Substituted derivatives of 1-aminobutane-3-ol, method for their preparing and medicinal agent

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

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

9 cl, 89 ex

 

The present invention relates to substituted derivatives of 1-aminobut-3-ol, to the way they are received, containing these compounds medicines and to the use of substituted derivatives of 1-aminobut-3-ol to obtain drugs.

Cyclic analogue of GABA (gamma-aminobutyric acid) gabapentin is a past clinical trials of antiepileptic drug. Gabapentin has also other interesting and important from a medical point of view by properties primarily as an analgesic. Interest therefore represent the structure of the new class, showing affinity to the binding site gabapentina. As before, when these indications, there is a need for substances with a similar gabapentin properties, such as similar analgesic effect.

The treatment of chronic not chronic pain medicine attaches great importance. Despite progress in this area successes there is still an urgent need for the establishment of effective therapy of pain. The urgency of developing new methods targeted, personalised patient treatment of chronic and nechanicky pain, involving among other things the successful and satisfactory for the patient's pain treatment, n who goes confirmation in numerous recently published scientific papers in the field of applied analgesics and fundamental studies of nociception.

Classical opioids, such as morphine, highly effective in the treatment of severe pain, including severe pain. However, their use is limited to such well-known side effects, such as respiratory depression, vomiting, taking sedatives, constipation and the development of tolerance. In addition, these opioids are ineffective when neuropathic or reappearance of pain suffered mainly cancer patients.

Based on the foregoing, the present invention was based on the task to obtain substances with new structure, which would have affinity to the binding site gabapentina and/or showed would be appropriate physiological efficiency, such as analgesia.

The object of the invention in accordance with this are substituted derivatives of 1-aminobut-3-ol of General formula I

in which R1and R2each independently from each other represents C1-With6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multi-substituted, or

R1and R2together form a (CH2)2-9the ring, which optionally may be substituted With1-With8the alkyl, which is what I branched or unbranched, saturated or unsaturated, unsubstituted or one - or multi-substituted, or aryl, which is unsubstituted or one - or multi-substituted,

R3and R4each independently from each other represents C1-With6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multiply substituted, With3-With6cycloalkyl, which is saturated or unsaturated, unsubstituted or one - or multi-substituted, phenyl, benzyl or phenethyl which is unsubstituted or one - or multi-substituted, or

R3and R4together form a ring and denote SN2CH2Och2CH2CH2CH2NR22CH2CH2or (CH2)3-6where

R22represents H, C1-With10alkyl or C3-With10cycloalkyl, each of which is saturated or unsaturated, branched or unbranched, single or multiply substituted or unsubstituted aryl or heteroaryl, each of which is one - or multiply substituted or unsubstituted, or linked via a saturated or unsaturated C1-With3alkyl aryl, C3-With10cycloalkyl or heteroaryl, each of which is one or many is obratno substituted or unsubstituted,

R5represents C1-With10alkyl, which is saturated or unsaturated, branched or unbranched, single or multiply substituted or unsubstituted, With3-With9cycloalkyl, which is saturated or unsaturated, aryl or heteroaryl, linked via a saturated or unsaturated C1-With3alkyl aryl bound via saturated or unsaturated C1-With3alkyl With3-With10cycloalkyl or linked via a saturated or unsaturated C1-With3alkyl heteroaryl, where each of the aryl, heteroaryl and cycloalkyl residues independently of each other may be unsubstituted or one - or multi-substituted residues, independently from each other selected from the group comprising F, Cl, Br, I, OR18, SR18, SO2R18, SO2OR18, CN, COOR18, NR19R20C1-With10alkyl, which is saturated or unsaturated, branched or unbranched, single or multiply substituted or unsubstituted, With3-With9cycloalkyl, which is saturated or unsaturated, unsubstituted or one - or multi-substituted, aryl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, and linked via a saturated or unsaturated C 1-With3alkyl aryl, C3-With9cycloalkyl or heteroaryl, each of which is unsubstituted or one - or multiply substituted, with

R18represents H, C1-With10alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted or one - or multiply substituted, With3-With9cycloalkyl, which is saturated or unsaturated, unsubstituted or one - or multi-substituted, aryl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, or linked via a saturated or unsaturated C1-With3alkyl aryl, C3-With9cycloalkyl or heteroaryl, each of which is unsubstituted or one - or multi-substituted,

R19and R20independently of one another represent H, C1-With10alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted or one - or multiply substituted, With3-With9cycloalkyl, which is saturated or unsaturated, unsubstituted or one - or multi-substituted, aryl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, or linked via a saturated or unsaturated C 1-With3alkyl aryl, C3-With9cycloalkyl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, or

R19and R20together form CH2CH2Och2CH2CH2CH2NR21CH2CH2or (CH2)3-6where

R21represents N or C1-With10alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted or one - or multi-substituted,

R6denotes H or aryl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, and

R7denotes halogen, CF3C1-With6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multiply substituted, With3-With9cycloalkyl, which is saturated or unsaturated, unsubstituted or one - or multi-substituted, aryl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, or linked via a saturated or unsaturated C1-With3alkyl aryl, C3-With9cycloalkyl or heteroaryl, each of which is unsubstituted or one - or multi-substituted, optionally in the form of their R is zametov, their pure diastereomers, 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 above form or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of a solvate, especially hydrates.

The proposed invention in connection associated with the binding site gabapentina and show a pronounced analgesic effect.

According to the invention under alkyl, respectively cycloalkenyl residues refers to saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or one - or multi-substituted. With1-With2alkyl represents a C1or2alkyl, C1-With3alkyl represents a C1C2or3alkyl, C1-With4alkyl represents a C1C2With3or4alkyl, C1-With5alkyl represents a C1C2With3With4or5alkyl, C1-With6alkyl represents a C1-With2-With3-With4-With5- or6-alkyl, C1-With7alkyl represents a C1-, the 2-With3-With4-With5-With6- or7-alkyl, C1-With8alkyl represents a C1-With2-With3-With4-With5-With6-C7or C8-alkyl, C1-With10alkyl represents a C1-With2-With3-With4-With5-With6-With7-C8-C9- or10-alkyl and C1-With18alkyl represents a C1-With2-With3-With4-With5-With6-With7-C8-C9-With10-With11C12-C13-C14-C15-C16-C17or C18-alkyl. Further, With3-With4cycloalkyl represents a C3- or4-cycloalkyl,3-With5-cycloalkyl represents a C3-With4- or5-cycloalkyl,3-With6cycloalkyl represents a C3-With4-With5- or6-cycloalkyl,3-With7cycloalkyl represents a C3-With4-With5-With6or7-cycloalkyl,3-With8cycloalkyl represents a C3-With4-With5-With6-With7or C8-cycloalkyl,4-C5cycloalkyl represents a C4- or5-cycloalkyl,4-C6cycloalkyl represents a C4-With5- or6-cycloalkyl,4 -C7cycloalkyl represents a C4-With5-With6- or7-cycloalkyl,5-With6cycloalkyl represents a C5- or6-cycloalkyl and C5-C7cycloalkyl represents a C5-With6- or7-cycloalkyl. The concept of "cycloalkyl" includes saturated cycloalkyl in which one or two carbon atoms replaced by a heteroatom is S, N or O. However, under the concept of "cycloalkyl" falls primarily one or several times, preferably once, unsaturated cycloalkyl 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, in addition, substituted, CHF2, CF3or CH2HE, as well as pyrazoline, oxadiazoline, [1,4] dioxane or dioxolane.

In the context of the present invention, the term "substituted"used in respect of alkyl and cycloalkyl, meaning odevaetsa, 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 "multiply substituted" residues, respectively "substituted" remains in the case of multiple substitution refers to multiple substitution and different, and the same atoms by identical or different substituents, for example three times the substitution of one and 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 OC1-3the 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" I mean the group-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2and CH2-CH2-CH2-CH2-CH2-CH2-and under the balance "(CH2)1-4" I mean the group-CH2-, -CH2-CH2-, -CH2-CH2-CH2- and-CH2-CH -CH2-CH2and so on

Under the aryl residue refers to a cyclic system with at least one aromatic ring, but without heteroatoms in only one of the rings. As example can be mentioned phenyl, naphthyl, fluoranthene, fluorenyl, tetralinyl or indanyl primarily N-fluorenyl or anthracene, which may be unsubstituted or one - or multi-substituted.

Under heteroaryl residue refers to heterocyclic systems with at least one unsaturated ring which may contain one or more heteroatoms from the group comprising nitrogen, oxygen and/or sulfur and which can also be single - or multi-substituted. From the group of heteroatoms include, for example, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazin, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxole, benzodioxan, carbazole, indole and hinzelin.

