Substituted derivatives of 2-pyridincyclohexane-1,4-diamine, method for their preparing and medicinal agent based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 9 ex

 

The present invention relates to substituted derivatives of 2-pyridinylamino-1,4-diamine, methods for their preparation, pharmaceuticals containing these compounds and to the use of substituted derivatives of 2-pyridinylamino-1,4-diamine to obtain drugs.

Heptadecapeptide nociceptin is an endogenous ligand ORL1-receptor (from the English. "opioid receptor-like receptor, such opioid receptor receptor) (Meunier and others, Nature 377, 1995, S. 532-535), which belongs to the family of opioid receptors and which can be found in many areas of the cerebral cortex and spinal cord (Mollereau, etc., FEBS Letters, 341, 1994, pp.33-38; Darland and others, Trends in Neurosciences, 21, 1998, s-221). This peptide has a high affinity with a value of Kd-score 56 PM (Ardati, etc., Mol. Pharmacol. 51, S. 816-824), and high selectivity in relation to the ORL1-receptor. ORL1-receptor homologous opioid μ-, κ- and δreceptors, and the amino acid sequence of peptide - nociceptin - has a high similarity with the amino acid sequences of known peptide opioids. Induced nociception activation of this receptor leads through relationship with Gi/o-proteins to inhibition of adenylate cyclase (Meunier and others, Nature 377, 1995, S. 532-535). At the cellular level there are also functional similarities between opioid μ-, κ- and δ-prescriptions the ora and ORL1-receptor on activated potassium channel (Matthes and others, Mol. Pharmacol. 50, 1996, p.447-450; Vaugham, etc., Br. J. Pharmacol. 117, 1996, s-1611) and inhibition of calcium channels in the L-, N - and P/Q-type (Conner and others, Br. J. Pharmacol. 118, 1996, p.205-207; Knoflach, etc., J. Neuroscience 16, 1996, s-6664).

In various experiments on animals peptide nociceptin manifests after its introduction in the interventricular region brain pronunication and hyperalgesia activity (Reinscheid and others, Science 270, 1995, s-794; Hara and others, Br. J. Pharmacol. 121, 1997, s.401-408). A similar effect can be explained by the inhibition induced stress analgesia (Mogil and others, Neurosci. Letters 214, 1996, S. 131-134, and Neuroscience 75, 1996, s-337). In this regard, it was possible to detect anxiolytic activity nociceptin (Jenck and others, Proc. Natl. Acad. Sci. USA 94, 1997, s-14858).

On the other hand, the results of various experiments on animals suggest that nociceptin, especially after intrathecal injection, also shows antinociceptive action. Nociceptin inhibits the activity stimulated Kanata or glutamate neurons in the ganglion posterior spinal root (Shu and others, Neuropeptides, 32, 1998, 567-571) or stimulated glutamate neurons of the spinal cord (Faber and others, Br. J. Pharmacol., 119, 1996, p.189-190), and also exhibits antinociceptive effect in the experiment on mice with otdergivanija tail (King and others, Neurosci. Lett., 223, 1997, 113-116), experience with simulation of the flexor reflex in the rat (Xu and others, NeuroReport 7, 1996, 2092-2094) and experience with formalin in rats (Yamamoto and others, Neuroscience, 81, 1997, c.249-254). When modeling neuropathic pain has also been able to identify the antinociceptive action nociceptin (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997), which is of particular interest insofar as the effectiveness nociceptin rises after axotomy spinal nerves. This differs from the classical opioids, the effectiveness of which under the same conditions decreases (Abdulla and Smith, J. Neurosci, 18, 1998, c.9685-9694).

ORL1-receptor is involved also in the regulation of other physiological and pathophysiological processes. These among others include learning and memory formation (Sandin and others, Eur. J. Newosci., 9, 1997, S. 194-197; Manabe and others, Nature, 394, 1997, c.577-581), auditory (Nishi and others, EMBO J., 16, 1997, c.1858-1864), digestion (Pomonis and others, NeuroReport, 8, 1996, c.369-371), regulation of blood pressure (Gumusel and other, Life Sci, 60, 1997, c.141-145; Campion and Kadowitz, Biochem. Biophys. Res. Comm., 234, 1997, c.309-312), epilepsy (Gutierrez and others, Abstract 536.18, Society for Neuroscience, 24 so that the Materials of the 28th annual conference, Los Angeles, 7-12 November 1998) and diuresis (Kapista and other, Life Sciences, 60, 1997, PL 15-21). In article Calo and others (Br. J. Pharmacol, 129, 2000, cc.1261-1283) provide an overview of the symptoms or biological processes in which the ORL1-receptor plays or with high probability could play a role. When this is called, in particular, analgesia, stimulate and regulation of digestion, influence μ-agonists, such as morphine, treatment of withdrawal symptoms, reduction potential of morphine as calling addictive substances, anxious, modulation of motor activity, memory disorders, epilepsy, modulating the release of neurotransmitters, especially glutamate, serotonin and dopamine, and thereby neurodegenerative diseases, effects on the cardiovascular system, causing an erection, diuresis, antinutrient, balance electrolytes, blood pressure, various types of dropsy, intestinal motility (diarrhoea), relaxing effect on the respiratory tract, reflex urination (incontinence). The article discussed the use of agonists and antagonists as a means of suppressing appetite, analgesics (including when combined with the introduction of opioids) or nootropic funds.

According to this connection that are associated with the ORL1 receptor and activate or inhibit it, have a variety of capabilities.

The present invention was based on the task to offer connections that would affect the system nociceptin/ORL1-receptor and thus would be suitable for use as or in the composition of medicines, intended primarily for the treatment of various diseases, which is according to the prior art in one way or another connected with this system accordingly, for use in the above mentioned in the above-described prior art evidence.

In accordance with this object of the present invention are substituted derivatives of 2-pyridinylamino-1,4-diamine of the General formula I

in which R1and R2independently of one another denote H or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or

the remains of R1and R2together form a ring and denote SN2CH2Och2CH2CH2CH2NR6CH2CH2or (CH2)3-6where

R6denotes N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via C1-3and the kilen aryl, With3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R3denotes H, C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, With3-8cycloalkyl, which is saturated or unsaturated, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted attached through With1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, SH, IT, F, Cl, I, Br, CN, NO2, OR26, NR27R28where

R26stands With1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, With3-8cycloalkyl, which is saturated or unsaturated, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym atom (F, Cl, Br, I, a group of NH2, NO2, CF3, CHF2CH2F, CH3With2H5With3H7With4H9, OCF3, OCHF2, OCH2F, och3OS2H5OS3H7 OS4H9SH and/or HE, or attached via a saturated or unsaturated C1-3alkyl aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym atom (F, Cl, Br, I, a group of NH2, NO2, CF3, CHF2CH2F, CH3With2H5With3H7With4H9, OCF3, OCHF2, OCH2F, och3OS2H5OS3H7OS4H9SH and/or HE,

R27and R28independently of one another denote H, C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, With3-8cycloalkyl, which is saturated or unsaturated, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym atom (F, Cl, Br, I, a group of NH2, NO2, CF3, CHF2CH3F, CH3With2H5With3H7With4H9, OCF3, OCHF2, OCH2F, och3OS2H5OS3H7OS4H9SH and/or HE, or attached via a saturated or unsaturated With1-3alkyl aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted whether what about the one or mnogosloinym atom F, Cl, Br, I, a group of NH2, NO2, CF3, CHF2CH2F, CH3With2H5With3H7With4H9, OCF3, OCHF2, OCH2F, och3OS2H5OS3H7OS4H9SH and/or HE, or

the remains of R27and R28together represent CH2CH2Och2CH2,

CH2CH2NR29CH2CH2or (CH2)3-6where

R29denotes H, C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, With3-8cycloalkyl, which is saturated or unsaturated, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym atom (F, Cl, Br, I, a group of NH2, NO2, CF3, CHF2CH2F, CH3With2H5With3H7With4H9, OCF3, OCHF2, OCH2F, och3OS2H5OS3H7OS4H9SH and/or HE, or attached via a saturated or unsaturated C1-3alkyl aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym atom (F, Cl, Br, I, a group of NH2, NO2, CF3, CHF2CH 2F, CH3With2H5With3H7With4H9, OCF3, OCHF2, OCH2F, och3OS2H5OS3H7OS4H9SH and/or HE,

