Benzamide derivatives or pharmaceutically acceptable salts of said derivatives, pharmaceutical composition based there on and application thereof

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

 

The present invention relates to new benzamide derivative or their salts, useful as pharmaceuticals, particularly as an inhibitor of activation of VR1 (vanilloideae receptor 1) the capsaicin receptor and medications.

Capsaicin, which is the main component of chili peppers, is an irritant and causes pain through activation of VR1 capsaicin receptor, is present in primary afferent sensory nerves (mainly C-fibers). VR1 was cloned [Nature 389: 816-824 (1997)] and found that this receptor is a nonselective cation channel with high CA2+the permeability.

VR1 is activated not only by capsaicin, but also the effects of heat or acid (proton) stimulation. In addition, it also found that associated with inflammatory substances such as ATP and bradykinin, acting on metabotropic receptor and regulate the activity of VR1 through activation of phospholipase C (PLC)/activation of protein kinase C (SW). Moreover, it is known that in mice with deficiency of VR1 is not only caused by the capsaicin pain reaction disappears, but also reduces hyperalgesia during inflammation [Nature 405: 183-187 (2000)]. Based on these facts we can conclude that VR1 is involved in pain sensation in different clinical conditions.

Kapcai is in pain through activation of VR1, but as you know, and, conversely, possesses analgesic action due to desensitization of afferent nerves in the continuous activation and, thus, inhibiting subsequent activation. Actually, capsaicinoids cream used to treat neuropathic pain, such as post herpetic neuralgia or pain in diabetic neuropathy, inflammatory pain, such as rheumatoid joint pain. In addition, it is believed that the reason that dysfunction of the urinary bladder observed in patients, such as with spinal cord injury and the like, is attenuated by injection of capsaicin or a similar substance, resiniferatoxin (RTX), in the bladder based on desensitization afferent nerves as in the case of analgesic action.

Not only desensitization induced by VR1 agonist, but also the VR1 antagonist possesses analgesic effect. It is established that capsazepine, long known as VR1 antagonist, is effective against neuropathic pain and inflammatory pain in animal models [J. Pharmacol. Exp. Ther. 304: 56-62 (2003)]. Endogenous ligand to VR1 is not installed, but reported many promising compounds. It is believed that the antagonist exhibits an analgesic effect by inhibiting the action VR1 competitive with these substances. Thus the m it should be expected that inhibition of the activation of VR1 will not only result in analgesic action, but will also ensure the prevention or treatment of symptoms and diseases related to activation of VR1.

In addition, it is assumed that the compounds having inhibitory activity against activation of VR1 will be useful for a variety of pain, including neuropathic pain and inflammatory pain, headaches, such as migraine and histamine headache, itching, urinary bladder diseases including overactive bladder and interstitial cystitis.

It was recently successfully conducted research on the compounds with inhibitory activity against activation of VR1. For example, in the description of international publication No. 02/08221 (patent document 1) indicated that pieperazinove derivatives represented by the General formula:

where G, Q, T and W are the same or different and each denotes N, CH or CR5A is absent or denotes O, S or the like, each of R3and R4independently means a hydrogen atom, halogen atom, hydroxy, amino, cyano, or the like, R5means cyano, hydroxy, amino or the like, and R9means halogen atom, cyano, nitro or the like (patent document 1 for further characters in the form of the (e)

can be used to treat chronic and acute pain, psoriasis, urinary incontinence, and the like as a receptor ligand of the receptor for capsaicin.

Further, in the description of international publication No. 03/014064 (patent document 2) indicated that the amine derivative represented by the General formula:

where Q denotes CH or N, Y represents a substituted naphthalene, R6means a hydrogen atom or methyl, R7means a hydrogen atom or methyl, X represents substituted benzene, substituted naphthalene or the like (publication to clarify the symbols in the formula),

can be used for the treatment of urinary incontinence, overactive bladder, chronic pain, neurogenic pain, postoperative pain, and the like.

In addition, in the description of international publication No. 03/068749 (patent document 3) indicated that the amide derivative represented by the General formula:

where X and Y indicate in the table above combination, P is phenyl or heteroaryl, or the like, each of R1and R2means halogen, alkyl, alkoxy, NR4R5or the like, R3means alkyl, alkoxy, phenyl or the like, which may be substituted, R2group, each of q, r and s is equal to 0 to 3 and each of R4and R 5means a hydrogen atom, alkyl, or R4and R5together with the nitrogen atom form a heterocyclic ring (publication to clarify the symbols in the formula),

can be used as a VR1 antagonist for the treatment and prevention of various pains.

In the application described compounds, where the combination of P and R3means biphenyl, but, compared with the connection, where biphenylyl cycle contains additional substituents R3all deputies are low molecular weight groups such as lower alkyl groups, halogen or substituted alkoxygroup.

On the other hand, described biphenylcarboxylic compounds having nitrogen-containing heterocycle, such as quinoline or tetrahydroquinolin, on the amide nitrogen. For example, in the description of international publication No. 01/21577 (patent document 4) and international publication No. 03/035624 (patent document 5) presents tetrahydroquinoline derivatives, and quinoline derivatives, respectively, with activity against obesity, based on antagonism to the MCH-receptor. In addition, in the description of international publication No. 98/41508 (patent document 6) and in the description of international publication No. 97/48683 (patent document 7) presents tetrahydroisoquinoline derivatives with anticonvulsant activity. However, all connections Ogre is Iceni compounds not having substituents, or with only low molecular weight substituents on biphenylenes cycle. Moreover, there is no description or suggestion relating to the inhibitory effect in relation to the activation of VR1 receptor.

As mentioned above, it is expected that the inhibitor of the activation of VR1 capsaicin receptor may serve as a therapeutic agent from a variety of pain, including inflammatory pain and neurogenic pain, migraine, histamine headache, diseases of the bladder, including overactive bladder, and the like. It is desirable to develop a new inhibitor of the activation of VR1 capsaicin receptor that differ in chemical structure from the above-mentioned known compounds and has additional improved the action.

Description of the invention

As a result of extensive studies on compounds having inhibitory activity against activation of VR1 capsaicin receptor, the present applicants found that the compound denoted by the following General formula (I), where benzene is connected with the D cycle (monocyclic or bicyclic hydrocarbon ring or a monocyclic or bicyclic heteroaromatic ring) via an amide bond, benzene is directly linked to E cycle (monocyclic or bicyclic at glevodorodnogo ring or monocyclic or bicyclic heteroaromatic ring and benzene optionally associated with A (amino group, monocyclic or bicyclic a heterocycle) through L (lower alkylene), has excellent inhibitory activity against activation of VR1. Thus, the present invention was completed. Namely, the invention relates to compounds represented by the following formula (I), and salts of the compounds, and pharmaceutical preparation containing these compounds as the active ingredient.

In this context, the invention includes compounds in which the cyclic group denoted by D, is a nitrogen-containing bicyclic a heterocycle, such as quinoline or tetrahydroisoquinoline, however, the connection differs in chemical structure from the specifically disclosed compounds described in patent document 3, from the point of view that benzene is associated with A (amino group, a monocyclic or a bicyclic heterocycle) through L (lower alkylene).

[1] Benzamidine derivative represented by Generalformula (I):

where the symbols have the following meanings:

L: low alkylen,

D cycle and E cycle: the same or different monocyclic or bicyclic hydrocarbon cycle or 5-12-membered monocyclic or bellicheck the th heteroaromatic cycle, containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O,

G cycle: 4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O,

R1-R9: the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -SH, -O-lower alkyl, -O-lower alkyl-NH-lower alkyl, -O-lower alkyl-N(lower alkyl)2, =O, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -S-lower alkyl, -SO-lower alkyl, -SO2-lower alkyl, -CN, -COOH, -C(=O)-O-lower alkyl, -C(=O)-NH2, -C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -NH-C(=O)-lower alkyl, -NH-SO2-lower alkyl, -SO2-NH2, -SO2-NH-lower alkyl, -C(=O)-lower alkyl, -NO2or nitrogen rich heterocycle,

R10: a hydrogen atom or lower alkyl,

R11-R15: the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, -S-lower alkyl, -SO-lower alkyl, -SO2-lower alkyl, =O, -C(=O)H, -C(=O)-lower alkyl, -COOH, -CN, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -C(=O)-NH2, -C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -C(=O)-aryl, -C(=O)-NH-aryl, -NH-C(=O)-lower alkyl, -NH-C(=O)-aryl, -NH-SO2-lower alkyl, -N(Nissi is alkyl)-SO 2-lower alkyl, -lower alkylene-NH-SO2-lower alkyl, -lower alkylene-NH-SO2-aryl, -C(=O)-O-lower alkyl, -lower alkylene-OH, -lower alkylene-C(=O)-NH-lower alkyl, -lower alkylene-C(=O)-N(lower alkyl)2-the inferior alkylen-C(=O)-NH2-the inferior alkylen-C(=O)-OH, -lower alkylene-O-lower alkyl, -lower alkylene-S-lower alkyl, -lower alkylene-O-C(=O)-lower alkyl, -lower alkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)2-the inferior alkylen-aryl, cycloalkyl, aryl, -(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -O-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -lower alkylene-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms of the same or different heteroatoms selected from the group comprising N, S and O), -C(=O)-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -lower alkylene-N(lower alkyl)-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from g is uppy, comprising N, S and O), or

-C(=O)-NH-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O) and

the above-mentioned monocyclic or the bicyclic heterocycle may have substituents selected from the group including atom(s) halogen(s), lower alkyl(s), -O-lower alkyl or-OH, and the same values used hereinafter,

or salt specified connection.

[2] the Compound according to the above p.[1], where the symbols denoted by D, E, R1-R9and R11-R15in the above formula (I)have the following meanings:

D cycle and E cycle: the same or different, benzene, naphthalene cycle or 5-12-membered monocyclic or bicyclic heteroaromatic cycle-containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O,

R1-R9: the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -SH, -O-lower alkyl, -O-lower alkyl-NH-lower alkyl, -O-lower alkyl-N(lower alkyl)2, =O, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -S-lower alkyl, -SO-lower alkyl, -SO2-lower alkyl, -CN, -COOH, -C(=O)-NH2, -C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2or-NH-C(=O)-lower alkyl,

R11-R15 : the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, -S-lower alkyl, -SO-lower alkyl, -SO2-lower alkyl, =O, -C(=O)H, -C(=O)-lower alkyl, -COOH, -CN, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -C(=O)-NH2, -C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -C(=O)-aryl, -C(=O)-NH-aryl, -NH-C(=O)-lower alkyl, -NH-C(=O)-aryl, -NH-SO2-lower alkyl, -N(lower alkyl)-SO2-lower alkyl, -C(=O)-O-lower alkyl, -lower alkylene-O-lower alkyl, -lower alkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)2-the inferior alkylen-aryl, cycloalkyl, aryl, 4-12 membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O, lowest alkylen-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -C(=O)-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms of the same or different heteroatoms selected from the group comprising N, S and O), -lower alkylene-N(lower alkyl)-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O) or-C(=O)-NH-(4-12-h is i.i.d. monocyclic or bicyclic a heterocycle, containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O).

As a preferred variant of the invention may be mentioned the compound responsible p.[3]of the compounds responsible PP.[4]-[9], represent preferred embodiments of, and connection that meets p.[10], is particularly preferred embodiment of the invention.

[3] the Compound according to the above p.[1], where a cycle, denoted by E in the above formula (I), means a benzene or titanovyi cycle, more preferably benzene.

[4] the Compound according to the above p.[3], where the component denoted by A in the above formula (I), corresponds to the following formula:

[4a] More preferably, the compound according to the above p.[4], where a cycle, denoted by G in the above formula (I), means a nitrogen-containing saturated a heterocycle, more preferably, a cycle selected from the group including tetrahydropyridine, tetrahydroquinolin, tetrahydroisoquinoline, piperidine, pyrrolidine, morpholine, ASEAN and 1,4-oxazepan, and the nitrogen atom of the cycle is associated with L.

[4b] More preferably, the compound according to the above p.[4], where a cycle, denoted by G in the above formula (I)is chosen from the group comprising m is Holin, piperidine and pyrrolidine, and the nitrogen atom of the cycle is associated with L.

