Spirocyclic derivatives of cyclohexane with affinity to orl1 receptor

FIELD: chemistry.

SUBSTANCE: described are spirocyclic derivatives of cyclohexane of general formula . Values of radicals are given in the formula of invention. The compounds have affinity to the ORL1 receptor and can be used for treating abstinence syndrome (withdrawal syndrome) and pain. Also described is a medicinal agent and use of formula (I) compounds for preparing respective medicinal agents.

EFFECT: increased effectiveness of using the compounds.

13 cl, 17 ex, 1 dwg

 

The present invention relates to spirocycles derivative of cyclohexane, methods for their preparation, pharmaceuticals containing these compounds and to the use spiritlessly derivatives of cyclohexane to obtain the drugs.

Heptadecapeptide nociceptin is an endogenous ligand ORL1-receptor (from the English. "opioid receptor-like" receptor"that is similar to the opioid receptor receptor) (Meunier and others, Nature 377, 1995, s-535), which belongs to the family of opioid receptors and which can be detected in many brain and spinal cord. This peptide has a high affinity for ORL1-receptor. ORL1-receptor homologous opioid µ-, κ - and δ-receptors, and the amino acid sequence of peptide - nociceptin - has a high similarity with the amino acid sequences of known opioid peptides. Induced nociception activation of this receptor leads by associating with Gi/o-proteins to inhibition of adenylate cyclase (Meunier and others, Nature 377, 1995, s-535).

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, c.792-794). A similar effect can be explained by the inhibition induced St is the ECCA analgesia (Mogil and others, Neuroscience 75, 1996, c.333-337). In this regard, it was possible to detect anxiolytic activity nociceptin (Jenck and others, Proc. Natl. Acad. Sci. USA 94, 1997, c.14854-14858).

On the other hand, the results of various experiments on animals suggest that nociceptin, especially after intrathecal injection, also shows antinociceptive action. Nociceptin shows antinociceptive effect when modeling various pains, for example, in the experiment on mice with otdergivanija tail (King and others, Neurosci. Lett., 223, 1997, c.113-116). When modeling neuropathic pain has also been able to identify the antinociceptive action nociceptin, 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 (Manabe and others, Nature, 394, 1997, c.577-581), auditory (Nishi and others, EMBO J., 16, 1997, c.1858-1864), as well as many other processes. In article Calo and others (Br.J.Pharmacol., 129, 2000, c.1261-1283) provide an overview of the symptoms or biological processes in which the ORL1-cocktail recipes. who plays or with high probability could play a role. When this is called, in particular, analgesia, stimulation and regulation of digestion, effect on µ-agonists, such as morphine, treatment of withdrawal symptoms (withdrawal), the reduction potential of opioids as 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 forms of dropsy, intestinal motility (diarrhoea), relaxing the 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. Along with this, it is in the treatment of pain, as well as with other designated indications opioid receptors, such as the µ-receptor, as well as other these subtypes of opioid receptors, in particular, δ - and κ-receptors, play VA the role. Positive results, therefore, can be achieved in those cases. when compounds exhibit its effect also in relation to specific opioid receptors.

Based on the foregoing, 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 according to the prior art in one way or another connected with this system, respectively, for use in the above mentioned in the above-described prior art evidence.

The object of the invention in accordance with this are spirocycles derivatives of cyclohexane General formula I

in which

R1and R2independently of one another denote H, SNO, saturated or unsaturated, branched or unbranched, one or mnogozalny or unsubstituted With1-C5alkyl, saturated or unsaturated, one or mnogozalny or unsubstituted With3-C8cycloalkyl or attached via C1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, which do

the remains of R1and R2together form a group of CH2CH2Och2CH2CH2CH2NR11CH2CH2or (CH2)3-6where

R11represents H, saturated or unsaturated, branched or unbranched, one or mnogozalny or unsubstituted With1-C5alkyl, saturated or unsaturated, one or mnogozalny or unsubstituted With3-C8cycloalkyl, one or mnogozalny or unsubstituted aryl or heteroaryl or attached through With1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R3denotes unsubstituted or mono - or mnogozalny heteroaryl or C1-C3heteroaryl,

W denotes NR4, O or S, where

R4represents H, saturated or unsaturated, branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, substituted or unsubstituted aryl or heteroaryl attached via C1-C3alkyl group, aryl, heteroaryl or cycloalkyl, each of which is one or mnogosloinym or unsubstituted, COR12, SO2R12where

R12represents H, saturated or unsaturated, branched Il is unbranched, one or mnogozalny or unsubstituted With1-C5alkyl, saturated or unsaturated, one or mnogozalny or unsubstituted With3-C8cycloalkyl, one or mnogozalny or unsubstituted aryl or heteroaryl or attached via C1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, OR13, NR14R15,

R5means =O, H, COOR13, CONR13, OR13saturated or unsaturated, branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, saturated or unsaturated, unsubstituted or one - or mnogozalny3-C8cycloalkyl, unsubstituted or one - or mnogozalny aryl or heteroaryl or attached through With1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym,

R6denotes H, F, Cl, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15saturated or unsaturated, branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, saturated or unsaturated, unsubstituted or one-or mnogozalny 3-C8cycloalkyl, unsubstituted or one - or mnogozalny aryl or heteroaryl or attached via C1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, or

R5and R6together form the group (CH2)nwhere n denotes 2, 3, 4, 5 or 6, when this individual hydrogen atoms can also be replaced by F, Cl, Br, I, NO2, CF3, OR13CN or C1-C5alkyl,

R7, R8, R9and R10independently from each other denote H, F, Cl, Br, I, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15With1-C5alkyl, unsubstituted or one - or mnogozalny3-C8cycloalkyl, unsubstituted or one - or mnogozalny aryl or heteroaryl or attached via C1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, while

R13represents H, saturated or unsaturated, branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, saturated or unsaturated, unsubstituted or one - or mnogozalny3-C8cycloalkyl, zamesheny or one or mnogozalny aryl or heteroaryl or attached via C 1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym,

R14and R15independently of one another denote H, saturated or unsaturated, branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, saturated or unsaturated, unsubstituted or one - or mnogozalny3-C8cycloalkyl, unsubstituted or one - or mnogozalny aryl or heteroaryl or attached via C1-C3alkyl aryl, C3-C8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, or

R14and R15together form the group-CH2CH2OCH2CH2,

CH2CH2NR16CH2CH2or (CH2)3-6where

R16represents H, saturated or unsaturated, branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl,

X denotes O, S, SO, SO2or NR17where

R17represents H, saturated or unsaturated, branched or unbranched1-C5alkyl, COR12or SO2R12,

in the form of the racemate, of the enantiomers, of the diastereomers, mixtures of enantiomers or diastereomers whether what about in the form of a single enantiomer or diastereoisomer, in the form of bases and/or salts of physiologically compatible acids or cations.

When the General disclosure of the values of the various residues, for example, R7, R8, R9and R10as the substituents of these residues, as, for example, OR13, SR13, SO2R13or COOR13one Deputy, for example, R13in the same connection it may take two or more residues, e.g., R7, R8, R9and R10different values.

Proposed in the invention compounds exhibit a high degree of binding with the ORL1 receptor, as well as with other opioid receptors.

Under the concepts of "C1-C5alkyl" and "C1-C3alkyl" according to the present invention refers to an acyclic saturated or unsaturated hydrocarbon residues, which may be branched or remotemachine, as well as unsubstituted or mono - or mnogosloinymi, 1, 2, 3, 4 or 5 C-atoms, respectively, with 1, 2 or 3 C-atoms, i.e. With1-C5alcalali,2-C5alkenyl and C2-C5alkinyl, respectively, With1-C3alcalali,2-C3alkenyl and C2-C3alkinyl. At the same time, alkenyl contain at least one double carbon-carbon bond, and alkinyl contain at least one triple carbon-carbon links the ü. Preferably the alkyl is selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, Etiler (vinyl), ethinyl, propinyl (-CH2CH=CH2, -CH=CH-CH3-C(=CH2)-CH3), PROPYNYL (-CH-C≡CH, -C≡C-CH3), 1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butynyl, pentenyl and pentenyl.

The term "cycloalkyl" or "C3-C8cycloalkyl" according to the present invention refers to a cyclic hydrocarbon containing 3, 4, 5, 6, 7 or 8 carbon atoms and can be saturated or unsaturated (but not aromatic), unsubstituted or one - or mnogosloinymi.