R4denotes H, C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted C(X)R7C(X)NR7R8C(X)OR9C(X)SR9or S(O2R9where

X denotes O or S,

R7denotes N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or attached via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted With1-4alkyl group, aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym,

R8denotes N or C1-4alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, or

the remains of R7and R8together form a ring and denote

CH2SN 2OCH2CH2CH2CH2NR10CH2CH2or (CH2)3-6where

R10denotes N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R9stands With1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or attached via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted With1-4alkyl group, aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym,

R5stands With3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, -CHR11R12, -CHR11-CH2/sub> R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, -C(Y)-CH2-CH2R12or-C(Y)-CH2-CH2-CH2R12where

Y represents O, S or N2,

R11denotes H, C1-7alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, or C(O)O-C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, and

R12denotes N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or

R4and R5together form a heterocycle with 3 to 8 atoms in the ring, which is saturated or unsaturated, one or mnogosloinym or unsubstituted and which optionally may be condensed with other rings,

not necessarily in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, especially physiologically compatible, the salts or salts with physiologically compatible acids or cations, or in the form of a solvate, especially hydrates.

All these proposed invention in connection, respectively, of the group of compounds exhibit an exceptionally high degree of binding with the ORL1 receptor.

In the context of the present invention under alkyl, respectively cycloalkenyl residues refers to saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or mono - or mnogosloinymi. With1-2alkyl represents a C1- or2-alkyl, C1-3alkyl represents a C1-C2- or3-alkyl, C1-4alkyl represents a C1-With2-With3- or4-alkyl, C1-5alkyl represents a C1-With2-With3-C4- or5-alkyl, C1-6alkyl represents a C1-With2-With3-C4-C5- or6-alkyl, C1-7alkyl represents a C1-With2-With3-With4-C5-With6- or7-alkyl, C1-8alkyl represents a C1-With2-With3-With4-C5-With6-C7or C8-alkyl, C1-10alkyl represents a C1-With2-With3-With4-C5-With6-With7-C8,- C9- or10and the keel, and1-18alkyl represents a C1-With2-With3-With4-C5;6-With7-C8,- C9-With10-With11-Ci2-C13-C14-C15-C16-C17or C18-alkyl. In addition, From3-4cycloalkyl represents a C3- or4-cycloalkyl,3-5cycloalkyl represents a C3-With4- or5-cycloalkyl,3-6cycloalkyl represents a C3-With4-With5- or6-cycloalkyl,3-7cycloalkyl represents a C3-With4-With5-With6or C7-cycloalkyl,3-8cycloalkyl represents a C3-With4-C5-With6-C7or C8-cycloalkyl,4-5cycloalkyl represents a C4- or5-cycloalkyl,4-6cycloalkyl represents a C4-C5- or6-cycloalkyl,4-7cycloalkyl represents a C4-C5-With6- or7-cycloalkyl,5-6cycloalkyl represents a C5- or6-cycloalkyl, and5-7cycloalkyl represents a C5-With6- or7-cycloalkyl. The term "cycloalkyl" includes saturated cycloalkyl group in which one or two carbon atoms replaced by a heteroatom (S, N or O). But in point is the adoption of "cycloalkyl" primarily included one or many times, preferably once, unsaturated cycloalkyl group without heteroatoms in the ring, if cycloalkyl is not an aromatic system. Preferred alkyl, respectively cycloalkenyl residues are methyl, ethyl, vinyl (ethynyl), propyl, allyl (2-propenyl), 1-PROPYNYL, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, as well as substituted, CHF2, CF3or CH2HE and pyrazoline, oxadiazoline, [1,4]dioxane or dioxolane.

In the context of the present invention, the term "substituted"used in respect of alkyl and cycloalkyl, implied, unless specifically stated otherwise, the substitution of at least one (and optionally also several) atom(s), hydrogen atom (F, Cl, Br, I, a group of NH2SH or HE, under the concept of "mnogosloinye balances, respectively, "substituted" remains in the case of multiple substitution refers to multiple substitution and different, and on the same atoms by identical or different substituents, for example a triple substitution on the same C-atom, as in the case of CF3whether is about being in different positions of the atoms, as in the case of-CH(OH)-CH=CH-CHCl2. The most preferred substituents are F, Cl and Oh. In cycloalkyl hydrogen residue may be replaced by OS1-3the alkyl or C1-3the alkyl (each of which is one or mnogosloinym or unsubstituted), primarily stands, ethyl, n-propylene, isopropyl group, CF3, a methoxy group or ethoxypropane.

Under the balance "(CH2)3-6" refers to the group-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2and CH2-CH2-CH2-CH2-CH2-CH2-under the rest "(CH2)1-4" refers to the group-CH2-, -CH2-CH2-, -CH2-CH2-CH2- and-CH2-CH2-CH2-CH2-under the rest "(CH2)4-5" refers to the group-CH2-CH2-CH2-CH2- and-CH2-CH2-CH2-CH2-CH2and so on

Under the aryl residue refers to a cyclic system with at least one aromatic ring but without heteroatoms including only one of the rings. As an example, you can call phenyl, raftiline, fluoroaniline, fluoroaniline, tetralinyl or indanamine primarily N-fluoroaniline or anthracene the global balances, which may be unsubstituted or mono - or mnogosloinymi.

Under heteroaryl residue refers to heterocyclic systems with at least one unsaturated ring, which contains one or more heteroatoms from the group comprising nitrogen, oxygen and/or sulfur, and which may also be one or mnogosloinymi. As an example related to the group heteroaryl residues can be called furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazin, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxole, benzodioxan, carbazole, indole and hinzelin.

The term "substituted"used in respect of aryl and heteroaryl, refers to the substitution of the aryl or heteroaryl group, R22, group, OR22, halogen, preferably F and/or Cl, a group of CF3group , CN group, NO2group NR23R24With1-6the alkyl (saturated), C1-6alkoxygroup,3-8cycloalexie,3-8cycloalkyl or2-6alkylene.

While the remainder R22represents H, C1-10alkyl, preferably1-6alkyl, aryl or heteroaryl, or attached via a saturated or unsaturated With1-3alkyl or through1-3alkylenes group and the ilen or heteroaryl residue, such aryl and heteroaryl residues may not themselves be substituted by aryl or heteroaryl groups, residues R23and R24can have identical or different meanings and represent H, C1-10alkyl, preferably1-6alkyl, aryl, or heteroaryl attached via a saturated or unsaturated With1-3alkyl or C1-3alkylenes group aryl or heteroaryl residue, and these aryl and heteroaryl residues may not themselves be substituted by aryl or heteroaryl groups, or residues R23and R24together represent CH2CH2OCH2CH2CH2CH2NR25CH2CH2or (CH2)3-6and the remainder R25represents H, C1-C10alkyl, preferably C1-C6alkyl, aryl or heteroaryl residue, or attached via a saturated or unsaturated With1-3alkyl or C1-C3alkylenes group aryl or heteroaryl residue, and these aryl and heteroaryl residues may not themselves be substituted by aryl or heteroaryl groups.

The term "salt" refers to each of the forms proposed in the invention the active substance, in which he takes ionic form, is therefore, its has a charge of either sign and is associated with a counterion (cation or anion), accordingly remains in solution. This also includes complexes of the active substance with other molecules and ions, primarily complexes formed through ionic interactions. While the term "salt" refers in the first place (which corresponds to a preferred variant implementation of the present invention, the physiologically compatible salts, especially physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or formed with a physiologically compatible acid or a physiologically compatible cation salt.

