Substituted derivatives of 4-aminocyclohexanol, method for their preparing and their using, medicinal agent possessing binding property with orl1-receptor

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.

10 cl, 1 tbl, 21 ex

 

The present invention relates to substituted derivatives of 4-aminocyclohexanol, to the way they are received, to medicines containing these compounds and to the use of substituted derivatives of 4-aminocyclohexanol to obtain drugs for the treatment of various diseases and painful conditions, especially pain.

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 other Nature 377, 1995, SS-535), which belongs to the family of opioid receptors and which can be found in many areas of the cerebral cortex and spinal cord (Mollereau, etc., FEBS Letters, 341, 1994, SS-38; Darland and others, Trends in Neurosciences, 21, 1998, SS-221). This peptide has a high affinity with a value of Kd-score PM (Ardati, etc., Mol. Pharmacol. 51, s-824), and high selectivity in relation to the ORL1-receptor. ORL1-receptor homologous opioid μ-, κ- and δreceptors, and the amino acid sequence of peptide - nociceptin - has a high similarity with the amino acid sequences of known peptide opioids. Induced nociception activation of this receptor leads through relationship with Gi/o-proteins to inhibition of adenylate cyclase (Meunier and other Nature 377, 1995, cc.532-535). At the cellular level, t is the train there are functional similarities between opioid μ -, κ- and δ-receptors and ORL1-receptor on activated potassium channel (Matthes and others, Mol. Pharmacol. 50, 1996, cc.447-450; Vaughan and others, Br. J. Pharmacol. 117, 1996, cc.1609-1611) and inhibition of calcium channels in the L-, N - and P/Q-type (Conner and others, Br. J. Pharmacol. 118, 1996, cc.205-207; Knoflach, etc., J. Neuroscience 16, 1996, cc.6657-6664).

In various experiments on animals peptide nociceptin manifests after its introduction in the interventricular region brain pronunication and hyperalgesia activity (Reinscheid and others, Science 270, 1995, cc.792-794; Nagy and others, Br. J. Pharmacol. 121, 1997, cc.401-408). A similar effect can be explained by the inhibition induced stress analgesia (Mogil and others, Neurosci. Letters 214, 1996, cc.131-134, and Neuroscience 75, 1996, cc.333-337). In this regard, it was possible to detect anxiolytic activity nociceptin (Jenck and others, Proc. Natl. Acad. Sci. USA 94, 1997, cc.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 inhibits the activity stimulated Kanata or glutamate neurons in the ganglion posterior spinal root (Shu and others, Neuropeptides, 32, 1998, 567-571) or stimulated glutamate neurons of the spinal cord (Faber and others, Br. J. Pharmacol., 119, 1996, cc.189-190), and also exhibits antinociceptive activity in the experience with otdergivanija tail in mice (King and others,Neurosci. Lett., 223, 1997, 113-116), experience with simulation of the flexor reflex in the rat (Xu and others, NeuroReport, 7, 1996, 2092-2094) and experience with formalin in rats (Yamamoto and others, Neuroscience, 81, 1997, cc.249-254).

When modeling neuropathic pain has also been able to identify the antinociceptive action nociceptin (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997), which is of particular interest insofar as the effectiveness nociceptin rises after axotomy spinal nerves. This differs from the classical opioids, the effectiveness of which under the same conditions decreases (Abdulla and Smith, J. Neurosci., 18, 1998, cc.9685-9694).

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

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

The present invention was based on the task to offer connections that would affect the system nociceptin/ORL1-receptor and thus would be suitable for the use of the program 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.

In accordance with this object of the present invention are substituted derivatives of 4-aminocyclohexanol General formula I

in which

R1and R2independently of one another denote H or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via C1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, R1and R2both cannot simultaneously denote H, or

the remains of R1and R2together form a ring and denote CH2CH2OCH2CH2CH2CH2NR5CH2CH2or (CH2)3-6where

R5denotes N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or what razvetvlenii, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R3stands With1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted, or attached via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted With1-4alkyl group, aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, and

R4stands With3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7, -C(Y)R7, -C(Y)-CH2R7, -C(Y)-CH2-CH2R7, -C(Y)-CH2-CH2-CH2R7or-R8-L-R9where

Y represents O, S or N2,

R6represents H, C1-7alkyl, which is saturated or the Nene is Sydenham, branched or unbranched, one or mnogosloinym or unsubstituted, or C(O)O-C1-6alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted,

R7represents N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym,

R8represents aryl or heteroaryl, each of which

is unsubstituted or mono - or mnogosloinym,

L represents-C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O-C(O)-, -O-, -S - or-S(O)2and

R9represents aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym,

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

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

Compounds that the possession is t some distant structural similarity proposed in the invention compounds known from the following patent publications:

from DE-OS-2839891, respectively, of the parallel patent US 4366172 (Lednicer and others), in which these compounds are described as having an analgesic effect, but whatever the ORL1-receptor, as well as of the following dedicated to the same theme articles:

- D.Lednicer and P.F. von Voightlander, J. Med. Chem. 22, 1979, s,

- D.Lednicer, P.F. von Voightlander and D.E.Emmert, J. Med. Chem. 23, 1980, s,

- D.Lednicer, P.F. von Voightlander and D.E.Emmert, J. Med. Chem. 24, 1981, s,

- D.Lednicer, P.F. von Voightlander and D.E.Emmert, J. Med. Chem. 24, 1981, s,

- P.F. von Voightlander, D.Lednicer, R.A.Lewis and D.D.Gay, "Endogenous and Exogenous Opiate Agonists and Antagonists", proceedings of the conference Proc. Int. Narc. Res. Club Conf. (1980), held in 1979, Ed. by Way E.Long, published by Pergamon, Elmsford, N.Y. International, Pergamon, 1980, cc.17-21,

- Kamenka and others, Eur. J. Med. Chem. Chim. Ther.; FR; 19, 3, 1984, cc.255-260,

- M.N.A. Rao and Rao, S.C., Indian Drugs, 22(5), 1985, cc. 252-257.

In the context of the present invention under alkyl, respectively cycloalkenyl residues refers to saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or mono - or mnogosloinymi. With1-2alkyl represents a C1- or2-alkyl, C1-3alkyl represents a C1-With2- or3-alkyl, C1-4alkyl represents a C1-C2-With3- or4-alkyl, C1-5 alkyl represents a C1-C2-With3-C4- or5-alkyl, C1-6alkyl represents a C1-With2-With3-With4-C5- or6-alkyl, C1-7alkyl represents a C1-With2-With3-With4-With5-With6- or7-alkyl, C1-8alkyl represents a C1-With2-With3-With4-C5-With6-C7or C8-alkyl, C1-10alkyl represents a C1-C2-With3-With4-With5-With6-C7-C8,- C9- or10-alkyl, C1-18alkyl represents a C1With2-With3-C4-With5-With6-With7-C8- 9-With10-With11-With12-C13-C14-C15-C16-C17or C18-alkyl. In addition, From3-4cycloalkyl represents a C3- or4-cycloalkyl,3-5cycloalkyl represents a C3-With4- or5-cycloalkyl,3-6cycloalkyl represents a C3-With4-C5- or6-cycloalkyl,3-7cycloalkyl represents a C3-With4-With5-With6- or7-cycloalkyl,3-8cycloalkyl represents a C3-With4-With5-With6-With7or C8-cycloalkyl,4- cycloalkyl represents a C4- or3-cycloalkyl,4-6cycloalkyl represents a C4-With5- or6-cycloalkyl,4-7cycloalkyl represents a C4-With5-With6- or7-cycloalkyl,5-6cycloalkyl represents a C5- or6-cycloalkyl, and5-7cycloalkyl represents a C5-With6- or7-cycloalkyl. The term "cycloalkyl" includes saturated cycloalkyl group in which 1 or 2 carbon atoms replaced by a heteroatom is S, N or O. However, in the concept of "cycloalkyl" primarily included one or several times, preferably once, unsaturated cycloalkyl group without heteroatoms in the ring, if cycloalkyl is not an aromatic system. Preferred alkyl, respectively cycloalkenyl residues are methyl, ethyl, vinyl (ethynyl), propyl, allyl (2-propenyl), 1-PROPYNYL, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, as well as substituted, CHF2, CF3or CH2HE and pyrazoline, oxadiazoline, [1,4]dioxane or ioxilan.