[4c] More preferably, the compound according to the above p.[4], where the cycle is denoted by D in the above formula (I)is chosen from the group comprising benzothiazole, quinoline, isoquinoline, indolin, tetrahydroquinolin, tetrahydroisoquinoline, 3,4-dihydro-2H-1,4-benzoxazin, dihydroquinoline and dihydroisoquinoline.

[4d] More preferably, the compound according to the above p.[4]still preferably, in the above p.[4a], more preferably, above p.[4b], where a cycle, denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group selected from the following formulas:

where the symbols have the following meanings:

R6aand R6b: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7a, R8a, R7band R8b: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

Or, the connection of the above p.[4]still preferably, in the above p.[4a], more preferably, above p.[4b], where a cycle, denoted by D in the above formula (I), together with the attached groups denoted by R6-R9the way the et group, choose from the following formula:

where the symbols have the following meanings:

R6cand R6d: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7c, R8c, R7dand R8d: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

[4e] the Compound according to the above p.[4], where at least one of the groups denoted by R13-R15means halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, -NH2, -N(lower alkyl)2, -C(=O)-NH2, -C(=O)-N(lower alkyl)2, -NH-C(=O)-lower alkyl, -C(=O)-O-lower alkyl, -lower alkylene-O-lower alkyl, aryl, -(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O) or lowest alkylen-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), and the other mean a hydrogen atom. More preferably, the compound according to the above p.[4], where at least one of the symbols denoted by R13-R15that means lower alkyl, -O-lower alkyl, -N(lower alkyl)2, -(4-12-member of the config monocyclic or bicyclic a heterocycle, containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O) or lowest alkylen-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), and other mean a hydrogen atom.

[5] the Compound according to the above p.[3], where the group denoted by A in the above formula (I)has the following formula:

where the symbols have the following meanings:

R11aand R12a: the same or different, a hydrogen atom, lower alkyl, halogen-substituted lower alkyl, -O-lower alkyl, -SO2-lower alkyl, -C(=O)H, -C(=O)-lower alkyl, -CN, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -C(=O)-NH2, -C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -C(=O)-aryl, -C(=O)-NH-aryl, -NH-C(=O)-lower alkyl, -NH-C(=O)-aryl, -NH-SO2-lower alkyl, -N(lower alkyl)-SO2-lower alkyl, -lower alkylene-NH-SO2-lower alkyl, -lower alkylene-NH-SO2-aryl, -C(=O)-O-lower alkyl, -lower alkylene-OH, -lower alkylene-C(=O)-NH-lower alkyl, -lower alkylene-C(=O)-N(lower alkyl)2-the inferior alkylen-C(=O)-NH2-the inferior alkylen-C(=O)-OH, -lower alkylene-O-lower alkyl, -lower alkylene-S-lower alkyl, -lower alkylene-O-C(=O)-lower alkyl, -lower alkylene-NH-lower alkyl, -lower alkylene-N(lower lcil) 2-the inferior alkylen-aryl, cycloalkyl, aryl, -(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -O-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -lower alkylene-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms of the same or different heteroatoms selected from the group comprising N, S and O), -C(=O)-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), -lower alkylene-N(lower alkyl)-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O) or-C(=O)-NH-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O), and

the above-mentioned monocyclic or the bicyclic heterocycle can be substituted by groups selected from the group including atom(s) halogen, lower alkyl(s), -O-lower alkyl or-OH.

[5a] the Connection given the WMD above p.[5], where R11ameans lower alkyl and R12ameans a group selected from the group comprising lower alkylene-O-lower alkyl, -lower alkylene-S-lower alkyl, -lower alkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)2-the inferior alkylene-OH, -lower alkylene-C(=O)-NH-lower alkyl, -lower alkylene-C(=O)-N(lower alkyl)2-the inferior alkylen-aryl, cycloalkyl, aryl, -(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O) and lowest alkylen-(4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O).

[5b] More preferably, the compound according to the above p.[5], where the cycle is denoted by D in the above formula (I), means a cycle selected from the group including benzothiazole, quinoline, isoquinoline, indolin, tetrahydroquinolin, tetrahydroisoquinoline, 3,4-dihydro-2H-1,4-benzoxazin, dihydroquinoline and dihydroisoquinoline.

[5c] More preferably, the compound according to the above p.[5], more preferably, the compound according to the above p.[5a], where a cycle, denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group selected from the following formulas:

where the symbols have the following meanings:

R6aand R6b: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7a, R8a, R7band R8b: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

Or, the connection of the above p.[5], more preferably a compound according to the above p.[5b], where a cycle, denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group selected from the following formulas:

where the symbols have the following meanings:

R6cand R6d: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7c, R8c, R7dand R8d: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

[6] the Compound according to the above p.[1], where R1-R5are the same or different and each means a hydrogen atom, halogen, halogen-substituted lower alkyl, lower alkyl, -N(lower alkyl)2or-O-lower alkyl.

[7] the Compound according to the above p.[1], where R6-R9are the same or different and each lake is achet a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, =O, -NH-lower alkyl, -N(lower alkyl)2, -CN, -C(=O)-NH2, -NH-SO2-lower alkyl, -SO2-NH2, -C(=O)-lower alkyl, -NO2or nitrogen rich heterocycle, more preferably a hydrogen atom, halogen, halogen-substituted lower alkyl, lower alkyl, -OH, =O, -N(lower alkyl)2or-SO2-NH2. Another preferred compound according to the above p.[1], where R6-R8are the same or different and each means a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl, and R9mean =O.

[8] the Compound according to the above p.[1], where R10in the above formula (I) means a hydrogen atom.

[9] the Compound according to the above p.[1], where the group denoted by L, denotes methylene or ethylene, preferably methylene.

[10] the Compound according to the above p.[1] or salt of the compounds, where benzamidine derivative represented by the above formula (I), means, at least one compound selected from the group includingN-1,3-benzothiazol-5-yl-2-{[cyclohexyl(isopropyl)amino]methyl}biphenyl-4-carboxamid,N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamid,N-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-ndol-6-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamid, 2-{[ethyl-(2-hydroxy-2-methylpropyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamid,N-(1-methyl-2-oxo-1,2-dihydroquinoline-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamid,N-(3-methyl-2-oxo-1,2-dihydroquinoline-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamid,N-(2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide, 2-{[ethyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamid,N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-3-(piperidine-1-ylmethyl)-4-(2-thienyl)benzamide, 2-{[ethyl(tetrahydro-2H-thiopyran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide, 2-{[isobutyl-(2-piperidine-1-retil)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamid,N,N-diethyl-4-[(4-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]carbonyl}biphenyl-2-yl)methyl]morpholine-3-carboxamide and 2-[(4-methyl-1,3'-bipiperidine-1'-yl)methyl]-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide.

In addition, the invention relates to pharmaceutical compositions containing benzamidine derivative, denoted by the above formula (I)or salt of the compounds and a pharmaceutically acceptable carrier. Preferably, the above is shown the pharmaceutical composition, which is the inhibitor of the activation of VR1, and, more preferably, the above pharmaceutical composition, which is a prophylactic or therapeutic agent against the pain.

In addition, other options for implementation include the use of benzamide derivative, denoted by the above formula (I), PP.[1]-[10] or salts of the compounds for industrial production of a prophylactic or therapeutic agent against pain and the method of prevention or treatment of pain, comprising introducing an effective amount of benzamide derivative, denoted by the above formula (I), PP.[1]-[10] or salts of the specified connection.

Hereinafter the invention is described in more detail.

Used in the description, the term "inhibitor of the activation of VR1 capsaicin receptor" is a common name as compounds (VR1 antagonist), linking the VR1 receptor and inhibiting the activation of VR1 through competition with the endogenous ligand, and compounds (VR1 agonist), desensitizing the nerves, in the presence of the receptor, and inhibiting subsequent activation by continuous activation of the receptor VR1. As an inhibitor of activation of VR1" preferred VR1 antagonist.

In the definition given in the description of the General structural formula, if not specified otherwise, the term "lower" means a linear or branched ug is irodou chain with 1-6 carbon atoms. Thus, the "lower alkyl" preferably denotes alkyl with 1-5 carbon atoms, and particularly preferred are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and 1,2-dimethylpropyl. As "lower alkylene" preferred linear alkylene, such as methylene, ethylene, propylene and butylene, and extensive alkylene, such as METROTILE. Particularly preferred methylene and ethylene.

"Halogen atom" includes fluorine atoms, chlorine, bromine and iodine. Particularly preferred fluorine atom and chlorine atom. "Halogen-substituted lower alkyl" means a group where the above-mentioned lower alkyl substituted by 1-3 Halogens, which are the same or different. Particularly preferred trifluoromethyl.

As a monocyclic or bicyclic hydrocarbon cycle" can be mentioned benzene, naphthalene, cycloalkyl cycles with 3 to 8 members in the loop, cycloalkenyl cycles with 4-8 members in the loop and aryl cycles, condensed with a saturated hydrocarbon cycles, where cycloalkyl or cycloalkenyl cycle condensed with benzene. Preferred are benzene, naphthalene, indan, tetrahydronaphthalen.

"Aryl" means aryl containing 6-14 carbon atoms, and more preferred phenyl or naphthyl.

"Cycloalkyl" preferably means cycloalkyl group with 3-10 atom is mi carbon which may contain bridging the communication (connection), and more preferred are the groups: cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and substituted.

"Nitrogen rich heterocycle" means a 5-8-membered saturated or partially unsaturated monocyclic heterocycle which contains one N atom and may optionally contain one heteroatom selected from N, S and O, and are preferred pyrolidine, piperidinyl, pieperazinove, asianova, diazepambuy, morpholinyl, thiomorpholine and tetrahydropyridines cycles.

"5-12-membered monocyclic or bicyclic heteroaromatic cycle-containing from 1 to 4 atoms, equal or different heteroatoms selected from the group comprising N, S and O" means a 5-6-membered monocyclic heteroaromatic cycle-containing from 1 to 4 atoms heteroatoms selected from the group comprising N, S and O, and bicyclic heteroaryl group, where the specified monocyclic heteroaromatic cycle condensed with the benzene ring cycle, or 5-6-membered monocyclic heteroaromatic cycle. These cycles can be partially saturated. Moreover, in the case when N atom or S atom included in the atoms of the cycle, the atom can form the oxide or dioxide. As a 5-6-membered monocyclic heteroaromatic cycle preferably is cycles: pyridine, the pyrimidine, pyrazin, pyridazine, triazine, pyrrole, furan, thiophene, thiazole, imidazole, oxazole, isothiazol, pyrazole, itsaso, thiadiazole, triazole and tetrazole. As bicyclic heterocycle preferred cycles: benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzimidazole, benzotriazole, benzothiadiazole, benzoxadiazole, quinoline, isoquinoline, naphthylidine, cinoxacin, hinzelin, phthalazine, cinnoline, indole, indazole, imidazopyridine, benzothiophen, benzothiophene-1,1-dioxide, benzofuran, dihydrobenzofuran, dihydro-1,3-benzoxazol, dihydro-1,3-benzothiazole, 1,3-benzodioxol, benzazepin, benzodiazepine, benzoxazin, tetrahydrobenzaldehyde, tetrahydrobenzene, tetrahydroquinolin, tetrahydroisoquinoline, tetrahydronaphthalen, tetrahydroquinoxalin, chroman, dihydroergotoxine, 3,4-dihydro-2H-1,4-benzothiazin, dihydrobenzofuran, 3,4-dihydro-2H-1,4-benzoxazin, isochroman, indolin and pteridine. More preferred are cycles of: pyridine, benzothiazole, benzoxazole, quinoline, isoquinoline, dihydroquinoline, dihydroisoquinoline, indolin, tetrahydroquinolin, tetrahydroisoquinoline, benzothiophen, 3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,4-benzothiazin and dihydro-1,3-benzoxazol.