The term "physiologically compatible salt with anions or acids in the context of the present invention refers to a salt of at least one of the proposed invention compounds, predominantly in the protonated, for example on the nitrogen, form, as the cation with at least one anion, which are physiologically compatible, especially when introduced into the body of a human and/or mammal. Such salts in the context of the present invention are primarily formed with a physiologically compatible acid salt, namely salts of the respective active ingredient with inorganic, respectively, of organic acids, which is the tsya physiologically compatible, first of all, when introduced into the human and/or mammal. As an example, physiologically compatible salts of certain acids can be called the salt of hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (some saccharine acid), monomethylaniline acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The most preferred salt is the hydrochloride.

The term "formed with a physiologically compatible acid salt" in the context of the present invention refers to salts of the respective active ingredient with inorganic, respectively organic acids which are physiologically compatible, especially when introduced into the body of a human and/or mammal. Most preferred is the hydrochloride. As an example, fisiologicas and compatible acids can be called hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (some saccharine acid), monomethylmercury acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.

The term "physiologically compatible salt with cations or bases" in the context of the present invention refers to a salt of at least one of the proposed invention compounds, mainly (deprotonated) acid as the anion with at least one, preferably inorganic, cation, which are physiologically compatible, especially when introduced into the body of a human and/or mammal. The most preferred salts are alkali and alkaline earth metals as well as salts with NH+4but first of all mono - or disodium, mono - or decaluwe, magnesium or calcium salts.

The term "formed with physiologically with the compatible cation salt" in the context of the present invention refers to a salt of at least one of the respective compounds as anion with at least one inorganic cation, which are physiologically compatible, especially when introduced into the body of a human and/or mammal. The most preferred salts are alkali and alkaline earth metals as well as salts with NH4+but first of all mono - or disodium, mono - or decaluwe, magnesium or calcium salts.

In one of the embodiments of the invention preferred are those substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I

R1and R2independently of one another denote H or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, or

the remains of R1and R2together form a ring and denote SN2CH2Och2CH2CH2CH2NR6CH2CH2or (CH2)3-6where

R6denotes N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, preferably

R1and R2independently of one another denote H or C1-4alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, or

ostad the R 1and R2together form a ring and denote (CH2)4-5first of all R1and R2independently of one another denote methyl or ethyl, or

the remains of R1and R2together form a ring and denote (CH2)5.

In accordance with another embodiment of the invention the preferred substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I

R3denotes H, C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, With3-8cycloalkyl, which is saturated or unsaturated, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted attached through With1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, SH, IT, F, Cl, I, Br, CN, NO2, NH2or or26where

R26represents C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, preferably

R3denotes H, C1-6alkyl, which is saturated or unsaturated branched or unbranched, one or mnogosloinym or unsubstituted, SH, IT, F, Cl, I, Br, CN, NO2, NH2or or26where

R26represents C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, first of all

R3denotes N.

In another embodiment of the invention the preferred substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I

R4denotes N, C(X)R7C(X)NR7R8C(X)OR9C(X)SR9or S(O2R9where

X denotes O or S, preferably

R4denotes N, C(X)R7C(X)NR7R8or C(X)OR9where

X denotes Oh, first of all

R4denotes H or C(O)R7where

R7preferably denotes N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, preferably denotes N or C1-3alkyl, which is saturated, unsubstituted, branched or unbranched, primarily denotes CH3.

In the following embodiment of the invention the preferred substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I,/p>

R4and R5together form a heterocycle with 3 to 8 atoms in the ring, which is saturated or unsaturated, one or mnogosloinym or unsubstituted, preferably with 5-7 atoms in the ring, from which, along with the obligatory N atom in the ring are 0-1 other heteroatoms selected from N, S and O,

while educated together the remnants of R4and R5a heterocycle optionally may be condensed with other rings, preferably aromatic and/or heteroaromatic rings, the latter in turn may be condensed with other aromatic and/or heteroaromatic rings, first of all formed together the remnants of R4and R5a heterocycle condensed with one or two other rings, preferably formed together the remnants of R4and R5a heterocycle condensed with two other rings such that R4and R5together form the fragment.

In accordance with the following variant of the preferred embodiment of the invention the substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I, R4denotes N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched single or mnogosloinym or unsubstituted, preferably denotes N or C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted primarily denotes N or C1-3alkyl, which is saturated, unbranched and unsubstituted.

According to another variant of the preferred embodiment of the invention the substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I

R5stands With3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, preferably

R5denotes cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthene, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroanthracene, pyridinyl, furanyl, benzofuranyl, pyrazolinones, oxadiazoline, DIOXOLANYL, substituted, pyrimidinyl, chinoline, ethenolysis, phthalazine or hintline, each of which is unsubstituted or mono - or mnogosloinym, first of all

R5denotes cyclopentyl, cyclohexyl, qi is lagati, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each of which is unsubstituted or mono - or mnogosloinym.

In accordance with the following embodiment of the invention the preferred substituted derivatives of 2-pyridinylamino-1,4-diamine, in which according to structural formula I

R5means-CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12- (Y)-CH2-CH2R12or-C(Y)-CH2-CH2-CH2R12where

Y represents O, S or N2preferably

R5means-CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12or-C(Y)-CH2-CH2R12where

Y denotes O or S, first of all

R5means-CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -C(Y)R12or-C(Y)-CH2R12where Y represents O.

In this embodiment, the most preferred compounds, in which the

R11denotes H, C1-4alkyl, which is the saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, or C(O)O-C1-4alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, preferably denotes H, C1-4alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, or C(O)O-C1-2alkyl, which is saturated, unbranched, single or mnogosloinym or unsubstituted primarily denotes N, CH3With2H5or C(O)O-CH3,

and/or equally preferred compounds in which

R12stands With3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, preferably

R12denotes cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthene, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroanthracene, pyridinyl, furanyl, benzofuranyl, pyrazolinones, oxadiazoline, DIOXOLANYL, hell is the Antilles, pyrimidinyl, chinoline, ethenolysis, phthalazine or hintline, each of which is unsubstituted or mono - or mnogosloinym, first of all

R12denotes cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each of which is unsubstituted or mono - or mnogosloinym.

The most preferred offer in the invention substituted derivatives of 2-pyridinylamino-1,4-diamine are then primarily compounds selected from the group including

the dihydrochloride of N-(4-dimethylamino-4-pyridine-2-illlogical)-N-[2-(1H-indol-3-yl)ethyl]acetamide", she polarity diastereoisomer,

trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, non-polar diastereoisomer,

trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, polar diastereoisomer,

trihydrochloride methyl ester (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid, non-polar diastereoisomer,

trihydrochloride methyl ester (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid,polar diastereoisomer,

the dihydrochloride (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid, non-polar diastereoisomer, optionally also in the form of their racemates, these or other pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, and optionally also in the form of acids or bases or in the form of other salts, especially physiologically compatible salts or salts with physiologically compatible acids or cations, or in the form of a solvate, especially hydrates.

Proposed in the invention compounds are toxicologically harmless and therefore suitable for use as a pharmaceutical active ingredient in medicines.

Accordingly another object of the present invention are drugs, containing at least one proposed therein substituted derivative 2-pyridinylamino-1,4-diamine, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of its acids or its bases or in the form of the th salts with physiologically compatible acids or cations, or in the form of a solvate, especially hydrates and optionally containing acceptable additives and/or auxiliary substances and/or optionally other active agents, such as opioid, preferably a potent opioid, primarily morphine, or an anaesthetic, preferably hexobarbital or halothane.

Proposed in the invention medicines in addition to at least one substituted derivative 2-pyridinylamino-1,4-diamine optionally contain acceptable additives and/or excipients, including carriers, fillers, solvents, diluents, dyes and/or binders, and can be used as liquid dosage forms in the form of injection solutions, drops or medicines, as well as semi-solid dosage forms in the form of granules, tablets, pills, patches, capsules, plasters or aerosols. The choice of auxiliary and other substances, and used their number depend on whether the drug for oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, transbukkalno, rectal or topical application, for example for application on skin, on mucous membranes or in the eyes. For oral administration suitable the composition is in the form of tablets, pills, capsules, granules, drops, medicines and syrups, and for parenteral, local, and inhalation use suitable solutions, suspensions, easily recoverable dry compositions, as well as sprays. Proposed in the invention substituted derivatives of 2-pyridinylamino-1,4-diamine in depot form, in dissolved form or embedded in a plaster, optionally with the addition of promote penetration through the skin of funds, also suitable for percutaneous introduction. Intended for oral or percutaneous injection dosage form can be a retard forms, which provide a slow release of the proposed invention substituted derivatives of 2-pyridinylamino-1,4-diamine. In principle, the composition proposed in the invention of medicines, you can include some other, well-known specialists active substances.