With regard to cycloalkyl this term also includes saturated or unsaturated (but not aromatic) cycloalkyl group in which one or two carbon atoms replaced by a heteroatom is S, N or O. Preferably3-C8cycloalkyl selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol and tetrahydropyranyl, dioxane, dioxolane, morpholine, piperidine, piperazinil, pyrazolinone and pyrrolidinyl.

Under the residue (CH2)3-6refers to the group-CH2-CH2-CH2 -, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2- and-CH2-CH2-CH2-CH2-CH2-CH2-.

The term "aryl" according to the present invention refers to carbocyclic system with at least one aromatic ring, but without heteroatoms in only one of the rings, in particular family, nattily, phenanthrene, fluoranthene, fluorenyl, indanyl and tetralinyl. Aryl residues can be condensed with other saturated, (partially) unsaturated or aromatic cyclic systems. Each aryl residue can be represented in unsubstituted or mono - or mnogoseriynom form, with aryl substituents may be identical or different, or may be located in any of the possible positions of the aryl. Especially preferred are phenyl or raftiline remains.

The term "heteroaryl" refers to 5-, 6 - or 7-membered cyclic aromatic residue containing at least 1, and under certain conditions 2, 3, 4 or 5 identical or different heteroatoms, and the heterocycle may be unsubstituted or mono - or mnogosloinym, and in the case of substituted heterocycle his substituents may be identical or different and can be in any possible position is the second of heteroaryl. The heterocycle can also be part of a bi - or polycyclic system. For your preferred heteroatoms include nitrogen, oxygen and sulfur. It is preferable to choose heteroaryl residue from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothiazyl, benzothiadiazoles, benzothiazolyl, benzotriazolyl, benzodioxolyl, benzodioxane, phthalazine, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazoles, purinol, indolizinyl, chinoline, ethenolysis, hintline, carbazolyl, phenazines, phenothiazines and oxadiazolyl, with the accession to the compounds of General formula I may be through any of the possible States of the cycle heteroaryl residue.

The term "substituted" as applied to alkyl according to the present invention is meant the substitution of one or more atoms of F, Cl, Br, I, -- CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkylaryl, NH-alkylglycerol, groups, NH-alkyl-HE, N(alkyl)2N(alkylaryl)2N(alkylglycerols)2N(cycloalkyl)2, N(alkyl-OH)2, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, S-alkylaryl, S-alkylglycerol, S-cycloalkyl, groups, S-alkyl-IT, S-alkyl-SH, HE, O-alkyl, O-the-Rila, O-heteroaryl, O-alkylaryl, O-alkylglycerol, O-cycloalkyl, groups, O-alkyl-HE, Cho, C(=O)1-C6the alkyl, C(=S)1-C6the alkyl, C(=O)aryl, C(=S) - aryl, C(=O)1-C6alkylaryl, C(=S)1-C6alkylaryl, C(=O)heteroaryl, C(=S)heteroaryl, C(=O)cycloalkyl, C(=S)cycloalkyl, a group of CO2N, CO2-alkyl, CO2-alkylaryl, group C(=O)NH2With(=O)NH-alkyl, C(=O)NH-aryl, C(=O)NH-cycloalkyl, groups C(=O)N(alkyl)2C(=O)N(alkylaryl)2With(=O)N(alkylglycerols)2With(=O)N(cycloalkyl)2, SO-alkyl, SO2-alkyl, groups of SO2NH2, SO3H, RO(O-C1-C6alkyl)2Si(C1-C6alkyl)3Si(C3-C8cycloalkyl)3Si(CH2-C3-C8cycloalkyl)3, Si(phenyl)3, cycloalkyl, aryl or heteroaryl, under mnogosloinymi refers to the remnants of the remnants, mnogosloinye, such as bilateral or tizamidine, either on different or on the same atoms, for example tizanidine on the same C-atom, as in the case of CF3or-CH2CF3or at various positions of the atoms, as in the case of-CH(OH)-CH=CH-CHCl2. If polyamidine the substituents may be identical or different values. Under certain conditions, a Deputy in turn also which may be substituted: in particular, Alkyl also includes-O-CH2-CH2-O-CH2-CH2HE.

The term "one or mnogozalny" in relation to the aryl, heteroaryl and cycloalkyl according to the present invention refers to a mono - or polyamidine, for example di-, tri-, Tetra - or pentamidine, one or more hydrogen atoms of the cyclic system of atoms F, Cl, Br, I, CN groups, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkylaryl, NH-alkylglycerol, NH-cycloalkyl, groups, NH-alkyl-HE, N(alkyl)2N(alkylaryl)2N(alkylglycerols)2N(cycloalkyl)2, N(alkyl-OH)2, NO2, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkylaryl, S-alkylglycerol, groups, S-alkyl-IT, S-alkyl-SH, HE, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkylaryl, O-alkylglycerol, groups, O-alkyl-HE, Cho, C(=O)1-C6the alkyl, C(=S)1-C6the alkyl, C(=O)aryl, C(=S) - aryl, C(=O)1-C6alkylaryl, C(=S)1-C6alkylaryl, C(=O)heteroaryl, C(=S)heteroaryl, C(=O)cycloalkyl, C(=S)cycloalkyl, a group of CO2H, CO2-alkyl, CO2-alkylaryl, group C(=O)NH2With(=O)NH-alkyl, C(=O)NH-aryl, C(=O)NH-cycloalkyl, groups C(=O)N(alkyl)2With(=O)N(alkylaryl)2C(=O)N(alkylglycerols)2With(=O)N(cycloalkyl)2, S(O)-alkyl, S(O)-Ari is om, SO2-alkyl, SO2-aryl, groups of SO2NH2, SO3H, CF3, =O, =S, alkyl, cycloalkyl, aryl and/or heteroaryl one or optionally different atoms (with the appropriate Deputy, in turn, may under certain conditions also replaced). Multiple substitution can be carried out using the same substituent or different substituents.

The term "salt" refers to each of the forms proposed in the invention the active substance, in which it takes ionic form, respectively, has an electric charge of either sign and is associated with a counterion (cation or anion), respectively, is in the 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 with stima salt with anions or acids according to the invention refers to a salt of at least one of the proposed invention compounds mainly in the protonated, for example, 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 according to the invention are primarily formed with a physiologically compatible acid salt, namely 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. 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, the hippuric acid and/or aspartic acid. Most preferably the salt is a hydrochloride, citrate and hemitite.

The term "formed with a physiologically compatible acid salt according to 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 are the hydrochloride and citrate. As examples of physiologically 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" according to the present invention refers to a salt of at least one of the image the shadow compounds, mostly (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, and ammonium salts, but primarily of mono - or disodium, mono - or decaluwe, magnesium or calcium salts.

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

According to one of preferred embodiments of the invention in its proposed spiritlessly derivatives of cyclohexane

R1and R2independently of one another denote H, saturated or unsaturated, branched or unbranched, one or mnogozalny or unsubstituted With1-C 2alkyl or

the remains of R1and R2together form a group of CH2CH2Och2CH2CH2CH2NR11CH2CH2or (CH2)3-6.

According to another preferred variant of the invention in its proposed spiritlessly derivatives of cyclohexane

R1and R2independently of one another denote H, a branched or unbranched, saturated or unsaturated, unsubstituted or one - or mnogozalny C1-C5alkyl or SNO,

R3denotes unsubstituted or mono - or mnogozalny heteroaryl,

R5denotes H, a branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl or COOR13,

R6denotes N or C1-C5alkyl,

R7, R8, R9and R10independently of one another denote H, a branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, F, Cl, Br, I, HE, co3, NH2, COOH, SOON3, NHCH3N(CH3)2or NO2.

According to the invention preferred such spirocycles derivatives of cyclohexane General formula I, in which

W denotes NR4, O or S, and

X denotes O, S, SO, SO2or NR17prepact the tion O or NR 17,

R1and R2independently of one another denote H, a branched or unbranched, one or mnogozalny or unsubstituted With1-C4alkyl or SNO,

R3denotes unsubstituted or mono - or mnogozalny heteroaryl,

R4denotes H, one or mnogozalny or unsubstituted C1-C3alkyl, (CH2)mH, where m is 0-2, and/or

R5and R6each respectively represents H and/or

R7, R8, R9and R10independently of one another denote H, a branched or unbranched, saturated or unsaturated, unsubstituted or one - or mnogozahodnoy1-C5alkyl or OC1-C3alkyl group, F, Cl, Br, I, CF3HE, SH, SCH3The co3, NH2, COOH, SOON3, NHCH3N(CH3)2or NO2,

however, particularly preferred are compounds in which W denotes NR4and X represents O.