"4-12-membered monocyclic or bicyclic a heterocycle containing from 1 to 4 atoms of same or different heteroatoms, in biraimah from the group comprising N, S and O" means, in addition to the above monocyclic or bicyclic heteroaromatic cycles, 4-8-membered saturated or partially unsaturated monocyclic and bicyclic heterocycle, the heterocycle obtained by condensation of a specified cycle with cycloalkyl cycle, cycloalkenyl cycle or a saturated or partially unsaturated monocyclic the heterocycle. Preferred are saturated or partially unsaturated monocyclic heterocycles, such as pyrrolidine, imidazolidine, pyrazolidine, Hinkley, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, ASEAN, Asian (octahydrate), 1,4-onazepam, azetidin, 1,2,3,6-tetrahydropyridine and imidazoline, and saturated or partially unsaturated bicyclic heterocycles, such as decahydroquinoline and decahydroquinoline. Preferred nitrogen-containing saturated heterocyclic compounds and, more preferably, cycles: pyrrolidine, piperidine, piperazine and morpholine.

When the Deputy designated as R7aor R8ain the formula below, this means that the Deputy may be linked to a carbon atom on any, as the left and right loops.

In addition, among the compounds according to the invention are geometric isomers, tautomers and optical is a mini-isomers depending on the kind of substituents. The invention encompasses mixtures of such isomers and individual isomers.

In some cases, the compounds according to the invention form acid additive salt. Also, in some cases, these compounds can form salts with bases. In particular, such salts include additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid and phosphoric acid; or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, aspartic acid and glutamic acid; salts with inorganic bases, such as salts of sodium, potassium, magnesium, calcium and aluminum; organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine; and ammonium salts and the like.

In addition, the invention encompasses hydrates of the compounds according to the invention, pharmaceutically acceptable various solvate, compounds having crystal polymorphism, and the like.

Compounds according to the invention also include compounds which are capable of developing the process of metabolism in vivo in connection represented by the above General formula (I), or salts of the compounds, so-called prodrugs. Group forming prodrug compounds according to the invention are groups described in Prog. Med. 5:2157-2161 (1985), and the groups described in "Iyakuhinn no Kaihatsu (Development of Medicines) published by Hirokawa Shoten, 1990, Vol.7, Bunshi Sekkei (Molecular Design), pp.163-198.

Ways to get

The following describes typical methods for producing compounds according to the invention.

In this regard, when carrying out the next way to obtain, depending on the type of functional groups, sometimes technically efficient to replace a functional group suitable protective groups at the stage of starting materials or intermediate compounds, i.e. groups that can easily turn into functional groups. Then the protective group can be removed as needed, which results in obtaining the desired connection. As such functional groups can be, for example, amino group, hydroxyl group, carboxyl group and the like. As such protective groups can be mentioned protective groups described in Protective Groups in Organic Synthesis 3rd edition (written by T. W. Green and P. G. M. Wuts, published by JOHN WILLY & SONS, INC), which can be appropriately used depending on the reaction conditions. The method described in the link, can the t to be applied for the introduction and removal of protective groups.

The method of obtaining 1

The method of obtaining 1 represents the reaction of the compound (I) by the condensation reaction of carboxylic acid and amine using the compound (II) and compound (III).

Consider the interaction can be carried out according to the conventional method using the compound (II) and amine derivative (III) in equimolar amounts or with an excess of one of these compounds, in the presence of a condensing agent. As the condensing agent, it is convenient to useN,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide,O-benzotriazol-1-yl-N,N,N',N'-tetramethylhexadecane (HBTU), carbonyldiimidazole, diphenylphosphoryl (DPPA), diethylphosphoramidite or the like. These condensing agents are used in equimolar amounts or with an excess amount of carboxylic acid. The solvent may be used a solvent which does not participate in the interaction,N,N-dimethylformamide (DMF), dioxane, tetrahydrofuran, diethyl ether, dichloroethane, dichloromethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide or a mixed solvent based on the specified dissolve the her and the solvent is usually chosen in accordance with the method used. In addition, depending on the methods of interaction can take place easier when carrying out the reaction in the presence of a base, such asNmethylmorpholine, triethylamine, trimethylamine, pyridine or 4-dimethylaminopyridine, or when using a base as a solvent. Usually this interaction is carried out in the temperature range of conditions cooling to room temperature, but sometimes it is preferable to carry out the interaction at elevated temperature, depending on the type of reaction acylation.

In addition, compound (I) can also be obtained by a method involving the introduction of a carboxylic acid into an active derivative and subsequent condensation of the resulting product with an amine. In this case, the interaction is done using the compound (II) and amine derivative (III) in equimolar amounts or with an excess of one of these compounds. As an active carboxylic acid derivative may be mentioned the active ester obtained by the interaction of the acid with a phenol compound such as p-NITROPHENOL or N-hydroxyamino connection, such as 1-hydroxysuccinimide, or 1-hydroxybenzotriazole, monoalkylammonium, mixed anhydride obtained when inter is actvie with an organic acid, the mixed anhydride of phosphate type, obtained by the interaction with diphenylphosphinylchloride and N-methylmorpholine, acid azide, received subsequent interaction of ester with hydrazine and alkylation, halogenmethyl, such as the acid chloride or bromohydrin and symmetrical anhydride. The interaction is carried out using the reagent activation in equimolar amounts relative to the compound (II) or in an excessive amount in relation to the specified connection. The reaction conditions in this case are consistent with the terms used in the case of the use of the condensing agent.

In addition, other interaction other than those specified above may be used in the case that lead to the formation of amide bonds.

The method of obtaining 2

where X represents a leaving group such as-Cl, -Br, -I, methanesulfonate or toluensulfonate, and the same applies in the future.

The method of obtaining 2 represents the reaction of the compound (I) by the reaction of nucleophilic substitution using the compounds (IV) and amine compounds A-H.

This cooperation is carried out using the compound (IV) and A-H in equimolar amounts or with an excess of one of these compounds in the temperature range of cooling conditions ice to avicennae temperature, adding a base (preferably potassium carbonate, sodium carbonate, sodium hydrogen carbonate, tert-butyl potassium, triethylamine, pyridine, N-methylmorpholine, sodium hydroxide), using as a solvent a solvent specified in the method of obtaining 1.

When the compound (I) according to the invention contain various side chains and functional groups, these compounds can be easily synthesized by using as starting materials compounds according to the invention or obtained intermediates through interactions that is obvious to the person skilled in the art, or the corresponding modified techniques. As examples may be mentioned the conversion of any of the substituents R1-R9the compound (I)obtained by the method of getting 1, or turning on the introduction of a specified substituent again. For example, can be used in the following interaction.

Connection, where any of the substituents R1-R9in the formula (I) means-SO2-NH2or CO-NH2can be obtained with the use of connections, where each of the respective substituents R1-R9means-SO3H or CO2H. the Interaction is carried out by condensation-SO3H or CO2H R1-R9with ammonia in the same conditions as the conditions otvechali the first response is received.

In addition, the connection, where the cycle D in the formula (I) is a saturated cycle and any of the substituents R1-R9in the formula (I) means-OH, can be obtained using a connection, where present Deputy means a carbonyl group, using the common methodology for response recovery. For example, the interaction may be carried out according to the method described inTetrahedron, 35, 567-607 (1979).

In addition, the connection, where the cycle D cycle E is a heterocycle and a heteroatom in the cycle oxidized to oxide can be synthesized by oxidation of heteroatom using methods for oxidation reactions. The interaction may be carried out according to the method described inJ. Hetrocycl. Chem.19, 237-240, (1982),J. Chem. Soc. Perkin Trans.1, 1949-1955, (1984).

The method of obtaining raw materials

The following describes typical methods of obtaining raw materials specified in the method of obtaining 1 and the method of obtaining 2.

(1) the Original compound (II)

The stage of starting material (II) for a method of obtaining 1 cover with the first stage on the eleventh stage.

where one of U and Q means-Br, -Cl, -I or-O-SO2-CF3and the other means-B(OH)2or-B(O-lower alkyl)2, P1means a protective group for carbox the La, such as methyl group, ethyl group, benzyl group or a tert-bucilina group, and X1means-Cl, -Br or-I, and the same applies in the future.

Initially, the first stage is the stage of obtaining the compound (VII) by reaction cross-combinations using the compounds (V) and compound (VI). The interaction may be carried out according to the method described inSynth. Commun., 11, 513-519 (1981),Synlett2000, No. 6, 829-831 andChem. lett., 1989, 1405-1408.

The second stage is the stage of obtaining (VIII) by treatment of compound (VII) halogenation agent. The interaction is carried out in the temperature range from room temperature to the boiling temperature under reflux, usingN-bromosuccinimide (NBS), bromine, sulfurylchloride or copper bromide as a halogenation agent, in a solvent such as carbon tetrachloride, chloroform or benzene, adding benzoyl peroxide, 2,2'-azobisisobutyronitrile,tert-butylhydroperoxide or tetranitroaniline or when exposed to light, as needed.

The third stage is a stage of obtaining compound (IXa) by removing the protective group P1compounds (VIII) and simultaneous hydrolysis of the groups X 1. This interaction can be carried out using conventional techniques for the basic hydrolysis of the halides. However, when the protective group is not removed by hydrolysis with a base, after hydrolysis of X1group of the compound (VIII), the reaction for removing the protective group may be carried out by hydrolysis with acid, such as hydrochloric acid or triperoxonane acid, or by recovery, such as catalytic hydrogenation. Can be used in conditions of interaction described in the aforementioned "Protective Groups in Organic Synthesis".

The fourth stage is the stage of obtaining the compound (X) by the oxidation reaction of compound (VIII). The interaction is carried out using an oxidizing agent, such asNmethylmorpholin-N-oxide, trimethylamine-N-oxide, sodium salt of 2-nitropropane, described inJ. Am. Chem. Soc., 71, 1767-1769 (1949), or nitrate of silver, in a solvent such as acetonitrile or ethanol, at temperatures from cooling with ice to the boiling temperature under reflux.

The fifth stage is a stage of obtaining the compound (XI) from the compound (X). The interaction is carried out using (methoxymethyl)triphenylphosphonium, (methoxymethyl)triphenylphosphonium or the like as the reactive agent, prisutstvie the base, such as n-utility,second-utility, sodium hydride, ortert-butylpotassium, in a solvent such as tetrahydrofuran, diethyl ether or cyclopentylmethyl ether, at temperatures from -78°C to high temperature.

The sixth stage is a stage of obtaining the compound (XIIa) via the condensation of compound (XI) with A-H by the reaction of reductive amination. The interaction is carried out, using triacetoxyborohydride sodium, sodium borohydride or the like as a reducing agent, adding an organic acid (preferably acetic acid, formic acid or p-toluensulfonate acid), a Lewis acid such as a salt of the metal (preferably, tetraisopropoxide), as needed. The interaction is carried out using a solvent, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran, at temperatures from cooling with ice to a high temperature.

The seventh stage and the eighth stage represents the stage of obtaining compound (XIIIa) and (XIIIb) by restoring the formyl group of compound (X) and (XI), respectively. The interaction may be carried out according to the method described inTetrahedron, 35, 567-607 (1979).

The ninth stage is a stage of receiving the Oia compound (XIVa) by halogenation of the hydroxyl group of compound (XIIIb), or by transformation of the specified group in the ether sulfonic acids. Halogenoalkane carried out using gelegenheid (preferably thionyl chloride, trichloride phosphorus, pentachloride phosphorus oxychloride phosphorus or tribromide phosphorus etc) or using triphenylphosphine and carbon tetrachloride, triphenylphosphine and tetrabromide carbon or the like. Conversion to ether sulfonic acids is carried out by treatment with methanesulfonanilide or p-toluensulfonate in the presence of a base (preferably triethylamine, pyridine or potassium carbonate). The specified transformation is carried out, using dichloroethane, methylene chloride, chloroform, dioxane or hexane as a solvent, in the temperature range from cooling with ice to heat up to the boiling temperature under reflux. In addition, when processing the obtained chloride, bromide or ether sulfonic acids using sodium iodide, potassium iodide or the like, can also be obtained iodide. As the solvent in this case, use acetone, 2-butanone, ethanol or the like.

Using the same reaction conditions as in the ninth stage, to the compound (XIIIa), the hydroxyl group of the compound (XIIIa) can be galogenirovannami or turned into the ether sulfonic acids.