The term "substituted" in respect of aryl and heteroaryl implied, if not stated otherwise, the substitution of the aryl or heteroaryl group, R23, OR23by halogen, preferably by F atoms and/or Cl, a group of CF3, CN, NO2, NR24R25C1-With6the alkyl (saturated), C1-With6alkoxygroup,3-With8cycloalkanes is, With3-With8cycloalkyl or2-With6alkylene.

While the remainder R23denotes H, C1-With10alkyl, preferably C1-With6alkyl, aryl or heteroaryl or linked via a saturated or unsaturated C1-With3alkyl or C1-With3alkylenes aryl group or heteroaryl, and these aryl and heteroaryl residues may not be substituted by aryl or heteroaryl, the remains of R24and R25have identical or different meanings and represent H, C1-With10alkyl, preferably C1-With6alkyl, aryl, heteroaryl or linked via a saturated or unsaturated C1-With3alkyl or C1-With3alkylenes aryl group or heteroaryl, and these aryl and heteroaryl residues may not be substituted by aryl or heteroaryl or residue R24and R25together represent CH2CH2Och2CH2CH2CH2NR26CH2CH2or (CH2)3-6and R26denotes H, C1-With10alkyl, preferably C1-C6alkyl, aryl or heteroaryl or linked via C1-C3alkyl, saturated or unsaturated, or via C1-C3alkylenes aryl group or heteroaryl, and these aryl and heteroaryl residues not what may be substituted by aryl or heteroaryl.

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 primarily physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids.

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 of alkaline 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 "physiologically compatible with the ü with anions or acids in the context of the present invention refers to a salt of at least one of the proposed invention compounds mainly in the protonated, for example, nitrogen, 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 is primarily formed with a physiologically compatible acid salt, namely salts of the respective active ingredient with inorganic, respectively organic acids which are physiologically compatible, especially when introduced into the body of a human and/or mammal. As an example, physiologically compatible salts of certain acids can be called the salt of hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydroλ6-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 is you. The most preferred salt is the hydrochloride.

In one of the preferred embodiments of the invention in its proposed substituted derivatives of 1-aminobut-3-ol of formula I

R6denotes H or heteroaryl or preferably is a residue of formula II

where

R9-R13each independently of one another denotes H, F, Cl, Br, I, CF3HE, OR14, OCF3, SR14, SO2CH3, SO2CF3C1-C6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multi-substituted, phenyl, which is unsubstituted or one - or multi-substituted, CN, COOR14or NO2or

R9and R10or R10and R11together form och2Oh or och2CH2O-ring and

R14represents C1-With6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multi-substituted, phenyl, benzyl, phenethyl or thiophenyl, each of which is unsubstituted or one - or multi-substituted.

In another particularly preferred embodiment of the invention in its proposed substituted derivatives of 1-AMI is obatan-3-ol of formula I

R1and R2together form a (CH2)2-5the ring, which optionally may be substituted C1-With6the alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multi-substituted, or phenyl which is unsubstituted or one - or multi-substituted, but preferably unsubstituted.

In another of the preferred embodiments of the invention in its proposed substituted derivatives of 1-aminobut-3-ol of the formula I R3and R4each independently from each other represents C1-With6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multiply substituted, preferably both represent CH3or

R3and R4together form a ring and denote SN2CH2NR22CH2CH2or (CH2)3-6first of all both represent (CH2)4-5or CH2CH2NR22CH2CH2where

R22represents N or C1-With6alkyl, which is saturated, branched or unbranched, and unsubstituted, primarily N or CH3.

In another of the preferred embodiments of the invention in the proposed therein is ameenah derivatives 1 aminobutane-3-ol of formula I

R5represents C1-With6alkyl, which is saturated or unsaturated, branched or unbranched, single or multiply substituted or unsubstituted, With5-C6cycloalkyl, phenyl, thiophenyl, furyl, benzofuranyl, benzothiophene, pyrrolyl, pyridinyl, pyrimidinyl, chinoline, ethenolysis, hintline, linked via a saturated or unsaturated C1-With3alkyl phenyl, linked via a saturated or unsaturated C1-With3alkyl With5-With6cycloalkyl or linked via a saturated or unsaturated C1-With3alkyl thiophenyl, furyl, benzofuranyl, benzothiophene, pyrrolyl, pyridinyl, pyrimidinyl, chinoline, ethenolysis or hintline, where each of the aryl, heteroaryl and cycloalkyl residues independently of each other may be unsubstituted or one - or multiply substituted, preferably

R5denotes phenyl or thiophenyl, which is unsubstituted or one - or multiply substituted, preferably an atom of F, Cl, Br, I, HE, O-C1-C4alkyl, C1-With6alkyl, NH2and/or SH, or linked via a saturated or unsaturated C1-With3alkyl phenyl, which is unsubstituted or one - or multiply substituted, preferably an atom of F, Cl, Br, I, HE, O-C1-C the alkyl, C1-With6the alkyl group NH2and/or SH, first of all

R5denotes phenyl, which is unsubstituted or one - or multiply substituted, preferably an atom of F, Cl, Br, I, a group HE co3OC2H5OS3H7, SH, CH3With2H5With3H7and/or C4H9.

In General, about Deputy R5it should be noted that the preferred those cases where R5means connected directly or via a saturated or unsaturated C1-With3alkyl aryl, heteroaryl or cycloalkyl that one - or multiply substituted, preferably residues, independently from each other selected from the group comprising F, Cl, Br, I, OR18, SR18, COOR18, NH2and C1-With10alkyl, which is saturated or unsaturated, branched or unbranched, single or multiply substituted or unsubstituted, R18represents N or C1-With6alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted or one - or multi-substituted, first of all residues, independently from each other selected from the group comprising F, Cl, Br, I, HE, O-C1-C4alkyl, C1-With6alkyl, NH2and/or SH, or which resumes the us.

In another preferred embodiment of the invention in its proposed substituted derivatives of 1-aminobut-3-ol of General formula I

R7represents C1-With6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or one - or multiply substituted, With5-C7cycloalkyl, which is saturated or unsaturated, unsubstituted or one - or multiply substituted, preferably cyclohexyl, phenyl, which is unsubstituted or one - or multi-substituted, linked via a saturated or unsaturated C1-C3alkyl phenyl, which in each case is unsubstituted or one - or multiply substituted, preferably

R7denotes phenyl, which is unsubstituted or one - or multi-substituted, linked via a saturated or unsaturated C1-C3alkyl phenyl, which in each case is unsubstituted or one - or multi-substituted.

In another of the preferred embodiments of the invention in its proposed substituted derivatives of 1-aminobut-3-ol of the formula I in if R5and/or R7denote bound via saturated or unsaturated C1-C3alkyl aryl, C3-C9cycloalkyl is or heteroaryl, then C1-C3the alkyl is linked via aryl, heteroaryl or cycloalkyl and represents-CH2-, -C2H4-With3H6-,-CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-,orpreferably-CH2-, -C2H4or

In another preferred embodiment of the invention proposed therein substituted derivatives of 1-aminobut-3-ol selected from the following group of compounds, including

2-benzyl-1-(2,4-dichlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-1-(3-Chlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-(2,5-dimethylbenzyl)cyclohexanol,

2-benzyl-1-(2-chloro-6-terbisil)-6-dimethylaminomethylphenol,

2-benzyl-1-(4-Chlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-(3-triptoreline)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(2-methylbenzyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(2-methoxyphenyl)cyclohexanol,

2-benzyl-1-(4-chloro-3-triptoreline)-6-dimethylaminomethylphenol,

2-benzyl-1-(2-Chlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-1-(3,5-dichlorophenyl)-6-dimethylaminomethylphenol, 2-benzyl-1-(3-chlorophenyl)-6-dimethylaminomethyl lovecanal,

2-benzyl-6-dimethylaminomethyl-1-(3-forfinal)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(5-fluoro-2-methoxyphenyl)cyclohexanol,

2-benzyl-1-cyclohexylmethyl-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-(4-methoxyphenyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-p-taillecavat,

2-benzyl-6-dimethylaminomethyl-1-(3-phenylpropyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-thiophene-2-illlogical,

2-benzyl-6-dimethylaminomethyl-1-phenylalanylglycyl,

2-benzyl-6-dimethylaminomethyl-1-(4-forfinal)cyclohexanol,

2-benzyl-6-dimethylaminomethylene-1-ol,

2-benzyl-6-dimethylaminomethyl-1-m-taillecavat,

2-benzyl-1-(4-tert-butylphenyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-vinylcyclohexane,