Assigned to the patient an amount of the active substance varies depending on the weight of the patient, route of administration, indications for use and the severity of the disease. Usually at least one proposed in the invention substituted derivative 2-pyridinylamino-1,4-diamine are introduced into the organism in a dose comprising 0.005 to 1000 mg/kg, preferably from 0.05 to 5 mg/kg body weight.

In the structure proposed in the invention medicinal means is all of them described above, most preferably in addition to at least one substituted derivative 2-pyridinylamino-1,4-diamine include also an opioid, preferably, a potent opioid, primarily morphine, or an anaesthetic, preferably hexobarbital or halothane.

In one preferred options contained in the medicinal product substituted derivative 2-pyridinylamino-1,4-diamine according to the invention is represented in the form of a pure diastereoisomer and/or enantiomer, in the form of the racemate or in the form of requiredno or equimolar mixture of the diastereomers and/or enantiomers.

As mentioned above in the description of the prior art, ORL1-receptor was identified primarily in the manifestation of pain. Therefore, the proposed invention substituted derivatives of 2-pyridinylamino-1,4-diamine can be used to obtain a medicinal product intended for the treatment of pain, especially acute, neuropathic or chronic pain.

Accordingly another object of the invention is the application of the proposed therein substituted derivatives of 2-pyridinylamino-1,4-diamine, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, especially fisiologicas is compatible salts or salts with physiologically compatible acids or cations, or in the form of a solvate, especially hydrates, for obtaining a medicinal product intended for the treatment of pain, especially acute, neuropathic or chronic pain.

As already mentioned in the introductory part of the description, ORL1-receptor along with the function he performs in the manifestation of pain, also plays a role in many other physiological processes that are important primarily from a medical point of view, in accordance with another object of the invention is the application of the proposed therein substituted derivatives of 2-pyridinylamino-1,4-diamine, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture in the presented form or in the form of their acids or their bases or in the form of their salts, especially physiologically compatible salts or salts with physiologically compatible acids or cations, or in the form of a solvate, especially hydrates, for obtaining a medicinal product intended for the treatment of States of fear, stress and related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, General impairment of cognitive abilities (to naivnyh dysfunction), disorders of learning and memory (as a nootropic), withdrawal symptoms (withdrawal), abuse of alcohol and/or drug and/or drug and/or alcohol and/or drug and/or medicament addiction, sexual disorders, cardiovascular diseases, hypotension, hypertension, sensation of tinnitus, pruritus, migraine, hearing loss, lack of intestinal motility disorders digestibility of food, anorexia, obesity, locomotor disorders of functions, diarrhoea, cachexia, urinary incontinence, respectively, as a muscle relaxant, anticonvulsant drugs or anesthetic, respectively, for joint the introduction into the body in the treatment of opioid analgesic or anaesthetic, for diuresis or antinatriuretic and/or anxiolysis.

In one variation of the above applications it may be preferable to use a substituted derivative 2-pyridinylamino-1,4-diamine in the form of a pure diastereoisomer and/or enantiomer, in the form of the racemate or in the form of requiredno or equimolar mixture of the diastereomers and/or enantiomers.

Another object of the present invention is a method of treatment, especially if there are symptoms of one of the above diseases or pathological States of the mammal or human, which, respectively, to the which, needs in the treatment of pain, especially chronic pain, which consists in the introduction into the body proposed in the invention substituted derivative 2-pyridinylamino-1,4-diamine in a therapeutically effective dose or proposed in the invention medicines.

The next object of the invention is a method for its proposed substituted derivatives of 2-pyridinylamino-1,4-diamine, are examined in more detail in the following description and examples.

To obtain the proposed invention substituted derivative 2-pyridinylamino-1,4-diamine of the formula I, in which R3denotes H, it is most expedient to use referred to in the subsequent description of the main method And the method, according to which

a) protected groups S1and S2cyclohexane-1,4-dione of formula II is subjected in the presence of the compounds of formula HNR01R02interaction with cyanide, preferably potassium cyanide, to obtain the protected N-substituted derivative of 1-amino-4-oxocyclohexanecarboxylate formula III

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R 06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

b) aminonitriles formula III combined with cyclopentadienylcobalt-1,5-Dien-cobalt(I) [cpCo(cod)] and irradiated in the atmosphere of acetylene with the formation of compounds of formula IVa

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

the compound of formula IVa otscheplaut protective group S1and S2with the formation of 4-for EDINOGO derived 4-aminocyclohexanone formula IV

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

g) 4-substituted derivative of 4-aminocyclohexanone formula IVa are hydroamination compound of the formula HNR04R05with the formation of a derivative of 2-pyridinylamino-1,4-diamine of formula V

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or su is iferouane and/or in the case of compounds, in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation before the formation of the compounds of formula I, with

R1, R2, R4and R5have these to offer in the invention compounds of formula I value, and

R01and R02independently of one another denote H, protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl,

With3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or

the remains of R01and R02together form a ring and denote SN2CH2Och2CH2CH2CH2NR06CH2CH2or (CH2)3-6where

R06denotes H protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or prazwell is authorized, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R04denotes H protected by a protective group N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted,

R05denotes H protected by a protective group N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, -C(Y)-CH2-CH2R12or-C(Y)-CH2-CH2-CH2R12where

Y denotes H2,

R11denotes N or C1-7alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, and

R12denotes N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or

R04and R together form a heterocycle with 3 to 8 atoms in the ring, which is saturated or unsaturated, one or mnogosloinym or unsubstituted, and

S1and S2independently from each other represent a protective group or together represent a protective group, preferably monoacetal.

To obtain the proposed invention substituted derivative 2-pyridinylamino-1,4-diamine of the formula I, in which R3denotes H, it is most expedient to use also referred to in the subsequent description of an alternative method And the method, according to which

a) protected groups S1and S2cyclohexane-1,4-dione of formula II is subjected to hydroamination compound of the formula HNR04R05with the formation of a derivative of 4-aminocyclohexanone formula VI

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R04and/or R05designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R04and/or R05denote N, less the th least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

b) derived 4-aminocyclohexanone formula VI is subjected in the presence of the compounds of formula R01R02interaction with cyanide, preferably potassium cyanide, to obtain the derived cyclohexanediyl formula VII

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

C) derived cyclohexanediyl formula VII unite with cyclopentadienylcobalt-1,5-Dien-cobalt(I) [cpCo(cod)] and irradiated in the atmosphere of acetylene with the formation of a derivative of 2-pyridinylamino-1,4-diamine of formula V

then, if necessary, in any sequence, and when the mu is the need to repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation before the formation of the compounds of formula I, with

R1, R2, R4and R5have these to offer in the invention compounds of formula I value, and

R01and R02independently of one another denote H, protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl,

With3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or

the remains of R01and R02sovmestimost ring and denote SN 2CH2Och2CH2CH2CH2NR06CH2CH2or (CH2)3-6where

R06denotes H protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl,

With3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R04denotes H protected by a protective group N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted,

R05means protected by a protective group N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, -C(Y)-CH2-CH2R12or-C(Y)-CH2-CH2-CH2R12where

Y denotes H2,

R11denotes N or C1-7 alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, and

R12denotes N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or

R04and R05together form a heterocycle with 3 to 8 atoms in the ring, which is saturated or unsaturated, one or mnogosloinym or unsubstituted, and

S1and S2independently from each other represent a protective group or together represent a protective group, preferably monoacetal.

