.W.Greene and P.G..Wuts, Protective Groups in Organic Synthesis " or " John Wiley and Sons: J.F.W.McOmis, Protective Groups in Organic Chemistry, Plenum Press.

Stage 4

In stage 4 conduct the condensation reaction between the compound (6) and compound (7) and thus obtained compound (8) according to the present invention. Compound 7 is a known compound or compound, which can easily be synthesized from known compounds according to, for example, the methods described in Cattanach et al., J. Chem. Soc.(C), (1971), 53-60; Capps et al., J. Am. Chem. Soc., (1953), 75, 697-699; Jaen et al. J. Heterocycl. Chem., (1987), 24, 1317-1319; and Campaigne et al., J. Heterocycl. Chem., (1979), 16(7), 1321-1324.

As for the condensation reaction in stage 4, it is possible to apply, for example, a method in which the compound (6) interacts with the halogenation of agent is or sulfanilamide agent in an inert solvent in the presence or in the absence of the base and thereby converts the hydroxyl group into an appropriate leaving group, and then to carry out the condensation reaction in an inert solvent in the presence or in the absence of base. If necessary, the reaction mixture you can add sodium bromide, potassium iodide, etc.

In the case when stage 4 is used halogenation agent, its examples include thionyl chloride, thienylboronic, phosphorylchloride, pentachloride phosphorus and carbon tetrachloride-triphenylphosphine.

In the case when stage 4 is used sulfonyloxy agent, its examples include methanesulfonate, benzosulphochloride, anhydride triftormetilfullerenov acid and N-phenyl-bis(triptoreline).

In the case when stage 4 apply the Foundation, its examples include organic amines, such as pyridine or triethylamine; and inorganic bases such as potassium carbonate, sodium bicarbonate or sodium hydroxide.

Examples of the inert solvent used in stage 4 include alcohols such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

Another option of conducting the study is 4-1

Alternatively, compound (8) can be also obtained by the interaction of the compound (6) with the phosphorus compound (such as triphenylphosphine or tributylphosphine) and diethylazodicarboxylate, di-tert-utilisability, etc. in an inert solvent. Examples of the inert solvent include ethers such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile and mixtures thereof.

Another option stage 4-2

Alternatively, compound (8) can also be obtained by oxidation in an inert solvent hydroxyl group in the compound (6) for its conversion into the aldehyde, and then the obtained compound (6) enter into interaction with the reducing agent in an inert solvent in the presence or in the absence of acid. The oxidation can be performed in the usual way, used for the oxidation of alcohol to aldehyde, in particular, the way in which applied sulfoxide and an activator (such as oxalicacid, N-chlorosuccinimide or dichlorocarbanilide); the method using perruthenate Tetra-n-Propylamine (VII) and N-methylmorpholine; SPO is trained, where used iodic acid, such as reagent dess-Martin (1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3-(1H)-one). For example, the oxidation can be carried out according to the method described in S.D.Burke and R.L.Danheiser, Oxidizing and Reducing Agents. Examples of acid, which is used at this stage include inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or organic acids such as p-toluensulfonate acid, methanesulfonate acid, triperoxonane acid, formic acid or acetic acid. Examples of the reducing agent, which is used at this stage include boron-containing reducing agents such as sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium or lithium borohydride. Examples of the inert solvent used at this stage include ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile and mixtures thereof.

The conversion of the substituent in the compound of the present invention - 1

By transformation of the substituent in the compound according to the present image is the shadow using known methods, you can obtain another compound of the present invention. For example, in the case when R1in the formula (1) represents alkoxycarbonyl group in the compound of the present invention, it is possible to obtain another compound of the present invention, in which R1in the formula (1) is a carboxyl group, by transformation alkoxycarbonyl group in the carboxyl group using a known method.

With the aim of turning alkoxycarbonyl group in R1in the formula (1) in the carboxyl group, the compound of the present invention, in which R1in the formula (1) represents alkoxycarbonyl group, it is possible to hydrolyze using acid or base. Examples of the acid that is used when carrying out the hydrolysis include inorganic acids such as hydrochloric acid, Hydrobromic acid, dilute sulfuric acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as triperoxonane acid or triftormetilfullerenov acid. Examples of the substrate that is used when carrying out the hydrolysis include inorganic bases such as sodium hydroxide or potassium hydroxide; and organic bases such as tert-butoxylate.

The conversion of the substituent in the compound of the present invention - 2

In addition, that case is, when R1in the formula (1) is a carboxyl group in the compound of the present invention, it is possible to obtain another compound of the present invention, in which R1in the formula (1) represents carbamoyl, alkylaminocarbonyl, dialkylaminoalkyl or cyclic aminocarbonyl group by conversion of the carboxyl group in carbamoyl, alkylaminocarbonyl, dialkylaminoalkyl or cyclic aminocarbonyl group using a known method.

For the conversion of the carboxyl group in R1in the formula (1) in carbamoyl, alkylaminocarbonyl, dialkylaminoalkyl or cyclic aminocarbonyl group of the compound of the present invention, in which R1in the formula (1) means a carboxyl group, can be lidirovat. As a way amidation you can apply the usual method of amidation of carboxylic acids; in particular, it is possible to use the method described in stage 2.

The scheme of reactions 2

The following describes the method of obtaining the compounds of the present invention for example, the following scheme of reactions 2. This method is a method of producing compound (10) of the present invention by transformation carbamoyl group in the compound (9) of the present invention in the cyano.