2-benzyl-6-dimethylaminomethyl-1-o-taillecavat,

2-benzyl-6-dimethylaminomethyl-1-(4-fluoro-3-were)cyclohexanol,

1,2-dibenzyl-6-dimethylaminomethylphenol,

2-benzyl-1-(4-chlorophenyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-phenylcyclohexanol,

2-dimethylaminomethyl-1-(2,5-dimetilfenil)-6-(3-methoxyphenyl)cyclohexanol,

1-cyclohexylmethyl-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

1-(2,4-dichlo is benzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-phenylalanylglycyl,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-o-taillecavat,

1-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-forfinal)-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-fluoro-4-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol,

1-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-methoxybenzyl)-6-(3-methoxyphenyl)cyclohexanol,

1-(4-chloro-3-triptoreline)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

1-(3,5-dichlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-phenylalanylglycyl,

1-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-o-taillecavat,

1-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(2,5-dimethylbenzyl)-6-methylcyclohexanol,

1-(2-chloro-6-terbisil)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(4-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-6-methyl-1-(3-methylbenzyl)cyclohexanol,

2-dimethylaminomethyl-6-methyl-1-(3-triptoreline)cyclohexanol,

1-(2-chloro-3-forfinal)-2-dimethylaminomethyl-6-methylcyclohexa the l

2-dimethylaminomethyl-6-methyl-1-(2-methylbenzyl)cyclohexanol,

2-dimethylaminomethyl-1-(2-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-terbisil)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(4-terbisil)-6-methylcyclohexanol,

1-(2-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3,5-dichlorophenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3-chlorophenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-forfinal)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-fluoro-4-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(4-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-6-methyl-1-p-taillecavat,

2-dimethylaminomethyl-6-methyl-1-(3-phenylpropyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-6-methyl-1-thiophene-2-illlogical,

2-dimethylaminomethyl-6-methyl-1-phenylalanylglycyl,

2-dimethylaminomethyl-6-methyl-1-fenetylline,

2-dimethylaminomethyl-1-(4-forfinal)-6-methylcyclohexanol,

1-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(4-fluoro-2-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(2-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(4-terbisil)-6-(3-methox is phenyl)cyclohexanol,

1-(3-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-p-taillecavat,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-(3-phenylpropyl)cyclohexanol,

2-dimethylaminomethyl-1,6-bis-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-thiophene-2-illlogical,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-fenetylline,

3-[3-dimethylaminomethyl-2-(4-forfinal)-2-hydroxycyclohexyl]phenol,

3-(3-dimethylaminomethyl-2-hydroxy-2-phenylcyclohexyl)phenol,

3-[2-(4-tert-butylphenyl)-3-dimethylaminomethyl-2-hydroxycyclohexyl]phenol,

3-(3-dimethylaminomethyl-2-hydroxy-2-vinylcyclohexane)phenol,

1-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

3-dimethylaminomethyl-2-(3-methoxyphenyl)bicyclohexyl-2-ol,

2-benzyl-6-dimethylaminomethyl-1-(4-triptoreline)cyclohexanol,

3-(2-benzyl-6-dimethylaminomethyl-1-hydroxycyclohexyl)phenol,

3-(2-tert-butyl-6-dimethylaminomethyl-1-hydroxycyclohexyl)phenol, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, first of all what about the physiologically compatible salts, or in the form of a solvate, especially hydrates, primarily in the form of hydrochloride.

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 drugs are those containing at least one proposed in the invention substituted derivative 1 aminobutane-3-ol, optionally along with acceptable additives and/or auxiliary substances and/or optionally with other active ingredients.

Proposed in the invention medicines in addition to at least one substituted derivative 1 aminobutane-3-ol 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 the CSOs, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, transbukkalno, rectal or topical application, such as application on skin, on mucous membranes or in the eyes. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, medicines and syrups, and for parenteral, local, and inhalation use suitable solutions, suspensions, easily recoverable dry compositions, as well as sprays. Proposed in the invention substituted derivatives of 1-aminobut-3-ol 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 1-aminobut-3-ol. In principle, the composition proposed in the invention of medicines, you can include some other, well-known specialists active substances.

Enter the patient number 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 od is proposed in the invention substituted derivative 1 aminobutane-3-ol are introduced into the organism in dosage, part of 0.005 to 1000 mg/kg, preferably from 0.05 to 5 mg/kg body weight.

In one preferred options contained in the medicinal product substituted derivative 1 aminobutane-3-ol 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.

Gabapentin is a well-known antiepileptic agent with anticonvulsant action. Along with this gabapentin is used and some other indications, in particular may be prescribed by the attending physician for migraine and bipolar disorders, as well as at high tide (for example, in the postmenopausal period) (M. Schrope, Modern Drug Discovery, September 2000, page 11). Gabapentin has therapeutic potential in other indications, as evidenced by the results of research conducted with the participation of the people as well as the results obtained when applying gabapentin in clinical practice (see J.S.Bryans, D.J. Wustrow, "3-Substituted GABA Analogs with Central Nervous System Activity: A Review", Med. Res. Rev. (1999), cc.149-177). In this review article will detail the action gabapentin. Thus, in particular, gabapentin is effective in the treatment of chronic pain and behavioral disturbances. However, the article says first and foremost about gabapentina against sudorojnoi and antiepileptic efficacy, as well as the possibility of its use in chronic and neuropathic pain, mainly in thermal hyperplasia, the mechanical allodynia and allodynia when exposed to cold. In addition, the application gabapentin effective for neuropathy caused by disorders of the nervous system, primarily in neuropathic pain, as well as pain associated with inflammation, and postoperative pain. Gabapentin is successfully used for mental disorders, primarily as an anxiolytic drug. Among other proven indications gabapentin should be called amyotrophic lateral sclerosis (ABS), reflex sympathetic dystrophy, spastic paralysis, tired leg syndrome, treating the symptoms and pain associated with multiple sclerosis, acquired nystagmus, treating the symptoms of Parkinson's disease, painful diabetic neuropathy and mental disorders, such as bipolar disorder, mood swings, manic behavior. Good results, as experience has shown, can be achieved using gabapentina when erythromelalgia pain, post-polio pain, trigeminal neuralgia and post-operative pain (Bryans und Wustrow (1999), see above). In General gabapentin is effective in the many neurodegenerative diseases, that is well known and is also supported by the examples given in the above article. As examples of such neurodegenerative diseases can be called Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy. Also known efficiency gabapentin at violation of function of the gastrointestinal tract.

All offered in the invention compounds displace gabapentin from it - until now also not yet exactly known science - binding site. It is said, however, suggests that the compounds according to the invention are associated with the same site as gabapentin, showing thereby through this binding site its physiological action that supposedly characterized the same profile as gabapentin. The validity of such assumptions about the identity of the steps in one and the same binding site confirms the analgesic effectiveness. So, in particular, the proposed invention in connection not only displace gabapentin from its binding site, but also display similar gabapentin a pronounced analgesic effect.

Another object of the invention in accordance with this is the application of the proposed substituted derivative 1 aminobutane-3-ol to obtain a medicinal product intended for the treatment of pain, first of all, neuropathic, chronic or acute pain.

Proposed in the invention compound suitable for the treatment of first symptoms associated with neuropathic pain, however, can also be applied at other related readings. Another object of the invention in accordance with this is the application of the proposed substituted derivative 1 aminobutane-3-ol to obtain a medicinal product intended for the treatment of migraine, hyperalgesia and allodynia primarily thermal hyperalgesia, mechanical hyperalgesia and allodynia, including allodynia when exposed to extreme cold, as well as for the treatment of pain associated with inflammation, or post-operative pain.

Proposed in the invention compounds can also be used in other indications. Another object of the invention in accordance with this is the application of the proposed substituted derivative 1 aminobutane-3-ol to obtain a medicinal product intended for the treatment of epilepsy, tides, ailments in postmenopausal period, amyotrophic lateral sclerosis (ABS), reflex sympathetic dystrophy, spastic paralysis, tired leg syndrome, acquired nystagmus, mental, respectively neurotic diseases disorders such as bipolar disorder, anxiety, panic attacks, mood swings, obsessive behaviour, depression and manic-depressive behavior, painful diabetic neuropathy, symptoms and pain associated with multiple sclerosis and Parkinson's disease, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy, disorders of the gastrointestinal tract, erythromelalgia or post-polio pain, neuralgia trigeminal or herpetic neuralgia, or as anti-convulsants, analgesic or anxiolytic.

This may be the preferred option, which is used substituted derivative 1 aminobutane-3-ol according to any one of items 1-11 of the claims presented in the form of a pure diastereoisomer and/or enantiomer, in the form of the racemate or in the form of requiredno or equimolar mixture of the diastereomers and/or enantiomers.