In the context of the present invention, the term "substituted"used in respect of alkyl and cycloalkyl, implied, unless specifically stated otherwise, the substitution of at least one (and optionally also several) atom(s), hydrogen atom (F, Cl, Br, I, a group of NH2SH or HE, under the concept of "mnogosloinye balances, respectively, "substituted" remains, in the case of multiple substitution refers to multiple substitution and different, and on the same atoms by identical or different substituents, for example a triple substitution on the same C-atom, as in the case of CF3or located in different positions of the atoms, as in the case of-CH(OH)-CH=CH-CHCl2. The most preferred substituents are F, Cl and Oh. In cycloalkyl hydrogen residue may be replaced by OS1-3the alkyl or C1-3the alkyl (each of which is one or mnogosloinym or unsubstituted), primarily stands, ethyl, n-propylene, isopropyl group, CF3, a methoxy group or ethoxypropane.

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

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

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

The term "substituted"used in respect of aryl and heteroaryl, refers to the substitution of the aryl or heteroaryl group, R82, group, OR82by halogen, preferably by F atoms and/or Cl, a group of CF3group , CN group, NO2group NR83R84With1-6the alkyl (saturated), C1-6alkoxygroup,3-8cycloalexie,3-8cycloalkyl or2-6alkylene.

While the remainder R82represents H, C1-10alkyl, preferably C1-6alkyl, aryl or heteroaryl, or attached via a saturated or unsaturated With1-3alkyl or through1-3alkylenes group aryl or heteroaryl residue, and these aryl and heteroaryl residues may not themselves be substituted by aryl or heteroaryl groups, residues R83and R84can have identical or different meanings and represent H, C1-10alkyl, preferably1-6alkyl, aryl, or heteroaryl attached via a saturated or unsaturated With1-3alkyl or C1-3alkylenes group aryl or heteroaryl residue, and these aryl and heteroaryl residues may not themselves be substituted by aryl or heteroaryl groups, or residues R83and R 84together represent CH2CH2OCH2CH2CH2CH2NR85CH2CH2or (CH2)3-6and the remainder R85represents H, C1-C10alkyl, preferably C1-C6alkyl, aryl or heteroaryl residue, or attached via a saturated or unsaturated With1-3alkyl or through1-C3alkylenes group aryl or heteroaryl residue, and these aryl and heteroaryl residues may not themselves be substituted by aryl or heteroaryl groups.

The term "salt" refers to each of the forms proposed in the invention the active substance, in which he takes ionic form, 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 the anions is or acid or formed with a physiologically compatible acid or a physiologically compatible cation salt.

The expression "physiologically compatible" means that the substance and primarily salt as such has when introduced into the human or mammal an appropriate tolerance for them, ie, for example, has on the body is undesirable from the point of view of physiology (for example toxic action.

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

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

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

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

In one of the embodiments of the invention among the above described proposed therein substituted derivatives of 4-aminocyclohexanol preferred those in which

R1and R2independently of one another denote H or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted, R1and R2both cannot simultaneously denote H,

or the remains of R1and R2together form a ring and denote CH2CH2Och2CH2CH2CH2NR5CH2CH2or (CH2)3-6where

R5denotes N or C1-8alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted, preferably

R1and R2independently of one another denote H

or1-4alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or not umestnim, thus R1and R2both cannot simultaneously denote H, or the residues R1and R2together form a ring and denote(CH2)4-5first of all R1and R2independently of one another denote methyl or ethyl, or the residues R1and R2together form a ring and denote (CH2)5.

In another embodiment of the invention among the above described proposed therein substituted derivatives of 4-aminocyclohexanol preferred those in which

R3denotes unsubstituted or mono - or mnogozalny3-8cycloalkyl or attached via saturated or unsaturated, unbranched, substituted or unsubstituted With1-4alkyl group, aryl, C3-8cycloalkyl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, preferably

R3denotes unsubstituted or mono - or mnogozalny3-6cycloalkyl or attached via saturated unbranched1-2alkyl group With5-6cycloalkyl, phenyl, naphthyl, anthracene, thiophenyl, benzothiophene, pyridyl, furyl, benzofuranyl, benzodioxolyl, indolyl, indanyl, benzodioxane, pyrrolyl, pyrimidyl or pyrazinyl, each of which is unsubstituted or mono - or mnogosloinym, first of all

R3means attached through saturated unbranched1-2alkyl group, phenyl, pyridyl, furyl or thiophenyl, each of which is unsubstituted or mono - or mnogosloinym.

In the following embodiment of the invention among the above described proposed therein substituted derivatives of 4-aminocyclohexanol preferred those in which

R4stands With3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, or R8-L-R9preferably

R4denotes cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthene, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroanthracene, pyridinyl, furanyl, benzofuranyl, pyrazolinones, oxadiazoline, DIOXOLANYL, substituted, pyrimidinyl, chinoline, ethenolysis, phthalazine or hintline, each of which is unsubstituted or mono - or mnogosloinym, or-R8-L-R9first of all

R4denotes cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene indolyl, naphthyl, benzothiazolyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each of which is unsubstituted or mono - or mnogosloinym, or R8-L-R9.

In the described directly above embodiment of the invention relating to the preferred values of R4, further preferred compounds in which

R8represents indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthene, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl or 1,2-dihydroanthracene, pyridinyl, furanyl, benzofuranyl, pyrazolinones, oxadiazoline, pyrimidinyl, chinoline, ethenolysis, phthalazine or hintline, each of which is unsubstituted or mono - or mnogosloinym,

L represents-C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O-C(O)-, -O-, -S - or-S(O)2and/or

R9represents indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthene, benzothiazolyl, benzotriazolyl, benzo[1,2,5]Ty who was Salil, 1,2-dihydroanthracene, pyridinyl, furanyl, benzofuranyl, pyrazolinones, oxadiazoline, pyrimidinyl, chinoline, ethenolysis, phthalazine or hintline, each of which is unsubstituted or mono-or mnogosloinym, preferably

R8represents indolyl, benzothiophene, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each of which is unsubstituted or mono - or mnogosloinym,

L represents-C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O-C(O)- or-S(O)2and/or

R9represents indolyl, benzothiophene, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each of which is unsubstituted or mono - or mnogosloinym, first of all

R8denotes unsubstituted indolyl,

L represents-S(O)2and

R9denotes unsubstituted phenyl.

In accordance with another embodiment of the invention among its proposed substituted derivatives of 4-aminocyclohexanol preferred those in which R4means-CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7, -C(Y)R7, -C(Y)-CH2R7, -C(Y)-CH2-CH2R7or-C(Y)-CH2-CH2-CH2R7where

Y represents O, S or the 2preferably

R4means-CHR6R7, -CHR6- CH2R7, -CHR6-CH2-CH2R7, -C(Y)R7, -C(Y)-CH2R7or-C(Y)-CH2-CH2R7where Y represents O or S, first of all

R4means-CHR6R7, -CHR6- CH2R7, -C(Y)R7or-C(Y)-CH2R7where

Y represents O.

In the described directly above embodiment of the invention relating to the preferred values of R4, further preferred compounds in which

R6denotes H, C1-4alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted, or C(O)O-C1-4alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted, preferably denotes N or C1-4alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted primarily denotes N, CH3or2H5.

In the described directly above embodiment of the invention relating to the preferred values of R4, further preferred compounds in which

R7oznachaet 3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, preferably

R7denotes cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthene, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroanthracene, pyridinyl, furanyl, benzofuranyl, pyrazolinones, oxadiazoline, DIOXOLANYL, substituted, pyrimidinyl, chinoline, ethenolysis, phthalazine or hintline, each of which is unsubstituted or mono - or mnogosloinym, first of all

R7denotes cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracene, indolyl, naphthyl, benzofuranyl, benzothiophene, indanyl, benzodioxane, benzodioxole, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each of which is unsubstituted or mono - or mnogosloinym.