Stage 5

Briefly, it is possible to obtain a connection (10) of the present invention by the interaction of the compound (9) with a dehydrating agent in an inert solvent in the presence or in the absence of base.

In the case when stage 5 apply the Foundation, its examples include organic amines such as pyridine, triethylamine or diisopropylethylamine; and inorganic bases such as potassium carbonate or sodium bicarbonate.

Examples of the dehydrating agent used in stage 5, include triperoxonane anhydride, the anhydride triftormetilfullerenov acid, the anhydride of benzoic acid, thionyl chloride, phosphorylchloride or phosphorous pentoxide.

Examples of the inert solvent used in stage 5, include ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile and mixtures thereof.

The reaction scheme 3

The following describes the method for obtaining compounds of the present invention, the following reaction scheme 3. This method is a method of producing compound (10) of the present invention from the compound (2) ilisiginde (4).

Stage 6

Stage 6 carried out by condensation reaction between compound (2) and the metal cyanide such as sodium cyanide, potassium cyanide or copper cyanide) and the result is a connection (11).

The reaction of condensation on the stage 6 can be realized, for example, by the method in which the compound (2) interacts with a halogenation agent, or sulfonium agent in an inert solvent in the presence or in the absence of a base and a hydroxyl group is converted into an appropriate leaving group, and then carry out the condensation reaction in an inert solvent in the presence or in the absence of base. If necessary, the reaction mixture you can add sodium bromide, potassium iodide, etc.

In the case when stage 6 is used halogenation agent, its examples include thionyl chloride, thienylboronic, phosphorylchloride, pentachloride phosphorus and carbon tetrachloride-triphenylphosphine.

In the case when stage 6 is used sulfonyloxy agent, its examples include methanesulfonate, benzosulphochloride, anhydride triftormetilfullerenov acid and N-phenyl-bis(triptoreline).

In the case when stage 6 apply the Foundation, its examples include organic amines such as pyridine, triethylamine or Diisopropylamine is n; and inorganic bases such as potassium carbonate, sodium bicarbonate or sodium hydroxide.

Examples of the inert solvent used in stage 6, include alcohols such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

Stage 7

Stage 7 represents the stage at which the compound (4), where R6= NH2make the connection (11). At this stage you can use the same conditions as described for stage 5 in reaction scheme 2.

Stage 8

Stage 8 is a stage in which the compound (11) is converted into a compound (12). At this stage, can be used in conditions that are listed for stage 3 in the reaction scheme 1 (in particular, the conditions disclosed in J. Med. Chem., 1985, 1621-28).

Stage 9

On Stage 9 get a connection (10) of the present invention by the interaction of the compound (12) with compound (7). At this stage you can use the same conditions described for stage 4 in the reaction scheme 1.

The reaction scheme 4

The following describes a method of obtaining a connection is in the present invention, the following reaction scheme 4. This method is a method of obtaining compound (13) of the present invention from compound (8).

Stage 10

On stage 10 receives the connection (14) the interaction of the compound (13) with compound (7) in an inert solvent in the presence or in the absence of base. The compound (13) is a known compound or compound, which can easily be synthesized from known compounds.

In the case when the stage 10 is applied to the base, its examples include organic amines such as pyridine, triethylamine or diisopropylethylamine; and inorganic bases such as potassium carbonate, sodium bicarbonate or sodium hydroxide.

Examples of the inert solvent used in stage 10, include alcohols such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

Stage 11

On stage 11 receives the connection (15) the interaction of the compound (14) with a lithium reagent or Grignard reagent (16) in inert the second solvent.

Examples of the inert solvent used in stage 10, include alcohols such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; halogenated hydrocarbons such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

In that case, if at the stage 11 is applied to the lithium reagent, the reagent represented by the formula Ar1-Li (where the value of Ar1listed above). Specific examples of the lithium reagent include finality, 4-formanilide, 3-formanilide, 2-formanilide, 4-methylphenylethyl, 3,4-dichlorophenylethyl, 4-methoxyaniline and 4-pyridylethyl.

In that case, if at the stage 11 is applied to the Grignard reagent, the reagent represented by the formula Ar1-MgW (where the value of Ar1above, and W stands for a chlorine atom, bromine or iodine). Specific examples of Grignard reagents include phenylmagnesium, 4-performancebased, 3-performanceupload, 2-performancemode, 4-methylphenylamine, 3,4-dichlorophenylamino, 4-methoxyacetanilide and 4-pyridylmethylamine.

Stage 12

On stage 12 connection (15) is converted into a compound (8) is really the image the structure. At this stage you can use the same conditions as described for stages 1 and 2 in the reaction scheme 1.

The reaction scheme 5

The following describes the method for obtaining compounds of the present invention, the following reaction scheme 5. This method is a method of obtaining compound (17) according to the present invention by the condensation reaction between the compound (16) and compound (7).

Stage 13

Briefly, it is possible to obtain a connection (17) of the present invention by the condensation reaction between the compound (16) and compound (7) in an inert solvent in the presence or in the absence of base. Compound (16) is a known compound or compound, which can easily be synthesized from known compounds.

In the case when the stage 13 is applied to the base, its examples include organic amines such as pyridine, triethylamine or diisopropylethylamine; and inorganic bases such as potassium carbonate, sodium bicarbonate or sodium hydroxide.