Another object of the invention is a method of treatment of a mammal or human in need of such treatment on the basis of important from a medical point of view of symptoms, which consists in the introduction to the patient a therapeutically effective dose of a substituted derivative of 1-aminobut-3-ol according to the invention or of a medicinal product according to the invention. The invention relates of prid is just to the appropriate treatment of pain, first of all, neuropathic, chronic or acute pain, migraine, hyperalgesia and allodynia primarily thermal hyperalgesia, mechanical hyperalgesia and allodynia, including allodynia under the influence of cold, and pain associated with inflammatory or post-operative pain, epilepsy, tides, ailments in postmenopausal period, amyotrophic lateral sclerosis (ABS), reflex sympathetic dystrophy, spastic paralysis, tired leg syndrome, acquired nystagmus, mental, respectively neurotic diseases disorders such as bipolar disorder, anxiety, panic attacks, mood swings, manic behavior, depression and manic-depressive behavior, painful diabetic neuropathy, symptoms and pain associated with multiple sclerosis or Parkinson's disease, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy, erythromelalgia or post-polio pain, neuralgia trigeminal or herpetic neuralgia.

Another object of the invention is a method of obtaining the proposed substituted derivative 1 aminobutane-3-ol, explain in more detail in the further description and examples.

General methodology the floor the treatment of compounds according to the invention

For the synthesis proposed in the invention compounds used in the reactions described in the literature (see R.C. Larock, Comprehensive Organic Transformations, 2nd ed., published by Wiley, New York (1999) and referred to in this publication sources), as well as practical experience gained by the applicant.

Substituted derivatives of 1-aminobut-3-ol of General formula I can be obtained by using a method which is characterized by the fact that β-aminoketone (referred to hereinafter as the basis of manniche) of formula Ia

in which R1-R4, R6and R7have one of the values specified above for formula I, and this reaction is particularly preferred for producing compounds where R6does not denote H, is subjected to the interaction with the ORGANOMETALLIC compound of formula III

in which Z denotes MgCl, MgBr, MgI or Li, a R5has one of the values specified above for formula I, is obtained the corresponding compounds of formula I.

The reaction between β-aminoketones formula Ia and a compound of the Grignard reagent of the formula III in which Z denotes MgCl, MgBr and MgI, or organolithium compound of formula III can be carried out in simple aliphatic ether, for example diethyl ether and/or tetrahydrofuran, at temperatures in the range from 70°to +60°C. Organolithium compound f is rmula III, in which Z denotes Cl, Br or I, can be obtained by the interaction of, for example, with a solution of n-utility in hexane due to the exchange of the halogen on Li.

To get β-aminoketones General formula Ia can be used in methods known from the literature (see Houben-Weyl, Methods der Organischen Chemie, E21b (1995), cc.1925-1929; M. Tramontini, L. Angiolini, Mannich Bases, Chemistry and Uses, ed-CRS Press (1994) and referred to in this publication sources). It is preferable to obtain β-aminoketone General formula Ia interaction of enamines of General formula IV, and this reaction is particularly preferred for producing compounds in which R6does not denote H,

with iminium salt of the General formula V

where Y preferably denotes Cl-, AlCl4-, Br-or I-.

Compounds in which R6denotes H, can be obtained similarly known from the literature by the method according to the classical reaction of manniche using salt Asnother or BuLi.

Enamines of General formula IV get known from the literature how the interaction of ketones of General formula VI

with secondary amines, preferably dimethylamine, pyrrolidine, piperidine or morpholine (see Acta Chem. Scand. 38 (1984), SS-53). Iminium salts of the General formula V receive p is known from the literature how the interaction of Amidala General formula VII

with anhydrides of the acids, for example with acetylchloride or thionyl chloride (see Houben-Weyl, Methods der Organischen Chemie, E21b (1995), cc.1925-1929). There is no need to allocate such iminium salts of the General formula V, as they can be formed in situ and then subjected to interaction with enamines of General formula IV with getting manniche General formula Ia (Angew. Chem. 106 (1994), cc.2531-2533). Because Annenkova tautomerism similar to keto-enol tautomerism, instead of enamines of General formula IV may also use Iminov General formula VIII

An alternative to this, the ketones of General formula VI can be directly subjected to interaction with iminium salts of the General formula V.

However, Mannich bases of the General formula Ia can be obtained directly by the interaction of enamines of General formula IV with an aromatic or heteroaromatic aldehyde of General formula IX

and a secondary amine of General formula HNR3R4X is also in the form of the corresponding hydrochloride HNR3R4×HCl, preferably in the presence of triethylamine, chlorotrimethylsilane and sodium iodide (Synlett 1997, SS-976).

Mannich bases of the General formula Ia are obtained by the above methods, depending on the reaction conditions, prepost is positive relative configuration of the General formula IIa

in which the amino group is in the anti-position to the R2. These compounds of General formula IIa can be obtained in the form of pure diastereomers by crystallization, including their salts, such as hydrochloride, or chromatographic separation.

In contrast, the reaction for obtaining manniche General formula Ia is carried out with 1,4-secondary amines of General formula X to inanam General formula XI

receive Alderney condensation of ketones of General formula VI with aromatic or heteroaromatic aldehydes of General formula IX, flows less stereoselectivity (patent US 4017637). Therefore, this approach is suitable for other possible stereoisomers.

When using chiral amines to obtain enamines of General formula IV or Iminov General formula VIII subsequent reaction of manniche allows you to get the Mannich bases of the General formula Ia with a large number of one of the enantiomers or even in the form of pure enantiomers (Houben-Weyl - der Organischen Chemie Methods, E21b, 1995, cc.1925-1929).

Mannich bases of the formula Ia in the form of pure enantiomers can also be obtained by aminomethylpyridine using enantiomerically ketones of formula VI (for values of R6and R7different the t other) or by splitting of the racemate by crystallization of the diastereomeric salts using for these purposes, chiral acids, preferably tartaric acid, derivatives of tartaric acid or almond acid (J. Gawronski, K. Gawronska, Tartaric and Malic Acids in Synthesis, published by Wiley, New York (1999) and referred to in this publication sources).

Formed by the reaction of aminomethylpyridine diastereomers Mannich bases can be obtained by dividing column chromatography or fractional crystallization of their hydrochloride from an appropriate organic solvent, such as 2-butanone or acetone, in diastereomerism.

As the ketones of formula VI used commercially available products, or synthesized using known literature methods.

Ketones of formula VI, where R7represents a C1-C6alkyl, aryl, heteroaryl, alkylaryl or alkylglycerol, can be obtained as described in the literature, the ways α-accession to the ketones of formula XII

For regioselective α-attach using a simple enol ethers, enolates or amoxicillian there are various ways described in the literature (see, for example, I. Kuwajima, and others, Journ. Am. Chem. Soc. 104 (1982), SS; N.O. House, Modern Synthetic Reactions, 2nd ed., publishing house of Benjamin, Menlo Park, California (1972); J.K. Rasmussen, Synthesis 1977, s; E.-i. Negishi and others, Tetrahedron Lett. 1979, SS). Use α-metallizovannyh hydrazones analiziruemykh keto is impressive as enolate equivalents consistent with obtaining carbonyl compounds, derived hydrazone, carrying metallation, interaction with halides and subsequent cleavage by oxidative hydrolysis results in α-substituted carbonyl compounds described in Enders and others (see D. Enders, W. Bettray, Pure Appl. Chem. 69 (1996), SS-580; Recent Advances in the Development of Highly Enantioselective Synthetic Methods and D. Enders in Asymmetric Synthesis, volume 3, Ed. by J.D. Morrison, published by Academic Press, Orlando, 1984, cc.275-339, Alkylation of Chiral Hydrazones). Using these methods, the use of chiral hydrazones can get enantiomerically ketones of formula VI (SAMP-method). Quantitative metallation of hydrazones can be successfully carried out using bases, such as, for example, diisopropylamide lithium, with the subsequent interaction metallizovannyh hydrazones with halides receive α-substituted hydrazones with high yield. Instead metallizovannyh hydrazones interaction with halides can be and metallogeny (see, for example, I. Paterson and others, Tetrahedron 46 (1990), cc.4663).

Another possibility to obtain a ketone of General formula VI is the oxidation of the corresponding alcohols of formula XIII

where R1, R2and R7have the same values as above for the General formula I.

The compounds of formula XIII can be obtained by hydroporinae, before occhialino using 9-borabicyclo[3.3.0]nonane as a reducing agent, followed by oxidative processing, preferably used for this purpose, the hydrogen peroxide in the alkaline range of pH values, from the corresponding olefin of formula XIVa and XIVb

where R1, R2and R7have the same values as above for the General formula I (see, for example, the NS Brown and others, Journ. Am. Chem. Soc.99 (1977), s).