In accordance with the following embodiment of the invention among its proposed substituted derivatives of 4-aminocyclohexanol preferred compounds selected from the group including

4-benzyl-4-dimethylamino-1-fenetylline, as well as its corresponding hydrochloride

4-dimethylamino-1,4-definitionsexual, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-[2-(2-forfinal)ethyl]cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-[2-(4-forfinal)ethyl]cyclohexanol, as well as its corresponding hydrochloride

4-dimethylamino-4-(2-terbisil)-1-fenetylline, as well as its corresponding hydrochloride

4-dimethylamino-4-(3-terbisil)-1-fenetylline, as well as its corresponding hydrochloride

4-dimethylamino-4-(4-terbisil)-1-fenetylline, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-[2-(3-forfinal)ethyl]cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-(2-terbisil)cyclohexanol, as well as its corresponding hydrochloride

4-(allylamino)-4-benzyl-1-fenetylline, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-(3-terbisil)cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-(4-terbisil)cyclohexanol, as well as its corresponding hydrochloride

1-benzyl-4-dimethylamino-4-(3-terbisil)cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-1-phenethyl-4-pyrrolidin-1-illlogical and its corresponding hydrochloride,

4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl)cyclohexanol,

1-benzo[b]thiophene-2-yl-4-benzyl-4-dimethylaminoethanol,

1-benzo[b]thiophene-3-yl-4-benzyl-4-dimethylaminoethanol,

1-benzofuran-2-yl-4-benzyl-4-dimethylaminoethanol,

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

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

Accordingly another object of the present invention are drugs, containing at least one proposed therein substituted derivative 4-aminocyclohexanol, not necessarily in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of acids or basis of any either in the form of salts, first of all physiologically compatible salts, or in the form of a solvate, especially hydrates and optionally containing acceptable additives and/or auxiliary substances and/or optionally other active ingredients.

Proposed in the invention medicines in addition to at least one proposed therein substituted derivative 4-aminocyclohexanol not necessarily contain acceptable additives and/or excipients, including carriers, fillers, solvents, diluents, dyes and/or binders, and can be used as liquid dosage forms in the form of injection solutions, drops or medicines, as well as semi-solid dosage forms in the form of granules, tablets, pills, patches, capsules, plasters or aerosols. The choice of auxiliary and other substances, and used their number depend on whether the drug for oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, transbukkalno, rectal or topical application, for example for application on skin, on mucous membranes or in the eyes. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, medicines and syrups, and for parenteral the tion, local and inhalation use suitable solutions, suspensions, easily recoverable dry compositions, as well as sprays. Proposed in the invention substituted derivatives of 4-aminocyclohexanol in depot form, in dissolved form or embedded in a plaster, optionally with the addition of promote penetration through the skin of funds, also suitable for percutaneous introduction. Intended for oral or percutaneous injection dosage form can be a retard forms, which provide a slow release of the proposed invention substituted derivatives of 4-aminocyclohexanol. In principle, the composition proposed in the invention of medicines, you can include some other, well-known specialists active substances.

Assigned to the patient an amount of the active substance varies depending on the weight of the patient, route of administration, indications for use and the severity of the disease. Usually at least one proposed in the invention substituted derivative 4-aminocyclohexanol injected into the body in a dosage comprising 0.005 to 1000 mg/kg, preferably from 0.05 to 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 substituted the CSOs derived 4-aminocyclohexanol also include opioid, preferably, a potent opioid, primarily morphine, or an anaesthetic, preferably hexobarbital or halothane.

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

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

Accordingly another object of the invention is the use of one of its proposed substituted derivatives of 4-aminocyclohexanol, not necessarily in the form of its racemate, its pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of its acids or its bases or in the form of its salts, especially physiologically the key compatible salts, or in the form of a solvate, especially hydrates, for obtaining a medicinal product intended for the treatment of pain, especially acute, visceral, neuropathic or chronic pain.

As already mentioned in the introductory part of the description, ORL1-receptor along with the function he performs in the manifestation of pain, also plays a role in many other physiological processes that are important primarily from a medical point of view.

Accordingly another object of the invention is the use of one of its proposed substituted derivatives of 4-aminocyclohexanol, not necessarily in the form of its racemate, its pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of its acids or its bases or in the form of its salts, especially physiologically compatible salts, or in the form of a solvate, especially hydrates, for obtaining a medicinal product intended for the treatment of States of fear, stress and related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, General impairment of cognitive abilities (cognitive dysfunction), disorders of learning is on and the memory (as a nootropic agents), abstinence (withdrawal), abuse of alcohol and/or drugs and/or drugs and/or alcohol and/or drug and/or medicament addiction, sexual disorders, cardiovascular diseases, hypotension, hypertension, sensation of tinnitus, pruritus, migraine, hearing loss, lack of intestinal motility disorders digestibility of food, anorexia, obesity, locomotor disorders of functions, diarrhoea, cachexia, urinary incontinence, respectively, as a muscle relaxant, anticonvulsant drugs, antitussives or anesthetic, respectively, for the co-introduction into the organism in the treatment of opioid analgesic or anaesthetic, for diuresis or antinatriuretic and/or anxiolysis.

In one variation of the above applications it may be preferable to use a substituted derivative 4-aminocyclohexanol 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 and/or along with substituted derivatives of 4-aminocyclohexanol also be used opioid, preferably a potent opioid, primarily morphine, or an anaesthetic, preferably hexobarbital or halothane.

Another object of the present invention is the FPIC of the b treatment, first of all, if there are symptoms of one of the above diseases or pathological States of the mammal or human, which, respectively, which is needed in the treatment of pain, especially chronic pain, which consists in introducing into the organism a therapeutically effective dose proposed in the invention substituted derivative 4-aminocyclohexanol or proposed in the invention medicines.

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

With the invention compounds are the most expedient way to get that is that

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

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06 designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01,and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

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

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01,and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

in connection Faure the uly IVa, obtained from the compounds of formula III, otscheplaut protective group S1and S2with the formation of 4-substituted derivative of 4-aminocyclohexanone formula IV

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01,and/or R02and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation,

g) 4-substituted derivative of 4-aminocyclohexanone formula IV is subjected to interaction with ORGANOMETALLIC reagents, preferably Grignard reagent or organolithium reagents of the formula metal-R4with the formation of the compounds of formula V

then, if necessary, in any sequence and optionally repeatedly carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01 and/or R02and/or R04,and/or R05and/or R06designate protected by a protective group H, at least once otscheplaut protective group and, if necessary, carry out the acylation, alkylation or sulfonation and/or in the case of compounds in which R01and/or R02and/or R04and/or R05and/or R06denote N at least once imposed protective group and, if necessary, carry out the acylation, alkylation or sulfonation before the formation of the compounds of formula I, with

R1, R2, R3, R4and R5have the above values, and

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

the remains of R01and R02together form a ring and denote SN2CH2Och2CH2CH2CH2NR05CH2CH or (CH2)3-6where

R05denotes H protected by a protective group N or C1-8alkyl or C3-8cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted aryl or heteroaryl, each of which is one or mnogosloinym or unsubstituted, or attached via C1-3alkylene aryl, C3-8cycloalkyl or heteroaryl, each of which is one or mnogosloinym or unsubstituted,

R04denotes H protected by a protective group N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7, -C(Y)R7, -C(Y)-CH2R7, -C(Y)-CH2-CH2R7, -C(Y)-CH2-CH2-CH2R7or-R8-L-R9where

Y represents O, S or N2,

R6represents H, C1-7alkyl, which is saturated or unsaturated, branched or unbranched, one or mnogosloinym or unsubstituted, or C(O)O-C1-6alkyl, which is saturated or unsaturated, branched or unbranched, single l is Bo mnogosloinym or unsubstituted,

R7represents N or C3-8cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym,

R8represents aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym,

L represents-C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O-C(O)-, -O-, -S - or-S(O)2and

R9represents aryl or heteroaryl, each of which is unsubstituted or mono - or mnogosloinym, and

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

In the above-described most appropriate method of obtaining proposed in the invention compounds of the protective group of atoms N, the values of which have R01, R02, R04, R05and/or R06, preferably selected from alkyl, benzyl and carbamates, for example FMOC, Z and Boc.

Below the invention is illustrated in the examples which do not limit its scope.

Examples

The following examples are offered in the invention compounds, as well as how they received and considered held with their use studies to determine their effectiveness.

For all examples, the following General description.

COI is Lithuania chemicals and solvents were purchased from traditionally offering them for sale manufacturers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc) or they synthesized their own.

Characteristics of the compounds were determined by analysis of NMR-spectroscopy, optionally in combination with other analytical methods such as thin layer chromatography, mass spectroscopy or GHUR.