According to a particularly preferred variant of the invention in its proposed spiritlessly derivatives of cyclohexane R1and R2independently from each other represent And or CH3while R1and R2at the same time not denote N.

According to another particularly preferred variant implementation and is gaining in its proposed spiritlessly derivatives of cyclohexane R 3denotes thienyl or pyridyl.

According to one of the most preferred embodiments of the invention in its proposed spiritlessly derivatives of cyclohexane residue R5denotes N, CH3SOON3or CH2HE, the remainder R6denotes H, residues R7, R8, R9and R10independently of one another denote H, a branched or unbranched, unsubstituted or mono - or mnogozalny C1-C5alkyl, F, Cl, Br, I, CF3HE co3, NH2, COOH, SOON3, NHCH3N(CH3)2or NO2preferably

the remains of R6, R7, R8, R9and R10denote H, or one of the residues R6, R7and R8denotes H, a branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, F, Cl, Br, I, HE, co3, COOH, SOON3, NH2, NHCH3N(CH3)2or NO2while other residues denote H, or two of the residues R6, R7, R8, R9and R10independently of one another denote H, a branched or unbranched, unsubstituted or mono - or mnogozalny1-C5alkyl, F, Cl, Br, I, HE, co3, COOH, SOON3, NH2, NHCH3N(CH3)2or NO2while other remnants of oznachaet N.

Particularly preferred are further such compounds in which W denotes NR4X denotes O, a R4represents N, CH3With2H5, acetyl, phenyl, benzyl or COR12primarily N.

According to a preferred variant embodiment of the invention in its proposed spiritlessly derivatives of cyclohexane R1and R2independently of one another denote H or CH3first of all SN3and R3denotes pyridyl or thienyl, and/or the residues R5, R6, R7, R9and R10denote N, and the remainder R8denotes H or F.

The most preferred are spirocycles derivatives of cyclohexane from a group including

1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluoren,

2-acetyl-1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluoren,

1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2-oxa-9-difluoro,

hemitite 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer,

the citrate of 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, polar diastereoisomer,

dimethanesulfonate 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]Indo is a, polar diastereoisomer,

the citrate of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer,

hemitite 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer,

the citrate of 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, polar diastereoisomer,

hemitite 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, non-polar diastereoisomer,

the citrate of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, polar diastereoisomer,

dimethanesulfonate 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, polar diastereoisomer,

hemitite 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, non-polar diastereoisomer,

the citrate of 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole,

the citrate of 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola,

the citrate of 1,1-[3-methylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole,

the citrate of 1,1-[3-methylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, and under certain conditions a mixture thereof.

Proposed in the invention compounds have, among other things, de is the effect on the ORL1-receptor, plays an important role in various diseases, and because of this they can be used as pharmaceutical active substance in the relevant medicinal product. Another object of the invention in accordance with this drugs are those containing at least one proposed therein spirocyclohexane derivative of cyclohexane, and if necessary, additives and/or auxiliary substances and/or under certain conditions, other active ingredients.

Proposed in the invention medicines in addition to at least one spirocycles cyclohexane derivative according to the invention contain, if necessary, 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, patches, including patches, applied by spray or aerosol. The choice of auxiliary and other substances, and used their number depend on whether the drug for oral, oral, parenteral, nutrion the CSOs, 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 compositions 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 spirocycles derivatives of cyclohexane in depot form, in dissolved form or embedded in a plaster, optionally with the addition of promote penetration through the skin of funds (activators percutaneous absorption), 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 spiritlessly derivatives of cyclohexane. Proposed in the invention spirocycles derivatives of cyclohexane can also be used intended for parenteral depo-forms with prolonged action, for example, implants or implanted pumps. In principle, the composition proposed in the invention medicinal cf the of funds, 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, method of administration, indications for use and the severity of the disease. Usually at least one proposed in the invention spirocyclohexane derivative of cyclohexane are introduced into the organism at a dose component from 0,00005 to 50 mg/kg, preferably from 0.001 to 0.5 mg/kg body weight.

In the structure proposed in the invention of medicines, all of them described above, most preferably in addition to at least one spirocycles derivative of cyclohexane to include another active ingredient, primarily opioid, preferably a potent opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.

In one preferred options contained in the medicinal product spirocyclohexane cyclohexane derivative 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 spirocycles the derivatives of cyclohexane can be used to obtain medicines designed for treatment of pain, especially acute, neuropathic or chronic pain.

Another object of the invention in accordance with this application is proposed therein spirocycles derivative of cyclohexane to obtain a medicinal product intended for the treatment of pain, especially acute, visceral, neuropathic or chronic pain.

During pharmacological studies, it was found that proposed in the invention compounds are particularly suitable for treating conditions related to the abuse of opioids, and can also be used as muscle relaxants, or anesthetics. Another object of the invention in accordance with this application is proposed therein spirocycles derivative of cyclohexane to obtain a medicinal product intended for the treatment of symptoms (syndrome), alcohol and/or drug and/or drug and/or alcohol and/or drug and/or drug addiction, as a muscle relaxant or anesthetic, respectively, for joint injections used in the treatment of opioid analgesic or anesthetic for the treatment of withdrawal symptoms and/or to reduce the tendency to opioids.

Another object of the invention is the use of the facilities is amago it spirocycles derivative of cyclohexane to obtain medicines designed for treatment of States of fear, stress and related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, General impairment of cognitive abilities (cognitive dysfunction), disorders of learning and memory (as a nootropic drugs), 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 anti-convulsants, for diuresis or antinatriuretic, anxiolysis, for modulation of motor activity, for modulation of the release of neurotransmitters and treatment related neurodegenerative diseases.

In one variation of the above applications it may be preferable to use spirocyclohexane derivative of cyclohexane 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 mlekovita is his or person, which, respectively, which is needed in the treatment of pain, especially chronic pain, which consists in the introduction into the body proposed in the invention spirocycles derivative of cyclohexane in a therapeutically effective dose or proposed in the invention medicines.

Another object of the invention is a method for its proposed spiritlessly derivatives of cyclohexane, discussed in a subsequent part of the description and in the examples. Suitable for this purpose first of all, hereinafter called the principal, the method of obtaining the proposed in the invention spirocycles derivative of cyclohexane, illustrated by the diagram below, where X, W, R1, R2, R3, R5, R6, R7, R8, R9and R10have the values specified for the proposed in the invention compounds of formula I, and R01and R02have values identical to the values of R1and R2specified for the proposed invention compounds of formula I, and optionally, independently of one another may represent a protective group, and providing means conduct described below the following stages:

To obtain the compounds of General formula Ia ketones of General formula And subjected to interaction with heteroaromatic the ski compounds of the General formula In adding the appropriate acid or its trimethylsilyl ether, for example, trimethylsilyl ether triftormetilfullerenov acid, acetic acid, phosphoric acid, methanesulfonic acid or triperoxonane acid, in an appropriate solvent, such as dichloroethane, dichloromethane, chloroform, acetonitrile, diethyl ether or nitromethane. Obtain the corresponding 4-aminocyclohexanone known from the literature (Lednicer, etc., J. Med. Chem. 23, 1980, c.424-430, WO 02/90317, US 4065573).

Another possibility of obtaining the proposed in the invention compounds is illustrated in the diagram below, where X, W, R3, R5, R6, R7, R8, R9and R10have these to offer in the invention compounds of formula I values

and R01and R02have values identical to the values of R1and R2specified for the proposed invention compounds of formula I, and optionally, independently of one another may represent a protective group.

Spirocycles derivatives of cyclohexane General formula I, in which X represents NR17where R17denotes COR12or SO2R12you can get interaction spiritlessly derivatives of General formula I, in which X represents NH, anhydride or acid chloride of the acid with the addition of an appropriate base, such as triethyl is in. This reaction is preferably carried out with the microwave radiation.

Spirocycles same derivatives of cyclohexane General formula I, in which X denotes SO or SO2you can get interaction spiritlessly cyclohexane derivatives of General formula I, in which X represents S, with an appropriate oxidizing agent, for example, N2About2.