In both the above methods a protective group of atoms N, the values of which have R01, R02, R04, R05and/or R06, preferably selected from alkyl, benzyl and carbamates, for example FMOC, Z and Boc.

In addition, in the main method And hydroamination in stage d) is preferably carried out in the presence of ammonium formate, ammonium acetate or NaCNBH3.

In the most preferred embodiment, the main method And, in addition, instead of gidroaminirovaniya compound of the formula HNR04R05at stage g), the compound of formula IV can be subjected to interaction with hydroxylamine and after the formation of the oxime to restore.

When executed by the attachment of the main method And irradiation in stage b) it is expedient to carry out within 5-7 h and/or at room temperature and/or in a saturated atmosphere of acetylene and/or in a protective gas atmosphere.

In the implementation of the alternative method And irradiation in stage b) it is expedient to carry out within 5-7 h and/or at room temperature and/or in a saturated atmosphere of acetylene and/or in a protective gas atmosphere.

To obtain one of the proposed invention substituted derivatives of 2-pyridinylamino-1,4-diamine you can also use referred to in the subsequent description of the main method B method, according to which

a) protected groups S1and S2cyclohexane-1,4-dione of formula II is subjected in the presence of the compounds of formula HNR01R02interaction with cyanide, preferably potassium cyanide, to obtain the protected N-substituted derivative of 1-amino-4-oxocyclohexanecarboxylate formula III

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06denote N at least once imposed protective is the Rupp and if necessary, conduct the acylation, alkylation or sulfonation,

b) aminonitriles formula III is subjected to interaction with ORGANOMETALLIC reagents, preferably Grignard reagent or organolithium reagents of the formula metal-2-pyridine-R3with the formation of compounds of formula IVa

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

the compound of formula IVa otscheplaut protective group S1and S2with the formation of 4-substituted derivative of 4-aminocyclohexanone formula IV

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and the and R 02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

g) 4-substituted derivative of 4-aminocyclohexanone formula IVa are hydroamination compound of the formula HNR04R05with the formation of a derivative of 2-pyridinylamino-1,4-diamine of formula V

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation and the and sulfonation before the formation of the compounds of formula I, thus

R1, R2, R3, R4and R5have these to offer in the invention compounds of formula I value, and

R01and R02independently of one another denote H, protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or

the remains of R01and R02together form a ring and denote SN2CH2Och2CH2CH2CH2NR06CH2CH2or (CH2)3-6where

R06denotes H protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is is one or mnogosloinym or unsubstituted,

R04denotes H protected by a protective group N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted,

R05denotes H protected by a protective group N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, -C(Y)-CH2-CH2R12or-C(Y)-CH2-CH2-CH2R12where

Y denotes H2,

R11denotes N or C1-7alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, and

R12denotes N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or

R04and R05together form a heterocycle with 3 to 8 atoms in the ring, which is saturated or unsaturated, one or mnogosloinym or unsubstituted, and

S1and S2independently from each other represent a protective group or together represent a protective group, predpochtite is correctly monoacetal.

Under alkylation refers to hydroamination, because it leads to the same result.

Another preferred object of the invention is referred to in the subsequent description of an alternative method B is a method of obtaining proposed in the invention substituted derivative 2-pyridinylamino-1,4-diamine, according to which

a) protected groups S1and S2cyclohexane-1,4-dione of formula II is subjected to hydroamination compound of the formula HNR04R05with the formation of a derivative of 4-aminocyclohexanone formula VI

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R04and/or R05designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R04and/or R05denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

b) derived 4-aminocyclohexanone formula VI is subjected in the presence of compounds of formulas is HNR 01R02interaction with cyanide, preferably potassium cyanide, to obtain the derived cyclohexanediyl formula VII

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

C) derived cyclohexanediyl formula VII is subjected to interaction with ORGANOMETALLIC reagents, preferably Grignard reagent or organolithium reagents of the formula metal-2-pyridine-R3and then otscheplaut protective group S1and S2with the formation of a derivative of 2-pyridinylamino-1,4-diamine of formula V

then, if necessary, in any sequence and optionally, n is once carried out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation before the formation of the compounds of formula I, with

R1, R2, R3, R4and R5have these to offer in the invention compounds of formula I value, and

R01and R02independently of one another denote H, protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or

the remains of R01and R02compatible with the local form a ring and denote SN 2CH2Och2CH2CH2CH2NR06CH2CH2or (CH2)3-6where

R06denotes H protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via C1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R04denotes H protected by a protective group N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted,

R05means protected by a protective group N or C3-8pilooski, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, -CHR11R12, -CHR11CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, -C(Y)-CH2-CH2R12or-C(Y)-CH2-CH2-CH2R12where

Y denotes H2,

R11denotes N or C1-7Ala is l, which is saturated or unsaturated, branched or unbranched, single or mnogosloinym or unsubstituted, and

R12denotes N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or one - or mnogosloinym, or

R04and R05together form a heterocycle with 3 to 8 atoms in the ring, which is saturated or unsaturated, one or mnogosloinym or unsubstituted, and

S1and S2independently from each other represent a protective group or together represent a protective group, preferably monoacetal.

In both the above methods B protective group atom N, the values of which have R01, R02, R04, R05and/or R06, preferably selected from alkyl, benzyl and carbamates, for example FMOC, Z and Boc.

In addition, in the main method B hydroamination in stage d) is preferably carried out in the presence of ammonium formate, ammonium acetate or NaCNBH3.

In the most preferred embodiment, the primary method B, except that, instead of gidroaminirovaniya compound of the formula HNR04R04at stage g), the compound of formula IV can be subjected to interaction with hydroxylamine and after the formation of the oxime to restore.

Similarly when is sushestvennee alternative method B in stage b) it is expedient to use the compound of the formula HNR 01R02in which the residue R01denotes H, when interacting with cyanide use TMS-CN and then enter, if necessary, the protective group for the remainder of R01.

Below the invention is additionally illustrated by examples, not limiting its scope.

Examples

The following examples serve for a more detailed explanation of the present invention without limiting, however, its scope.

The output of the compounds obtained in the examples below, is not optimized.

All temperatures are listed in the unadjusted values.

The concept of "simple" air " below indicated with diethyl ether, the abbreviation "EA" refers to ethyl acetate, and the abbreviation "CHM" refers to dichloromethane. The term "equivalents" are indicated by an equivalent amount of substances, reduction of tPL" refers to melting point, respectively, in the temperature range of the melting, the abbreviation "CT" refers to room temperature, the abbreviation "vol.%" indicated volume percent, the abbreviation "wt.%" indicated weight percents, and the abbreviation "M" refers to the concentration in moles/L.

As stationary phase in column chromatography was used silica gel 60 (0,040-0,063 mm) of the firm E. Merck, Darmstadt.

In the analysis of thin-layer chromatography (TLC) used a ready plates for TLC you what the resolution will be about (DHWR) type silica gel 60 F 254 company E. Merck, Darmstadt.

The ratio between the quantities of solvents, the mixture which was used for chromatographic analyses, in all cases specified in volume ratios (about./vol.).

Example 1: the dihydrochloride of N-(4-dimethylamino-4-pyridine-2-illlogical)-N-[2-(1H-indol-3-yl)ethyl]ndimethylacetamide, non-polar diastereoisomer

200 g of 1,4-dioxaspiro[4,5]decane-8-it was mixed with 200 ml of methanol, 1680 ml of an aqueous solution of dimethylamine (40 wt%), 303 g of dimethylamine hydrochloride and 200 g of potassium cyanide and stirred for about 65 hours Obtained white suspension was extracted four times a simple ether portions at (800 ml), the combined extracts were concentrated, the residue was dissolved in about 500 ml of dichloromethane and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated. In this way received 265 g of 8-dimethylamino-1,4-dioxaspiro[4,5]decane-8-carbonitrile in the form of a white solid.