Hydroxyl derivative of formula XIII can also be obtained through catalisano the cuprate disclosure of relevant oxirane derivatives (epoxides) of formula XV with nucleophiles, preferably compounds Grignard or organolithium compounds of the type R7-Z (XVI) (see, for example, S. Huyn and others, Tetrahedron Lett. 1979, SS; J.K. Whitesell and others, Chimia 40 (1986), z), where Z has the same meaning as indicated for formula III, a R7represents a C1-C6alkyl, aryl, heteroaryl, alkylaryl or alkylglycerol. Due to enzymatic cleavage of the racemates can also be obtained alcohols of formula XIII in the form of pure enantiomers:

The alcohols of formula XIII, in which R7is a halogen, can be obtained, for example, the interaction oxirane derivatives of formula XV with lithium halides in the presence of acids to produce in this way the corresponding alcohols of formula XIII, where R7 represents a halogen (J.S. Bagwa and others, Tetrahedron Lett. 32 (1991), s). The compounds of formula X, in which R7represents bromine, can be obtained by the interaction of olefins of formula XIVa and XIVb with N-bromosuccinimide in water (S.O. Guss, Journ. Am. Chem. Soc.77 (1955), s).

Substituted derivatives of 1-aminobut-3-ol of the formula I, in which R5represents a phenol group, can be obtained from methoxyaniline derivatives by selective ether cleavage, for example, using diisobutylaluminium in an aromatic hydrocarbon, for example toluene, at a temperature in the range from 60 to 130°With (Synthesis 1975, s; DBF 2409990, 2409991 and Chem. Abstr. 84 (1974), s).

In addition, derivatives of 1-aminobut-3-ol of the formula I, in which R5represents a phenol group, can be obtained from the relevant benzisoxazol by restorative dibenzylamine. This reaction dibenzylamine preferably in the presence of platinum or palladium absorbed on a carrier, such as activated carbon as a catalyst and in the presence of hydrogen in a solvent such as acetic acid or With1-C1alkilany alcohol, at a pressure of from 1 to 100 bar and temperatures in the range from 20 to 100°C.

The salt formation

The compounds of formula I are well known method to translate into their salts with physiologically by preelimination, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (some saccharine acid), monomethylmercury acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The process of salt formation is preferably carried out in a solvent such as diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone and/or 2-butanone or in the water. To obtain hydrochloride suitable, in addition, trimethylchlorosilane in aqueous solution.

The synthesis of compounds in which R6does not denote hydrogen

These compounds were obtained according to the methods described in the literature (see, for example, Risch and others, Houben-Weyl, Methods der Organischen Chemie, E21b (1995), SS-1929; Angew. Chem. 106 (1994), SS-2533; Synlett 1997, SS-976).

Below the invention is explained in more detail by examples, which do not limit its scope.

Examples

The following examples describe redlagaemye in the invention compounds as well as their preparation and studies to determine their effectiveness.

For all examples, the following General provisions.

Used chemicals and solvents were purchased from traditionally offering them for sale manufacturers (companies Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc) or synthesized independently.

The analysis was performed using NMR spectroscopy, ESI-mass spectroscopy and/or GHUR.

In a pre-heated, and then cooled in an atmosphere of inert gas to -10°the reaction vessel was placed dissolved in THF Foundation of manniche (400 µl of 0.5 mol/l). Thereafter, with stirring, was added 2 equivalents of the prepared Grignard reagent or organolithium reagent (0,5 mol/l in THF or diethyl ether, 800 μl). The reaction mixture was stirred at room temperature. After 3 h, re-cooled to -10°and hydrolyzed in a solution of ammonium chloride. Then the reaction mixture was twice extracted with ethyl acetate and 40°With concentrated under vacuum.

For research and analysis of chlorinated compounds were obtained using ESI-mass-spectrogram, and for research and analysis of other compounds were obtained using the NMR-spectrum.

Example of synthesis of the hydrochloride of 1-(3-chlorophenyl)-2-dimethylaminomethyl-6-(4-methoxyphenyl)cyclohexanol

Stage 1: 2-(4-methoxyphenyl)cyclohexanol

The reaction was carried out in an atmosphere of nitrogen as protective gas. of 19.4 g (0,8 mol) of magnesium shavings were mixed in 50 ml of dried tetrahydrofuran. Then was added dropwise 100 ml (150 g, and 0.8 mole) of 1-bromo-4-methoxybenzene dissolved in 300 ml of absolute tetrahydrofuran, so that the reaction mixture boiled. Then for a further 1 h the mixture was heated under reflux, after which it was cooled to 10°C. Further, when the temperature of the portions was added 14.9 g of copper iodide and stirred for 1 h and Then was added dropwise 81 ml (78,6 g to 0.8 mole) 7-oxabicyclo[4.1.0]heptane, dissolved in 160 ml of dried tetrahydrofuran, so that the internal temperature of the highly exothermic reaction does not exceed 25° (cooled with acetone/dry ice). Upon completion of the process of adding during the night was stirred at room temperature.

For carrying out the hydrolysis, the reaction mixture while cooling with ice bath was first mixed with 90 ml of water then was added dropwise a mixture of 17 g of ammonium chloride, 50 ml of concentrated hydrochloric acid and 350 ml of water. After separation of the phases the aqueous phase was extracted three times with 250 ml of diethyl ether. The combined organic phases are twice the industry is Ali a saturated solution of sodium bicarbonate in portions of 150 ml After filtration through 200 g of silica gel was dried over sodium sulfate. After removal of the solvent received 150 g (89% of theory) of waxy crystals light yellow color, which without further purification was used in the next stage.

Stage 2: 2-(4-methoxyphenyl)cyclohexanone

146 g (of 0.71 mole) of 2-(4-methoxyphenyl)cyclohexanol from stage 1 was dissolved in 600 ml of diethyl ether. Under vigorous stirring and cooling with ice bath was added dropwise a solution of 69.9 g (to 0.23 mole) of sodium dichromate (as dihydrate), 355 ml of water and 53.2 ml of concentrated sulfuric acid so that the internal temperature did not exceed 10°C. Upon completion of the process of adding during the night was stirred at room temperature. After separation of the phases the aqueous phase was extracted twice more with 200 ml of diethyl ether. The combined organic phases are washed twice with 200 ml of saturated sodium hydrogen carbonate solution and dried over sodium sulfate. After removal of the solvent the resulting oil was distilled and the temperature 128-134°and a pressure of 0.05 bar caught convert fraction. After crystallization from n-hexane obtained 130 g (90% of theory) of colourless crystals with a melting point of 90°C.

Stage 3: 2-dimethylaminomethyl-6-(4-methoxyphenyl)cyclohexanone

200 g (0,98 mole) of 2-(4-methoxyphenyl)cyclohexanone from stage 2 and 91 g (1 mol) of methylene chloride, dimethylamine was stirred at room temperature in 1000 ml of dry acetonitrile. After adding 1 ml of acetylchloride stirring continued for another 3 h at room temperature, was formed colorless transparent solution. Then to the reaction mixture was added dropwise 2000 ml dried simple ether when this hydrochloride is precipitated in the form of crystals. In this way received 160 g (56% of theory) of colorless crystals. Then from the hydrochloride with dichloromethane/sodium hydroxide released the substrate and after drying the solution by distillation of the dichloromethane was removed.

The above example is somewhat universal, as in this example, we can illustrate the possibility of using known literature methods for producing compounds where R6denotes N.

Stage 4: 1-(3-chlorophenyl)-2-dimethylaminomethyl-6-(4-methoxyphenyl)cyclohexanol, hydrochloride.

The reaction was carried out in an atmosphere of nitrogen as protective gas. of 18.3 g (of 0.75 mol) of magnesium shavings were mixed in 150 ml of dried tetrahydrofuran. Then was added dropwise 88 ml (144 g of 0.75 mole) of 1-bromo-3-chlorobenzene dissolved in 500 ml of absolute tetrahydrofuran, so that Acciona the mixture is boiling. Then the mixture for 1 h was heated under reflux, after which it was cooled to 10°C. Then was added dropwise 131 g (0.5 mole) 2-dimethylaminomethyl-6-(4-methoxyphenyl)cyclohexanone from stage 3, dissolved in 400 ml of dried tetrahydrofuran, so that the internal temperature did not exceed 20°C. Upon completion of the process of adding was stirred over night at room temperature.