Examples of the inert solvent used in stage 13, include alcohols such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as toluene or benzene; galagedera the hydrocarbons, such as chloroform or dichloromethane; amides, such as dimethylformamide or N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile, water and mixtures thereof.

On each of the above stages the number of compounds and solvents used in the implementation of the reaction, time of reaction, temperature and pressure in the reaction system, etc. can be selected depending on the stage. In addition, compounds obtained at each stage, can be cleaned using conventional cleaning methods, such as recrystallization, re-precipitation or purification using chromatography.

The use of compounds of the present invention as a medicine

As shown in the examples below, the compound of the present invention has a potent inhibitory effect on the binding α2-adrenergic receptors and in the preferred embodiment of the present invention shows selectivity for subtypes α2/α2. Thus, the connection of the present invention can be effectively used for the prevention or treatment of diseases which can be attributed α2-adrenergic receptors (in particular, depression, anxiety and schizophrenia). More specifically, the compound of the present invention can be used as a drug, this ka is the inhibitor binding α2-adrenergic receptors or as a preventive or therapeutic agent from the above diseases. The compound of the present invention can be entered individually or in combination with pharmaceutically or pharmacologically acceptable carriers or diluents. In the case where the connection of the present invention is administered as an inhibitor of binding α2-adrenergic receptors or as a preventive or therapeutic agent from the above diseases, the compound of the present invention can treatment be administered orally or parenterally. Alternatively, the compound of the present invention can be administered orally or parenterally after cooking preparations containing specified compound as an active ingredient. Parenteral administration can be accomplished by intravenous injection.

In that case, when the above drugs are administered orally, the compound of the present invention can be introduced in the form of granules, capsules, tablets, medical drops, lozenges, hard candies, powders, aerosols and the like by mixing the compounds of the present invention with diluents, excipients, disintegrants, binders, lubricants, antioxidants, coatings, surfactants, plasticizers, paints the representatives, the perfumes/fragrances, etc. In such preparations may be added to the appropriate sweeteners or flavors. In that case, when the above drugs are administered parenterally, the compound of the present invention can be introduced in the form of injections, drip enema, eye drops, creams, plasters, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, etc. Preparations of the compounds of the present invention can be prepared in the usual way.

Examples of excipients that can be used in these preparations include mannitol, xylitol, sorbitol, glucose, white sugar, lactose, crystalline cellulose, a mixture of crystalline cellulose and sodium carboxymethyl cellulose, calcium phosphate, wheat starch, rice starch, corn starch, potato starch, natrocarbonatite, dextrin, α-cyclodextrin, β-cyclodextrin, carboxyvinyl polymer, light silicic anhydride, titanium oxide, alumosilicate magnesium, polyethylene glycol and triglyceride fatty acids with carbon chain of medium length.

Examples of disintegrants that can be used in these preparations include nitrosamino hydroxypropylcellulose, carboxymethylcellulose, calcixerollic, sodium carboxymethyl cellulose, nitrocresols/type (actisol), starch, crystalline cellulose, hydroxypropylmethyl and partially Pregelatinised starch.

Examples of binders which can be used in these preparations include methylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, gum Arabic, ethylcellulose, polyvinyl alcohol, pullulan, Pregelatinised starch, agar, resin tragant, sodium alginate and propylene glycol alginate.

Examples of lubricants that can be used in these preparations include stearic acid, magnesium stearate, calcium stearate, polyxystra, cetanol, talc, hydrogenated oil, fatty acid sucrose, dimethylpolysiloxane, microcrystalline wax, beeswax and white beeswax.

Examples of antioxidants that can be used in these preparations include dibutylaminoethanol (EIT), propylgallate, butylhydroxyanisole (BHA), α-tocopherol and citric acid.

Examples of coatings that can be used in these preparations include hypromellose, hydroxypropylcellulose, methylcellulose, ethylcellulose, phthalate of hydroxypropylmethylcellulose, acetate-succinate of hydroxypropylmethylcellulose, carboximetilzellulozu, acetate-phthalate cellulose, diethylaminoacetate polyvinylacetal is, the copolymer aminoalkylsilane, acetate-succinate of hydroxypropylmethylcellulose, a copolymer of methacrylate, acetate-trimellitate cellulose (CAT), the phthalate of polyvinylacetal and shellac.

Examples of surfactants that can be used in these preparations include polyoxyethylene gidrirovannoe castor oil, glycerol monostearate, monostearate sorbitan, monopalmitate sorbitan, monolaurate sorbitan, a block copolymer of polyoxyethylene and polyoxypropylene, Polysorbate, sodium lauryl sulfate, macrogol and an ester of a fatty acid sucrose.

Examples of plasticizers that can be used in these preparations include triethylcitrate, triacetin and cetanol. Examples of dyes that can be used in these preparations include tar pigments and titanium oxide. Examples of perfumes/fragrances that can be used in these preparations include citric acid, adipic acid, ascorbic acid and menthol.

In the case where the connection of the present invention is administered orally, the compound can be entered from 1 to 6 times a day, for example, with a dose of from 1 to 2000 mg per administration. In the case where the connection of the present invention is administered parenterally, the connection can be entered from 1 to 6 times a day, for example, with a dose of from 0.1 to 500 MGSA one time. The dose of the compounds of the present invention may be appropriately selected depending on the age, body weight and symptoms of the patient, the treatment is performed.