Spirocycles derivatives of cyclohexane, in which R3denotes 3-thienyl, and R1denotes CH3and R2denotes H, can be obtained according to the following scheme, where R' and R"' independently from each other represent a protective group, followed by explanations:

When implementing this method in the methyl group of 3-methylthiophene by methods known in the art, for example, synthesized by using N-bromosuccinimide in an inert solvent, such in particular as benzene, adding initiator, such as benzoyl peroxide, and optionally when heated introducing a leaving group such as halogen, preferably bromine.

Thus obtained product, for example, 3-brometalia, when using a source of cyanide, such in particular as sodium cyanide, for example, in the presence of a Quaternary ammonium salt, such, for example, ka is tetrabutylammonium, optional when heated, transferred to the corresponding nitrile.

Thus obtained thiophene-3-ylacetonitrile in the presence of acrylic ester or ether 3-bromopropionic acid used in excess, preferably in the amount of 2.3 mol. equivalent, as well as in the presence of an appropriate base, for example sodium amide, expose, not necessarily when heated, the exchange reaction in an aprotic solvent, for example toluene.

Thus obtained esters of 5-cyano-2-oxo-5-thiophene-3-enciklopedicheskogo acid by methods known in the art can omelet and dicarboxylate, preferably by heating under reflux in a mixture of concentrated hydrochloric acid and glacial acetic acid.

Ketogroup obtained is described by 4-oxo-1-thiophene-3-enciclopedicanyfile can be protected by well-known specialists methodology suitable protective group, preferably by acetalization, particularly preferably by conversion to protective Ethylenedioxy, most preferably by heating the ketone in toluene in the presence of ethylene glycol and an acid catalyst, for example, para-toluensulfonate acid, when heated, preferably under reflux.

Thus obtained 8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-carbonitril by well-known specialists of the method by saponification of the nitrile group can be converted to the corresponding carboxylic acid, for example, in an alkaline medium, preferably using sodium hydroxide in ethylene glycol, using the back of the refrigerator.

Thus obtained 8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid by known experts methodology can be converted to the corresponding isocyanate, preferably with the help of reactions by type of rearrangement of kurzius. It is preferable to translate carboxylic acid isocyanate using diphenyl ether acidopathies acid in the presence of triethylamine in anisole at reflux.

Thus obtained 8-isocyanato-8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane can be translated, for example, using lithium aluminum hydride in an aprotic solvent, preferably tetrahydrofuran, in the appropriate methylimidazolidine.

Thus obtained methyl-(8-thiophene-3-yl-1,4-dioxaspiro[4.5]Dec-8-yl)amine can by acid catalysis by removal of the protective group of the first to turn in 4-methylamino-4-thiophene-3-illlogical and then, for example, an interaction with compounds of General formula to turn in spirocycles derivatives of cyclohexane.

Examples

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

The output obtained in primorosamente not optimized.

All temperatures are listed in the unadjusted values.

The concept of "simple ether" refers to diethyl ether, the abbreviation "EA" refers to ethyl acetate; the abbreviation "CHM" refers to dichloromethane, the abbreviation "DMF" refers to dimethylformamide, reduction of "DMSO" refers to dimethyl sulfoxide, and the abbreviation "THF" refers to tetrahydrofuran. The term "equivalent" refers to the equivalent number 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 term "mole" refers to the concentration in moles/L.

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

In the analysis of thin-layer chromatography (TLC) used a ready plates for TLC high resolution (DHWR) type silica gel 60 F 254 firms Emags, 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: 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluoren, the mixture Diaz is eriosoma

4-dimethylamino-4-pyridine-2-illlogical (4,37 g, 20 mmol) and 2-(1H-indol-3-yl)ethylamine ("tryptamine", 3.2 g, 20 mmol) was dissolved in argon atmosphere in a dry Meon (200 ml). After 24 h, during which time the reaction proceeded, the Meon drove, yellow oily residue suspended in 1,2-dichloroethane (200 ml), then added triperoxonane acid (20 ml), and within 2 h and stirred at RT. For further processing the mixture was diluted with water (100 ml) and NaOH (5 mol/l) pH value was adjusted to 11. After adding EA (50 ml) to the residue under stirring, the precipitated white solid, which was separated by vacuum filtration through a Frit. The solid is washed with water (3×25 ml) and dried in vacuum. 1,1-(3-dimethylamino-3-(pyridin-2-yl)pentamethylene)-3,4-dihydro-1H-2,9-diazafluoren received in the form of a mixture of diastereoisomers (4.9 g of a white solid substance, tPL122-125°C).

Example 2: 2-acetyl-1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluoren

Is obtained analogously to example 1 1,1-(3-dimethylamino-3-(pyridin-2-yl)pentamethylene)-3,4-dihydro-1H-2,9-diazafluoren (200 mg, of 0.56 mmole) was dissolved in pyridine (5 ml), then was added dropwise acetanhydride (484 μl, 5.6 mmole) and within 5 days was stirred at RT. For further processing pyridine drove by rotary evaporator, the residue was diluted with water (10 ml), with the aid of the d 5-molar NaOH pH value was adjusted to 11 and was extracted with EA (3×10 ml). From the combined organic extracts precipitated solid substance was separated by vacuum filtration and dried. As a result he received 160 mg of a white solid substance in the form of pure diastereoisomers. 150 mg (0.37 mmole) of this solid was dissolved in hot ethanol (10 ml) and mixed with a hot solution of citric acid (72 mg, 0.37 mmole) in ethanol (1 ml). After cooling to about 5°C. the mixture was left to stand for 4 h, then concentrated to dryness. In this way, citrate, 2-acetyl-1,1-(3-dimethylamino-3-(pyridin-2-yl)pentamethylene)-3,4-dihydro-1H-2,9-diazafluoren was obtained with the yield 222 mg (white frothy substance, tPL108-112°C).

Example 3: the Citrate of 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene-3,4-dihydro-1H-2-oxa-9-difluorine

In the atmosphere of argon, 4-dimethylamino-4-pyridine-2-illlogical (218 mg, 1 mmol) and 2-benzo[b]thiophene-2-retinol (178 mg, 1 mmol) was dissolved in absolute DHM (5 ml), then added methanesulfonyl acid (3 ml) and the mixture was stirred for 3 days at RT. For further processing, the reaction mixture was mixed with ice (5 g) and water (30 ml). After neutralization with sodium bicarbonate (4.4 g, 52 mmole) and add 5-molar NaOH (1 ml) was added DHM (10 ml), the organic phase was separated, and the aqueous phase was extracted with DHM (2×30 ml). The combined organic phase after drying was concentrated and the OST is OK (375 mg) was separated by chromatography on silica gel (45 g, eluent: EA/methanol, for the first time in the ratio of 10:1, for the second time in the ratio of 4:1, then only methanol). The crude product was obtained with the yield 143 mg (0,377 mmole) as a white solid (tPL155-168°C), then this solid substance was dissolved in ethanol (10 ml) at 50°C, was mixed with citric acid (72 mg, 0,377 mmole), dissolved in warm ethanol (3 ml)was stirred for 2 h at RT and concentrated to a volume of 5 ml. Fallen thus precipitated solid was separated by vacuum filtration and washed with ethanol (2×1 ml). The citrate of 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2-oxa-9-difluorine was obtained with the yield 179 mg (white solid, tPL189-191°C).

Example 4: Hemitite 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer

4-dimethylamino-4-pyridine-2-illlogical (654 mg, 3 mmole) and 2-(1H-indol-3-yl)ethanol (tryptophol", 483 mg, 3 mmole) was previously placed in DHM (50 ml), then for 3 min was added methanesulfonyl acid (400 μl, 6.2 mmole) and stirred for 70 h at RT. For further processing, the reaction mixture was mixed with 2-molar NaOH (15 ml)was stirred for 20 min, after which the organic phase is separated and the remaining aqueous phase was isolated by shaking with dichloromethane (3×20 ml). The combined organic phases are promyvaiut (2×30 ml), was dried, filtered and concentrated. The resulting residue was chromatographically on silica gel and the base nonpolar diastereoisomer the target product was obtained with the yield 123 mg 108 mg (0.3 mmole) of this base was dissolved in hot ethanol (15 ml), mixed with hot ethanolic solution of citric acid (58 mg, 0.3 mmole 1 ml) and the mixture was left for 12 h at 5°C. the Formed solid substance was separated by vacuum filtration. In this way hemitite nonpolar diastereoisomer 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole was obtained with the yield 79 mg (white solid, tPL255-260°C).