For carrying out the hydrolysis, the reaction mixture while cooling with ice bath was mixed with 1000 ml of 20%aqueous solution of ammonium chloride. After separation of the phases the aqueous phase was extracted three times with 250 ml of diethyl ether. The combined organic phases are washed twice with a saturated solution of sodium bicarbonate in portions of 100 ml. After removal of the solvent received 166 g (93% of theory) of light yellow oil as crude product.

The resulting crude product was submitted and filled by silica gel column size 8×60 cm and suirable with ethyl acetate/methanol in a ratio of 1:1. The result was of 91.7 g of pure reason (52% of theory). This base was dissolved in 920 ml of 2-butanone and mixed with 31,1 ml trimethylchlorosilane and 4,4 ml of water. During the night at 4-5°in the form of crystals fell out of 58.7 g (31.4% of theory) of the hydrochloride with a melting point 243°C.

Examples

Example No.The name of the connection
12-benzyl-1-(2,4-dichlorobenzyl)-6-dimethylaminomethylphenol
22-benzyl-1-(3-Chlorobenzyl)-6-dimethylaminomethylphenol
32-benzyl-6-dimethylaminomethyl-1-(2,5-dimethylbenzyl)cyclohexanol
42-benzyl-1-(2-chloro-6-terbisil)-6-dimethylaminomethylphenol
52-benzyl-1-(4-Chlorobenzyl)-6-dimethylaminomethylphenol
62-benzyl-6-dimethylaminomethyl-1-(3-triptoreline)cyclohexanol
72-benzyl-6-dimethylaminomethyl-1-(2-methylbenzyl)cyclohexanol
82-benzyl-6-dimethylaminomethyl-1-(2-methoxyphenyl)cyclohexanol

Example No.The name of the connection
92-benzyl-1-(4-chloro-3-triptoreline)-6-dimethylaminomethylphenol
102-benzyl-1-(2-Chlorobenzyl)-6-dimethylaminomethylphenol
112-benzyl-1-(3,5-dichlorophenyl)-6-dimethylaminomethylphenol
122-benzyl-1-(3-chlorophenyl)-6-dimethylaminomethylphenol
132-benzyl-6-dimethylaminomethyl-1-(3-forfinal)cyclohexanol
142-benzyl-6-dimethylaminomethyl-1-(5-fluoro-2-methoxyphenyl)cyclohexanol
152-benzyl-1-cyclohexylmethyl-6-dimethylaminomethylphenol
162-benzyl-6-dimethylaminomethyl-1-(4-methoxyphenyl)cyclohexanol
172-benzyl-6-dimethylaminomethyl-1-p-taillecavat
182-benzyl-6-dimethylaminomethyl-1-(3-phenylpropyl)cyclohexanol
192-benzyl-6-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol
202-benzyl-6-dimethylaminomethyl-1-thiophene-2-illlogical
212-benzyl-6-dimethylaminomethyl-1-phenylalanylglycyl
222-benzyl-6-dimethylaminomethyl-1-(4-forfinal)cyclohexanol
232-benzyl-6-dimethylaminomethylene-1-ol
242-benzyl-6-dimethylaminomethyl-1-m-taillecavat
252-benzyl-1-(4-tert-butylphenyl)-6-dimethylaminomethylphenol
262-benzyl-6-dimethylaminomethyl-1-vinylcyclohexane
272-benzyl-6-dimethylaminomethyl-1-about-that is illlogical
282-benzyl-6-dimethylaminomethyl-1-(4-fluoro-3-were)cyclohexanol
291,2-dibenzyl-6-dimethylaminomethylphenol
302-benzyl-1-(4-chlorophenyl)-6-dimethylaminomethylphenol
312-benzyl-6-dimethylaminomethyl-1-phenylcyclohexanol
322-dimethylaminomethyl-1-(2,5-dimetilfenil)-6-(3-methoxyphenyl)cyclohexanol
331-cyclohexylmethyl-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
341-(2,4-dichlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
352-dimethylaminomethyl-6-(3-methoxyphenyl)-1-phenylalanylglycyl
362-dimethylaminomethyl-6-(3-methoxyphenyl)-1-o-taillecavat
371-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
382-dimethylaminomethyl-1-(3-forfinal)-6-(3-methoxyphenyl)cyclohexanol
392-dimethylaminomethyl-1-(3-fluoro-4-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol
401-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
412-dimethylaminomethyl is-1-(3-methoxybenzyl)-6-(3-methoxyphenyl)cyclohexanol
421-(4-chloro-3-triptoreline)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol

Example No.The name of the connection
431-(3,5-dichlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
442-dimethylaminomethyl-6-(3-methoxyphenyl)-1-phenylalanylglycyl
451-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
462-dimethylaminomethyl-6-(3-methoxyphenyl)-1-o-taillecavat
471-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol
482-dimethylaminomethyl-1-(2,5-dimethylbenzyl)-6-methylcyclohexanol
491-(2-chloro-6-terbisil)-2-dimethylaminomethyl-6-methylcyclohexanol
501-(4-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol
512-dimethylaminomethyl-6-methyl-1-(3-methylbenzyl)cyclohexanol
522-dimethylaminomethyl-6-methyl-1-(3-triptoreline)cyclohexanol
531-(2-chloro-3-forfinal)-2-dimethylaminomethyl-6-methylcyclohexanol
542-emailmyname-6-methyl-1-(2-methylbenzyl)cyclohexanol
552-dimethylaminomethyl-1-(2-methoxyphenyl)-6-methylcyclohexanol
562-dimethylaminomethyl-1-(3-terbisil)-6-methylcyclohexanol
572-dimethylaminomethyl-1(4-terbisil)-6-methylcyclohexanol
581-(2-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol
591-(3,5-dichlorophenyl)-2-dimethylaminomethyl-6-methylcyclohexanol
601-(3-chlorophenyl)-2-dimethylaminomethyl-6-methylcyclohexanol
612-dimethylaminomethyl-1-(3-forfinal)-6-methylcyclohexanol
622-dimethylaminomethyl-1-(3-fluoro-4-methoxyphenyl)-6-methylcyclohexanol
632-dimethylaminomethyl-1-(4-methoxyphenyl)-6-methylcyclohexanol
642-dimethylaminomethyl-6-methyl-1-p-taillecavat
652-dimethylaminomethyl-6-methyl-1-(3-phenylpropyl)cyclohexanol
662-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol
672-dimethylaminomethyl-6-methyl-1-thiophene-2-illlogical
682-dimethylaminomethyl-6-methyl-1-phenylalanylglycyl
692-dimethylene the o-methyl 6-methyl-1-fenetylline
702-dimethylaminomethyl-1-(4-forfinal)-6-methylcyclohexanol
711-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
722-dimethylaminomethyl-1-(4-fluoro-2-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol
732-dimethylaminomethyl-1-(2-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol
742-dimethylaminomethyl-1-(4-terbisil)-6-(3-methoxyphenyl)cyclohexanol
751-(3-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
762-dimethylaminomethyl-6-(3-methoxyphenyl)-1-p-taillecavat
772-dimethylaminomethyl-6-(3-methoxyphenyl)-1-(3-phenylpropyl)cyclohexanol

3-(3-dimethylaminomethyl-2-hydroxy-2-phenylcyclohexyl)phenol
Example No.The name of the connection
782-dimethylaminomethyl-1,6-bis-(3-methoxyphenyl)cyclohexanol
792-dimethylaminomethyl-6-(3-methoxyphenyl)-1-thiophene-2-illlogical
802-dimethylaminomethyl-6-(3-methoxyphenyl)-1-fenetylline
813-[3-dimethylaminomethyl-2-(4-forfinal)-2-hydroxycyclohexyl]phenol
82
833-[2-(4-tert-butylphenyl)-3-dimethylaminomethyl-2-hydroxycyclohexyl]phenol
843-(3-dimethylaminomethyl-2-hydroxy-2-vinylcyclohexane)phenol
851-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol
863-dimethylaminomethyl-2-(3-methoxyphenyl)bicyclohexyl-2-ol
872-benzyl-6-dimethylaminomethyl-1-(4-triptoreline)cyclohexanol
883-(2-benzyl-6-dimethylaminomethyl-1-hydroxycyclohexyl)phenol
893-(2-tert-butyl-6-dimethylaminomethyl-1-hydroxycyclohexyl)phenol

Pharmacological studies

In the analysis of binding used gabapentin order to identify the binding and the affinity of some of the invention compounds, selected as an example. The affinity of the compounds according to the invention was determined by the displacement of gabapentin from its binding site. If these compounds have the ability to displace gabapentin from its binding site, it can be expected that they are comparable with gabapentina pharmacological properties, for example, as active substances against pain or epilepsy. According to the NSS data specified analysis of the proposed invention compounds can effectively suppress gabapentin, i.e. to oust him. As was established during this biochemical analysis, the tested compounds possess, therefore, the affinity is not known up to the present time the binding site gabapentin.