Examples, reference examples and examples test

Further, the present invention is described in detail with reference to the following reference examples, examples and sample tests. However, the present invention these examples are not limited.

Reference example 1

Synthesis of bis(4-forfinal)methanol

A solution of 4-ferramenta ((Jn 19 : 26 g) in tetrahydrofuran (280 ml) is cooled to minus 78°C and to it under stirring for 10 min or longer added dropwise n-utility (2,66 M in hexane solution; 42 ml). The reaction mixture was stirred for 1 h, maintaining the specified temperature. Then to the mixture with stirring for 10 min or more is added dropwise 4-forbindelse (12,42 g). The reaction mixture was stirred for 2 h, maintaining the specified temperature. Then to the reaction mixture are added a saturated aqueous solution of ammonium chloride and allow the mixture to warm to room temperature. The tetrahydrofuran is removed under reduced pressure and the resulting residue extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried soo what hatom sodium and concentrate under reduced pressure. The resulting residue is purified column chromatography on silica gel and get listed in the name of the connection (of 8.28 g).

Reference example 2

Synthesis of 2,2-bis(4-forfinal)acetic acid

To concentrated sulfuric acid (440 ml) in a bath with ice slowly add bis(4-forfinal)methanol (10,97 g)obtained in reference example 1. To the mixture dropwise over 50 min add formic acid (120 ml). Then the reaction mixture is allowed to warm to room temperature, left for 17 h, poured on ice (5 l) and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated under reduced pressure. The resulting residue is triturated in hexane and get the target connection (6,36 g).

Reference example 3

Synthesis of methyl 2,2-bis(4-forfinal)-5-hydroxydecanoate

(1) Concentrated sulfuric acid (1.5 ml) are added to 2,2-bis(4-forfinal)acetic acid (6.2 g; obtained in reference example 2) in methanol (60 ml) and stirred for 30 minutes the mixture was poured on ice and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried with sodium sulfate, concentrated under reduced pressure and dried, obtaining methyl 2,2-bis(4-forfinal)ACE is at (6,53 g).

(2) Tetrahydrofuran (3 ml) is added to sodium hydride (0,60 g) and get the suspension. To the resulting suspension at room temperature under stirring is added dropwise methyl-2,2-bis(4-forfinal)acetate (3,93 g; obtained above in stage (1)) in dimethyl sulfoxide (15 ml). Then to the resulting mixture at room temperature under stirring is added dropwise 2-(3-bromopropane)tetrahydro-2H-Piran (at 3.35 g) in dimethyl sulfoxide (10 ml). The resulting mixture was stirred for 1 h To the reaction mixture an aqueous solution of ammonium chloride and extracted with a mixture of ethyl acetate. The organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and obtain methyl 2,2-bis(4-forfinal)-5-(2-tetrahydropyranyloxy)pentanoate (4,45 g).

(3) Methanol (25 ml) is added to methyl 2,2-bis(4-forfinal)-5-(2-tetrahydropyranyloxy)pentanoate (Android 4.04 g)obtained above in stage (2), and receive a solution, to which is added p-toluensulfonate acid (0.50 g), the mixture is then stirred for 3 hours To the resulting reaction mixture is added saturated aqueous sodium hydrogen carbonate solution (5 ml)and then evaporated mixture under reduced pressure. To the residue water is added (5 ml) and extracted with ethyl acetate. The organic layer is dried soo what hatom sodium and concentrated under reduced pressure, getting listed in the title compound (3,05 g).

Example 1

Synthesis of methyl 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanoate (compound 1)

(1) Tetrahydrofuran (20 ml) is added to methyl 2,2-bis(4-forfinal)-5-hydroxypentanal (3.0 g)obtained in reference example 3, and receive a solution to which was added with stirring tetrabromide carbon (3,14 g). The resulting mixture was stirred for 5 minutes Then add triphenylphosphine (2,48 g) and stirred for 30 minutes, the Reaction mixture was concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and get methyl-2,2-bis(4-forfinal)-5-bromopentanoate (2,46 g).

(2) methyl-2,2-bis(4-forfinal)-5-bromopentanoate (1,72 g)obtained above in stage (1), add isopropanol (7 ml), diisopropylethylamine (1.45 g) and hydrochloride 1,2,3,4-tetrahydro-benzo[4,5]furo[3,2-c]pyridine (0,94 g)and then stirred at 110°C for 15 hours To the resulting mixture is added a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and get the specified name with the unity (1.77 g).

Receive an NMR spectrum of the synthesized compounds. The following results are obtained.

1H-NMR (300 MHz, CDCl3d 7,42-7,39 (m, 1H) 7,34-7,31 (m, 1H) 7,26-to 7.18 (m, 6H) 7,02-to 6.95 (m, 4H) of 3.69 (s, 3H) 3,49 (s, 2H) 2,82-2,79 (users, 4H) 2,58 (t,J= to 7.15 Hz, 2H) 2,44-2,39 (m, 2H) 1,39 is 1.34 (m, 2H).

Example 2

Synthesis of the hydrochloride of 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanol acid (compound 2)

Concentrated hydrochloric acid (15 ml) was added to methyl 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanoate (1.0 g)obtained in example 1 and the resulting mixture is stirred at a temperature of 150°C for 3.5 hours the mixture left at room temperature to cool and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and dissolved in methanol (5 ml). To the resulting solution was added 4 mol/l solution of hydrogen chloride in ethyl acetate (1.5 ml). The mixture is stirred and then concentrated under reduced pressure. The resulting residue is crystallized from ethyl acetate and thus receive specified in the title compound (0.18 g).