Example 1

Total possible way to obtain proposed in the invention compounds

The proposed invention in connection receive on the basis of suitably protected, for example by monoacetals, cyclohexane-1,4-dione of formula II. Its interaction with potassium cyanide in the presence of a secondary amine get protected N-substituted derivative of 1-amino-4-oxocyclohexanecarboxylate formula III

In the interaction of aminonitriles formula III with ORGANOMETALLIC reagents, preferably Grignard reagent or organolithium reagents, the substitution occurs nitrile functions, resulting in the subsequent removal of carbonyl protective group receive a 4-substituted derivative 4-aminocyclohexanone formula IV

Intermediate compounds of formula IV can then their interaction with ORGANOMETALLIC reagents, preferably Grignard reagent or organolithium reagents, keeping the work proposed in the invention derivatives of 4-aminocyclohexanol formula I

Example 2: Determination of binding ORL1-receptor

Derivatives of 4-aminocyclohexanol General formula I were investigated in the experiment binding to receptor using3N-nociceptin/orphanin FQ and membranes of recombinant cells CHO-ORL1. This experiment was carried out according to the method described by Ardati, etc. (Mol. Pharmacol., 51, 1997, cc.816-824).3N-nociceptin/orphanin FQ used in these experiments at a concentration of 0,5 nm. When conducting analyses on binding to the receptor protein of the cell membrane used at the rate of 20 μg per 200 μl mixture containing 50 mm Hepes (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid) pH 7.4, 10 mm MgCl2and 1 mm etc. Binding to the ORL1 receptor was determined by adding to each sample sample 1 mg covered agglutinins 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 measure of affinity is the value of Ki(inhibition constant).

Compound of example No.The value of Ki(mcmash)
40,02
5
60,03
70,04
80,05
90,03
100,20
110,02
12

Compound of example No.The value of Ki(mcmash)
130,06
140,90
150,40
160,89
170,04
180,13
190,045
200,15
210,15

Example 3: Checking analgesic action experience with otdergivanija tail in mice

Analgesic effectiveness of the proposed in the invention compounds were investigated in the experiment with a focused beam (otdergivanija tail) on mice using the method described by D'amour and Smith (J. Pharm. Exp. Ther. 72, 1941, cc.74-79). The studies used NMRI mice weighing 20-24 g Each animal individually placed in special cells for experiments and on the base of the tail guided focused thermal beam from an electric lamp (Tail-flick-Typ 50/08/1 .be, Labtec, Dr. Hess). The intensity of the emitted is imago lamp radiation was tuned in such a way, to the period of time passing from the moment the lamp is switched on until a sudden otdergivanija tail (the latent period for the development of pain)was untreated animals from 3 to 5 C. Such preliminary experiments with mice were performed twice for five minutes before putting them proposed in the invention compounds and obtained during these measurements the average value was calculated as the average value of prior experience.

Measurements for determining the period of time that passes before the reaction (OTDELENIE tail) to painful stimulus (heat ray), were respectively 20, 40 and 60 min after intravenous administration to mice of the investigated compounds. Analgesic effect was calculated as the increase in the duration of the latent period for the development of pain (% of the maximum duration of irradiation (MDPO)) according to the following formula:

[(T1-T0)/(T2-T0)]×100.

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

To determine the dependence of the effect from each dose studied redlagaemyi in the invention compounds were administered to the animals in 3-5 logarithmically increasing doses including in each case the threshold and the maximum effective dose, and using regression analysis to determine the values of the ED50. The values of the ED50expected at the moment of maximum action, occurring within 20 min after intravenous injection of the analyte.

Proposed in the invention compounds that are used in these studies showed a pronounced analgesic effect. The results are presented in the table below.

Compound of example No.% MDPE (in parentheses indicate the dose in mg/kg, which was intravenously injected investigated the connection)ED50(mg/kg intravenous
4100(1)0,015
5100(1)0,040
698(1)0,055
793(1)0,10
897(1)0,093
9100(1)0,089
1097(1)0,16
1199(1)0,059
1290(1)
1397(10)
14 78(1)
1592(1)
16100 (1)0,028
17100(1)0,15
1863 (10)
19100(1)0,04

Example 4: the Hydrochloride of 4-benzyl-4-dimethylamino-1-fenetylline

To 200 g of 1,4-dioxaspiro[4.5]decane-8-it has consistently added 1,68 l aqueous solution of dimethylamine (40%vol), 200 ml of methanol, 200 g of potassium cyanide and 303 g of dimethylamine hydrochloride and the reaction mixture for 65 h was stirred at room temperature. The obtained white suspension was extracted four times with diethyl ether portions at (800 ml), the combined extracts were first concentrated and then dissolved in 500 ml of dichloromethane, the organic phase was separated, dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received 265 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in the form of a white solid.

50 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile was dissolved in 400 ml of tetrahydrofuran (THF) of analytical purity (ASC), in an atmosphere of nitrogen was added 214 ml of a 2.0 molar solution of benzylmagnesium in TG and was stirred over night at room temperature. For processing under ice cooling was added 200 ml of saturated solution of ammonium chloride, the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 250 ml), the combined organic phases were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude (8-benzyl-1,4-dioxaspiro[4.5]Dec-8-yl)dimethylamine (78,4 g) without further purification was stirred for 24 h at room temperature in a mixture of 200 ml conc. hydrochloric acid (32 wt.%) and 120 ml of water. Then the reaction mixture was first washed three times in diethyl ether in portions of 100 ml, followed by cooling with ice podslushivaet the addition of sodium hydroxide solution (32 wt.%), thrice was extracted with dichloromethane portions of 100 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received of 50.4 g of 4-benzyl-4-dimetilaminokhalkona in the form of a brown solid.

to 25.0 g of 4-benzyl-4-dimetilaminokhalkona was dissolved in 150 ml of tetrahydrofuran ASC, while cooling in an ice bath was added in nitrogen atmosphere 151 ml of 1.0-molar solution of ventilazione in THF and stirred overnight at whom atoi temperature. For processing under ice cooling was added 150 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 80 ml), the combined organic phases were extracted three times with diluted hydrochloric acid (5 wt.%) portions 70 ml), the combined aqueous extracts were washed with 50 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane portions 80 ml), the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (32,6 g) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). 3.5 g of the obtained non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1-fenetylline was dissolved in 28 ml of 2-butanone, then at room temperature was added 103 µl of water, and then the 1.44 ml trimethylchlorosilane and was stirred over night at room temperature. Precipitated precipitated white solid was separated by vacuum filtration, washed with diethyl ether and dried in a vacuum generated by an oil pump. In this way received 2,47 g of the hydrochloride of the non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1-finitistic hexanol.

Example 5: the Hydrochloride of 4-dimethylamino-1,4-difeniltsiklopropanona

45 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile was dissolved in 250 ml of tetrahydrofuran ASC, in an atmosphere of nitrogen was added 238 ml of 1.0-molar solution of ventilazione in THF and stirred overnight at room temperature. For processing under ice cooling was added 100 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether in portions of 200 ml), the combined organic phases are then washed with 100 ml water and 100 ml saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. Obtained as a yellow oil crude dimethyl(8-phenethyl-1,4-dioxaspiro[4.5]Dec-8-yl)amine (54,1 g) without further purification in the next 24 hours was stirred at room temperature in a mixture of 120 ml conc. hydrochloric acid (32 wt.%) and 70 ml of water. Then the reaction mixture was first washed three times with diethyl ether in portions of 50 ml, and then under ice cooling was podslushivaet the addition of sodium hydroxide solution (32 wt.%), thrice was extracted with dichloromethane portions of 100 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual count is the number of solvent was removed in vacuum. In this way got to 35.7 g of crude 4-dimethylamino-4-fenetylline in the form of a slowly crystallizing brown oil.

7,58 g of 4-dimethylamino-4-fenetylline was dissolved in 45 ml of tetrahydrofuran ASC, while cooling in an ice bath under nitrogen atmosphere was added 43 ml of a 1.0-molar solution of ventilazione in THF and stirred overnight at room temperature. For processing under ice cooling was added 43 ml of a solution of ammonium chloride (20 wt.%) and thrice was extracted with diethyl ether portions 80 ml, after which the combined organic phases were extracted three times with diluted hydrochloric acid (5 wt.%) portions 70 ml), the combined aqueous extracts were washed with 50 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane portions 80 ml), the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (to 9.57 g) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). 938 mg of the obtained non-polar diastereoisomer of 4-dimethylamino-1,4-difeniltsiklopropanona was dissolved in 7.5 ml of 2-butanone, at room temperature we use the and 26 μl water, and then 371 μl of trimethylchlorosilane and was stirred over night at room temperature. Precipitated precipitated white solid was separated by vacuum filtration, washed with diethyl ether and dried in a vacuum generated by an oil pump. In this way got to 1.00 g of the hydrochloride of the non-polar diastereoisomer of 4-dimethylamino-1,4-difeniltsiklopropanona.