Example 5: the Citrate of 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, polar diastereoisomer

Analogously to example 4 also received 415 mg of the polar diastereoisomer 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole. 400 mg (1.1 mmole) of this diastereoisomer was dissolved in hot ethanol (12 ml) and then added hot ethanolic citric acid solution (a total of 211 mg, 1.1 mmole 2 ml). The mixture was left for 2 h at 5°C, then concentrated to dryness. In this way, citrate polar diastereoisomer 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole was obtained with the yield 612 mg (vitreous t is ardoe substance of white color, tPL96-100°C).

Examples 6 and 7: Dimethanesulfonate 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (example 6) and the citrate of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (example 7)

4-dimethylamino-4-(2-thienyl)cyclohexanone (223 mg, 1 mmol) and 2-(1H-indol-3-yl)ethanol (161 mg, 1 mmol) was dissolved in absolute DHM and then added methanesulfonyl acid (0,071 ml, 1.1 mmole). Next was stirred for 16 h at RT, while the polar diastereoisomer of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole precipitated in the form of dimethanesulfonate (example 6). The result was a light gray solid with a yield of 25% (117 mg, tPL132°C).

The filtrate was mixed with 1-molar NaOH (20 ml) and for 16 h and was stirred at RT. The organic phase was separated, the aqueous phase was extracted and the combined organic phases were concentrated. Got a mixture of substances, which were separated by chromatography [silica gel G (20 g), EA/methanol in a ratio of 8:1]. In this way non-polar diastereoisomer 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole was obtained with the yield of 54% (196 mg, tPL235-238°C), and polar diastereoisomer with the release of 10% (38 mg).

To obtain citrate non-polar diastereoisomer 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-,3,4,9-tetrahydropyrido[3,4-b]indole (170 mg, 0,46 mmole) was dissolved by heating in ethanol (50 ml) and was mixed with citric acid (98 mg, of 0.51 mmole) in ethanol (5 ml). Next was stirred for 1 h at RT. Citrate (example 7) was obtained as colorless connection with the release of 60% (153 mg, tPL222-225°C).

Examples 8 and 9: Hemitite 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (example 8) and the citrate of 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (example 9)

4-dimethylamino-4-(3-thienyl)cyclohexanone (223 mg, 1 mmol) and 2-(1H-indol-3-yl)ethanol (161 mg, 1 mmol) was dissolved in absolute DHM (50 ml) and mixed with methanesulfonic acid (0,13 ml, 2.0 mmole). The mixture for 2 days was stirred at RT, with some polar diastereoisomer 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole precipitated in the form of methansulfonate. A solid substance was separated by vacuum filtration, washed DHM and got it with the release of 12% (55 mg). The filtrate was mixed with 0.5-molar NaOH (20 ml) and was stirred for 2 h at RT. While non-polar diastereoisomer 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole precipitated in the form of a colorless solid after filtration it was obtained with the yield of 38% (138 mg) with tPL291-294°C. the Organic phase of the filtrate was separated, and the aqueous phase was extracted with D The M (2×20 ml). From the combined organic phases obtained mixture diastereoisomers (184 mg, 50%). After dilution with methanol (10 ml) was dissolved only polar diastereoisomer 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (45 mg, 12%, tPL235-238°C), and the remainder represented a non-polar diastereoisomer.

To obtain citrate non-polar diastereoisomer 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (111 mg, 0.3 mmole) suspended when heated at 50°C. in ethanol (35 ml) and was mixed with citric acid (60 mg, 0.31 in mmole) in ethanol (5 ml). Then was stirred for 16 h at RT. Fallen in sediment hemitite (example 8) was separated by vacuum filtration and washed with ethanol (2×5 ml). The result was a colorless compound with a yield of 79% (110 mg, tPL246-250°C).

Polar diastereoisomer (81 mg, 0.22 mmole) was dissolved in ethanol (20 ml)was mixed with citric acid (46 mg, 0.24 mmole) in ethanol (3 ml) and for 16 h and was stirred at RT. Transparent mixture was concentrated to a volume of 3 ml, was mixed with diethyl ether (40 ml) and was stirred 15 min at room temperature. Polar citrate precipitated in the form of a colorless solid, which was 63% (77 mg, tPL245-248°C).

Examples 10 and 11: Hemitite 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydro the Iranian[3,4-b]-6-farindola (example 10) and the citrate of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola (example 11)

4-dimethylamino-4-(2-thienyl)cyclohexanone (223 mg, 1 mmol) and 5-fluoro-2-(1H-indol-3-yl)ethanol (179 mg, 1 mmol) was previously placed in absolute DHM (50 ml) and mixed with methanesulfonic acid (0,13 ml, 2.0 mmole). The mixture for 20 h and was stirred at RT, then was mixed with 0.5-molar NaOH (20 ml), and within 2 h and stirred at RT. The organic phase was separated, and the aqueous phase was extracted with DHM. Organic phases were obtained mixture diastereoisomers 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola (382 mg). Then this mixture was recrystallized from propan-2-ol (70 ml). When this precipitate was becoming non-polar diastereoisomer (165 mg, 43%). From the filtrate after concentration was allocated a mixture of diastereoisomers (211 mg). After separation of this mixture by chromatography [silica gel G (40 g), EA/cyclohexane in the ratio of 1:1 (400 ml), EA (400 ml), EA/methanol in the ratio of 4:1 (300 ml)] received non-polar diastereoisomer (67 mg, 17%, tPL225-230°C) and the polar diastereoisomer (110 mg, 29%, tPL197-202°C) as colorless solids.

To obtain citrate non-polar diastereoisomer (165 mg, 0.43 mmole) suspended when heated in ethanol (50 ml) and was mixed with citric acid (93 mg, 0.48 mmole) in ethanol (5 ml). Then was stirred for 30 min at 50°C and for 16 h at RT. Hemitite was separated by vacuum filtration and washed with the ethanol. Colorless compound was obtained with a yield of 54% (111 mg, tPL199-201°C) (example 10).

Polar diastereoisomer (91 mg, 0,236 mmole) was dissolved in ethanol (15 ml) at 40°C, was mixed with citric acid (52 mg, of 0.27 mmole) in ethanol (5 ml), and within 2 h and stirred at RT. Then the solution was concentrated to a volume of 3 ml, was mixed with simple ether (40 ml) and for 16 h and was stirred at RT. In the polar hemitite precipitated in the form of a colorless solid, which was 93% (106 mg, tPL137-140°C) (example 11).

Examples 12 and 13: Dimethanesulfonate 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola (example 12) and hemitite 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola (example 13)

4-dimethylamino-4-(3-thienyl)cyclohexanone (446,6 mg, 2 mmole) and 5-fluoro-2-(1H-indol-3-yl)ethanol (394,4 mg, 2 mmole) was dissolved in absolute 1,2-dichloroethane (30 ml) and mixed with methanesulfonic acid (0,13 ml, 2 mmole). Then the mixture for 20 h and was stirred at RT. Fallen in sediment methanesulfonate polar diastereoisomer was separated by vacuum filtration and washed with 1,2-dichloroethane. Light grey solid is obtained with a yield of 76% (733 mg, tPL143-145°C) (example 12).

The filtrate was mixed with 1-molar NaOH (30 ml), and within 2 h and stirred at RT. While nonpolar GeoStereo the Omer precipitated in the form of a colorless solid, the output of which was 8% (58.5 mg). The phases of the filtrate were separated and the aqueous phase was extracted with DHM. The combined organic phase contained a mixture of diastereoisomers (300,3 mg).

To obtain citrate mixture of diastereoisomers (126 mg, of 0.33 mmole) suspended when heated at 50°C. in ethanol (100 ml) and was mixed with citric acid (69,2 mg of 0.36 mmole) in ethanol (5 ml). Then within 2 hours and was stirred at RT and kept overnight at 10°C. Precipitated in the sediment hemitite nonpolar diastereoisomer was separated by vacuum filtration. Colorless compound was obtained with a yield of 60% (94 mg, tPL227-229°C) (example 13).