Example 3

Synthesis of amide hydrochloride 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanol acid (compound 3)

(1) dimetilformamid (2 ml) are added to the hydrochloride 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanol acid (0.3 g), synthesized in example 2 and receive a suspension. To this suspension was added 1-hydroxybenzotriazole (0.15 g) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.15 g). The mixture was stir at room temperature for 15 minutes Then added to the mixture of 28%aqueous ammonia solution and stirred for another 1 h, the Reaction mixture was poured into ice water and the precipitated precipitate was separated by filtration. The resulting crude crystals are purified column chromatography on silica gel and thus receive amide 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanol acid (0,19 g).

(2) ethyl Acetate (2 ml) is added to the amide 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentanol acid (0.06 g)obtained above in stage (1)to prepare a solution. To the resulting solution was added 4 mol/l solution of hydrogen chloride in ethyl acetate (0,07 ml). The mixture is stirred and then concentrated under reduced pressure. The resulting residue is crystallized from diethyl ether and thus receive specified in the title compound (0,017 g).

Example 4

Synthesis of the hydrochloride of 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-bis(4-forfinal)pentenenitrile (compound 4)

1,4-Dioxane (2.5 ml) and pyridine (0.04 g) are added to amide 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,-bis(4-forfinal)pentanol acid (0.1 g), obtained in example 3. The mixture is cooled to 0°C in a bath with ice, and thereto is added dropwise with stirring triperoxonane anhydride (0.05 g). Then the mixture for 30 min, allowed to warm to room temperature and stirred for 15 minutes the reaction mixture is poured into ice water and extracted with chloroform. The organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel and dissolved in ethyl acetate (3 ml), to obtain the solution. Added 4 mol/l solution of hydrogen chloride in ethyl acetate (0.1 ml), stirred and concentrated under reduced pressure. The resulting residue is crystallized from diethyl ether and thus receive specified in the title compound (0,134 g).

Example 5

Synthesis of the hydrochloride of 5-(3,4-dihydro[1]benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane

5-Bromo-2,2-diphenylpentane (1.08 g) and hydrochloride 1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridine (0,72 g) is suspended in methanol (1,72 ml). To the resulting suspension add diisopropylethylamine (1,11 g), and then with stirring, boil the mixture under reflux for 40 hours, the Reaction mixture was concentrated under reduced pressure. The residue cleaned the Ute column chromatography on silica gel and dissolved in ethanol (5 ml), to obtain the solution. To the resulting solution was added 4 mol/l solution of hydrogen chloride in ethyl acetate (0,73 ml), then stirred and concentrated under reduced pressure. The resulting residue is crystallized from ethanol (4 ml) and thus receive specified in the title compound (0.85 grams).

Examples 6-18

Connection from 6 to 18 or their salts (see table 1 hereinafter) are obtained analogously to the method described in example 5. In particular, synthesize the following compounds.

Compound 6:

5-(3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

Compound 7:

5-(3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane (hydrochloride);

Compound 8:

2,2-diphenyl-5-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pentanethiol (hydrochloride);

Compound 9:

5-(5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2,2-diphenylpentane (hydrochloride);

The connection 10:

5-(8-fluoro-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane;

The connection 11:

5-(8-chloro-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane (hydrochloride);

The connection 12:

5-(8-methyl-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane (hydrochloride);

The connection 13:

5-(8-methoxy-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylpentane (hydrochloride);

The connection 14:

22-diphenyl-5-(8-triptoreline-3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)pentenenitrile (hydrochloride);

The connection 15:

2-(4,4-diphenylbuta)-1,2,3,4-tetrahydro-[1]-benzofuro[3,2-c]pyridine (hydrochloride);

The connection 16:

9-[3-(3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)propyl]-N-xanthochromia (hydrochloride);

The connection 17:

4-(3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylbutane;

The connection 18:

6-(3,4-dihydro-[1]-benzofuro[3,2-c]pyridine-2(1H)-yl)-2,2-diphenylhexane.

Structure, physical properties, etc. of the compounds obtained in the individual examples given below in table 1.

Example test 1. The experiment on the binding of α2-adrenergic receptors

(1) Experiment on linking α2-adrenergic receptors

This experiment is carried out on the improved technique described Uhlen et al., Journal of Pharmacology and Experimental Therapeutics (1994), 1558-1565. In brief, cells COS-1 expressing α2-adrenergic receptors person, homogenized in 50 mm buffer Tris-HCl (pH 7.4)containing hydrochloride 12.5 mm magnesium and 1 mm EDTU. The obtained homogenate was centrifuged twice at 48000 x g for 20 min at 4°C. the Precipitate is suspended in 50 mm buffer Tris-HCl (pH 7.4)containing hydrochloride 12.5 mm magnesium and 1 mm EDTU, and get a protein concentration of 150 μg/ml of the above suspension use in experiments on the binding as a sample of untreated membrane. The sample is untreated membranes (0.5 ml, 75 µg of protein) for 60 min interacts with [3N] MC (final concentration of 0.08 nm) at 25°C. Upon completion of the reaction, the reaction mixture is filtered under vacuum on the filter, GF/B glass fibre pre for 2 h, incubated in 0.3%solution of polyethylenimine, while for experiments on the binding used by the harvester cells. The filter is placed in a glass test tube containing 8 ml of Aquasol 2, and the radioactivity on the filter is measured by liquid scintillation counter. The amount of binding in the presence of 10 μm rauwolscine take for nonspecific binding. The value obtained by subtracting a value of nonspecific binding from total binding in the absence of 10 μm rauwolscine, accept for specific binding. Each of the test compounds dissolved in 100%dimethyl sulfoxide and added to the sample membrane simultaneously with [3N] MCK. The values of the IC50calculated from inhibition curves in the concentration range from 0.1 nm to 1 μm. The results are shown in table 2.