The compound of exampleSuppression gabapentina %, 10 mcmole
8255
8148
7653
7554
4558

Study of analgesic efficacy in mice in the test for pain.

Analgesic efficacy of the compounds according to the invention was investigated in mice in the test on pain induced by familienaam (according to the modified method described in I.C. Hendershot and J. Forsaith in Journ. Pharmacol. Exp.Ther. 125 (1959), SS-240). For these purposes, as experimental animals used male NMRI mice weighing 25-30 g Groups of 10 animals each, were selected for testing one dose of the test substance in 10 min after intravenous injection of the test compound was intraperitoneally injected with the dose of 0.3 ml/mouse of a 0.02%aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; this solution is prepared by adding 5% ethanol and with exposure in leading the th bath at 45° C). Animals with the purpose of monitoring alone was placed in a special cell. Then through 5-20 min after injection of finishinga using a push-button counter counting the number of induced pain extensor movements (so-called behavioral response to pain, i.e. in this case, the bowing of the body with stretching of the hind limbs). As control was used animals that were injected only with saline salt.

In experiments with test compounds from some of the examples were determined by the number of animals that were appropriate response ("reacting animals"):

The compound of exampleReacting animals/control animals (pain)
8510/10 (46.4 mg/kg; intravenous)
863/10 (21,5 mg/kg; oral)
872/10 (10 mg/kg; intravenous)
882/10 (10 mg/kg; intravenous)
893/10 (10 mg/kg; intravenous)

1. Substituted derivatives of 1-aminobut-3-ol of General formula I

in which R1and R2together form a (CH2)2-9-ring

R3and 4each independently from each other represents C1-C6alkyl, which is branched or unbranched, saturated, unsubstituted; benzyl or phenethyl which is unsubstituted,

R5represents C1-C10alkyl, which is saturated or

unsaturated, branched or unbranched, unsubstituted; C3-C9cycloalkyl, which is saturated, phenyl or 5-membered possibly condensed with a benzene ring structurai heteroaryl, linked via a saturated or unsaturated C1-C3alkyl phenyl, linked via a saturated or unsaturated C1-C3alkyl, C3-C9cycloalkyl and linked via a saturated or unsaturated C1-Salkil 5-membered possibly condensed with a benzene ring structurai heteroaryl, where each of the aryl, heteroaryl and cycloalkyl residues independently of each other may be unsubstituted or one - or multi-substituted residues

independently from each other selected from the group comprising F, Cl, Br, I, OR18C1-C10alkyl, which is saturated or unsaturated, branched or unbranched and may be single - or multi-substituted by halogen atoms, with

R18not only is em a N, C1-C10alkyl, which is saturated, branched or unbranched, unsubstituted,

R6denotes H and

R7represents C1-C6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted, With3-C9cycloalkyl, which is saturated, unsubstituted; phenyl, which is unsubstituted or one - or multi-substituted, or linked via a saturated C1-C3alkyl phenyl which may be unsubstituted or one - or multi-substituted, the substituents can be independent selected from the group F, Cl, Br, I, OR18C1-C10alkyl, which is saturated or unsaturated, branched or unbranched, in free form or in the form of their physiologically acceptable salts.

2. Substituted derivatives of 1-aminobut-3-ol according to claim 1, wherein R1and R2together form a (CH2)2-5-ring.

3. Substituted derivatives of 1-aminobut-3-ol according to any one of claims 1 and 2, wherein R3and R4each independently from each other represents C1-C6alkyl, which is branched or unbranched, saturated, unsubstituted, preferably both represent CH3.

4. Substituted derivatives of 1-aminobutane-ol according to any one of claims 1 to 3, wherein R5represents C1-C6alkyl, which is saturated or unsaturated, branched or unbranched, unsubstituted; C5-C6cycloalkyl; phenyl, thiophenyl, benzothiophene, linked via a saturated or unsaturated C1-C3alkyl phenyl, linked via a saturated or unsaturated C1-C3alkyl, C3-C6cycloalkyl or linked via a saturated or unsaturated C1-C3alkyl thiophenyl, benzothiophene, where each of these aryl, heteroaryl and cycloalkyl residues independently of each other may be unsubstituted or one - or multi-substituted as indicated in claim 1, preferably R5denotes phenyl or thiophenyl, which are unsubstituted or one - or multiply substituted, preferably an atom of F, Cl, Br, I, HE, C1-C4the alkyl, C1-C6the alkyl, or linked via a saturated or unsaturated C1-C3alkyl phenyl, which is unsubstituted or one - or multiply substituted, preferably an atom of F, Cl, Br, I, HE, O-C1-C4the alkyl, C1-C6the alkyl, first of all

R5denotes phenyl, which is unsubstituted or one - or multiply substituted, preferably an atom of F, Cl, Br, I, a group About whom, Och3OS2H5OS3H7CH3C2H5With3H7and/or C4H9.

5. Substituted derivatives of 1-aminobut-3-ol according to any one of claims 1 to 4, characterized in that

R7represents C1-C6alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted; C5-C7cycloalkyl, which is saturated, unsubstituted, preferably cyclohexyl; phenyl, which is unsubstituted or one - or multi-substituted, or linked via a saturated or unsaturated C1-C3alkyl phenyl, which in each case is unsubstituted or one - or multi-substituted as indicated in claim 1, preferably

R7denotes phenyl, which is unsubstituted or one - or multi-substituted, or linked via a saturated or unsaturated C1-C3alkyl phenyl, which in each case is unsubstituted or one - or multi-substituted as indicated above.

6. Substituted derivatives of 1-aminobut-3-ol according to any one of claims 1 to 5, characterized in that, if R5and/or R7denote bound via saturated or unsaturated C1-C3alkyl phenyl, C3-C9cycloalkyl or heteroaryl, C1-C3 alkyl linked through the phenyl, heteroaryl or cycloalkyl and represents-CH2-, -C2H4-With3H6- ,- ≡C-, -CH=CH-, -CH=CH-CH2-, -CH2-CH=CH -,- ≡CH2- or-CH2With≡S-, preferably-CH2-, -C2H4or≡With-.

7. Substituted derivatives of 1-aminobut-3-ol according to any one of claims 1 to 7, characterized in that they are selected from the following group of compounds, including:

2-benzyl-1-(2,4-dichlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-1-(3-Chlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-(2,5-dimethylbenzyl)cyclohexanol,

2-benzyl-1-(2-chloro-6-terbisil)-6-dimethylaminomethylphenol,

2-benzyl-1-(4-Chlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-(3-triptoreline)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(2-methylbenzyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(2-methoxyphenyl)cyclohexanol,

2-benzyl-1-(4-chloro-3-triptoreline)-6-dimethylaminomethylphenol,

2-benzyl-1-(2-Chlorobenzyl)-6-dimethylaminomethylphenol,

2-benzyl-1-(3,5-dichlorophenyl)-6-dimethylaminomethylphenol,

2-benzyl-1-(3-chlorophenyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl is-1-(3-forfinal)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(5-fluoro-2-methoxyphenyl)cyclohexanol,

2-benzyl-1-cyclohexylmethyl-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-(4-methoxyphenyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-n-taillecavat,

2-benzyl-6-dimethylaminomethyl-1-(3-phenylpropyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol,

2-benzyl-6-dimethylaminomethyl-1-thiophene-2-illlogical,

2-benzyl-6-dimethylaminomethyl-1-phenylalanylglycyl,

2-benzyl-6-dimethylaminomethyl-1-(4-forfinal)cyclohexanol,

2-benzyl-6-dimethylaminomethylene-1-ol,

2-benzyl-6-dimethylaminomethyl-1-m-taillecavat,

2-benzyl-1-(4-tert-butylphenyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-vinylcyclohexane,

2-benzyl-6-dimethylaminomethyl-1-o-taillecavat,

2-benzyl-6-dimethylaminomethyl-1-(4-fluoro-3-were)cyclohexanol,

1,2-dibenzyl-6-dimethylaminomethylphenol,

2-benzyl-1-(4-chlorophenyl)-6-dimethylaminomethylphenol,

2-benzyl-6-dimethylaminomethyl-1-phenylcyclohexanol,

2-dimethylaminomethyl-1-(2,5-dimetilfenil)-6-(3-methoxyphenyl)cyclohexanol,

1-cyclohexylmethyl-2-dimethylaminomethyl is l-6-(3-methoxyphenyl)cyclohexanol,

1-(2,4-dichlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-phenylalanylglycyl,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-o-taillecavat,