The tenth stage is a stage of obtaining the compound (XII) the way the interaction of the compound (VIV) with A-H. The interaction is carried out in the same conditions as described for the method of obtaining 2.

The eleventh stage is a stage of obtaining the compound (II) by removing the protective group P1compound (XII). The reaction unprotect preferably can be carried out using the techniques described in the aforementioned "Protective Groups in Organic Synthesis".

(2) the Original compound (IV)

The stage of starting compound (IV) for a method of obtaining cover 2 from the twelfth stage of the fifteenth stage.

First, the compound (IV) can be obtained by the sequential implementation of the twelfth and fifteenth stages. The interaction can be accomplished by condensation of the compound (IX) and compound (III) in the same way as in the production method of 1, and then halogenoalkanes hydroxyl group of the obtained compound (XV) or the conversion of the specified group in the ether sulfonic acids, as the ninth stage.

In addition, it is possible to obtain the compound of formula (IV), where X means X1, that is, the compound (IVa)by the thirteenth stage and fourteenth stage. Namely, by treating the compound (IX) under the reaction conditions of halogenation according to the ninth stage, halogenoalkane hydroxyl group and conversion of the carboxyl group to gelegenheid osushestvlenie, and amide bond can be obtained by carrying out the interaction of the formed gelegenheid (XVI) with separately obtained amine derivative (III). The interaction is carried out in ethylene dichloride, methylene chloride or the like in the presence of a base (pyridine, triethylamine, potassium carbonate or sodium bicarbonate) at temperatures from cooling to room temperature, or at elevated temperature, depending on the type of acyl interactions.

Further, it is also possible to synthesize the compound (IV) by removing the protective group P1compounds (XIV) and condensation of the obtained carboxylic acid with the amine compound (III) in the same conditions as for a method of obtaining 1.

Thus obtained compounds according to the invention can be isolated and purified in the form of the free compounds or the corresponding salts, using the common chemical operations such as extraction, precipitation, fractional chromatography, fractional crystallization and recrystallization. Salt compounds can be obtained by treating the free compounds according to the conventional methods of salt formation.

In addition, in the case where the connection according to the invention contain asymmetric carbon, there are optical isomers. Such optical isomers can be obtained FPIC is the means of transferring in diastereomeric salt with an optically active acid or base, with further fractionated crystallization and separation of optical isomers using conventional methods such as column chromatography or synthesis using optically active starting material.

The best way of carrying out the invention

EXAMPLES

Next, the method of obtaining the compounds according to the invention is explained in detail using the following examples. In this regard, methods of obtaining raw materials designated as standard examples.

The standard example 1

In 150 ml of water is suspended to 55.9 g of sodium carbonate and 38.6 g of phenylboronic acid. Add 51,4 g of ethyl 4-bromo-3-methylbenzoate dissolved in 400 ml of toluene, and then adding 4.0 g tetranitroaniline, and then heated for 2 hours to the boiling temperature under reflux. After cooling the reaction solution to room temperature, spend filtration using celite, and the organic layer extracted with toluene. After drying the organic layer over anhydrous magnesium sulfate the solvent is removed by evaporation and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate), obtaining of 50.4 g of ethyl 2-methylbiphenyl-4-carboxylate as a colourless oil.

The standard example 2

In 130 ml of carbon tetrachloride is kind of dissolve 10 g of ethyl 2-methylbiphenyl-4-carboxylate, the resulting mixture was heated to 90°C and then add 1.0 g of NBS and 136 mg of 2,2'-azobisisobutyronitrile. After heating the reaction mixture up to the boiling temperature under reflux add to 6.78 g of NBS and the resulting mixture heated to the boiling temperature under reflux for one and a half hours. After cooling the reaction solution to room temperature, the precipitate is removed by filtration, the filtrate water is added and the organic layer is extracted with carbon tetrachloride. After drying the organic layer over anhydrous magnesium sulfate the solvent is removed by evaporation, getting to 13.6 g of ethyl 2-(methyl bromide)biphenyl-4-carboxylate as a white solid.

The standard example 3

In 50 ml of DMF is dissolved to 13.6 g of ethyl 2-(methyl bromide)biphenyl-4-carboxylate, and then add a suspension of 50 ml of DMF, and 6.2 ml of piperidine and 9.2 g of potassium carbonate, followed by stirring for 3 hours at room temperature. To the reaction solution was added water, the resulting mixture was extracted with ethyl acetate and the resulting organic layer is dried over anhydrous magnesium sulfate, followed by removal of solvent by evaporation. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia), receiving of 12.6 g of ethyl 2-(piperidine-1-ylmethyl)Biff the Il-4-carboxylate as a pale yellow oil.

Standard examples 4-16

Connection standard examples 4-16 presented in the table below, receive the same manner as in example 3.

The standard example 17

In 150 ml of ethanol is dissolved 11 g of ethyl 2-(piperidine-1-ylmethyl)biphenyl-4-carboxylate and then add 51 ml of 1M aqueous sodium hydroxide under ice cooling, followed by stirring at room temperature for 10 hours. Under ice cooling to the reaction solution was added 51 ml of 1M aqueous hydrochloric acid and then the solvent is removed by evaporation, receiving of 12.6 g of a light pink solid which is a mixture of 2-(piperidine-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalents of sodium chloride.

Standard examples 18-40

Connection standard examples 18-30 presented in the following tables, getting in the same way as in example 17.

Connection standard examples 31-35 presented in the table below, receive the same manner as in example 3.

Connection standard examples 36-40 presented in the table below, receive the same manner as in example 17.

The standard example 41

In 100 ml of acetonitrile is dissolved 9.3 g of ethyl 2-(methyl bromide)biphenyl-4-carboxylate is then added at room temperature 7.0 g N-methylmorpholin-N-oxide, followed by stirring for 4 hours. To the reaction solution was added water and then extracted with ethyl acetate. The resulting organic layer is dried over anhydrous magnesium sulfate. After removal of the solvent by evaporation, the obtained residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate)to give 4.94 g of ethyl 2-formylphenyl-4-carboxylate as a white solid.

The standard example 42

Suspension 17.1 g (methoxymethyl)triphenylmethylchloride in 150 ml of tetrahydrofuran is cooled to -78°C and to the suspension is added dropwise 1.59 M solution of n-utility in hexane, followed by stirring for 30 minutes. Next, after heating the reaction solution to -40°C and stirring for 10 minutes this solution is again cooled to -78°C and added dropwise, over a period of 20 minutes of 4.2 g of ethyl 2-formylphenyl-4-carboxylate, dissolved in 20 ml of tetrahydrofuran. The reaction solution is heated from -50°C to 10°C for a period of 12 hours, followed by stirring at room temperature for 4 hours. The reaction solution is evaporated and to the residue is added ethyl acetate and water, followed by separation of the organic layer. The organic layer is dried over anhydrous magnesium sulfate, the solvent is removed by evaporation and the floor is obtained residue purified by chromatography on a column of silica gel (hexane:ethyl acetate), receiving 1.66 g of colorless oil. The product is dissolved in 50 ml of 1,2-dichloroethane and add 25 ml of formic acid at room temperature, followed by stirring for 51 hours. To the reaction solution was added water and ethyl acetate, carry out the operation to separate and the organic layer is dried over anhydrous magnesium sulfate. After removal of the solvent by evaporation the residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate)to give 1.06 g of ethyl 2-(2-oxoethyl)biphenyl-4-carboxylate as a white solid.

The standard example 43

In 20 ml of 1,2-dichloroethane was dissolved 1.06 g of ethyl 2-(2-oxoethyl)biphenyl-4-carboxylate and then add 3,95 ml of piperidine, 589 μl of acetic acid and 1.09 g of triacetoxyborohydride sodium, followed by stirring for 3 hours. To the reaction solution was added water and chloroform, and the obtained operation for separation of the organic layer is dried over anhydrous magnesium sulfate, followed by removal of solvent by evaporation. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia), which gives 1.3 g of oily ethyl 2-(piperidine-1-retil)biphenyl-4-carboxylate.

The standard example 44

Connection standard example 44, are presented in the table below, get the W is way as in example 17, using ethyl 2-(piperidine-1-retil)biphenyl-4-carboxylate as the starting material.

Standard examples 45-56

Connection standard example 45, are presented in the table below, receive the same manner as in example 1.

Connection standard example 46, are presented in the table below, receive the same manner as in example 2.

Connection standard examples 47-50 presented in the table below, receive the same manner as in example 3.

Connection standard examples 51-56 presented in the table below, receive the same manner as in example 17.

The standard example 57

To 160 ml of 1,2-dichloroethane add 14,71 g 2-(hydroxymethyl)biphenyl-4-carboxylate and there is added 0.5 ml of DMF and 11,75 ml of thionyl chloride. After stirring the reaction solution for 1 hour while heating to the boiling temperature under reflux add 8 ml of thionyl chloride at room temperature and the resulting mixture is stirred for 3 hours when heated to the boiling temperature under reflux. After cooling to room temperature, the reaction solvent is evaporated under reduced pressure and to the residue is added 200 m is 1,2-dichloroethane. While cooling with ice add 8,07 g 1,3-benzothiazol-5-amine and 17.4 ml of pyridine, followed by stirring at room temperature. The reaction solvent is removed by evaporation under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate), giving 11,23 gN-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide as a yellow foamy mass.

The standard example 58

In 50 ml of methylene chloride was dissolved 2.5 g of 6-nitroindoline and then add 6,37 ml of triethylamine. Under ice cooling is added dropwise 3.51 g of methanesulfonamide, the reaction solution was stirred at room temperature for 3 hours and then add ice-cold water, followed by stirring for 1 hour. The reaction solvent is removed by evaporation under reduced pressure, to the residue add 1M aqueous solution of hydrochloric acid and usageprice the product is separated by filtration, thereby obtaining to 3.52 g of 1-methylsulphonyl-6-nitroindoline in the form of a brown solid.

The standard example 59

11.5 ml of DMF is dissolved 500 mg of 6-nitro-2H-benzothiazin-3(4Hit and there add 114 mg of sodium hydride, 55% purity, with ice cooling, followed by stirring for 30 minutes at room temperature. To the reaction solution add the 444 μl under the conditions and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added 2 ml of methanol under ice cooling, followed by stirring for 10 minutes at room temperature. Then add water and the organic layer extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and then the solvent is removed by evaporation. The resulting residue is purified by chromatography on a column of silica gel (chloroform)to give 308 mg of 4-methyl-6-nitro-2H-1,4-benzothiazin-3(4Hit.

Standard examples 60 and 61

Connection standard examples 60 and 61, are presented in the table below, receive the same manner as in example 59.

The standard example 62

7.4 ml of tetrahydrofuran was dissolved 160 mg of 2-chloro-5-nitro-1,3-benzothiazole and there add to 1.86 ml of a 1M solution of dimethylamine in tetrahydrofuran, followed by stirring for 16.5 hours. To the reaction solution was added water and the organic layer extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate the solvent is removed by evaporation. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate)to give 173 mgN,N-dimethyl-5-nitro-1,3-benzothiazol-2-amine as a yellow solid.

The standard example 63

13.5 ml of a 2M solution of dimethylamine in tet is hydrofuran dissolve 2.0 g of 2,3-dichloropyridine, followed by stirring for 6 hours at 100° C in the conditions of a sealed ampoule. After cooling the reaction solution to room temperature, add a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure, getting 693 mg of yellow oil. Then 693 mg of the obtained yellow oil was dissolved in 5 ml of concentrated sulfuric acid and slowly add the mixed solution of 1.2 g of fuming nitric acid and 0.7 ml of concentrated sulfuric acid. After stirring for 30 minutes under ice cooling to the reaction solution add chilled water and then add sodium carbonate until then, until the solution becomes alkaline. Add ethyl acetate, the organic layer is extracted, dried over sodium sulfate and filtered, and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate), giving 347 mg of 3-chloro-N-methyl-5-nitropyridine-2-amine as a yellow solid.