(1) Experiment on linking α2-adrenergic receptors

This experiment is carried out on the improved technique described Uhlen et al., Journal of Pharmacology and Experimental Therapeutics (1994), 1558-1565. In brief, cells COS-7 expressing α2-adren the receptor human homogenized in 50 mm buffer Tris-HCl (pH 7.4)containing hydrochloride 12.5 mm magnesium and 1 mm EDTU. The obtained homogenate was centrifuged twice at 48000 × g for 20 min at 4°C. the Precipitate is suspended in 50 mm buffer Tris-HCl (pH 7.4)containing hydrochloride 12.5 mm magnesium and 1 mm EDTU, and get the protein concentration of 200 μg/ml of the above suspension use in experiments on the binding as a sample of untreated membrane. A sample of the untreated membrane (0.1 ml, 20 μg of protein, the volume of the reaction mixture, 0.2 ml) for 60 min interacts with [3N] MC (final concentration 1 nm) at 25°C. Upon completion of the reaction, the reaction mixture is filtered under vacuum on the filter GF/C glass fiber, which is roughly within 2 hours incubated in 0.3%solution of polyethylenimine using harvester Filtermate cell. On the tablet add Microscinti-0 (40 μl) and measure the radioactivity using a counter Top Count (Perkin Elmer). The amount of binding in the presence of 10 μm rauwolscine take for nonspecific binding. The value obtained by subtracting a value of nonspecific binding from total binding in the absence of 10 μm rauwolscine, accept for specific binding. Each of the test compounds dissolved in 100%DMSO and added to the sample membrane simultaneously with [3N] MCK. The values of the IC50calculated from inhibition curves in the concentration range from 0.1 nm to 10 μm. The results are shown in table 2.

Table 2

As shown in tables 1 and 2, the compound of the present invention has a selective inhibitory effect on the binding α2-adrenergic receptors.

Industrial applicability

The compound of the present invention is chemically and pharmacologically applicable as a new connection, a cyclic amine, MES or its pharmaceutically acceptable salt.

Because the connection of the present invention has an inhibitory action, especially against binding α2-adrenergic receptors, the compound can be effectively used as a preventive or therapeutic agent for disorders that can be attributed α2-adrenergic receptors, in particular depression, anxiety or schizophrenia.

1. Connection cyclic amine represented by the following formula (1), or its pharmaceutically acceptable salt

where X is O, S, NR2(where R2represents a hydrogen atom, a C1-C12alkyl group);
when X is O or S, R1represents a hydrogen atom, a cyano, a carboxyl group, a C2-C13alkoxycarbonyl group or karbamoilnuyu group;
and when X is NR2(g is e, the value of R 2above), R1represents cyano;
Ar1and Ar2the same or different and each represents an aryl group which may be substituted by 1-3 halogen atoms;
or Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form a group represented by the following formula (b):

(where S cycle and the cycle T of the same and every means benzene; Y means O);
cycle means In benzene which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, C1-C12alkyl, C1-C8halogenation, C1-C12alkoxy, C1-C8halogenlampe;
n means an integer from 1 to 10; and
p and q are the same or different and each denotes an integer of 1 or 2.

2. Connection cyclic amine or its pharmaceutically acceptable salt according to claim 1,
where X is O or S;
R1means a hydrogen atom, a cyano, a carboxyl group, a C2-C13alkoxycarbonyl group or karbamoilnuyu group;
Ar1and Ar2the same or different and each means a phenyl group or naftalina group, each of which may be substituted by 1-3 halogen atoms;
or Ar1and Ar2together with the neighbouring atoms is carbon, to which they are attached, form a group represented by any of formula (g):

(where R4and R5each means a hydrogen atom; Y represents O);
cycle means In benzene which may be substituted by 1-3 substituents, independently selected from the group comprising halogen atoms, C1-C12alkyl, C1-C8halogenation, C1-C12alkoxy, C1-C8halogenlampe;
n means an integer from 1 to 5; and
p and q are different and each denotes an integer of 1 or 2.

3. Connection cyclic amine or its pharmaceutically acceptable salt according to claim 1,
where X is NR2(where R2represents a hydrogen atom or a C1-C12alkyl group);
R1means cyano;
Ar1and Ar2the same or different and each means a phenyl group or naftalina group, each of which may be substituted by 1-3 halogen atoms; or Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form a group represented by the formula (g):

(where R4and R5each means a hydrogen atom; a Y means O);
cycle means In benzene which may be substituted by 1-3 substituents, independently selected from the group comprising halo atoms is s, C1-C12alkyl, C1-C8halogenation, C1-C12alkoxy, C1-C8halogenoalkane group;
n means an integer from 1 to 5; and
p and q are different and each denotes an integer of 1 or 2.