Example 14: the Citrate of 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole

4-methylamino-4-thiophene-2-illlogical (418,6 mg, 2.0 mmole) and 2-(1H-indol-3-yl)ethanol (322,4 mg, 2.0 mmole) was dissolved in 50 ml DHM and quickly mixed with triftormetilfullerenov acid (0,18 ml, 2,03 mmole). After 20 h stirring at RT the mixture for 20 min were mixed together and added with 20 ml of 2-molar NaOH. Then the organic phase was separated, and the aqueous phase was extracted with DHM. The combined organic phase was concentrated in vacuum to dryness and the resulting residue is suspended in 25 ml of methanol. Colorless solid substance was separated by vacuum filtration and the way with the release of 363 mg (51%) was obtained 1,1-[3-methylamino-3-(2-tenlperature]-1,3,4,9-tetrahydropyrido[3,4-b]indole.

To obtain citrate this 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole (352 mg, 1.0 mmol) was dissolved in hot ethanol (30 ml) and was mixed with citric acid (200 mg, 1.04 million mmole) in hot ethanol (5 ml). The mixture is then left to stand for 15 hours at 5°C. Precipitated in the sediment citrate was separated by vacuum filtration, having received it in the form of a colorless compound with a yield of 69% (377 mg, tPL201-203°C) (example 14).

Example 15: the Citrate of 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola

4-methylamino-4-thiophene-2-illlogical (418,6 mg, 2.0 mmole) and 2-(5-fluoro-1H-indol-3-yl)ethanol (358,3 mg, 2.0 mmole) was dissolved in 50 ml DHM and quickly mixed with triftormetilfullerenov acid (0,18 ml, 2,03 mmole). After 20 h stirring at RT the mixture for 20 min were mixed together and added with 20 ml of 2-molar NaOH. Then the organic phase was separated, and the aqueous phase was extracted with DHM. The combined organic phase was concentrated in vacuum to dryness and the resulting residue suspended in methanol. Colorless solid substance was separated by vacuum filtration and the way with the release of 697 mg (94%) was obtained 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-Florinda.

To obtain citrate simple spiritlessly ester (680 mg, of 1.84 mmole) was dissolved in hot ethanol (50 ml) and mixed with what imoney acid (384 mg, 2.0 mmole) in hot ethanol (10 ml). The mixture is then left to stand for 15 hours at 5°C. Precipitated in the sediment citrate was separated by vacuum filtration, having received it in the form of a colorless compound with a yield of 67% (694 mg, tPL207-209°C) (example 15).

3-brometalia

N-bromosuccinimide (35,6 g of 0.20 mol) and benzoyl peroxide (0.4 g, 0,0013 mol) for 90 min at 90°With portions was added to a mixture of 3-methylthiophene (22 g, 0,203 mol) and benzoyl peroxide (0.4 g, 0,0013 mole) in dry benzene. After completion of the reaction (monitoring by thin layer chromatography), the mixture was cooled to 0°C and filtered. The filtrate was concentrated in vacuum. The result was 34 g of 3-brometalia (red-brown liquid).

Thiophene-3-ylacetonitrile

Sodium cyanide (a 12.03 g of 0.25 mole) and catalytic amount of bromide, Tetra-n-butylamine was added to a mixture of 3-brometalia (29 g, of 0.16 mol) in dichloromethane (175 ml) and water (50 ml). The reaction mixture was stirred using a reverse refrigerator. After completion of the reaction (monitoring by thin layer chromatography) the organic phase was separated and washed with water (3×500 ml), dried over sodium sulfate and concentrated in vacuum. After chromatographic purification (silica gel, 3%ether acetic acid in n-hexane) was obtained 9 g of thiophene-3-ylacetonitrile (44%, red-brown liquid).

Ethyl ester 5-C the ANO-2-oxo-5-thiophene-3-enciklopedicheskogo acid

To thiophene-3-ylacetonitrile (27.5 g and 0.22 mole), dissolved in 350 ml of toluene, was added ethyl ester 3-bromopropionic acid (96,14 g of 0.53 mol). Then for 1 h at a temperature in the range from 0 to 10°With portions was added sodium amide (74,03 g to 1.9 mol). After the reaction mixture for approximately 1 hour and was stirred using a reverse refrigerator. After completion of the reaction (monitoring by thin layer chromatography), the excess sodium amide was dissolved at 0-5°C. a mixture of acetic acid and water (500 ml, 2:1 ratio). The organic phase was separated and neutralized with sodium hydrogen carbonate solution (300 ml), dried over sodium sulfate and concentrated in vacuum. Resulted in 40 g of ethyl ester of 5-cyano-2-oxo-5-thiophene-3-enciklopedicheskogo acid (yellow liquid).

4-oxo-1-thiophene-3-enciclopedicanyfile

Ethyl ester of 5-cyano-2-oxo-5-thiophene-3-enciklopedicheskogo acid (40 g, of 0.14 mole), dissolved in a mixture of concentrated hydrochloric acid (200 ml) and glacial acetic acid (400 ml)was heated with stirring under reflux for approximately 4 hours After completion of the reaction (monitoring by thin layer chromatography) was added water (100 ml) and neutralized aqueous sodium hydroxide, and then was extracted with ether acetic acid (2×400 ml). Organic is ABC washed with sodium hydrogen carbonate solution (200 ml) and water (100 ml), was dried over sodium sulfate and concentrated in vacuum. After purification by column chromatography (silica gel, 25%ether acetic acid in n-hexane) was obtained 12.5 g of 4-oxo-1-thiophene-3-enciclopedicanyfile (42%, solid pale yellow color).

8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile

To 4-oxo-1-thiophene-3-enciclopedicanyfile (22 g, 0,107 mole)dissolved in toluene (500 ml), was added a catalytic amount of para-toluensulfonate acid and ethylene glycol (13.3 g, of 0.21 mol). Then the reaction mixture for about 2 hours and was stirred using a reverse refrigerator. After completion of the reaction (monitoring by thin layer chromatography) toluene phase was separated, washed with sodium hydrogen carbonate solution (200 ml), dried over sodium sulfate and concentrated in vacuum. The result was 25 g 8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (95%, colorless solid).

8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid

8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (25 g, 0,095 mole)dissolved in ethylene glycol (226 ml), was added potassium hydroxide (28 g, 0,5 mol). Then the reaction mixture for about 12 hours was stirred using a reverse refrigerator. After the reaction is completed (control using tanksley the Oh chromatography) the pH value of the mixture of diluted hydrochloric acid was set to approximately 1. The precipitate was filtered and dried. The result obtained 15 g of 8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (55%, solid pale yellow color).

8-isocyanato-8-thiophene-3-yl-1,4-dioxaspiro[4.5]Decan

8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (15 g, 56 mmol)dissolved in anisole (160 ml)was added diphenyl ether acidopathies acid (15,4 g, 56 mmol) and triethylamine (5,66 g, 55 mmol). Then the reaction mixture was heated to 90-100°C with a holding time at this temperature within 2 hours After completion of the reaction (monitoring by thin layer chromatography) was purified column chromatography (silica gel, 10%ether acetic acid in n-hexane). The result was 6 g 8-isocyanato-8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane (41%, colorless liquid).

Methyl(8-thiophene-3-yl-1,4-dioxaspiro[4.5]Dec-8-yl)Amin

8 isocyanato-8-thiophene-3-yl-1,4-dioxaspiro[4.5]decane (6 g, and 22.6 mmole)dissolved in dry THF (70 ml)at a temperature in the range from 0 to 5°With portions added alumoweld lithium (1.7 g). Then the reaction mixture for about 1.5 h was stirred using a reverse refrigerator. After completion of the reaction (monitoring by thin layer chromatography) excess alumoweld lithium decomposed with a saturated aqueous solution of sodium sulfate (20 ml). Forming the I residue was filtered through cellit. The filtrate was concentrated, and then was extracted with ether acetic acid (3×100 ml). The organic phase was separated, dried over sodium sulfate and concentrated in vacuum. After purification column chromatography (silica gel, 50%ether acetic acid in n-hexane) was obtained 2.5 g of methyl(8-thiophene-3-yl-1,4-dioxaspiro[4.5]Dec-8-yl)amine (43%, white solid with a low melting point).

Example 16: the Citrate of 1,1-[3-methylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole

Specified in the title compound was obtained analogously to example 14 from 4-methylamino-4-thiophene-3-illlogical and 2-(1H-indol-3-yl)ethanol.

Example 17: the Citrate of 1,1-[3-methylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola

Specified in the title compound was obtained analogously to example 15 from 4-methylamino-4-thiophene-3-illlogical and 2-(5-fluoro-1H-indol-3-yl)ethanol.