The standard example 64

In 20 ml of tert-butyl alcohol dissolved 1.4 g of 1-methyl-6-nitro-1H-indole and then add, dividing into four portions, 3.5 g of N-bromosuccinimide. After stirring at room temperature for 4 hours, the reaction solution is concentrated at below the nom pressure. To the residue water is added and the organic layer extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate evaporated solvent. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate), giving 2,44 g of 3,3-dibromo-1-methyl-6-nitro-1,3-dihydro-2H-indol-2-it is in the form of a yellow solid.

The standard example 65

To 2.00 g of 1-methylsulphonyl-6-nitroindoline and a mixed solvent of 100 ml ethanol and 100 ml of tetrahydrofuran, add 300 mg of 10% palladium/charcoal in an argon atmosphere, followed by stirring at room temperature in a hydrogen atmosphere for 3 hours. The reaction solution is filtered through celite and the organic solvent removed from the filtrate under reduced pressure. To the residue is added 200 ml of a mixed solvent of methanol, ethyl acetate and tetrahydrofuran. In an argon atmosphere was added 1 g of a mixture of 10% palladium/charcoal and the mixture was stirred at room temperature for 3 hours in hydrogen atmosphere. The reaction solution is filtered through celite and the organic solvent removed from the filtrate under reduced pressure, obtaining 1.66 g of 1-methylsulphonyl-6-aminoindole in the form of a light yellow solid.

Standard examples 66-71

Connection standard examples 66-71, presents privedennoi following table receive the same manner as in example 65.

The standard example 72

In 70 ml of toluene was dissolved 3.2 g of ethyl 4-formyl-3-nitrobenzoate and then 5.75 g of methyltriphenylphosphonium, followed by stirring for 6 hours when heated to the boiling temperature under reflux. After cooling, the reaction solution was concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate), giving 3,63 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-EN-1-yl]-3-nitrobenzoate as a white solid.

The standard example 73

To a mixture of 1.8 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-EN-1-yl]-3-nitrobenzoate, 32 ml of ethanol and 32 ml of tetrahydrofuran added 640 mg of 10% palladium/charcoal in an argon atmosphere, followed by stirring at room temperature in a hydrogen atmosphere for 2 hours. The reaction solution is filtered through celite and the organic solvent removed from the filtrate under reduced pressure. To the residue are added 50 ml of methanol and 2 drops of concentrated hydrochloric acid, followed by stirring for 30 minutes at 60°C. After cooling to room temperature the reaction solution is concentrated under reduced pressure and to the residue is added water and chloroform, and then perform the operation on R is seleniu. The organic layer is dried over anhydrous sodium sulfate and the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate), giving of 1.16 g of ethyl 2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxylate as a white solid.

The standard example 74

In 10 ml of toluene is suspended 200 mg of 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxylic acid and then add 268 mg diphenylphosphinite (DPPA), 722 mgtert-butyl alcohol and is 0.135 ml of triethylamine, followed by stirring for 14 hours when heated to the boiling temperature under reflux. After cooling, the reaction solution was concentrated under reduced pressure, to the residue water is added and the organic layer extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate the solvent is removed by evaporation. To the residue add 5 ml of 4M hydrochloric acid in ethyl acetate, followed by stirring at room temperature for 7 hours. Then the reaction solution is concentrated under reduced pressure. To the residue is added saturated aqueous sodium bicarbonate and the organic layer is extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate the solvent is removed by evaporation. Received about who headed the remainder of purify by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia), giving 80 mg of 7-amino-1-methyl-3,4-dihydroquinoline-2(1H)-it is in the form of a white solid.

The standard example 75

Suspension 329 mg of 3-chloro-N-methyl-5-nitropyridine-2-ylamine, 489 mg of iron powder and 9 ml of acetic acid was stirred at 60°C for 2 hours. After cooling the reaction solution to room temperature, add the ethanol and the solution is filtered through celite. The filtrate is concentrated under reduced pressure and add ethyl acetate and saturated aqueous sodium bicarbonate solution. To the resulting separation of the organic layer, add 1M aqueous sodium hydroxide solution, followed by separation. The resulting organic layer is dried over anhydrous sodium sulfate and filtered, and then the resulting filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (chloroform:methanol)to give 193 mg of 3-chloro-2-methylamino-5-aminopyridine in the form of a brown oil.

Standard examples 76-124

Connection standard example 76, are presented in the table below, receive the same manner as in example 1.

Connection standard example 77, presented in the table below, receive the same manner as in example 2.

Connection standard examples 78-80 presented in the cm is authorized in the table below, get in the same way as in example 3.

Connection standard examples 81-83 presented in the table below, receive the same manner as in example 17.

Connection standard examples 84-89 presented in the following tables, getting in the same way as in example 1.

Connection standard examples 90-95 presented in the table below, receive the same manner as in example 2.

Connection standard examples 96-124 presented in the following tables, getting in the same way as in example 3.

The standard example 125

2,4-Dinitrobenzaldehyde dissolved in dioxane and water, add methyl acrylate, triethylenediamine at room temperature and the resulting mixture is stirred, receiving methyl 2-[(2,4-dinitrophenyl)(hydroxy)methyl]acrylate.

Standard examples 126-162

Connection standard examples 126-162 presented in the following tables, getting in the same way as in example 17.

The standard example 163

N-(8-Chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-triptorelin hydrolyzing with sodium hydroxide, getting 6-amino-8-chloro-2H-1,4-benzoxazin-3(4H)-he.

Standard examples 164-166

Connection standard is a specific example 164, presented in the table below, receive the same manner as in example 41.

Connection standard example 165, presented in the table below, receive the same manner as in example 42.

Connection standard example 166, presented in the table below, receive the same manner as in example 43.

The standard example 167

Ethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate and tetrahydro-4H-Piran-4-one is treated with triacetoxyborohydride sodium in the presence of acetic acid, getting ethyl 2-{[ethyl(tetrahydro-2H-Piran-4-yl)amino]methyl}biphenyl-4-carboxylate.

Standard examples 168-189

Connection standard examples 168-170 presented in the table below, get, using the same reagents as the standard example 167.

Connection standard example 171, presented in the table below, receive the same manner as in example 57.

Connection standard example 172, presented in the table below, receive the same manner as in example 58.

Connection standard examples 173-175 presented in the table below, receive the same manner as in example 59.

AfterN-alkylation carried out the eat the same way, as in example 59, the compounds according to the standard examples 176-177 presented in the table below, obtained by hydrolysis of the ester group in the same way as in example 17.

Connection standard examples 178-179 presented in the table below, receive the same manner as in example 63.

The standard example 180

Methyl 2,6-dichloro-5-fornicatin treated with dimethylamine in a sealed ampoule, receiving methyl 2-chloro-6-(dimethylamino)-5-fornication, which is then subjected to interact in an atmosphere of hydrogen, in the presence of palladium/charcoal, receiving methyl 6-(dimethylamino)-5-fornication.

Standard examples 181-182

Connection standard examples 181-182 presented in the following tables, receive the same manner as in example 65.

The standard example 183

Ethyl (2S)-2-(2,4-dinitrophenoxy)propanoate subjected to reaction recovery under the action of palladium/charcoal in an atmosphere of hydrogen in ethanol, giving (2S)-6-amino-2-methyl-2H-1,4-benzoxazin-3(4H)-he.

Standard examples 184-186

Connection standard example 184, presented in the table below, receive the same manner as in example 183.

Connection standard examples 185-186 presented in prevedeno the following table receive the same manner as in example 72.

The standard example 187

Palladium/charcoal are added to the ethanol solution of dimensional ether [2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid and the interaction is carried out in a hydrogen atmosphere, getting 6-amino-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-it.

The standard example 188

Connection standard example 188, presented in the table below, receive the same manner as in example 187.

The standard example 189

Methyl 3-amino-4-(1-hydroxy-3-methoxy-2-methyl-3-oxopropyl)benzoate treated with hydrochloric acid in 1,4-dioxane, receiving methyl 3-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate.

The standard example 190

Methyl 4-[(1E)-3-ethoxy-2-methyl-3-oxoprop-1-EN-1-yl]-3-nitrobenzoate and palladium/charcoal are added to ethanol and the resulting mixture is stirred in hydrogen atmosphere, receiving methyl 3-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxylate.

Standard examples 191-198

Connection standard examples 191-198 presented in the following tables, receive the same manner as in example 74.

The standard example 199

Methyl 2-[(2,4-dinitrophenyl)(hydroxy)methyl]acrylate is subjected to interaction in ethanol in the presence of palladium/charcoal, in an atmosphere of hydrogen, olucha 7-amino-3-methylinosine-2(1H)-he.

The standard example 200

4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid and diethylamine dissolved in DMF, add at room temperature 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and the resulting mixture is stirred, gettingtert-butyl 2-[(diethylamino)carbonyl]morpholine-4-carboxylate.

Standard examples 201-203

Connection standard examples 201-203 presented in the table below, receive the same manner as in example 201.

The standard example 204

N-(3-AMINOPHENYL)ndimethylacetamide treated with cinnamoylcocaine in the presence of a base and then obtained N-[3-(acetylamino)phenyl]-3-phenylacrylate treated with aluminium chloride, which gives N-(2-oxo-1,2-dihydroquinoline-7-yl)ndimethylacetamide.

The standard example 205

N-(3-AMINOPHENYL)ndimethylacetamide handle 2-nitrophenylacetonitrile in the presence of triethylamine, and then the obtained compound is treated with iodomethane and potassium carbonate. Then the product is treated with thioglycolic acid, which gives N-[3-(methylamino)phenyl]ndimethylacetamide.

The standard example 206

Connection standard example 206, are presented in the table below, receive the same manner as in example 204.

The standard example 207

a 1.2 M solution of N-(2-oxo-1,2-dihydroquinoline-7-yl)ndimethylacetamide in the art hydrochloric acid-ethanol is heated to the boiling temperature under reflux, getting 7-aminoquinoline-2(1H)-he.

The standard example 208

Connection standard example 208, presented in the table below, receive the same manner as in example 207.

The standard example 209

2-Chloro-1,5-dinitro-3-(trifluoromethyl)benzene is treated diversilobum ester of malonic acid in the presence of sodium hydride, getting dimensiony ester [2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid.

The standard example 210

Connection standard example 210, presented in the table below, receive the same manner as in example 209.

The standard example 211

Ethyl-5,6-dichloronicotinic, (2,4-dimethoxybenzyl)aminogidrohlorid and triethylamine is added to the chloroform and the resulting mixture was stirred at room temperature, receiving 5-chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinate.

The standard example 212

5-Chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinate is treated with sodium hydroxide in ethanol, receiving 5-chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinic acid. To add connection toluene, diphenylphosphoryl (DPPA),tert-butyl alcohol and triethylamine, and the resulting mixture is stirred while heating to the boiling temperature under reflux. The compound obtained is treated triperoxonane KIS is Auteuil, that gives 3-chloropyridin-2,5-diamine.

The standard example 213

1-Methyl-5-nitro-1H-indole-2,3-dione is treated with TRIFLUORIDE (diethylamino)sulfur, getting 3,3-debtor-1-methyl-5-nitro-1,3-dihydro-2H-indol-2-it.

The standard example 214

3,3-Debtor-1-methyl-5-nitro-1,3-dihydro-2H-indol-2-he is subjected to hydrogenation reactions using the catalyst of Raney Ni, in a stream of hydrogen, which gives 5-amino-3,3-debtor-1-methyl-1,3-dihydro-2H-indol-2-it.

The standard example 215

5-Nitro-3-(trifluoromethyl)pyridin-2(1H)-he is treated with thionyl chloride and then the resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine is treated with dimethylamine, receivingN,Ndimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine.

The standard example 216

In the presence of potassium carbonate 1-fluoro-2,4-dinitrobenzene is treated with ethyl (2S)-(-)-2-hydroxypropanoate getting ethyl (2S)-2-(2,4-dinitrophenyl)propionate.

The standard example 217

Connection standard example 217, presented in the table below, receive the same manner as in example 216.

The standard example 218

Triperoxonane anhydride is added to a mixed solution of 6-amino-2H-1,4-benzoxazin-3(4H)-she and a mixture of chloroform-tetrahydrofuran, getting 2,2,2-Cryptor-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ndimethylacetamide.