4. Connection cyclic amine or its pharmaceutically acceptable salt according to claim 1,
where X is O or S;
R1means a hydrogen atom, a cyano, a carboxyl group, a C2-C6alkoxycarbonyl group or karbamoilnuyu group;
Ar1and Ar2the same or different and each means a phenyl group which may be substituted by 1-3 halogen atoms;
or Ar1and Ar2together with the neighboring carbon atoms to which they are attached, form N-xanthene-9-ilen group;
cycle means In benzene, in which one of its hydrogen atoms may be substituted by a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, triptorelin group or cryptomaterial;
n means an integer from 2 to 4; and
p and q are different and each denotes an integer of 1 or 2.

5. Connection cyclic amine or its pharmaceutically acceptable salt according to claim 1,
where X is NR2(where R2represents a hydrogen atom, methyl group or ethyl group);
R1means cyano;
Ar1and Ar2about encovi or different and each means a phenyl group, which may be substituted by 1-3 halogen atoms;
cycle means In benzene, in which one of its hydrogen atoms may be substituted by a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, triptorelin group or cryptomaterial;
n means an integer from 2 to 4; and
p and q are different and each denotes an integer of 1 or 2.

6. Inhibitor binding α2-adrenergic receptors, including the connection of a cyclic amine or its pharmaceutically acceptable salt according to any one of claims 1 to 5.

7. The pharmaceutical composition inhibiting the binding α2-adrenergic receptors containing compound cyclic amine or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I)

, where R is selected from ethyl, n-propyl, iso-propyl, n-butyl and allyl; R' is selected from hydrogen, straight, branched or cyclic C1-C4alkyl; straight, branched or cyclic C1-C3alkoxy; fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x=0, 1, 2, y=1, 2, 3 under the condition that, x+y=3; R" is selected from hydrogen, fluorine and chlorine, with the condition that, R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine; R3 is selected from hydrogen and straight, branched or cyclic C1-C5alkyl; R4 is selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic or organic cations, and COR4', where R' is straight, branched or cyclic C1-C5alkyl, phenyl, benzyl or phenethyl; R7 is selected from methyl and ethyl; one of A and B is sulphur, and the other is C-R2; when A is S, R2 is selected from hydrogen and methyl, with the condition that R2 is methyl only when R3 is not hydrogen; and when B is S, R2 is hydrogen; and to any tautomer thereof, as well as to a pharmaceutical composition which contains formula (I) compound, to a method of producing said compounds and to a method of treating diseases which are a result of autoimmune response or pathologic inflammation.

EFFECT: new compounds are disclosed, which can be used in treating diseases which are a result of autoimmune response or pathologic inflammation.

35 cl, 2 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: medicine.

SUBSTANCE: invention relates to the method for production of the compound of the formula (1a), being an inhibitor of thrombocyte aggregation (1a), where X is halogen atom. The method includes interaction of compounds of the formula (II), (II), where X has above mentioned value and Y and Z independently from each other are leaving groups, with optically active alkamine with formation of diastereoisomers admixture.

EFFECT: development of the new advantageous method for production of the bioactive compound.

48 cl, 24 ex

FIELD: chemistry.

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

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

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the method for preparation of hexachloroantimonates of 2,3-dihydro[1,3]thiazolium of general formula wherein R1 is alkyl or phenyl, R2 is alkyl, phenyl or hydrogen, R1+R2 is cycloalkyl by the interreaction of 4,6-dimethyl-2-pyrimidinsulfenyl chloride with corresponding olefine in presence of antimony pentachloride in equimolar ratio in the media of methylene chloride.

EFFECT: claimed compounds can be used in production of pharmaceutical preparations and biologically active substances.

2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

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

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

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

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

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

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds consistent with the general formula (I) or the general formula (II) where: R1 = H; Z = O or S; P1 = CR5R6, P2 = CR7R8, Q = CR9R10; each of R5, R6, R7, R8, R9 and R10 denotes H; Y = CR12R13-CO, where R12, R13 is selected from C0-7-alkyl; C3-6-cycloalkyl or phenyl-C0-7-alkyl; and where the phenyl ring doesn't have to be substituted R19, specified below; in the group (X)0, X = CRI4R15, where R14 and R15 are independently selected from C0-7-alkyl, and o represents a number from zero to three; (W)n, W = O, S, C(O), S(O) or S(O)2 or NR16, where R16 denotes H, and n equals zero or one; (V)m, V = C(O), NHC(O), C(O)NH or CR17R18, where R17 and R18 denotes H, and m represents a number from zero to three, on condition that, when m is more than one, (V)m contains a maximum of one carbonyl group; U = a stable 5-7-member monocyclic or 8-11-member dicyclic ring, which is saturated or non-saturated and which has from zero to four heteroatoms selected from: , where R19 represents: C0-7-alkyl, C3-6-cycloclkyl, Ar-C0-7-alkyl, O-C0-7-aklyl, NH-C0-7-alkyl, N(C0-7-alkyl)2, O-phenyl, S-phenyl; or, as a part of CHR19 or CR19 group, R19 can represent a halogen; where Ar represents a stable 5- or 6- member monocyclic or stable 9- or 10- member dicyclic ring, which is unsaturated as determined earlier for U, and where Ar doesn't have to be substituted R19, which is of importance specified above; C0-7-alkyl represents a stable linear or a branched aliphatic carbon chain, which contains from 0 to 7 carbon atoms, which doesn't have to be substituted with one, two or three halogen atoms and doesn't have to contain one or few heteroatoms selected from O, N and S, where the heteroatom is present only when C0-7-alkyl contains as a minimum one carbon atom; C3-6-cycloalkyl relates to C0-7-alkyl, certainly higher than the additionally contained carboxyl ring, which doesn't have to be substituted with one or more halogens, selected from F, Cl, Br and I or heteroatoms, selected from N, O, S; A represents O; B, D and G are independently selected from: CR19, where R19 is as specified above or N; E represents O or S; J, L, M, R, T, T2, T3 and T4 which are independently selected from: CR19 and N, where R19 is as specified above; T5 represents N; q represents a number from one to three, determining in this way a 5-, 6- or 7- member ring or its salt, hydrate or solvate. The bonds of the general formula (I) or the general formula (II), represent cruzipain inhibitors and inhibitors of other cisteinproteases and can be used as therapeutic agents, for example, in cases of Chagas disease or for confirmation of target oriented therapeutic bonding.