Example 6: the Hydrochloride of 4-benzyl-4-dimethylamino-1-[2-(2-forfinal)ethyl]cyclohexanol

11.4 g of lithium aluminum hydride was added to 100 ml of tetrahydrofuran ASC, in an atmosphere of nitrogen was heated under reflux, was added dropwise 50 g 2-florfenicol acid dissolved in 400 ml of tetrahydrofuran ASC, and the reaction mixture was heated for a further two hours. For processing under cooling in an ice bath is added dropwise with stirring was added 72 ml of water, and then 250 ml policecontributing hydrochloric acid (16 wt.%). Next, the reaction mixture was twice extracted with diethyl ether portions 250 ml combined extracts were twice washed with sodium hydrogen carbonate solution (5 wt.%) portions of 100 ml, dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received with 40.2 g of 2-(2-forfinal)ethanol.

50 g of 2-(2-forfinal)ethanol, 19 ml of concentrated sulfuric acid is you, and 58 ml of aqueous Hydrobromic acid (47 wt.%) was heated in a stainless steel autoclave to 100° C and kept at this temperature during the night. After cooling, diluted with 500 ml of water, was extracted twice with dichloromethane portions 250 ml combined extracts were dried over potassium carbonate, filtered, concentrated and the residual solvent was removed in vacuum. In this way got to 61.8 g of 1-(2-bromacil)-2-fervently.

624 mg of magnesium was stirred in nitrogen atmosphere in 13 ml of tetrahydrofuran ASC and then added about a third of the solution 4,69 g of 1-(2-bromacil)-2-fervently in 13 ml of tetrahydrofuran ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise 2,97 g of 4-benzyl-4-dimetilaminokhalkona dissolved in 13 ml of tetrahydrofuran ASC, and the reaction mixture was stirred over night. For processing under ice cooling was added 26 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 40 ml), the combined organic phases are washed with 50 ml water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 30 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), three extrage is ovali dichloromethane portions 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (4,39 g) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way received 1.50 g non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1-[2-(2-forfinal)ethyl]cyclohexanol, of which analogously to example 4 received, 1.56 g of the corresponding hydrochloride.

Example 7: Hydrochloride 4-benzyl-4-dimethylamino-1-[2-(4-forfinal)ethyl]cyclohexanol

Similarly, 1-(2-bromacil)-2-fervently of 4-florfenicol acid was obtained 1-(2-bromacil)-4-torbenson.

841 mg of magnesium was stirred in nitrogen atmosphere in 17 ml of tetrahydrofuran ASC and added about a third of the solution 6,32 g of 1-(2-bromacil)-2-fervently in 17 ml of tetrahydrofuran ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise of 4.00 g of 4-benzyl-4-dimetilaminokhalkona dissolved in 17 ml of tetrahydrofuran ASC, and the reaction mixture was stirred over night. For processing under ice cooling was added 35 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase DV is GDI was extracted with diethyl ether portions 40 ml, the combined organic phases are washed with 50 ml water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 30 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (4,39 g) was chromatographically on silica gel. In this way received 1,08 g non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1 -[2-(4-forfinal)ethyl]cyclohexanol, which is similar to example 4 was 1.10 g of the corresponding hydrochloride.

Example 8: the Hydrochloride of 4-dimethylamino-4-(2-terbisil)-1-fenetylline

of 1.16 g of magnesium was stirred in nitrogen atmosphere in 20 ml of diethyl ether ASC and added about a third of the solution to 6.19 g of 2-formanilide in 25 ml of diethyl ether ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise a solution of 5.00 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml of diethyl ether ASC and the reaction mixture was peremeshivayu throughout the night. For processing under ice cooling was added 36 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 50 ml) and the combined organic phases are successively washed with 20 ml water and 20 ml of saturated solution of sodium chloride. The resulting crude [8-(2-terbisil)-1,4-dioxaspiro[4.5]Dec-8-yl]dimethylamine (7,34 g) without further purification at room temperature was stirred for 24 h in a mixture of 18 ml conc. hydrochloric acid (32 wt.%) and 10 ml of water. Then the reaction mixture was first washed three times with diethyl ether in portions of 50 ml, then, while cooling with ice, the pH value was adjusted to 9 by adding aqueous ammonia (25 wt.%), thrice was extracted with dichloromethane portions of 50 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received 5,80 g of 4-dimethylamino-4-(2-terbisil)cyclohexanone in the form of a yellow solid.

5,79 g of 4-dimethylamino-4-(2-terbisil)cyclohexanone was dissolved in 35 ml of tetrahydrofuran ASC, while cooling in an ice bath under nitrogen atmosphere was added 42 ml of a 1.0-molar solution of ventilazione in THF and stirred overnight at room temperature. For processing when Oh is Adeney ice was added 42 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 50 ml), the combined organic phases are washed with 30 ml of water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions of 50 ml, the combined aqueous extracts were washed with 50 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane portions of 50 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (7,76 g) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way received 1,33 g non-polar diastereoisomer of 4-dimethylamino-4-(2-terbisil)-1-fenetylline, of which analogously to example 4 received 536 mg of the corresponding hydrochloride.

Example 9: the Hydrochloride of 4-dimethylamino-4-(3-terbisil)-1-fenetylline

925 mg of magnesium was stirred in nitrogen atmosphere in 19 ml of diethyl ether ASC and added about a third of a solution of 4.95 g of 3-formanilide in 19 ml of diethyl ether ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour, the Le which was added dropwise a solution of 4.00 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml of diethyl ether ASC and the reaction mixture was stirred over night. For processing under ice cooling was added 29 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 50 ml) and the combined organic phases are successively washed with 20 ml water and 20 ml of saturated solution of sodium chloride. The resulting crude [8-(3-terbisil)-1,4-dioxaspiro[4.5]Dec-8-yl]dimethylamine (5.75 g yellow solid) without further purification at room temperature was stirred for 24 h in a mixture of 14 ml conc. hydrochloric acid (32 wt.%) and 8 ml of water. Then the reaction mixture was first washed three times with diethyl ether portions to 30 ml, and then while cooling with ice, the pH value was adjusted to 9 by adding aqueous ammonia (25 wt.%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received 4.71 g of 4-dimethylamino-4-(3-terbisil)cyclohexanone in the form of a yellow solid.

of 4.67 g of 4-dimethylamino-4-(3-terbisil)cyclohexanone was dissolved in 28 ml of tetrahydrofuran ASC, while cooling in an ice bath under nitrogen atmosphere was added 34 ml of a 1.0-molar solution of ventilazione in THF and PE is masively over night at room temperature. For processing under ice cooling was added 34 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 40 ml), the combined organic phases are washed with 25 ml of water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 25 ml diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (6,12 g of a yellow resin) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way received 1.28 g non-polar diastereoisomer of 4-dimethylamino-4-(3-terbisil)-1-fenetylline, of which analogously to example 4 was of 1.30 g of the corresponding hydrochloride.

Example 10: the Hydrochloride of 4-dimethylamino-4-(4-terbisil)-1-fenetylline

925 mg of magnesium was stirred in nitrogen atmosphere in 19 ml of diethyl ether ASC and added about a third of a solution of 4.95 g of 4-formanilide in 19 ml of diethyl ether ask the Remaining solution was continuously added dropwise pic the e beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise a solution of 4.00 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml of diethyl ether ASC and the reaction mixture was stirred over night. For processing under ice cooling was added 29 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 50 ml) and the combined organic phases are successively washed with 20 ml water and 20 ml of saturated solution of sodium chloride. The resulting crude [8-(4-terbisil)-1,4-dioxaspiro[4.5]Dec-8-yl]dimethylamine (USD 5.76 g of yellow solid) without further purification at room temperature was stirred for 24 h in a mixture of 14 ml conc. hydrochloric acid (32 wt.%) and 8 ml of water. Then the reaction mixture was first washed three times with diethyl ether portions to 30 ml, and then while cooling with ice, the pH value was adjusted to 9 by adding aqueous ammonia (25 wt.%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received 4,70 g of 4-dimethylamino-4-(4-terbisil)cyclohexanone in the form of a yellow solid.