A solution of 4.5 g of 8-dimethylamino-1,4-dioxaspiro[4,5]decane-8-carbonitrile, 50 mg cyclopentadienylcobalt-1,5-Dien-cobalt(I) [cpCo(cod)] and 100 ml of toluene were placed in a reaction vessel in counterflow with protective gas/acetylene. After saturation acetylene reaction solution was irradiated with vigorous stirring and at a temperature of 25°C for 6 hours the Reaction was stopped, turning off lights, stopped the supply of air and the reaction RA the solution was concentrated. The resulting crude product (vs. 5.47 g) was dissolved in a mixture of water (8.7 ml) and concentrated hydrochloric acid (15 ml) and was stirred over night at RT. For processing washed with diethyl ether (3×100 ml), the phases were separated, the pH value of the aqueous phase was adjusted at alkaline with 32 wt.%-aqueous sodium hydroxide solution, after which it was extracted with dichloromethane (3×100 ml), the combined extracts were dried (Na2SO4), filtered and concentrated. In this way received and 3.72 g of 4-dimethylamino-4-pyridine-2-illlogical.

To a solution of 4-dimethylamino-4-pyridine-2-illlogical (873 mg) and tryptamine (640 mg) in dry tetrahydrofuran (40 ml) and anhydrous 1,2-dichloroethane (10 ml) in an argon atmosphere was added acetic acid (0,448 ml) and was stirred for 15 minutes After adding triacetoxyborohydride sodium (1.2 g) the reaction mixture for three days was stirred in an argon atmosphere at room temperature. For recycling the solvent was removed in vacuo, the residue was dissolved in 1 N. caustic soda solution (40 ml) and diethyl ether (40 ml), the phases were separated, the aqueous phase was extracted with diethyl ether (2×30 ml), the organic phases were combined, dried and concentrated. The resulting crude product was divided by column chromatography on silica gel using methanol and methanol/ammonia (100:1). So the m received by non-polar diastereoisomer N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine as a white solid (617 mg, tPL150-152°).

N'-[2-(1H-Indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine (250 mg) was dissolved in dry pyridine (5 ml)was mixed with acetic anhydride (0,64 ml) and was stirred for 22 h at room temperature. Then the reaction mixture was mixed with a small amount of ice and then concentrated. The residue was dissolved in 1-molar sodium hydroxide solution (20 ml) and ethyl acetate (20 ml) and stirred. The residue obtained white solid, which was separated by vacuum filtration (86 mg). The aqueous phase of the filtrate was extracted with ethyl acetate (2×20 ml). The combined organic extracts after drying was concentrated. Thus obtained residue was identical to the previously obtained solid substance. Both substances together. In this way received 219 mg of N-(4-dimethylamino-4-pyridine-2-illlogical)-N-[2-(1H-indol-3-yl)ethyl]ndimethylacetamide (tPL209-210° (C), 195 mg of which at moderate temperatures up to 40°was dissolved in 2-butanone (25 ml) and using chlorotrimethylsilane (0,303 ml) were transferred into the corresponding dihydrochloride (white solid, 219 mg, tPL244-247°C).

Example 2: trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, non-polar diastereoisomer

Obtained in accordance with example 1 N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-illlogical-1,4-diamine (342 mg) was dissolved in 2-butanone (20 ml) and using chlorotrimethylsilane (0,59 ml) were transferred into the appropriate trihydrochloride (solid beige color 408 mg).

Example 3: trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, polar diastereoisomer

Analogously to example 1 also received 171 mg of the polar diastereoisomer N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, which was dissolved in 2-butanone (20 ml) and using chlorotrimethylsilane (0,297 ml) were transferred into the appropriate trihydrochloride (171 mg of a beige solid, tPL225-230°).

Example 4: trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, non-polar diastereoisomer

The hydrochloride of the methyl ester of L-tryptophan (1.01 g) was intensively stirred for 15 min with 1,2-dichloroethane (20 ml) and a saturated solution of NaHCO3(20 ml) and then the aqueous phase was extracted with 1,2-dichloroethane (2×20 ml). After drying over Na2S04the organic phase was concentrated to a volume of 40 ml and in an atmosphere of argon was mixed with 4-dimethylamino-4-pyridine-2-altilogix.com (873 mg). To the resulting clear solution was added glacial acetic acid (0,448 ml) and Na2SO4(2 g). After reaction for 15 min, the reaction mixture was mixed with NaBH(SLA)3(1.2 g) and in four days was stirred at room temperature. For processing the mixture was mixed with a saturated solution of NaHCO3(40 ml) and premesis is whether within 15 minutes The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic phase after drying, concentrated, resulting in a light brown oil. The mixture of substances were separated by chromatography on silica gel using a mixture of ethyl acetate/methanol (ratio 4:1) and methanol. The obtained non-polar product (820 mg of a slightly oily compound) was dissolved in 2-butanone (50 ml) and using chlorotrimethylsilane (1,22 ml) were transferred to trihydrochloride (719 mg of a white hygroscopic solid substance, [α]D20=19,85 (Meon,=1,33)).

Example 5: trihydrochloride methyl ester (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid, polar diastereoisomer

Analogously to example 4 also received 284 mg of the polar diastereoisomer methyl ester (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid, which is dissolved in 2-butanone (15 ml) were transferred using chlorotrimethylsilane (of 0.43 ml) in the appropriate trihydrochloride (171 mg of a white solid, tPL170-175°, [α]D20=17,61 (Meon,=1,45)).

Example 6: dihydrochloride (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-[1H-indol-3-yl)propionic acid, non-polar diastereoisomer

To the solution obtained in accordance with example the m 4 nonpolar diastereoisomer trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine (378 mg) in ethanol (20 ml) was added to 1.7 N. KOHN (8,8 ml). After 70 h the mixture was concentrated, the residue in the form of a yellow oil was dissolved in water (10 ml), the aqueous phase washed with ethyl acetate (3×20 ml) and was mixed with 5.5 N. HCl (9.0 ml). Next, the aqueous phase was concentrated and the residue was videlacele ethanol (2×20 ml). The remaining KCl was separated, and the filtrate was concentrated and washed by a simple ether. In this way received a non-polar diastereoisomer dihydrochloride (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid (307 mg, [α]D20=20,69 (Meon,=1,213)).

Example 7: determination of binding ORL1-receptor

Derivatives of 2-pyridinylamino-1,4-diamine of the General formula I were investigated in the experiment binding to receptor using3N-nociceptin/orphanin FQ and membranes of recombinant cells CHO-ORL1. This experiment was carried out according to the method described by Ardati, etc. (Mol. PharmacoL, 51, 1997, cc.816-824).3N-nociceptin/orphanin FQ used in these experiments at a concentration of 0.5 nm. When conducting analyses on binding to the receptor protein of the cell membrane used at the rate of 20 μg per 200 μl mixture containing 50 mm Hepes (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid) pH 7.4, 10 mm MgCl2and 1 mm etc. Binding to the ORL1 receptor was determined by adding to each sample sample 1 mg covered agglutinins of seedlings of wheat the Itza balls for SPA assay (Scintillation Proximity Assay) (firm Amersham-Pharmacia, Freiburg), incubation of the mixture for one hour at room temperature and follow-up measurements in a scintillation counter type Trilux, Wallac, Finland). The measure of affinity is the value Toi(inhibition constant), expressed in microns, are shown in table 1.

Table 1

The compound of exampleORL1, Ki/mcm
10,18
20,013
30,34
40,093
50,47
60,28

Example 8: check analgesic action experience with otdergivanija tail in mice

Each of the mice are individually placed in the cell for experiments and on the base of the tail guided focused thermal beam from an electric lamp (Tail-flick-Typ 50/08/1 .bc extension, Labtec, Dr. Hess). The intensity emitted by the lamp radiation was tuned so that the amount of time that passes from the moment the lamp is switched on until a sudden otdergivanija tail (the latent period for the development of pain)was untreated mice from 3 to 5 C. Such preliminary experiments with mice were performed twice within five minutes prior to the introduction of solutions containing one of the offer and the acquisition of compounds, accordingly, one of the comparative solutions, and obtained in these measurements the average value was calculated as the average value of prior experience.