The standard example 219

2,2,2-Cryptor-N-(3-oxo-3,-dihydro-2H-1,4-benzoxazin-6-yl)ndimethylacetamide treated with N-chlorosuccinimide in DMF, receiving N-(8-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-triptorelin.

Standard examples 220-221

Connection standard examples 220-221 presented in the table below, receive the same manner as in example 219.

The standard example 222

Ethyl 3-chloro-4-hydroxy-5-methylbenzoate process anhydride of triftoratsetata in the presence of a base, getting ethyl 3-chloro-5-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate.

The standard example 223

Ethyl 2-({ethyl[(2-nitrophenyl)sulfonyl]amino}methyl)biphenyl-4-carboxylate is treated with thioglycolic acid in the presence of a base, getting ethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate.

The standard example 224

1-Chloro-2-methylpropan-2-ol is treated with ethylamine, getting 1-(ethylamino)-2-methylpropan-2-ol.

The standard example 225

Tert-butil-2-[(diethylamino)carbonyl]morpholine-4-carboxylate is treated with an ethyl acetate 4M solution of hydrochloric acid in ethyl acetate, receivingN,N-diethylpropion-2-carboxyhemoglobin.

Standard examples 226-229

Connection standard examples 226-229 presented in the table below, receive the same manner as in example 225.

The standard example 230

(2R,6S)-2,6-Dimethylpiperazine process is di-tert-butylcarbamoyl, getting 4-butoxycarbonyl-2,6-dimethylpiperazine, which is then treated with acetylchloride in dichloromethane in presence of triethylamine, which gives 1-acetyl-4-butoxycarbonyl-2,6-dimethylpiperazine. After that connection is treated with hydrochloric acid, receiving (2R,6S)-1-acetyl-2,6-dimethylpiperazine.

The standard example 231

(2-piperidine-1-retil)amine is treated with 2-methylpropanoate in the presence of triethylamine, receiving 2-methyl-N-(2-piperidine-1-retil)propanamide.

The standard example 232

Connection standard example 232, presented in the table below, receive the same manner as in example 231.

The standard example 233

(2R,6S)-1-Acetyl-2,6-dimethylpiperazine restore lydialydia, receiving (2R,6S)-1-ethyl-2,6-dimethylpiperazine.

The standard example 234

3-(Isobutylamino)propyl-2-methylpropanoate restore lydialydia, receiving N-(3-hydroxypropyl)-2-methylpropanamide.

The standard example 235

Connection standard example 235, presented in the table below, receive the same manner as in example 234.

Example 1

In 20 ml of 1,2-dichloroethane suspended 500 mg of a mixture of 2-(piperidine-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalents of sodium chloride and then added 174 mg 3 marks aniline, dissolved in 2 ml of 1,2-dichloroethane. While cooling with ice add 694 mg O-benzotriazol-1-yl-N,N,N',N'-tetramethylethylenediamine and 211 μl of N-methylmorpholine, followed by stirring for 30 hours at room temperature. To the reaction solution was added water and the organic layer is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, followed by removal of solvent by evaporation. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia), which givesN-(3-methoxyphenyl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide. The compound was dissolved in 3 ml of ethyl acetate and then added 1 ml of an ethyl acetate 4M hydrochloric acid. The solvent is removed by evaporation and carry out crystallization from ethanol, getting 103 mgN-(3-methoxyphenyl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxymethylated in the form of a white solid powder.

Example 2

A mixture of 227 mg of 3-aminophenol, 3-(piperidine-1-ylmethyl)biphenyl-4-carboxylic acid (2,08 mmol) and sodium chloride are suspended in 7 ml of DMF and then added at room temperature 599 mg of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, followed by stirring for 10 hours. To the reaction solution was added ethyl acetate and 1M aqueous solution of hydrochloric acid is you and sodium bicarbonate is added to aqueous layer, received by the Department, until the aqueous layer becomes alkaline. To the aqueous layer add ethyl acetate and perform the operation of division. The resulting aqueous layer is dried over anhydrous magnesium sulfate and then the solvent is removed by evaporation. The obtained white solid was dissolved in ethanol and added 4M an ethyl acetate solution of hydrochloric acid followed by removal of solvent by evaporation. To the obtained residue, add ethanol and water and carry out crystallization, getting 436 mgN-(3-hydroxyphenyl)-3-(piperidine-1-ylmethyl)biphenyl-4-carboxymethylated in the form of a white powder.

Examples 3-9

Compound in examples 3-5, are presented in the table below, receive the same manner as in example 2.

Compound in examples 6-9, presented in the table below, receive the same manner as in example 1.

Example 10

To 30 ml of thionyl chloride is added 500 mg of a mixture of 2-(piperidine-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalents of sodium chloride and 1 drop of DMF, followed by stirring for 2 hours at room temperature. The reaction solution is concentrated under reduced pressure and to the residue is added toluene followed by concentration under reduced pressure. After drying of the residue under reduced pressure on billaut 20 ml of methylene chloride. Under ice cooling to the reaction mixture 277 mg of 3,4,5-trichloroaniline and 0.59 ml of triethylamine and the resulting mixture was stirred at room temperature for 3 hours and at 40°C during the night. The reaction mixture was concentrated under reduced pressure and the residue purified by chromatography on a column of silica gel (chloroform:methanol: aqueous ammonia)to giveN-(3,4,5-trichlorophenyl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide. The compound is dissolved in chloroform and added 1 ml of 4M dioxane solution of hydrochloric acid. The solvent is removed by evaporation and the resulting oil is crystallized from diethyl ether, receiving 450 mgN-(3,4,5-trichlorophenyl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxymethylated in the form of a white powder.

Examples 11-99

Connection example 11, are presented in the table below, receive the same manner as in example 10.

Connection examples 12-43 presented in the following tables, receive the same manner as in example 1.

Connection examples 44-99 presented in the following tables, getting in the same way as in example 10.

Example 100

To 10 ml of chloroform, add 250 mgN-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide and 169 mg of piperidine-4-carboxamide, followed by stirring for 3 day is at room temperature. The reaction solvent is removed by evaporation under reduced pressure and the residue purified by chromatography on a column of silica gel (chloroform:methanol)to give the substance in the form of a yellow foam. To the obtained substance is added 2 ml of ethanol and 1 ml of an ethyl acetate 4M solution of hydrochloric acid, followed by removal of solvent under reduced pressure. The residue is crystallized (ethanol:water:ethyl acetate)to give 205 mg of 1-({4-[(1,3-benzothiazol-5-ylamino)carbonyl]biphenyl-2-yl}methyl)piperidine-4-carboxymethylated.

Examples 101-111

Connection examples 101-111 presented in the following tables, getting in the same way as in example 100.

Example 112

In 5 mlN,N-dimethylacetamide was dissolved 230 mgN-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide and then added under ice cooling 252 mg of m-chloroperbenzoic acid, followed by stirring for 24 hours at room temperature. To the reaction solution add 5 ml of water and 1016 mg hydrosulfite sodium, in two portions, followed by stirring for 2 hours at room temperature. To the reaction system, water is added and the organic layer extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent is removed by evaporation. Received estato is purified by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia), getting a yellow oil. The specified oil is dissolved in 5 ml of ethyl acetate and then added 1 ml of an ethyl acetate 4M hydrochloric acid. The solvent is removed by evaporation and the resulting solid product is recrystallized from ethanol, giving 61 mgN-(4-methyl-1,1-dioxo-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxymethylated in the form of a white powder.

Example 113

Compounds according to example 113, presented in the table below, receive the same manner as in example 10.

Example 114

In 15 ml of methanol is suspended 250 mgN-(3-oxo-2,3-dihydro-1H-1-inden-5-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide and then add 40 mg of sodium borohydride at room temperature. The reaction solution was stirred at room temperature for 1 hour and then add 5 ml of water. The reaction solution is evaporated under reduced pressure. After dissolving the precipitate obtained in the mixed solution of chloroform and water, the solution extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and then filtered, and the solvent is removed by evaporation. The resulting residue is dissolved in 10 ml of ethanol and then added 0.5 ml of an ethyl acetate 4M hydrochloric acid. The solvent is removed by evaporation and the resulting residue is recrystallization from ethanol, that gives 113 mgN-(3-hydroxy-2,3-dihydro-1H-1-inden-5-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxymethylated in the form of a white powder.

Examples 115-181

Connection examples 115-121 presented in the following tables, receive the same manner as in example 1.

Connection examples 122-123 presented in the table below, receive the same manner as in example 2.

Connection examples 124-181 presented in the following tables, getting in the same way as in example 10.

Example 182

In 20 ml of DMF is dissolved 500 mg of 4-{[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]carbonyl}biphenyl-2-yl)methylmethanesulfonate, 123 mgN-methylhexan-1-amine, 177 mg of potassium carbonate and 212 mg of potassium iodide, followed by stirring for 3 hours at 70°C. After the operation for separating the solvent is removed by evaporation. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol:aqueous ammonia), which gives a colorless viscous mass. Add ethanol and 0.4 ml of an ethyl acetate 4M hydrochloric acid and the solvent is removed by evaporation. The residue is washed with a mixture of (2-propanol:ethanol)to give 233 mg of 2-{[hexyl(methyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)biphenyl-4-carboxymethylated as Belogorodka substances.

Examples 183-196

Connection examples 183-196 presented in the following tables, getting in the same way as in example 182.

Example 197

To 0.7 ml of a solution of 19 mgN-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide 1,4-dioxane add 0.1 ml solution12 mg of 4-(4-chlorophenyl)pyrrolidin-3-methylcarbazole inN-methyl-2-pyrrolidinone and then added 14 mg of potassium carbonate and 12 mg of potassium iodide, followed by stirring for 1 day at room temperature. To the filtrate obtained by filtering the reaction solution, add 0.4 ml of ethyl acetate, extracted, passing through diatomaceous column, containing 0.1 ml of water and elute 0.4 ml of ethyl acetate. The solvent from the eluate is removed by evaporation under reduced pressure and the resulting residue purified by preparative method GHUR (column: Symmetry (registered trademark) C18 5 μm, 19 mm × 100 mm, solvent: a mixture of MeOH/0.1% of HCOOH-H2O = 10/90 (0 min) - 10/90 (1 min) - 100/0 (9 min) - 100/0 (12 min), flow rate: 30 ml/min), receiving 0.4 mg of methyl(3R,4S)-1-({4-[(1,4-benzothiazole-5-ylamino)carbonyl]biphenyl-2-yl}methyl)-4-(4-chlorophenyl)pyrrolidin-3-carboxylate.

Examples 198-232

Connection examples 198-232 presented in the following tables, getting in the same way as in example 197.

Structural formulas and physical properties of the above the data connections over standard examples of compounds according to the examples below in table 1-38. In addition, the compounds presented in the following tables 39 and 40, can easily be obtained in about the same way as the methods described in the above sample, examples, or methods of production, or the use of slightly modified methods obvious to the person skilled in the art, after reading these ways. In this regard, the symbols in the tables have the following meanings.

Rf: standard example number, Ex: example number, No: compound number, Structure: structural formula salt: salt (2HCl:dihydrochloride, is not described in the form of free base), Me: methyl group, Et: ethyl group, Ac: acetyl group, iPr: isopropyl group, nPr: n-sawn group, tBu: tert-bucilina group, Boc: tert-butoxycarbonyl group, Ph: phenyl group, Ts: p-toluensulfonyl group, Ms: methanesulfonyl group, DATA: data on physical properties, NMR spectrum, nuclear magnetic resonance NMR (TMS (TMS)internal standard:1H-NMR: 400 MHz or 300 MHz, solvent for the case when not specifically listed: DMSO-d6(DMSO-d6), FP: FAB-MS(FAB-MC) (M+H)+H: retention time on GHWR the following conditions GHUR (minute).

Conditions

Column: Wakosil-II 5C18 AR 2 mm H 30 mm, solvent: a mixture of MeOH/5 mm triperoxonane acid-H2O = 10/90 (0 min) - 100/0 (4,0 min) - 100/0 (4.5 min), flow rate: 1.2 ml/min

Industrial applicability

Because the connection is in the present invention have excellent inhibitory activity against activation of VR1 capsaicin receptor, these compounds are useful as pharmaceuticals, in particular, therapeutic agents against various types of pain, including neuropathic pain and inflammatory pain, headaches, such as migraine and histamine headache, itching, urinary bladder diseases including overactive bladder and interstitial cystitis, and the like.