Research on the effectiveness of the proposed in the invention compounds

Determination of binding ORL1-receptor

Derivatives of cyclohexane 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, c.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 in 200 µl of the 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 from wheat germ 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 degree of affinity are listed in table 1 in the form of nanomolar values of Kior as expressed in percentage of the degree of inhibition C = 1 ám.

Determination of binding to µ-receptor

The degree of affinity to opioid µ-receptor of a person was determined using a homogeneous mixture in titration microplate. To this end each of the tested spiritlessly derivatives of cyclohexane over 90 min were incubated at RT in serial dilutions with a preparation containing the receptor membranes (15-40 μg of protein per 250 μl of incubation mixture) Cho-K1 cells expressing opioid µ-receptor human drug containing RB-HOM receptor membrane firms NEN, Zaventem, Belgium), in the presence of [3H]-naloxone as a radioactive ligand (NET719, firm NEN, Zaventem, Belgium) at a concentration of 1 nmol/l and 1 mg covered agglutinins of poroshkovanii balls for SPA-analysis firm Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 μl. As the incubation buffer used Tris-HCl at a concentration of 50 mmol/l, supplemented to 0.05 wt.% of sodium azide and 0.06 wt.% bovine serum albumin. To determine nonspecific binding was further added naloxone at a concentration of 25 mcmole/L. After a 90-minute incubation titration microplates for 20 min, centrifuged at 1000 g and measured the radioactivity in a scintillation β-counter (type Microbeta-Trilux, the company Perkin Elmer Wallac, Freiburg, Germany). Later in percentage was determined by the degree of displacement of the radioactive ligand from its binding to opioid µ-receptor humans at concentrations of the analyzed compounds 1 µmol/l and the values obtained were expressed as the relative degree of inhibition (% inhibition) of the specific binding. On the basis of percentage of degree of displacement, due to the different concentrations of the tested compounds of General formula I partially expected concentration inhibition (IC50-values), providing a 50%degree of displacement of the radioactive ligand. By appropriate conversion, using the equation of Cheng-Prusoff received the Ki values for the analyzed compounds.

Example No. ORL1 Ki [nm] or % inhibitionORµ-NaI Ki [nm] or % inhibition
11,602,80
349%140,00
40,490,08
529%210,00
637%47%
70,560,27
80,260,12
100,660,09
1141%53%
1259%150,00
130,610,08

Study of analgesic efficacy in the experiment on mice with otdergivanija tail

Each of the mice are individually placed in the cell for experiments and on the base of the tail sent Spock zirovanii heat beam from an electric lamp (Tail-flick-Typ 50/08/1 .bc extension, Labtec, Dr. Bess). 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 proposed in the invention compounds, respectively, of 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) according to the following formula:

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

Example No.OTDELENIE tail (mouse, IV) ED50
73.5 g/kg
100,028 mg/kg
130,027 mg/kg

The compound from example 7 was characterized in mice, more action, manifested in muscle relaxation and narcotic effect.

In contrast to the pure µ-opioid (such as morphine) of the compound from example 7 has a reduced rate of "place preference (see Tzschentke, T.M., Prog. Neurobiol. 56, 1998, c.613-672).

Experience in mice with jumping as a manifestation of the syndrome

Experience in the study of behavioral responses manifested in their respective movements, in this case, the jumping, conducted on mice according to the method Saelens and others, 1971.

Test compounds were administered to the animals intraperitoneally for two days a total of 7 times. 5 times they were introduced on the first day at 9.00, 10.00, 11.00 is, at 13.00 and 15.00 h, and in the Torah day at 9.00 11.00 o'clock the First three times of the compounds were administered in ascending doses (scheme dosing, and then at a dose equal to the third dose. The manifestation of the syndrome was initiated 2 h after the last injection with naloxone (30 mg/kg (intraperitoneally). Immediately after this, the animals were placed singly to monitor them in transparent boxes (height 40 cm and a diameter of 15 cm) and within 15 minutes were counting the number of jumps performed by the animals in each of the 5-minute intervals. Morphine in the described experiments were used in the same dose as a comparison or standard.

The syndrome quantify, counting the number of jumps performed by the animals within 0-10 minutes after administration of naloxone. This determines the number of animals in each group who made more than 10 hops for 10 min, and refer them to the animals with a positive response ("% positive animals"). In addition, determine the average frequency of jumps in each group of animals. Each group uses 12 animals.

The severity of naloxone-induced withdrawal syndrome, manifested in the jumping mice, depending on the administered dose of the compound from example 7 in graphical form shown in the accompanying description of the drawing.

The results obtained indicate full p is the pressure of the syndrome, manifested in the Bouncing.

1. Spirocycles derivatives of cyclohexane General formula I

in which R1and R2independently of one another denote H or a saturated, branched or unbranched, unsubstituted With1-C5alkyl, or the residues R1and R2together form the group (CH2)3-6,
R3denotes heteroaryl selected from pyridyl, teinila, thiazolyl and imidazolyl, each of which is unsubstituted or odnosnie atom (F, Cl, Br, I or a saturated, branched or unbranched, unsubstituted With1-C5the alkyl,
W denotes NR4, O or S,
where R4denotes H,
R5denotes H,
R6denotes H or a saturated, branched or unbranched, unsubstituted With1-C5alkyl,
R7, R8, R9and R10independently from each other denote H, F, Cl, Br, I or or13,
where R13denotes H, a saturated, branched or unbranched, unsubstituted With1-C5alkyl, or attached via C1-C3alkyl unsubstituted phenyl, and
X denotes O or NR17where
R17denotes H, COR12or SOR12,
where R12denotes a saturated, branched or unbranched, unsubstituted With1-C5alkyl unsubstituted phenyl; unsubstituted or one-deputizing atom Cl benzothiazyl; saturated, unsubstituted With3-C8cycloalkyl; attached via a saturated or unsaturated, branched or non-branched C1-C3alkyl, unsubstituted or one - or mnogozalny the F atom, Cl atom, or a saturated, branched or unbranched, unsubstituted OS1-C5the alkyl phenyl; attached via a saturated, branched or non-branched C1-C3alkyl unsubstituted saturated With3-C8cycloalkyl; attached via a saturated, branched or non-branched C1-C3alkyl unsubstituted thienyl; or NR14R15,
where R14and R15independently of one another denote H or attached via a saturated, branched or non-branched C1-C3alkyl and unsubstituted or mono - or mnogozalny atom Cl phenyl,
in the form of mixtures of enantiomers or diastereomers or in the form of one single diastereoisomer, as well as salts of physiologically compatible acids.

2. Spirocycles derivatives of cyclohexane according to claim 1, characterized in that
R1and R2independently of one another denote H or CH3while R1and R2at the same time not denote N.

3. Spirocycles derivatives of cyclohexane according to claim 1, trichomona fact, what
W denotes NR4, a
X denotes O,
R1and R2independently of one another denote H, a branched or unbranched, unsubstituted With1-C4alkyl,
R3denotes unsubstituted pyridyl or thienyl,
R4denotes H,
R5and R6denote N and/or
R7, R8, R9and R10independently from each other denote H, F, Cl, Br or I.

4. Spirocycles derivatives of cyclohexane according to claim 1, wherein R1and R2denote SN3and R3denotes thienyl or pyridyl.

5. Spirocycles derivatives of cyclohexane according to claim 1, wherein W denotes NR4X denotes O, and R4denotes N.

6. Spirocycles derivatives of cyclohexane according to one of claims 1 to 5, selected from the group including
1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluoren,
2-acetyl-1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluoren,
1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2-oxa-9-difluoro,
hemitite 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer,
the citrate of 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, polar diastereoisomer,
dimethanesulfonate 1,1-[3-dimetilan is but-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, polar diastereoisomer,
the citrate of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer,
hemitite 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, non-polar diastereoisomer,
the citrate of 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole, polar diastereoisomer,
hemitite 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, non-polar diastereoisomer,
the citrate of 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, polar diastereoisomer,
dimethanesulfonate 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, polar diastereoisomer,
hemitite 1,1-[3-dimethylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, non-polar diastereoisomer,
the citrate of 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido [3,4-b]indole,
the citrate of 1,1-[3-methylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola,
the citrate of 1,1-[3-methylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]indole,
the citrate of 1,1-[3-methylamino-3-(3-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrido[3,4-b]-6-farindola, and under certain conditions a mixture thereof.