After that, the mice intravenously injected with a solution proposed in the invention compounds of General formula I, as well as comparative solutions. Measurements for determining the period of time that passes before the reaction (OTDELENIE tail) to painful stimulus (heat ray), were respectively 10, 20, 40 and 60 min after intravenous administration to mice of the investigated solutions. Analgesic effect was calculated as the increase in the duration of the latent period for the development of pain (% of the maximum possible antinociceptive effect (MVAD)) according to the following formula:

% MAD=[(T1-T0)/(T2-T0)]×100.

In this formula, the time T0indicates the duration of the latent period before the introduction contains the active substance of the drug, the time T1indicates the duration of the latent period after injection contains the active substance of the drug, and the time T2indicates the maximum duration of exposure to heat beam (equal to 12).

Proposed in the invention compounds that are used in these studies, showed analgesic effect. In the following table 2 selectively is redstavleny the results of several such experiments.

Table 2
Compound of example No.% MVD compared with the control group
171 (10)
491 (10)
Note: in parentheses indicate the dose in mg/kg, which was injected intravenously corresponding connection.

Example 9: the solution proposed in the invention substituted derivative 2-pyridinylamino-1,4-diamine for parenteral use

38 g of one of the proposed invention substituted derivatives of 2-pyridinylamino-1,4-diamine, in this case, the compounds of example 1 are dissolved at room temperature in 1 liter of water for injection and then the addition of anhydrous glucose for injection, the solution was transferred to isotonic.

1. Substituted derivatives of 2-pyridinylamino-1,4-diamine of the General formula I

in which R1and R2independently of one another denote H, a branched or unbranched1-8alkyl or C3-8cycloalkyl,

R3denotes H, a branched or unbranched1-8alkyl or C3-8cycloalkyl,

R4denotes H, a branched or unbranched1-8alkyl or C(X)R where X denotes Oh,

R7denotes a branched or unbranched1-8alkyl or C3-8cycloalkyl,

R5refers to a group-CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12,

where R11denotes H, a branched or unbranched1-7alkyl or C(O)O-C1-6alkyl, and

R12denotes H, C3-8cycloalkyl or five-membered nitrogen containing heteroaryl, optionally condensed with a benzene ring, in the form of their racemates or pure stereoisomers, especially enantiomers or diastereomers, or in the form of bases or a physiologically compatible acid additive salts.

2. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 1, characterized in that

R1and R2independently of one another denote H or a branched or unbranched1-8alkyl, preferably

R1and R2independently of one another denote H or a branched or unbranched1-4alkyl, first of all

R1and R2independently of one another denote methyl or ethyl.

3. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 1, characterized in that

R3oboznachaet is H, branched or unbranched1-6alkyl, first of all, R3denotes N.

4. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 1, characterized in that

R4denotes N, C(X)R7,

where X denotes Oh, and

R7denotes H or a branched or unbranched1-3alkyl primarily denotes CH3.

5. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 1, wherein R4denotes H or a branched or unbranched1-8alkyl preferably denotes H or a branched or unbranched1-6alkyl primarily denotes H or a branched or unbranched1-3alkyl.

6. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 1, characterized in that

R5means-CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12.

7. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 6, wherein R11denotes H, a branched or unbranched1-4alkyl or C(O)O-C1-4alkyl preferably denotes H, a branched or unbranched1-4alkyl or C(O)O-C1-2alkyl primarily denotes N, CH3C2H5or C(O)O-CH3.

8. Substituted carried the major 2-pyridinylamino-1,4-diamine according to claim 1, characterized in that

R12stands With3-8cycloalkyl or five-membered nitrogen containing heteroaryl, optionally condensed with a benzene ring, preferably

R12denotes cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indolyl, pyrrolyl, benzotriazolyl, first of all

R12denotes cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indolyl,pyrrolyl.

9. Substituted derivatives of 2-pyridinylamino-1,4-diamine according to claim 1, characterized in that they are selected from a group including

the dihydrochloride of N-(4-dimethylamino-4-pyridine-2-illlogical)-N-[2-(1H-indol-3-yl)ethyl]acetamide", she polarity diastereoisomer,

trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, non-polar diastereoisomer,

trihydrochloride N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-illlogical-1,4-diamine, polar diastereoisomer,

trihydrochloride methyl ester (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid, non-polar diastereoisomer,

trihydrochloride methyl ester (S)-2-(4-dimethylamino-4-pyridine-2-enciklopedije)-3-(1H-indol-3-yl)propionic acid, polar diastereoisomer,

the dihydrochloride (S)-2-(4-dimethylamino-4-pyridine-2-icicle exil-amino)-3-(1H-indol-3-yl)propionic acid, non-polar diastereoisomer, in the form of their racemates or pure stereoisomers, especially enantiomers or diastereomers, or in the form of bases or a physiologically compatible acid additive salts.

10. Drug having analgesic activity and containing at least one substituted derivative 2-pyridinylamino-1,4-diamine according to claim 1 or 9 in the form of their racemates or pure stereoisomers, especially enantiomers or diastereomers, or in the form of bases or a physiologically compatible acid additive salts, and optionally containing acceptable additives and/or auxiliary substances and/or optionally other active agents, such as opioid, preferably a potent opioid, primarily morphine, or an anaesthetic, preferably hexobarbital or halothane.

11. The method of obtaining substituted derivative 2-pyridinylamino-1,4-diamine according to claim 1, in which R3denotes H, namely, that

a) protected groups S1and S2cyclohexane-1,4-dione of formula II is subjected in the presence of the compounds of formula HNR01R02interaction with cyanide, preferably potassium cyanide, to obtain the protected N-substituted derivative of 1-amino-4-oxocyclohexanecarboxylate formula III

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

b) aminonitriles formula III is combined with the cyclopent-vinylcyclooctane-1,5-Dien-cobalt(I) [cpCo(cod)] and irradiated in the atmosphere of acetylene with the formation of compounds of formula IVa

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02denote N at least once imposed the safety group, and if necessary, conduct the acylation, alkylation or sulfonation,

the compound of formula IVa otscheplaut protective group S1and S2with the formation of 4-substituted derivative of 4-aminocyclohexanone formula IV

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

g) 4-substituted derivative of 4-aminocyclohexanone formula IV is subjected to hydroamination compound of the formula HNR04R05with the formation of a derivative of 2-pyridinylamino-1,4-diamine of formula V

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and the and R 05designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation before the formation of the compounds of formula I, with

R1, R2, R4and R5have specified in claim 1 values, and

R01and R02independently of one another denote H, protected by a protective group H, branched or unbranched1-8alkyl or C3-8cycloalkyl,

R04denotes H protected by a protective group H or branched or unbranched1-8alkyl,

R05refers to a group-CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12where

R11denotes H or a branched or non-branched C1-7alkyl, and R12denotes H, C3-8cycloalkyl or five-membered nitrogen containing heteroaryl, optionally condensed with a benzene ring, and S1and S2independently from each other represent is a protective group, or together represent a protective group, preferably monoacetal.

12. The method of obtaining substituted derivative 2-pyridinylamino-1,4-diamine according to claim 11, characterized in that the protective group of atoms N, the values of which have R01, R02, R04and/or R05selected from alkyl, benzyl and carbamates.

13. The method of obtaining substituted derivative 2-pyridinylamino-1,4-diamine according to claim 11, characterized in that hydroamination in stage d) is carried out in the presence of ammonium formate, ammonium acetate or NaCNBH3.

14. The method of obtaining substituted derivative 2-pyridinylamino-1,4-diamine according to claim 11, characterized in that instead of gidroaminirovaniya compound of the formula HNR04R05at stage g), the compound of formula IV is subjected to interaction with hydroxylamine and after the formation of the oxime restore.

15. The method of obtaining substituted derivative 2-pyridinylamino-1,4-diamine according to claim 11, characterized in that the irradiating at the stage b) also hold for 5-7 h and/or at room temperature and/or in a saturated atmosphere of acetylene and/or in a protective gas atmosphere.