Excellent inhibiting activity of the compounds according to the invention in relation to the activation of VR1 capsaicin receptor is confirmed by the following test methods.

The test example 1

Test for receptor binding using cells stably expressing VR1

1) Obtaining cells stably expressing VR1 person

Primary full-size cDNA encoded VR1 person receive the following way. Originally performed reverse transcription of mRNA of the human brain, using mRNA-dependent DNA polymerase for the synthesis of the first cDNA strands. Then, using the first strand cDNA as template, perform the test with polymerase PCR amplification according to the method of "hot start"using Taq DNA polymerase. The above PCR performed initially by conducting thermal denaturation at 98°C (1 min) and then repeating the cycle, including 98°C (15 sec)/63°C (30 seconds)/72°C (3 min), 35 times using olig the nucleotide, consisting of a base sequence from 424 to 443 in the known cDNA sequences VR1 human (GenBank AJ277028.1), as a sense primer and an oligonucleotide probe comprising a complementary sequence of bases from 3082 up to 3100 as antisense primer.

Amplified fraction DNA clone using pCR-XL-TOPO vector (TOPO XL PCR Cloning Kit; Invitrogen, USA). The obtained plasmid DNA fermented using restrictase EcoRI, releasing pure VR1-cDNA, which is then integrated into the plasmid pcDNA3.1(+) (Invitrogen, USA). The above operations of genetic engineering is carried out according to known methods (Sambrook, J. et al, Molecular Cloning-A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY, 2001) and the instructions attached to the individual reagents.

Next, perform the transduction obtained pcDNA3.1-VR1 in HEK293 cells or cells CHO-K1. Cells VR1/HEK293 get using DMEM medium (Invitrogen, USA)containing 10% FBS, 100 μg/ml streptomycin, 100 U/ml penicillin and 400 μg/ml G418, and VR1 cells/CHO get using HumF12 medium (Invitrogen, USA)containing 10% FBS, 100 μg/ml streptomycin, 100 U/ml penicillin and 400 μg/ml G418, receiving cell line, stably expressing VR1 person. Cells stably expressing the receptor, passedout in the respective above-mentioned environment.

2) the Method of producing membranes

After culturing the above-mentioned cells VR1/HEK293 steklyannyh Petri dishes in a large number of medium is removed and cells are scraped, adding ice PBS. The obtained cells are centrifuged at 1000 rpm at 4°C for 10 minutes. Once added to the obtained precipitate buffer for homogenization (25 mm Tris-HCl, 220 mm sucrose, pH 7,4) and homogenizing the mixture is performed with centrifugation at 2200 rpm, at 4°C, for 10 minutes. The resulting supernatant centrifuged at 30,000×g, at 4°C, for 20 minutes and treated by adding 25 mm Tris-HCl, pH 7,4 to the obtained precipitate, and centrifugation at 30000×g, at 4°C, for 20 minutes, repeat twice. The precipitate is suspended in 25 mm Tris-HCl, pH 7.4 and the protein content determined using a coloring solution for the analysis of protein (BioRad, USA). Thus obtained membrane preparation stored at -80°C.

3) Test for receptor binding

The test is carried out using a modified method [Neurosci. 57: 747-757 (1993)]. Analytical buffer (25 mm Tris-HCl, 0.025% of BSA, pH 7,4) (147 μl), 3 μl of the test compound, 50 μl of [3H]RTX (about 50,000 houses./min; Perkin-Elmer Life Science, USA), 100 μl of the above-mentioned membrane preparation (protein about 25 μg) is mixed and incubated at 37°C for 60 minutes, and then incubated on ice for 10 minutes. Ice α1-acid protein (AGP; Sigma) is added in an amount of 200 μg/50 μl, and then additionally incubated for 5 minutes. is incubatio complete fast filtering the mixture using a filter GF/B (Perkin-Elmer Life Science, USA). After seven flush 25 mm ice Tris-HCl buffer (pH 7,4) the radioactivity of the filter was measured using a liquid scintillation counter (2500TR; Packard, USA). As for specific binding from the total binding of [3H]RTX and membrane fractions of cells stably expressing VR1 man, the percentage of substituted 1 µm RTX, is viewed as a specific binding due to the VR1 receptor. Evaluation of test compounds carried out as follows. Namely, the decrease in binding when adding the connection is defined as a relative value, taking the reduction of binding of adding RTX 100%. Then the value of the IC50calculated by the method of logistic regression.

For example, the compounds of examples 1, 7, 21, 33, 60, 71, 78, 85, 87, 110, 117, 122, 123, 129, 130, 143, 163, 170, 181 and 195 give the value of the IC50equal to 1 μm or less. Based on this test it can be concluded that the compounds according to the invention have affinity to the receptor VR1.

The test example 2

The study absorption45CA

using stably expressing cells VR1

Cells VR1/CHO seeded in 96-well white culture plate at a density of 30,000 cells per well. After 24 hours of cultivation in the above environment, the environment is replaced by 25 μl of analytical buffer (PBS, 0.1 mm CaCl 2, 1 mm MgCl2, 10 mm HEPES, 10 mm glucose, 0.025% of BSA, pH of 7.4) followed by incubation for 10 minutes at 37°C. the wells add 25 μl of a mixed solution of approximately 4 BCF45Ca, capsaicin (Sigma, USA), brought to a final concentration of 300 nm, and the test compound, followed by incubation for 10 minutes at 37°C. a Mixed solution washed three times with buffer for washing (PBS, 0.1 mm CaCl2, 1 mm MgCl2)add 17 ál of 0,1N. NaOH and 100 μl of liquid scintillator (microscinti-PS; Perkin-Elmer Life Science, USA) and measure the radioactivity using a scintillation counter for microplate (Top Count; Perkin-Elmer Life Science, USA). Specific absorption45Ca receptor VR1 induced by capsaicin, defined as the reduction caused by 10 μm capsazepine, VR1 antagonist, (Sigma, USA), compared with the total absorption45Ca in cells upon stimulation with 300 nm capsaicin. Evaluation of test compounds carried out as follows. Namely, the decrease in absorption when adding the connection is defined as a relative value, taking the reduction in the absorption of adding capsazepine for 100%. Then the value of the IC50calculated by the method of logistic regression.

As a result, the compounds according to the invention possess a strong inhibitory activity against absorption45Ca by VR1.

The test example 3

COI is food using capsaicin

The test is carried out according to [Neuropharmacol. 31: 1279-1285 (1992)]. The introduction of 1.6 μg of capsaicin in the sole of the foot mouse (ddY, male, age 4-5 weeks) causes a scraping motion with his paw. Measuring the time of development scraping motion paw within 5 minutes after administration, evaluate the inhibitory effect on the expression of pain. The test compound administered intraperitoneally injected 30 minutes before injection of capsaicin or administered orally 45 minutes before injection of capsaicin. Evaluation of the test compounds is carried out, determining the extent of inhibition for each group receiving the test connection and taking the time symptoms scraping motion with his paw in the group receiving the solvent for 100%.

As a result, the compounds according to the invention possess a strong inhibitory effect on the expression of pain as in the case of intraperitoneal introduction, and in the case of oral administration. As for the characteristic of the compounds corresponding to the examples, the degree of inhibition for the group receiving the test compound orally (30 mg/kg)given below in table 41.

Table 41
ConnectionThe degree of inhibition (%)ConnectionThe degree of inhibition (%)
Example 33 66Example 12369
Example 7876Example 12991
Example 8586Example 13062
Example 8767Example 17068
Standard connection1)17 (262))
1)Connection example 115 in patent document 1.

2)Value by oral administration of 100 mg/kg

On the other hand, in this study the connection example 115, described in the above patent document 3, do not show significant inhibitory activity even at a dose of 100 mg/kg

On the basis of examples of tests 1-3, since the compounds according to the invention are notable, the overwhelming effect based on inhibition of the activation of the receptor VR1, it is expected that these compounds will be effective pain relievers.

Pharmaceutical composition containing one or more types of the compounds according to the invention and pharmaceutically acceptable salts of these compounds as an active ingredient, can be represented in the form of tablets, powders, fine granules, granules, capsules, pills, liquids is her injection solutions, suppositories, ointments, casic, and the like, which are used carriers and fillers commonly used for the formulation, and other additives, administered orally or parenterally.

As solid compositions for oral administration according to the invention using tablets, powders, granules and the like. For such solid compositions one or more active substances are mixed with at least one inactive diluent, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate-magnesium aluminate, and the like. According to the conventional methods, the composition may contain auxiliary substances, other than the inactive diluent, for example, lubricants such as magnesium stearate, a disintegrator such as cellulose, glycolate, calcium, stabilizers, soljubilizatory or promotes the decomposition of funds. If necessary, tablets and pills may be coated forming the shell means, able to dissolve in the stomach and intestines.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, and the like, and contains commonly used inactive dilute the Lee, for example, purified water or ethyl alcohol. The composition may contain auxiliary agents such as soljubilizatory contributing to the dissolution of funds, moisturizing and suspendresume tools, sweeteners, corrigentov, flavorings and preservatives.

Injections for parenteral administration comprise aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Thinners for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Solvents for non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (trade mark) and the like.

Such compositions can optionally contain additives, including isotonic means, preservatives, humectants, emulsifiers, dispersing funds, stabilizers, soljubilizatory and contributing to the dissolution of funds. These compositions can be sterilized by filtration through, for example, inhibiting bacteria filter, by mixing with bacterial means, or by irradiation. These compositions can also be obtained in the form of aseptic solid compositions, and compositions can be used after dissolution in asepticism the th water or aseptic solvent for injection before use.

Clinical dose of the compounds according to the invention for the person selected to meet the symptoms, body weight, age, sex of patients, and the like. However, the dose is approximately from 0.1 to 500 mg per day for an adult in the case of oral administration, and from 0.01 to 100 mg, in the case of parenteral administration, the daily dosage administered once a day or dividing into several doses. Because the dose may vary depending on various conditions, in some cases, sufficient is a smaller dose than the specified upper limit.

1. Benzamidine derivative represented by the General formula (I)

where the symbols have the following meanings:

or.

L is a lower alkylene,

E. the cycle represents a benzene or a 5-membered heteroaromatic ring containing a sulfur atom as a heteroatom;

D cycle represents a monocyclic or bicyclic hydrocarbon cycle, such as naphthalene or benzene, optionally condensed with C5-7cycloalkyl; 6-membered monocyclic heteroaromatic cycle-containing nitrogen atom as the heteroatoms, or a 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 atoms Odie is ukovich or different heteroatoms, selected from the group comprising N, S and O,

G cycle is a 5-7-membered monocyclic saturated or partially saturated, a heterocycle or a 10-membered ring of the bicyclic heterocycle containing 1 to 3 atoms, equal or different heteroatoms selected from the group comprising N, S and O,

R1-R9are the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, =O, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -S-lower alkyl, -SO-lower alkyl, -SO2-lower alkyl, -C(=O)-NH2-C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -NH-SO2-lower alkyl, -SO2-NH2, -SO2-NH-lower alkyl, -C(=O)-lower alkyl, -NO2,

R6-R9represent a 6-membered saturated monocyclic heterocycle containing a nitrogen atom as a heteroatom;

R10represents a hydrogen atom,

R11-R15represents identical or different hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, -COOH, -CN, -C(=O)-NH2-C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -NH-C(=O)-lower alkyl, -lower alkylene-NH-SO2-phenyl, -C(=O)-O-lower alkyl, -lower alkylene-OH, -lower alkylene-C(=O)-NH-lower alkyl, -lower alkyl is n-C(=O)-N(lower alkyl) 2-the inferior alkylen-C(=O)-NH2-the inferior alkylen-C(=O)-OH, -lower alkylene-O-lower alkyl, -lower alkylene-O-C(=O)-lower alkyl, -lower alkylene-phenyl, C3-6cycloalkyl, phenyl, -(5-6-membered saturated, unsaturated monocyclic heterocycle containing a nitrogen atom or an oxygen or sulphur as heteroatoms, or the bicyclic heterocycle containing 1 heteroatom selected from the group comprising N and O), -O-(7-membered ring of the bicyclic heterocycle containing 2 identical atom selected from O), -lower alkylene-(6-membered monocyclic saturated, the heterocycle containing a nitrogen atom as a heteroatom), -C(=O)-(6-membered monocyclic saturated a heterocycle containing 1 nitrogen atom as a heteroatom), and

the above-mentioned monocyclic or the bicyclic heterocycle can be substituted by halogen atom(s), lower alkyl(s), -O-lower alkyl or-HE, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where D cycle, R1-R9and R11-R15have the following meanings:

D cycle represents a monocyclic or bicyclic hydrocarbon cycle, such as naphthalene or benzene, 6-membered monocyclic heteroaromatic cycle-containing nitrogen atom as the heteroatoms, or a 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 atoms on Yakovych or different heteroatoms, selected from the group comprising N, S and O,

R1-R9are the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, =O, -NH2, -NH-lower alkyl, -N(lower alkyl)2, -S-lower alkyl, -SO-lower alkyl, -SO2-lower alkyl, -C(=O)-NH2-C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -SO2-NH2,

R11-R15represents the same or different, a hydrogen atom, halogen atom, lower alkyl, halogen-substituted lower alkyl, -OH, -O-lower alkyl, -COOH, -CN, -C(=O)-NH2-C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -NH-C(=O)-lower alkyl, -C(=O)-O-lower alkyl, -lower alkylene-O-lower alkyl, -lower alkylene-phenyl, C3-6cycloalkyl, phenyl, -(5-6-membered saturated, unsaturated monocyclic heterocycle containing a nitrogen atom as a heteroatom, or the bicyclic heterocycle containing 1 heteroatom selected from the group comprising N and O), -lower alkylene-(6-membered monocyclic saturated, the heterocycle containing a nitrogen atom as a heteroatom), -C(=O)-(6-membered monocyclic saturated, a heterocycle containing 1 nitrogen atom as a heteroatom).

3. The compound according to claim 2 wherein the group denoted by a in the above formula (I), corresponds to the following formula:

where a cycle of G and R13-R15take the same values as in the above formula (I).

4. The compound according to claim 3, where the cycle denoted by G in the above formula (I), means a nitrogen-containing saturated the heterocycle, and the nitrogen atom of the cycle is associated with L.

5. The compound according to claim 3, where the cycle denoted by G in the above formula (I)is a cycle selected from the group comprising morpholine, piperidine or pyrrolidine, and the nitrogen atom of the cycle is associated with L.

6. The compound according to claim 3, where the cycle is denoted by D in the above formula (I)is a cycle selected from the group including benzothiazole, quinoline, isoquinoline, indolin, tetrahydroquinolin, tetrahydroisoquinoline, 3,4-dihydro-2H-1,4-benzoxazin, dihydroquinoline and dihydroisoquinoline.

7. The compound according to claim 3, where the cycle is denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group selected from the following formulas:

where the symbols have the following meanings:

R6aand R6b: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7a, R8a, R7band R8b: the same or different, a hydrogen atom, halogen atom, lower alkyl rehalogenating lower alkyl.

8. The compound according to claim 3, where the cycle is denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group selected from the following formulas:

where the symbols have the following meanings:

R6sand R6d: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7c, R8c, R7dand R8d: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

9. The compound according to claim 2 wherein the group denoted by a in the above formula (I)has the following formula:

where the symbols have the following meanings:

R11aand R12arepresent the lowest alkylene-O-lower alkyl, -lower alkylene-phenyl, C3-6cycloalkyl, phenyl, -(6-membered saturated monocyclic heterocycle containing an oxygen atom or sulfur as a heteroatom), lowest alkylen-(6-membered monocyclic saturated, the heterocycle containing a nitrogen atom as a heteroatom).

10. The connection according to claim 9, where the cycle is denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group, the choice is emuu of the following formulas:

where the symbols have the following meanings:

R6Aand R6b: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7a, R8a, R7band R8b: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

11. The connection according to claim 9, where the cycle is denoted by D in the above formula (I), together with the attached groups denoted by R6-R9forms a group selected from the following formulas:

where the symbols have the following meanings:

R6cand R6d: the same or different, a hydrogen atom, lower alkyl or halogen-substituted lower alkyl and

R7c, R8c, R7dand R8d: the same or different, a hydrogen atom, halogen atom, lower alkyl or halogen-substituted lower alkyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt of the compounds, where benzamidine derivative represented by the above formula (I), means, at least one compound selected from the group comprising N-1,3-benzothiazol-5-yl-2-{[cyclohexyl(isopropyl)amino]methyl}biphenyl-4-carboxamide, N-(1-methyl-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamid, N-(3,3-dimethyl-2-oxo-2,3-dihydro-1N-indol-6-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide, 2-{[ethyl-(2-hydroxy-2-methylpropyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide, N-(1-methyl-2-oxo-1,2-dihydroquinoline-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide, N-(3-methyl-2-oxo-1,2-dihydroquinoline-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide, N-(2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamid, 2-{[ethyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide, N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-3-(piperidine-1-ylmethyl)-4-(2-thienyl)benzamide, 2-{[ethyl(tetrahydro-2H-thiopyran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide, 2-{[isobutyl-(2-piperidine-1-retil)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide, N,N-diethyl-4-[(4-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]carbonyl}biphenyl-2-yl)methyl]morpholine-3-carboxamide, 2-[(4-methyl-1,3'-bipiperidine-1'-yl)methyl]-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide, 2-(piperidine-1-ylmethyl)-N-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide, N-(2-oxo-1,2-dihydroquinoline-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide, 4'-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidine-1-and is methyl)biphenyl-4-carboxamid, N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(2-methylpyrrolidine-1-yl)methyl]biphenyl-4-carboxamide, N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide, N-[1-(2-foradil)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide and N-[(2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide.

13. Pharmaceutical composition having inhibitory activity against activation of the receptor VR1 containing benzamidine derivative represented by the General formula (I) according to claim 1, or pharmaceutically acceptable salt of the specified derivative and a pharmaceutically acceptable carrier.

14. The composition according to item 13, which is the inhibitor of the activation of VR1.

15. The composition according to item 13, which is a prophylactic or therapeutic agent against the pain.

16. Application benzamide derivative represented by the General formula (I) according to claim 1, or pharmaceutically acceptable salts of the specified derivative to obtain a prophylactic or therapeutic agent against the pain.

17. A method of preventing or treating pain comprising the administration to a mammal an effective amount of benzamide derivative represented by the General formula (I) according to claim 1, or pharmaceutically acceptable salts of the specified derivative.

18. The connection of claim 8, where m is Nisha least one of R13-R15represents a lower alkyl, -O-lower alkyl, piperidinyl or lower alkylene-piperidinyl, while others are hydrogen.

19. The compound according to claim 1 or its pharmaceutically acceptable salt, where benzamide derivative represented by formula I is N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(2-piperidine-1-yl)methyl]biphenyl-4-carboxamide.

20. The compound according to claim 1 or its pharmaceutically acceptable salt, where benzamide derivative represented by formula I is 2-{[ethyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide.

21. The compound according to claim 1 or its pharmaceutically acceptable salt, where benzamide derivative represented by formula I is a 4'-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide.

22. The compound according to claim 1 or its pharmaceutically acceptable salt, where benzamide derivative represented by formula I is N-[(2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-2-(piperidine-1-ylmethyl)biphenyl-4-carboxamide.

23. The compound according to claim 1 or its pharmaceutically acceptable salt, where benzamide derivative represented by formula I is N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(2-methylpyrrolidine-1-yl)methyl]iphenyl-4-carboxamide.

24. The compound according to claim 1 or its pharmaceutically acceptable salt, where benzamide derivative represented by formula I is 2-[(2,5-dimethylpiperidin-1-yl)methyl]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) or their pharmaceutically acceptable salts wherein R1 and R2 are similar or different and chosen independently from group comprising aryl and heteroaryl. Each of them as a substitute comprises optionally from one to sic groups chosen from group comprising the following groups: (a) halogen atom; (b) -OCF3 or -OCHF2; (c) -CF3; (d) -CN; (e) alkyl; (f) R18-heteroaljyl; (k) hydroxyl; (l) alkoxyl comprising cyclopropylmethoxyl, and (s) trifluoroalkoxyl; R3 means hydrogen atom (H); R4, R5, R7 and R8 are similar or different and chosen independently from group comprising H, -OH, alkyl, heteroalkyl and

under condition that if Z and/or X means nitrogen atom (N) then all radicals R4, R5, R7 and R8 don't mean -OH; R6 means -C(O)R15; R9 and R10 mean H; R11 is chosen from group comprising H and alkyl; R12 is chosen from group comprising H and alkyl; R13 is chosen from group comprising alkyl and alkoxyl; R14 means H; R15 is chosen from group comprising -NR16R17, -OR16 and alkyl wherein R16 and R17 are similar or different and chosen independently from group comprising H and alkyl; R18 means a substitute chosen from group comprising lower alkyl, halogen alkyl, halogenalkyl, alkoxycarbonyl, dialkylamino-group and piperidinyl; X and Z are similar or different and chosen independently from carbon atom (C) and N. Proposed compounds possess properties of inhibitor of 17β-hydroxysteroid dehydrogenase of type 3. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical composition.

16 cl, 23 tbl, 651 ex

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry.

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

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of compositions formulated as follows or its salt, solvate or prodrug of medical agent for treatment or prevention of disease state mediated by glucokinase (GLK). Besides, given invention concerns new group of composition formulated as (I) and to method of specified compositions production. The invention enables to widen range of agents used for treatment or prevention of disease conditions mediated by glucokinase (GLK) where each of R1, R2, R3, n and m has values specified in the description.

EFFECT: increased efficiency.

19 cl, 51 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: organic chemistry, medicine, pharmacy, cosmetology.

SUBSTANCE: invention relates to novel biphenylmethylthiazolidinedions of the general formula (I): , their salts, and to their optical and geometrical isomers possessing agonistic activity with respect to PPARγ receptors, to pharmaceutical and cosmetic compositions based on thereof, and to their using for preparing composition used in treatment of different cutaneous diseases. In compound of the formula (I) R1 means radical of the following formula (a): or (b): ; R2 and R3 mean hydrogen atom; X means binding groups showing the following structures: -CH2-N(R8)-CO-, -N(R8)-CO-N(R9)- that can be read from left to right or vice versa; R4 means phenyl substituted with group R10, pyrrolyl, naphthyl, biphenyl, indenyl, benzothienyl and all these groups can be mono- or di-substituted with group R11 and/or R12, group -(CH2)n-(CO)qR13, adamantyl, cyclopentylethyl, group -(CH2)n-O-R13; R5 means hydroxyl or alkoxyl with 1-19 carbon atoms; R6 means group -OR14. Values R8, R9, R10, R11, R12, R13, n and q are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

25 cl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of tetrahydrocarbazole of the formula (I): wherein n = 0, 1 or 2; X represents -NH or oxygen atom (O); each R is a similar or different radical and chosen independently from group consisting of halogen atom, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group; each R1 is a similar or different radical and chosen independently from group consisting of halogen, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group and wherein each m means 2 independently; each R10 is a similar or different radical and chosen independently from alkylene; each p and q is chosen independently from 0, 1, 2, 3, 4 or 5; each R2 is a similar or different radical and chosen independently from group consisting of hydrogen atom (H), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl and -R10OH; ring A represents phenyl, naphthyl or heteroaryl wherein heteroaryl represents monocyclic 5-7-membered aromatic ring or condensed bicyclic aromatic ring system consisting of two such aromatic rings that comprise one or two nitrogen atoms and/or sulfur atoms, and to their pharmaceutically acceptable salts, solvates, esters and amides. Compounds of the formula (I) possess effect against disorders caused by HPV-infection and useful in treatment of human papilloma. Also, invention relates to a pharmaceutical composition based on compounds of the formula (I) and its using in preparing drugs for their using in treatment and prophylactic of states or disorders caused by HPV-infection.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

Up!