7. The method of obtaining spiritlessly cyclohexane derivatives according to one of claims 1 to 6, the tives such as those what adduct of General formula

where the residues R01and R02are specified for R2values are adding the acid, for example triftormetilfullerenov acid, methanesulfonic acid or triperoxonane acid, in an appropriate solvent, such as dichloroethane, dichloromethane, interaction with the adduct of the General formula

in which the residues R5-R10and W are specified in claim 1 values, a Z denotes XY, where Y represents N and X represents O or NH.

8. The method of obtaining spiritlessly cyclohexane derivatives according to claim 1, in which X represents NR17and R17denotes COR12, characterized in that spirocyclohexane derivative of cyclohexane, in which X represents NH, adding bases, such as pyridine, is subjected to the interaction with the anhydride.

9. The method of obtaining spiritlessly cyclohexane derivatives of the General formula Ib

wherein the thiophene-3-yl-acetonitrile is subjected to interaction with ether 3-bromopropionic acid, amyraut, decarboxylases nitrile group by saponification transferred to the carboxylic acid, and then the isocyanate is further subjected to interaction with a reducing agent such as lithium aluminum hydride, and adding to the slots, for example triftormetilfullerenov acid or methanesulfonic acid, in an appropriate solvent, such as dichloroethane, dichloromethane, is subjected to the interaction with the adduct of the General formula

in which Z denotes XY, where Y represents N and X represents O and W represents NH, and the remaining R5-R10have specified in claim 1 values.

10. Drug containing at least one spirocyclohexane cyclohexane derivative according to one of claims 1 to 6, in the form of mixtures of enantiomers or diastereomers or in the form of one single diastereoisomer, as well as in the form of salts with physiologically compatible acids, optionally containing appropriate additives and/or auxiliary substances, and is intended for treatment of abstinence (withdrawal) or pain.

11. Application spirocycles cyclohexane derivative according to one of claims 1 to 6, in the form of mixtures of enantiomers or diastereomers or in the form of one single diastereoisomer, as well as in the form of salts with physiologically compatible acids, for obtaining a medicinal product intended for the treatment of pain, especially acute, neuropathic pain.

12. Application spirocycles cyclohexane derivative according to one of claims 1 to 6 to obtain a medicinal product intended for the treatment of C is upotreblenia alcohol and/or drugs, and/or drugs and/or alcohol and/or drugs and/or drug addiction, as a muscle relaxant or anesthetic, respectively, for joint injections used in the treatment of opioid analgesic or anesthetic for the treatment of symptoms (syndrome) and/or to reduce the tendency to opioids.

13. Application spirocycles cyclohexane derivative according to one of claims 1 to 16 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 (cognitive dysfunction), disorders of learning and memory (as a nootropic drugs), 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 anti-convulsants, for diuresis or antinatriuretic, anxiolysis, for modulation of motor activity, for modulation of the release of neurotransmitters and treatment related neurodegenerative diseases.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to salts sulfoxides derived, namely the hydrochloride or the fumarate of 1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro[benzo(C)thiophene-1(3H),4'-piperidine]-(2S)-oxide, which have a good absorption when taken orally and demonstrate excellent antagonistic activity as receptor NK1and receptor NK2

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: chemistry.

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

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) , where R1 is hydrogen, C1-C7 alkyl; R2 is C1-C7 alkyl, aryl, C1-C7 haloalkyl or C3-C8 cycloalkyl; R3, R4 each independently represents hydrogen, halogen, C1-C7 alkoxy, C1-C7 alkylsuphonyl; R5 is hydrogen, halogen, C1-C7 alkyl, C1-C7 haloalkoxy, or aryloxy, or is -NR7R8, where R7 and R8 represent C1-C7 alkyls, or R7 and R8 together with the nitrogen atom to which they are bonded can form a 4-7-member heterocycloalkyl group, which can be substituted with one or more substitutes selected from a group consisting of halogen, C1-C7 alkyl, C1-C7 alkoxy, hydroxyl, phenyl and di(C1-C7)alkylamino; R6 is hydrogen or together with R5 can form a 5- or 6-member heterocycloalkyl group which can be substituted with one or more halogens; and their pharmaceutically acceptable salts of acid compound, except the range of compounds given in paragraph 1 of the formula of invention. The invention also relates to medicine based on said compounds, with activity of allosteric enhancer of GABA-B receptors and use of compounds of the formula to prepare medicines used in treating central nervous system disorders, including anxiety and depression.

EFFECT: novel compounds are obtained and described, which can be used for preparing medicines used in treating central nervous system disorders, including anxiety and depression.

14 cl, 58 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

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

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

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

FIELD: pharmacology.

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

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new quinazoline derivative or its pharmaceutically acceptable acid-additive salt. Quinazoline derivative is described with general formula (I): , where Z is NH; m is 2; the first R1 group located in 5th position is chosen from isopropoxy and tetrahydropyran-4-yloxy; the second R1 group located in 7th position is chosen from ethoxy or propoxy substituted with chlorine or certain substituted or unsubstituted heterocycles containing at least one or two N atoms and at least one O atom together with N atom; n is 0 or 1; R3 group located in 5th or 6th position of 2,3-methylenedioxypyridine-4-yl group, is chosen from Cl or Br. Besides, there is disclosed pharmaceutical composition used as antiinvasive agent to control distribution and/or treat solid cancer, containing this quinazoline derivatives combined with pharmaceutically acceptable diluent or carrier. Declared quinazoline derivatives possess considerable antineoplastic action ensured with effective inhibition of one or more nonreceptor protein kinases, specific to tyrosine, referring to Src linase family.

EFFECT: treatment of cancer in homoiotherms and human.

11 cl, 2 tbl, 22 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

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

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

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel derivatives of diazaspiropiperidine of the formula I: , where A-B is -CH2-CH2-, -CH2-O- or -O-CH2-; X is hydrogen or hydroxy; R1 is aryl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, cyano, CF3, -OCF3, (lower) alkoxy, -SO2-(lower)alkyl, or heteroaryl with two nitrogen atoms; R2 is phenyl optionally substituted by one or more substitutes selected out of group including haloid, (lower) alkyl, CF3 or (lower) alkoxy; R3 is hydrogen or (lower)alkyl; n is 0, 1 or 2; and their pharmaceutically acceptable salts.

EFFECT: medicine based on compounds of the formula 1 and their application in obtaining medicine for neuropathological and neuropsychiatric disease treatment.

12 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (1) where: R1 represents hydrogen atom, halogen, CP3, (1-3C)alkoxy group, m is an integer within 1 to 4, provided when m is equal to 2, 3 or 4, R1 substitutes can be either identical or different, R2 represents hydrogen atom, alkyl (1-6C) group optionally substituted with alkoxy group, cycloalkyl (3-6C) group, -CH2OH, -CH2OCH3, acetyl group, benzyl group optionally substituted with amino group, or group Q of the following composition (2): were: [ ]n symbolically represents -(CH2)n-, where n is an integer within 0 to 7, R3 represents hydrogen atom or alkyl (1-3C) group, R4 represents hydrogen atom, alkyl (1-6C) group optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkoxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, amido group dialkyl, carboxyl group, saturated, unsaturated or partially saturated mono- or dicyclic 5-10-meroud ring optionally substituted with one or more groups, chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or alkyl (1-3C) group substituted with saturated, unsaturated or partially saturated five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen from alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl group, or (R3+R4) together with nitrogen atom, they are attached to, represent saturated, unsaturated or partially saturated mono- or dicyclic five- or hexamerous ring optionally containing one or more heteroatoms, such as nitrogen atom, oxygen atom or sulphur atom, optionally substituted with one or more groups chosen of alkyl group, aryl group, fluorine, chlorine, bromine, hydroxyl group, alkyloxy group, aryloxy group, acyloxy group, amino group, alkylamino group, dialkylamino group, arylamino group, thio group, alkylthio group, arylthio group, cyano group, oxo group, nitro group, acyl group, amido group, alkylamido group, dialkylamido group, carboxyl groups, as well as to all stereoisomers, to pharmaceutically acceptable salts. Additionally, the invention concerns pharmaceutical compositions and application of compounds.

EFFECT: production of new biologically active compounds with agonist activity to ORL1 receptors.

9 cl, 488 ex, 2 tbl

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