 

Same patents:

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new crystalline form of substance known as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (general name is omeprazole), titled in present description as C form omeprazole. Claimed omeprazole has the next pattern obtained by powdered X-ray diffraction:

valuesof dÅrelative intensity9.5-9.6very strong7.9-8.0strong7.4-7.5weer7.2very strong5.9-6.0medium5.6medium5.1-5.2very strong4.88-4.90weer4.81-4.84weer4.65-4.67medium4.57-4.60medium4.48-4.51strong4.34-4.36medium4.16-4.19weer3.94-3.97weer3.72-3.73strong3.58-3.59medium3.46-3.47strong3.29-3.30medium3.23-3.25strong3.19-3.20medium3.11-3.12weer3.03-3.04weer

Methods for production of C form omeprazole, pharmaceutical composition for treatment of gastrointestinal diseases, containing target product in combination with pharmaceutically acceptable excipients, and application of C form omeprazole in preparation of drug for treatment of gastrointestinal diseases also are described.

EFFECT: new drug for treatment of gastrointestinal diseases.

13 cl, 8 dwg, 3 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of novel derivatives of 4,5-dihydro-1H-pyrazole that are strong antagonists of cannabinoid (CB1) receptor and useful in treatment of diseases associated with disorders of cannabinoid system. Compounds have the general formula (Ia) or (Ib) wherein symbols are given in the invention claim. Also, invention relates to method for synthesis of these compounds, their using, intermediate compounds for synthesis of proposed compounds and to a pharmaceutical composition comprising at least one of these compounds as an active component.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 1 tbl, 100 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to piperidine- and piperazine-substituted N-hydroxyformamides of the general formula (I) or their pharmaceutically acceptable salts wherein B represents phenyl group monosubstituted at 3- or 4-position with halogen atom or trifluoromethyl group or bisubstituted at 3- and 4-position with halogen atom (that can be similar or distinct); or B represents 2-pyridyl or 2-pyridyloxy-group monosubstituted at 4-, 5- or 6-position with halogen atom, trifluoromethyl group, cyano-group or (C1-C4)-alkyl; or B represents 4-pyrimidinyl group possibly substituted with halogen atom or (C1-C4)-alkyl at 6-position; X represents carbon or nitrogen atom; R1 represents trimethyl-1-hydantoin-(C2-C4)-alkyl or trimethyl-3-hydantoin-(C2-C4)-alkyl group; or R1 represents phenyl or (C2-C4)-alkylphenyl monosubstituted at 3- or 4-position with halogen atom, trifluoromethyl group, thio-group, (C1-C3)-alkyl or (C1-C3)-alkoxy-group; or R1 represents phenyl-SO2NH-(C2-C4)-alkyl; or R1 represents 2-pyridyl or 2-pyridyl-(C2-C4)-alkyl; or R1 represents 3-pyridyl or 3-pyridyl-(C2-C4)-alkyl; or R1 represents 2-pyrimidine-SCH2CH2; or R1 represents 2- or 4-pyrimidinyl-(C2-C4)-alkyl possibly monosubstituted with one of the following substitutes: halogen atom, trifluoromethyl, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, 2-pyrazinyl possibly substituted with halogen atom, or 2-pyrazinyl-(C2-C4)-alkyl possibly substituted with halogen atom. Also, invention describes a method for synthesis (variants) of compounds of the formula (I) and a pharmaceutical composition. Compounds can be used as inhibitors of metalloproteinases and useful in such morbidity states as inflammatory and allergic ones.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

12 cl, 1 tbl, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, heterocyclic compounds.

SUBSTANCE: invention describes anthrapyridone compounds of the general formula: wherein R means (C1-C4)-alkyl; Y means amino-group; X means -NH-A-NH- wherein A represents (C1-C6)-polymethylene, xylylene, dicyclohexylmethylene possibly substituted with methyl in cyclohexyl moiety, or their salts, and an aqueous composition of purple ink based on thereof. Purple ink comprising indicated anthrapyridone compounds possesses chromatic tones and brightness suitable for jet printing and give images possessing the excellent stability with respect to light, gas and water.

EFFECT: improved and valuable properties of compound and composition.

13 cl, 6 tbl, 5 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: pharmacy.

SUBSTANCE: invention relates to the improved formulation of aripiprazole showing the reduced hygroscopicity. These formulations are not converted to hydrate and not loss the initial solubility being even the medicinal preparation comprising anhydrous apipiprazole crystals are stored for a long time. Also, invention describes method for preparing these formulation and pharmaceutical composition based on thereof.

EFFECT: improved and valuable pharmaceutical properties of agent.

22 cl, 32 dwg, 7 tbl, 28 ex

FIELD: organic chemistry, medicine, physiology.

SUBSTANCE: invention relates to agents for regulation (maintaining or suppression) of physical working ability and/or adaptation to different variants represented by solvated complex compounds of the general formula (I): Katm+[L1qEL2]Ann- x p.Solv (I) wherein L1 means aminothiols of the formula: R1NHCH(R2)(CH2)1-2SR3 wherein R1 means hydrogen atom (H), (C1-C20)-alkyl or RCO; R means (C1-C19)-alkyl; R2 means H or carboxyl; R3 means H, (C1-C20)-alkyl, (C2-C20)-alkenyl or benzyl; q = 1, 2 or 3; L2 means halogen atom, water and/or organic ligand. For example, bis-(N-acetyl-L-cysteinato)aquozinc (II) diheptahydrate suppresses physical working ability and in the dose 50 mg/kg increases reviving time of mice by 6 times and cats - by 2.8fold under conditions of acute hypoxia with hypercapnia, and increases reviving time of mice by 4 times under conditions of acute hypobaric hypoxia. Under the same conditions the known antihypoxic agents amtizol, acizol or mexidol are inactive or less active significantly by their activity. Bis-(N-acetyl-L-cysteinato)-ferrous (II) pentahydrate is more active as compared with the known antihypoxic agents and protects experimental animals in 4 variants of hypoxia. Bis-(N-acetyl-L-cysteinato)zinc (II) sulfate octahydrate is similar to enumerated compounds by its antihypoxic activity.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 dwg, 11 tbl, 33 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I):

wherein R1 represents the following groups:

wherein * means the addition point; R4 means fluorine, chlorine, bromine atom, -CF3, -N=C, -CH3, -OCF3 or -CH2OH; R5 means chlorine, bromine atom or -OCH3; R6 means -CH3 or chlorine atom; R7 means -CH3 or chlorine atom; R8 means -CH3, fluorine, chlorine atom or -CF3; R2 represents pyridyl or group:

or ; R3 represents hydrogen or fluorine atom, and their tautomers, E-isomers or Z-isomers, racemates, enantiomers and salts also that are inhibitors of activity of tyrosine kinase KDR and FLT. Also, invention describes medicinal agents comprising the claimed compounds and designated for treatment of diseases associated with inhibition of activity of kinase KDR and FLT.

EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl

The invention relates to compounds of formula (I):

< / BR>
in which Y represents-CH - or-N-; R1means hydrogen, halogen, trifluoromethyl, (C1-C4)-alkyl; R2means methyl or ethyl; each of R3and R4means hydrogen; X is (C1-C6)-alkyl or phenyl

The invention relates to new derivatives phenylalkylamines acid, having superior activity in lowering blood sugar levels in the blood, and their pharmacologically acceptable salts or pharmaceutically acceptable esters, compositions comprising the specified connection as the active ingredient for the treatment or prevention of hyperglycemia; their use as a medicinal product for treatment or prevention of hyperglycemia; or the treatment or prevention of hyperglycemia, in which a warm-blooded animal is administered a pharmacologically effective amount of the compounds

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

FIELD: organic chemistry, medicine, clinical pharmacology.

SUBSTANCE: invention relates to agents used in treatment of pain. Method involves administration to a patient the effective dose of enantiomer of compounds of the formula (Ib) or the formula (IIb) or their mixture. Method provides the antihyperanalgesic effect in acute and chronic pain.

EFFECT: valuable medicinal properties of derivatives.

5 cl, 1 tbl

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