4,69 g of 4-dimethylamino-4-(4-forb nil)cyclohexanone was dissolved in 28 ml of tetrahydrofuran ASC, while cooling in an ice bath under nitrogen atmosphere was added 34 ml of a 1.0-molar solution of ventilazione in THF and during the night was stirred at room temperature. For processing under ice cooling was added 34 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 40 ml), the combined organic phases are washed with 25 ml of water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 25 ml diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (6,40 g of a yellow resin) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). Thus obtained 1.45 g non-polar diastereoisomer of 4-dimethylamino-4-(4-terbisil)-1-fenetylline, of which analogously to example 4 was obtained 1.44 g of the corresponding hydrochloride.

Example 11: Hydrochloride 4-benzyl-4-dimethylamino-1-[2-(4-forfinal)ethyl]cyclohexanol

Similarly, 1-(2-bromacil)-2-fervently 3-f is organisationnel acid was obtained 1-(2-bromacil)-3-torbenson.

757 mg of magnesium was stirred in nitrogen atmosphere in 15 ml of tetrahydrofuran ASC and added about a third of the solution 5,69 g of 1-(2-bromacil)-3-fervently in 16 ml of tetrahydrofuran ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise of 3.60 g of 4-benzyl-4-dimetilaminokhalkona dissolved in 16 ml of tetrahydrofuran ASC, and the reaction mixture was stirred over night. For processing under ice cooling was added 31 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 40 ml), the combined organic phases are washed with 30 ml of water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 30 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (3,96 g) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). This way is Lucile 301 mg of the nonpolar diastereoisomer of 4-benzyl-4-dimethylamino-1-[2-(4-forfinal)ethyl]cyclohexanol, of which analogously to example 4 was 254 mg of the corresponding hydrochloride.

Example 12: Hydrochloride 4-benzyl-4-dimethylamino-1-(2-terbisil)cyclohexanol

757 mg of magnesium was stirred in nitrogen atmosphere in 15 ml of diethyl ether ASC and added about a third of a solution of 4.05 g of 2-formanilide in 15 ml diethyl ether ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise of 3.60 g of 4-benzyl-4-dimetilaminokhalkona dissolved in 40 ml of diethyl ether ASC, and the reaction mixture was stirred over night. For processing under ice cooling was added 31 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 40 ml), the combined organic phases are washed with 30 ml of water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 30 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in Vacu the IU. The resulting crude product (5,02 g) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way received 2,44 g non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1-(2-terbisil)cyclohexanol, which is similar to example 4 was 2,53 g of the corresponding hydrochloride.

Example 13: Hydrochloride 4-(allylamino)-4-benzyl-1-fenetylline

A mixture of 9 ml of water, with 5.3 ml of hydrochloric acid (32 wt.%), 8 ml of methanol and 17.5 g of allylmethylamine, 8.00 g of 1,4-dioxaspiro[4.5]decane-8-she and 8.0 g of potassium cyanide was stirred at room temperature for 65 hours Obtained yellowish-white suspension was extracted four times with diethyl ether portions 25 ml combined extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. Thus obtained 11.3 g of 8-(allylmethylamine)-1,4-dioxaspiro[4.5]decane-8-carbonitrile in the form of a light brown liquid.

To be 14.8 ml of a 2.0 molar solution of benzylmagnesium in THF under nitrogen atmosphere was added dropwise a solution of 3.50 g of 8-(allylmethylamine)-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 35 ml of tetrahydrofuran ASC and during the night was stirred at room temperature. For processing under ice cooling was added 25 ml of a saturated solution of chlorite is and ammonium, the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 25 ml), the combined organic phases were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude allyl(8-benzyl-1,4-dioxaspiro[4.5]Dec-8-yl)methylamine (5,41 g) without further purification at room temperature was stirred for 24 h in a mixture of 13 ml conc. hydrochloric acid (32 wt.%) and 7.5 ml of water. Then the reaction mixture was first washed three times with diethyl ether in portions of 50 ml, and then under ice cooling was podslushivaet the addition of sodium hydroxide solution (32 wt.%), thrice was extracted with dichloromethane portions of 100 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received 3,55 g of 4-(allylamino)-4-benzylchloride.

To be 14.8 ml of a 1.0-molar solution of ventilazione in THF under nitrogen atmosphere was added dropwise a solution of 3.50 g of 4-(allylamino)-4-benzylchloride in 21 ml of tetrahydrofuran ASC and during the night was stirred at room temperature. For processing under ice cooling was added 19 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase three times ek who was tragically diethyl ether in 20 ml, the combined organic phases were washed with 20 ml water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions of 20 ml, the combined aqueous extracts were washed with 20 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane portions of 50 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (4,00 g brown resin) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way received 2,04 g non-polar diastereoisomer of 4-(allylamino)-4-benzyl-1-fenetylline, of which analogously to example 4 received 807 mg of the corresponding hydrochloride.

Example 14: Hydrochloride 4-benzyl-4-dimethylamino-1-(3-terbisil)cyclohexanol

757 mg of magnesium was stirred in nitrogen atmosphere in 15 ml of diethyl ether ASC and added about a third of a solution of 4.05 g of 3-formanilide in 15 ml diethyl ether ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise of 3.60 g of 4-benzyl-4-dimetilaminokhalkona, alvarenga in 30 ml of diethyl ether ASC, and the reaction mixture was stirred over night. For processing under ice cooling was added 31 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 40 ml), the combined organic phases were washed with 20 ml water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 30 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (4,91 g of a yellow resin) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way received 1,93 g non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1-(3-terbisil)cyclohexanol as a white solid, which analogously to example 4 was 2,09 g of the corresponding hydrochloride.

Example 15: Hydrochloride 4-benzyl-4-dimethylamino-1-(4-terbisil)cyclohexanol

757 mg of magnesium was stirred in nitrogen atmosphere in 15 ml of diethyl ether ASC and added about a third of a solution of 4.05 g of 4-formanilide 15 m is diethyl ether ASC The remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise of 3.60 g of 4-benzyl-4-dimetilaminokhalkona dissolved in 30 ml of diethyl ether ASC, and the reaction mixture was stirred over night. For processing under ice cooling was added 31 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 40 ml), the combined organic phases were washed with 20 ml water, was extracted three times with diluted hydrochloric acid (5 wt.%) portions 40 ml), the combined aqueous extracts were washed with 30 ml of diethyl ether, the pH value was adjusted to 9 with ammonia solution (25 wt%), thrice was extracted with dichloromethane 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (5,08 g of a yellow resin) was chromatographically on silica gel using a mixture of diethyl ether/hexane (volume ratio 1:1). In this way gained 2.24 g non-polar diastereoisomer of 4-benzyl-4-dimethylamino-1-(4-terbisil)cyclohexanol as a white solid, which analogously to example poluchili 2,32 g of the corresponding hydrochloride.

Example 16: Hydrochloride, 1-benzyl-4-dimethylamino-4-(3-terbisil)cyclohexanol

925 mg of magnesium was stirred in nitrogen atmosphere in 19 ml of diethyl ether ASC and added about a third of a solution of 4.95 g of 3-formanilide in 19 ml of diethyl ether ask the Remaining solution was continuously added dropwise after the beginning of the formation of the Grignard reagent, upon completion of the addition was stirred for one hour and then was added dropwise a solution of 4.00 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml of diethyl ether ASC and the reaction mixture was stirred over night. For processing under ice cooling was added 29 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was twice extracted with diethyl ether portions 50 ml) and the combined organic phases are successively washed with 20 ml water and 20 ml of saturated solution of sodium chloride. The resulting crude [8-(3-terbisil)-1,4-dioxaspiro[4.5]Dec-8-yl]dimethylamine (5.75 g yellow solid) without further purification at room temperature was stirred for 24 h in a mixture of 14 ml conc. hydrochloric acid (32 wt.%) and 8 ml of water. Then the reaction mixture was first washed three times with diethyl ether portions to 30 ml, and then while cooling with ice, the pH value was adjusted to 9 by adding aqueous ammonia (25 wt.%), three times were extracted dichlo the methane portions 40 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received 4.71 g of 4-dimethylamino-4-(3-terbisil)cyclohexanone in the form of a yellow solid.

of 4.67 g of 4-dimethylamino-4-(3-terbisil)cyclohexanone like getting 4-dimethylamino-4-(4-terbisil)-1-fenetylline were subjected to interaction with a 1.0-molar solution of benzylmagnesium in THF. After chromatography on silica gel obtained non-polar diastereoisomer of 1-benzyl-4-dimethylamino-4-(3-terbisil)cyclohexanol as in example 4 was transferred into the corresponding hydrochloride with exit 261 mg.