1-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-forfinal)-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-fluoro-4-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol,

1-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-methoxybenzyl)-6-(3-methoxyphenyl)cyclohexanol,

1-(4-chloro-3-triptoreline)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

1-(3,5-dichlorobenzyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-phenylalanylglycyl,

1-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-o-taillecavat,

1-(3-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(2,5-dimethylbenzyl)-6-methylcyclohexanol,

1-(2-chloro-6-terbisil)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(4-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl is l-6-methyl-1-(3-methylbenzyl)cyclohexanol,

2-dimethylaminomethyl-6-methyl-1-(3-triptoreline)cyclohexanol,

1-(2-chloro-3-forfinal)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-6-methyl-1-(2-methylbenzyl)cyclohexanol,

2-dimethylaminomethyl-1-(2-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-terbisil)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(4-terbisil)-6-methylcyclohexanol,

1-(2-Chlorobenzyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3,5-dichlorophenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

1-(3-chlorophenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-forfinal)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(3-fluoro-4-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-1-(4-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-6-methyl-1-p-taillecavat,

2-dimethylaminomethyl-6-methyl-1-(3-phenylpropyl)cyclohexanol,

2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol,

2-dimethylaminomethyl-6-methyl-1-thiophene-2-illlogical,

2-dimethylaminomethyl-6-methyl-1-phenylalanylglycyl,

2-dimethylaminomethyl-6-methyl-1-fenetylline,

2-dimethylaminomethyl-1-(4-forfinal)-6-methylcyclohexanol,

1-(3-Chlorobenzyl)-2-dimethyl shall aminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(4-fluoro-2-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(2-methoxyphenyl)-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-1-(4-terbisil)-6-(3-methoxyphenyl)cyclohexanol,

1-(3-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-p-taillecavat,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-(3-phenylpropyl)cyclohexanol,

2-dimethylaminomethyl-1,6-bis-(3-methoxyphenyl)cyclohexanol,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-thiophene-2-illlogical,

2-dimethylaminomethyl-6-(3-methoxyphenyl)-1-fenetylline,

3-[3-dimethylaminomethyl-2-(4-forfinal)-2-hydroxycyclohexyl]phenol,

3-(3-dimethylaminomethyl-2-hydroxy-2-phenylcyclohexyl)phenol,

3-[2-(4-tert-butylphenyl)-3-dimethylaminomethyl-2-hydroxycyclohexyl]phenol,

3-(3-dimethylaminomethyl-2-hydroxy-2-vinylcyclohexane)phenol,

1-(4-chlorophenyl)-2-dimethylaminomethyl-6-(3-methoxyphenyl)cyclohexanol,

3-dimethylaminomethyl-2-(3-methoxyphenyl)bicyclohexyl-2-ol,

2-benzyl-6-dimethylaminomethyl-1-(4-triptoreline)cyclohexanol,

3-(2-benzyl-6-dimethylaminomethyl-1-hydroxycyclohexyl)phenol,

3-(2-tert-butyl-6-dimethylaminomethyl-1-hydroxycyclohexyl who yl)phenol,

in free form or in the form of their physiologically acceptable salts, primarily hydrochloride.

8. Drug with analgesic effect, containing at least one substituted derivative 1 aminobutane-3-ol according to any one of claims 1 to 7 optionally along with acceptable additives and/or auxiliary substances and/or optionally with other active ingredients.

9. The method of obtaining substituted derivative 1 aminobutane-3-ol according to any one of claims 1 to 7, namely, that β-aminoketone formula 1A

where R1-R4, R6and R7have the meanings indicated in claim 1 for formula I,

subjected to interaction with the ORGANOMETALLIC compound of formula III

in which Z denotes MgCl, MgBr, Mgl, or Li,

R5matter specified in claim 1 for formula I,

obtaining the result of the corresponding compounds of formula I.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to the field of pharmaceutical chemistry and synthetic organic chemistry and represents the asymmetric synthesis of the key intermediate compound in obtaining DULOXETINE - antidepressant tools

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel O-substituted derivatives of 6-methyltramadol of the general formula (I) being optionally as their racemates, their pure stereoisomers but primarily as enantiomers or diastereomers, or as mixtures of stereomers being primarily as enantiomers or disatereomers in any their ratio in the mixture as a presented formulation or as their physiologically compatible salts. In the general formula (I) the value R means hydrogen atom (H), (C1-C3)-alkyl that can be saturated or unsaturated, branched or a direct, unsubstituted or substituted with -O-(C1-C3)-alkyl-group or OH-group, -CH2-(C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl or thienyl group. Also, the invention relates to a method for synthesis of compounds of the general formula (I) by interaction of 2-dimethylaminomethyl-6-methylcyclohexanone of the formula (I) with metal-organic compound of the formula (III) wherein Z means Li; R has values given in the formula (I). The synthesized compounds of the formula (I) if necessary are converted to their physiologically compatible salts and/or racemates that are subjected for cleaving. Also, invention relates to a pharmaceutical composition.

EFFECT: improve method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 sch, 2 tbl, 30 ex

The invention relates to the chemistry of aminoalcohols, in particular, to an improved process for the preparation of tramadol - 2-dimethyl aminomethyl-1-(3-methoxyphenyl)cyclohexanol

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints

The invention relates to possess analgesic activity of new substituted Cycloheptane General formula I

in which R1IT denotes, O-C1-C6alkyl, R2represents C1-C6alkyl, (CH2)(1-2)-aryl, and R3means (CH2)(0-1)-C5-C7cycloalkyl, (CH2)(0-2)-aryl, and the rest of the aryl can be substituted one or more times, HE, F, Cl, CF3C1-C6the alkyl, in the form of their racemate or enantiomer, in the form of bases, and salts physiological acceptable acids

The invention relates to an improved process for the preparation of enantiomers of O-demethyltramadol, with a strong analgesic action, which unlike opioid analgesics has no known side effects

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to new application method for adamantine derivative, namely (3-hydroxy-1-adamantyl-)-1-ethylamine hydrochloride of formula I as inhibitor of 1-type herpes simplex virus reproduction. Said derivative is useful in inhibition of both sensitive and resistant to main antiherpes pharmaceuticals (e.g. acyclovir) virus strains. Substance of present invention has activity by 10-times higher than tromantadin and by 5-times higher than etmantin.

EFFECT: new antiherpes drug.

2 tbl, 2 ex

The invention relates to a method for producing derivatives benzothiophenes formula I, including the interaction of amerosport formula (II) or its salt with the compound of the formula (III) or its reactive derivative, the oxidation of the resulting product in the presence of 2,2,6,6-tetramethylpiperidine-1-oxide and then liaising with ridom in the conditions of a Wittig reaction with subsequent optional unprotect

The invention relates to new aralkylamines derivatives and their salts of interest as medicines, especially as a means of improving brain function, which can be shown senile dementia, Alzheimer's disease, etc

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present innovation deals with developing preparations based upon essential oils to treat inflammatory diseases of respiratory organs and motor system. The composition suggested contains chitosan and essential oils of different plants upon emulsion foundation. The method suggested could be applied as an additional remedy for external application at treating inflammatory diseases of respiratory organs, degenerative and inflammatory diseases of motor system. The composition is of high spectrum of action and prolonged analgesic effect.

EFFECT: higher efficiency of application.

11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation refers to medicinal preparations applied for treating puerperal purulent-catarrhal endometritis and mastitis in cows and to the method of applying the present medicinal preparations. The suggested preparation for treating puerperal purulent-catarrhal endometritis, serous, seroso-catarrhal and subclinical mastitis in cows includes 1.4-di-N-oxide 2.3-bis-(oxymethyl) quinoxaline, trecresan (cresacin), dimethyl sulfoxide, propandiol 1.2 at the following ratio, (g/%): 1.4-di-N-oxide 2.3-bis-(oxymethyl) quinoxaline 1.0-1.2; trecresan (cresacin) 3.0-3.18; dimethyl sulfoxide 10.0-10.5; propandiol 1.2 20-25; distilled water - the rest. The innovation deals with intra-uterine introduction of the preparation suggested at the dosage of about 70-100 ml once daily for about 4-5 d. Moreover, this preparation should be introduced into affected part of the udder at the dosage of 10 ml once daily for 3-5 d. The innovation enables to shorten the multiplicity of introduction and accelerate the terms of recovery.

EFFECT: higher efficiency of therapy.

4 cl, 2 ex, 6 tbl

FIELD: organic chemistry, amino acids.

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

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

Up!