EFFECT: new bonds which posses helpful biological properties have been discovered.

27 cl, 156 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to heterocycle-substituted tricyclic compounds of the formula (I): or their pharmaceutically acceptable salts wherein R means hydrogen atom; R1 and R2 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R3 means hydrogen atom; n1 and n2 = 0-3 independently under condition that they both do not mean 0; Het means pyridyl wherein pyridyl is added to B through cyclic carbon atom and it comprises from 1 to 4 substitutes (W) chosen independently from group comprising -NR4R5, -NHCOR26, -NHSO2R16; R21 means aryl and R21 means heteroaryl wherein heteroaryl represents furyl, thienyl, pyridyl, thiazolyl, pyrrolidinyl, azethidinyl; R4 and R5 mean hydrogen atom or alkyl comprising 1-6 carbon atoms, or R4 and R5 mean in common -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)2NR7-(CH2)2- wherein R7 means hydrogen atom or alkyl comprising 1-6 carbon atoms; R8, R, R10 and R11 mean hydrogen atom; B means -(CH2)n4CR12=CR12a(CH2)n5 wherein n4 and n5 = 0-2 independently; R12 and R12a are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R21 means from 1 to 3 substitutes chosen independently from group comprising hydrogen atom, trifluoromethyl, trifluoromethoxy, halogen atom, cyano, alkyl comprising 1-6 carbon atoms, alkoxy group comprising 1-6 carbon atoms, or -CR29(=NOR28); R22 means -COR23, -S(O)R31, -S(O)2R31 or -COOR27; R23 means cycloalkyl comprising 3-7 carbon atoms, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, cycloalkyl comprising 3-7 carbon atoms containing from 1 to 3 substitutes chosen from group comprising halogen atom, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy group and alkoxy group comprising 1-6 carbon atoms, aryl, aryl-(C2-C6)-alkyl; R27 means alkyl comprising 1-6 carbon atoms, phenyl or benzyl; R28 and R29 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R31 means alkyl comprising 1-6 carbon atoms, halogenalkyl comprising 1-6 carbon atoms, aryl, aryl-(C1-C6)-alkyl. Also, invention relates to pharmaceutical compositions containing these substances and their using for preparing a drug used in treatment of thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, heart failure and cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 11 tbl, 9 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel condensed furan compounds of general formula I: , wherein circle X represents benzene, pyridine, or the like; Y optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted piperidyl, oxo-substituted pyrrolydyl, or oxo-substituted morpholino group; R3 hydrogen and the like; and R4 is hydrogen, or a pharmaceutically acceptable salt thereof, which are useful as drugs, especially as inhibitor of activated blood coagulation factor A, as well as intermediate compounds.

EFFECT: expanded synthetic possibilities in furan series and increased choice of biologically active compounds.

16 cl, 85 tbl, 481 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrrolo[3,2-c]pyridine derivatives of formula (I) or their pharmaceutically acceptable salts in which R1 is hydrogen; straight or branched C1-C6alkyl group optionally substituted with one or more substitutes selected from a group consisting of C1-C5alkoxy, hydroxyl, C3-C7 cycloalkyl, C1-C3 alkylthiazolyl and 1,3-dioxolanyl; straight or branched C2-C6 alkenyl group; straight or branched C2-C6 alkynyl group; C3-C7cycloalkyl group; or benzyl group optionally substituted with one or more substitutes selected from a group consisting of halogen, C1-C3alkyl and C1-C3alkoxy, R2 is a straight or branched C1-C6 alkyl group, R3 is hydrogen; straight or branched C1-C6 alkyl group; straight or branched C2-C6alkenyl group; or a benzyl group optionally substituted with one or more halogens, and R4 is 1,2,3,4-tetrahydroisoquinolinyl group; a benzyloxy group optionally substituted with one or more halogens; or an amine group substituted with one or two substitutes selected from a group consisting of hydrogen, straight or branched C1-C5alkylcarbonyl, phenoxycarbonyl, benzyl, optionally substituted with one or more halogens, and benzoyl, optionally substituted with one or more halogens, as well as to method of producing said compounds and a pharmaceutical composition with inhibitory effect on a proton pump containing these compounds.

EFFECT: new compounds are obtained and described, which exhibit excellent inhibitory effect on a proton pump and can provide reversible inhibitory effect on a proton pump.

7 cl, 82 ex, 2 tbl

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