Example 17: Hydrochloride 4-benzyl-1-phenethyl-4-pyrrolidin-1-illlogical

A mixture of 55 ml of water and 33 ml of hydrochloric acid (32 wt.%), 50 ml of methanol, 127 ml of pyrrolidine, 50.0 g of 1,4-dioxaspiro[4.5]decane-8-she and 50.0 g of potassium cyanide was stirred for 65 h at room temperature. The obtained light brown suspension was extracted four times with diethyl ether in 50 ml combined extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way got to 76.7 g of 8-pyrrolidin-1-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile in view of the light brown liquid.

To 127 ml of a 2.0 molar solution of benzylmagnesium in THF under nitrogen atmosphere was added dropwise a solution of 40.0 g of 8-pyrrolidin-1-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 150 ml of tetrahydrofuran ASC and during the night was stirred at room temperature. For processing under ice cooling was added 50 ml of a saturated solution of ammonium chloride, the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 50 ml), the combined organic phases were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude 1-(8-benzyl-1,4-dioxaspiro[4.5]Dec-8-yl)pyrrolidin (54,0 g yellow solid) without further purification at room temperature was stirred for 24 h in a mixture of 128 ml conc, hydrochloric acid (32 wt.%) and 74 ml of water. Then the reaction mixture was first washed twice with diethyl ether in portions of 50 ml, and then under ice cooling was podslushivaet the addition of sodium hydroxide solution (32 wt.%), thrice was extracted with dichloromethane portions of 100 ml, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. In this way received of 40.3 g of 4-benzyl-4-pyrrolidin-1 illlogical.

<> To 23,3 ml of 1.0-molar solution of ventilazione in THF under nitrogen atmosphere and cooled in an ice bath was added dropwise a solution of 4.00 g of 4-benzyl-4-pyrrolidin-1 illlogical in 40 ml of tetrahydrofuran ASC and during the night was stirred at room temperature. For processing under ice cooling was added 25 ml of a solution of ammonium chloride (20 wt%), the phases were separated, the aqueous phase was extracted three times with diethyl ether portions 50 ml), the combined organic phases were dried over sodium sulfate, filtered, concentrated and the residual solvent was removed in vacuum. The resulting crude product (of 6.26 g of brown oil) was chromatographically on silica gel using methanol/ethyl acetate (volume ratio 1:1). In this way received 2,48 g non-polar diastereoisomer of 4-benzyl-1-phenethyl-4-pyrrolidin-1-illlogical, of which analogously to example 4 was 1.98 g of the corresponding hydrochloride.

Example 18: 4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl)cyclohexanol

A solution of N-methylindole (1,50 mg, 3,81 mmole) in dry THF (20 ml) was cooled in a stream of argon to -5°C. then was added dropwise tert-utility (4.19 mmole, 2,47 ml of 1.7 molar solution in pentane) so that the reaction temperature did not exceed 0°C. Upon completion of addition reacts the district and the mixture was stirred for further two hours at 0° C. After that, when 0°C was added dropwise a solution of 4-benzyl-4-dimetilaminokhalkona (3,88 mg, 3,81 mmole) in dry THF (7 ml). The mixture was stirred for 15 min at 0°and then for four hours at room temperature. Then the reaction was stopped by adding to the reaction mixture saturated solution of ammonium chloride (20 ml), the organic phase was separated, and the aqueous phase was extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuum. Purification was performed rapid chromatography on silica gel using a mixture of cyclohexane/ethyl acetate (volume ratio 4:1). In this way received 456 mg of 4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl)cyclohexanol with a melting point 105-107°°C.

Example 19: 1-benzo[b]thiophene-2-yl-4-benzyl-4-dimethylaminoethanol

A solution of benzo[b]thiophene (1,50 mg of 3.73 mmole) in 20 ml of dry THF was cooled in a stream of argon to -5°C. then was added dropwise tert-utility (4,47 mmole, 2,63 ml of 1.7 molar solution in pentane) so that the reaction temperature did not exceed 0°C. Upon completion of addition the reaction mixture was stirred for two hours at 0°C. After that, when 0°C was added dropwise a solution of 4-benzyl-4-dimetilaminokhalkona (3,86 mg of 3.73 is mole) in dry THF (8 ml). The mixture was stirred for 15 min at 0°and then for five hours at room temperature. Then the reaction was stopped by adding to the reaction mixture saturated solution of ammonium chloride (30 ml), the organic phase was separated, and the aqueous phase was extracted four times with dichloromethane (25 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuum. Purification was performed rapid chromatography on silica gel using a mixture of cyclohexane/ethyl acetate (volume ratio 9:1). In this way received 517 mg of 1-benzo[b]thiophene-2-yl-4-benzyl-4-dimethylaminoethanol with a melting point 128-131°C.

Example 20: 1-benzo[b]thiophene-3-yl-4-benzyl-4-dimethylaminoethanol a Solution of 3-bromo-1-benzo[b]thiophene (1.90 mg, 4,22 mmole) in 30 ml of dry diethyl ether in a stream of argon was cooled to -78°C. After dropwise cautiously added n-utility (5,07 mmole, 3,17 ml of 15%by weight solution in hexane) in such a way that the reaction temperature did not exceed -75°C. For the completion of the addition, the reaction mixture was stirred for two hours at -78°C. Then at -78°C was added dropwise a solution of 4-benzyl-4-dimetilaminokhalkona (977 mg, 4,22 mmole) in dry diethyl ether (10 ml). The mixture was stirred for four hours at -78°C, after which ment the NGO was heated to room temperature (approximately twelve hours). Then the reaction was stopped by adding to the reaction mixture saturated solution of ammonium chloride (30 ml), the organic phase was separated, and the aqueous phase was extracted four times with dichloromethane (25 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuum. Purification was performed rapid chromatography on silica gel using a mixture of cyclohexane/ethyl acetate (volume ratio 7:3). In this way received 324 mg of 1-benzo[b]thiophene-3-yl-4-benzyl-4-dimethylaminoethanol with a melting point 158-160°C.

Example 21: 1-benzofuran-2-yl-4-benzyl-4-dimethylaminoethanol

A solution of benzo[b]furan (612 mg, 5,12 mmole) in dry THF (40 ml) was cooled in a stream of argon to -8°C. then was added dropwise tert-utility (6,22 mmole, 4,14 ml of 1.5 molar solution in pentane) so that the reaction temperature did not exceed -5°C. Upon completion of addition the reaction mixture was stirred for two hours at -5°C. Then at 0°C was added dropwise a solution of 4-benzyl-4-dimetilaminokhalkona (1.20 g, 5,18 mmole) in dry THF (10 ml). The mixture was stirred for one hour at 0°and then for four days at room temperature. Then the reaction was stopped by adding to the reaction mixture saturated solution of ammonium chloride (20 ml), the organic phase is separated, and the aqueous phase was extracted four times with dichloromethane portions to 30 ml combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuum. Purification was performed rapid chromatography on silica gel using a mixture of cyclohexane/ethyl acetate (volume ratio 8:2). In this way received 380 mg of 1-benzofuran-2-yl-4-benzyl-4-dimethylaminoethanol with a melting point 121-124°C.

Example No.
4hydrochloride 4-benzyl-4-dimethylamino-1-fenetylline
5hydrochloride 4-dimethylamino-1,4-difeniltsiklopropanona
6hydrochloride 4-benzyl-4-dimethylamino-1-[2-(2-forfinal)ethyl]cyclohexanol
7hydrochloride 4-benzyl-4-dimethylamino-1-[2-(4-forfinal)ethyl]cyclohexanol
8hydrochloride 4-dimethylamino-4-(2-terbisil)-1-fenetylline
9hydrochloride 4-dimethylamino-4-(3-terbisil)-1-fenetylline
10hydrochloride 4-dimethylamino-4-(4-terbisil)-1-fenetylline
11hydrochloride 4-benzyl-4-dimethylamino-1-[2-(3-forfinal)ethyl]cyclo is hexanol
12hydrochloride 4-benzyl-4-dimethylamino-1-(2-terbisil)cyclohexanol
13hydrochloride 4-(allylamino)-4-benzyl-1-fenetylline
14hydrochloride 4-benzyl-4-dimethylamino-1-(3-terbisil)cyclohexanol
15hydrochloride 4-benzyl-4-dimethylamino-1-(4-terbisil)cyclohexanol
16hydrochloride of 1-benzyl-4-dimethylamino-4-(3-terbisil)cyclohexanol
17hydrochloride 4-benzyl-1-phenethyl-4-pyrrolidin-1-illlogical
184-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl)cyclohexanol
191-benzo[b]thiophene-2-yl-4-benzyl-4-dimethylaminoethanol
201-benzo[b]thiophene-3-yl-4-benzyl-4-dimethylaminoethanol
211-benzofuran-2-yl-4-benzyl-4-dimethylaminoethanol

1. Substituted derivatives of 4-aminocyclohexanol General formula I

in which R1and R2independently of one another denote H or C1-8alkyl, which is saturated or unsaturated and unsubstituted, R1and R2both cannot simultaneously denote H, Il the residues R 1and R2together form a ring and denote (CH2)3-6,

R3means attached via saturated or unsaturated, branched or unbranched and unsubstituted1-4alkyl group, phenyl, unsubstituted or substituted with halogen, and

R4denotes heteroaryl selected from 5-membered heteroaryl in which heteroatoms selected from nitrogen atoms, oxygen or sulfur, each of which is condensed with the benzene ring and is unsubstituted or one-deputizing1-8by alkyl; CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7where,

R6represents H,

R7represents phenyl which may be unsubstituted or mono - or mnogosloinym atoms of halogen,

not necessarily in the form of their physiologically acceptable salts, especially physiologically compatible acids.

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

R1and R2independently of one another denote H or C1-4alkyl, R1and R2both cannot simultaneously denote H, or the residues R1and R2together form a ring and denote (CH2)4-5first of all R and R2independently of one another denote methyl or ethyl, or the residues R1and R2together form a ring and denote (CH2)5.

3. Substituted derivatives of 4-aminocyclohexanol according to claim 1, wherein R3means attached through saturated unbranched C1-2alkyl group, phenyl, unsubstituted or one - or mnogozalny, halogen.

4. Substituted derivatives of 4-aminocyclohexanol according to claim 1, wherein R4represents indolyl, benzothiophene, benzofuran, benzothiazole, benzotriazolyl, benzo[1,2,5]thiazolyl, each of which is nezametnym or one-deputizing C1-8-alkyl, especially

R4represents indolyl, benzothiazolyl, benzofuranyl, benzothiophene, each of which is unsubstituted or onesemester C1-8-alkyl.

5. Substituted derivatives of 4-aminocyclohexanol according to claim 1, characterized in that

R4means-CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7preferably

R4means-CHR6R7, -CHR6-CH2R7.

6. Substituted derivatives of 4-aminocyclohexanol according to claim 1, characterized in that they are selected from a group including

4-benzyl-4-dimethylamino-1-fenetylline, as well as with testwuide hydrochloride

4-dimethylamino-1,4-definitionsexual, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-[2-(2-forfinal)ethyl]cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-[2-(4-forfinal)ethyl]cyclohexanol, as well as its corresponding hydrochloride

4-dimethylamino-4-(2-terbisil)-1-fenetylline, as well as its corresponding hydrochloride

4-dimethylamino-4-(3-terbisil)-1-fenetylline, as well as its corresponding hydrochloride

4-dimethylamino-4-(4-terbisil)-1-fenetylline, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-[2-(3-forfinal)ethyl]cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-(2-terbisil)cyclohexanol, as well as its corresponding hydrochloride

4-(allylamino)-4-benzyl-1-fenetylline, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-(3-terbisil)cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-4-dimethylamino-1-(4-terbisil)cyclohexanol, as well as its corresponding hydrochloride

1-benzyl-4-dimethylamino-4-(3-terbisil)cyclohexanol, as well as its corresponding hydrochloride

4-benzyl-1-phenethyl-4-pyrrolidin-1-illlogical, is also its corresponding hydrochloride

4-benzyl-4-dimethylamino-1 -(1-methyl-1H-indol-2-yl)cyclohexanol,

1-benzo [b]thiophene-2-yl-4-benzyl-4-dimethylaminoethanol,

1-benzo[b]thiophene-3-yl-4-benzyl-4-dimethylaminoethanol and

1-benzofuran-2-yl-4-benzyl-4-dimethylaminoethanol, not necessarily in the form oftheirphysiologically acceptable salts, especially physiologically compatible acids.

7. Drug, possessing properties of binding OPL1-receptor containing at least one substituted derivative 4-aminocyclohexanol according to claim 1, optionally in the form of its physiologically acceptable salts, and optionally containing acceptable additives and/or auxiliary substances.

8. The use of substituted derivative 4-aminocyclohexanol according to one of claims 1 to 6, optionally in the form of its physiologically acceptable salts, for obtaining a medicinal product intended for the treatment of pain, especially acute, visceral, neuropathic or chronic pain.

9. The use of substituted derivative 4-aminocyclohexanol according to claim 1, optionally in the form of its physiologically acceptable salts, for obtaining a medicinal product intended for the treatment of diseases mediated by functioning OPL1-receptor, such as a state of fear, epilepsy, heart-SOS is vascular disease.

10. The method of obtaining substituted derivative 4-aminocyclohexanol according to claim 1, namely, that

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

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

the compound of formula IVa, obtained from the compounds of formula III, otscheplaut protective group S1and S2with the formation of 4-substituted derivative of 4-aminocyclohexanone formula IV

g) 4-substituted derivative of 4-aminocyclohexanone formula IV is subjected to interaction with ORGANOMETALLIC reagents, preferably Grignard reagent or organolithium reagent of the formula metal-R4with the formation of the compounds of formula V

where R3and R4 have specified in claim 1 values, and

R01and R02independently of one another denote With1-8alkyl, which is saturated unbranched and unsubstituted or

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

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



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

The invention relates to new derivatives of benzodioxole, benzofuran, dihydrobenzofuran and benzodioxane or their pharmaceutically acceptable solvate of General formula I

< / BR>
where Q1and Q2every means independently hydrogen or halogen;

X is CH2CH or oxygen;

Y represents CR3, CR3R4or (CH2)nwith n = 1-4;

Z denotes CH2CH or oxygen;

R means hydrogen, halogen or alkyl WITH1-4in both cases;

m denotes 1 or 2;

R1means1-6-alkyl, C3-6-cycloalkyl,1-3-haloalkyl,1-6-alkylamino,2-6alkenyl,1-4-alkoxy(C1-4)alkyl, C1-C4-alkylthio(C1-4)alkyl or triptorelin-C1-4;

R2means hydrogen, halogen or C1-4-alkyl; and

R3and R4each independently mean hydrogen or C1-4-alkyl,

containing pharmaceutical compositions for the treatment of sleep disorders, and disorders associated with disturbance of circadian rhythms

The invention relates to benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H, Cl, Br, OH or OA;

R3denotes benzyl or itself known protective for the amine function group;

X denotes a CN, COON, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Het;

R4and R5each independently of one another denotes H, A or benzyl;

A denotes alkyl with 1-4 C-atoms;

Ph denotes phenyl;

Het represents imidazol-1-yl, triazole-1-yl or tetrazol-1-yl; and

Py denotes a pyridyl;

and their salts

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylsulfonyl derivatives of the formula (I): , wherein Ar means naphthyl or phenyl substituted optionally with halogen atom or (C1-C6)-alkoxy-group; R1 means (C1-C6)-alkyl; R2 means hydrogen atom or (C1-C6)-alkyl, or their pharmaceutically acceptable salts or solvates. Proposed compounds show affinity to HT6 receptors. Also, the claim describes pharmaceutical compositions comprising indicated compounds, their using as therapeutic agents and a method for their preparing. Compounds can be useful in treatment of some disturbances in the central nervous system (CNS).

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

12 cl, 1 tbl, 12 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

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EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

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and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

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EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

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