1-phenyl-2-dimethylaminomethylene-1-olavie compounds, methods for their preparation and medicinal products based on them

 

(57) Abstract:

Describes the new 1-phenyl-2-dimethylaminomethylene-1-olavie compounds of General formula I where X is O or S, R1means H or hydroxy - or mercaptohexanol group that represents benzyl, dialkylanilines or trialkylsilyl, C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkyl or halogenated C1-C6alkyl, grouping refers to or R2means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkenyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, in the form of their bases or salts of physiologically acceptable acids. The compounds exhibit analgesic activity. Describes how they receive and the drug based on them for the treatment of severe pain and do not cause any side effects typical of Opodo. 5 S. and 6 C.p. f-crystals, 2 tab.

The invention relates to 1-phenyl-2 - dimethylaminomethylene-1-alowyn compounds, method of their production and to their use in medicines.

Treatment of chronic and nechanicky painful States plays in medicine vanwildanu opioid drugs, highly obezbolivajuschem treatment. The urgent need to implement practical measures targeted, taking into account individual patient treatment of chronic and nechanicky painful conditions, and must be taken into account successful and satisfactory for patients treating their pain, is reflected in a recent numerous scientific publications on applied analgesic, as well as fundamental studies of nociception.

Opioids used for many years for pain treatment, although they cause a number of side effects, such as psychological dependence, respiratory depression, inhibitory effects on the gastro-intestinal tract and constipation. For this reason, their use is permissible only when proper precautions, requiring special regulations, especially in cases, for example, when drugs are prescribed for a long period of time or in high dosage (see Goodman, Gilman's "The Pharmacological Basis of Therapeutics", published by Pergamon Press, new York, 1990).

Tramadolhydrochlorid, he (1RS,2RS)-2-dimethylaminomethyl-1-(3-methoxyphenol this active substance has a strong analgesic effect, not calling, unlike opioids, known side effects (see Journ. Pharmacol. Exp. Ther. 267. 331 (1993)). Tramadol is a racemate and consists of equal amounts of (+)- and (-)-enantiomers. In vivo this active substance forms a metabolite O-desmethyltramadol, also presented in the form of a mixture of enantiomers. Studies have shown that both enantiomers of tramadol and enantiomers of tramadol metabolites contribute to the achievement of analgesic effect (see Journ. Pharmacol. Exp. Ther. 260, 275 (1992)).

From the publication of An. Quim., 69 (7-8), 915-920 (1973) known 1,2,4,4-chetyrehskatnye cyclohexanone compounds used as antispasmodics.

In Belgium patent BE 616646 described 1,2,4,4-chetyrehskatnye cyclohexanone connection with antitussive effect.

In Arzneimittel-Forsch. 13, 991-999 (1963) describes 1,2,4-triple-substituted cyclohexanols compounds. Some of these compounds possess antispasmodic effect.

Underlying the invention, the task consisted in the development and creation of analgesic action of substances intended for treatment of severe pain and do not cause any side effects typical of opioids. In addition, with the in when treating tramadol, the manifestation of side effects, such as nausea and vomiting.

It was found that the requirements set forth in the creation of new substances that meet certain 1-phenyl-2-dimethylaminomethylene-1-olavie connection. These compounds differ analgesic action significantly superior in its effectiveness of tramadol. Thus they can be used under particularly severe painful conditions for which treatment the use of opioids, average efficiency is insufficient. Therefore, the compounds according to the invention can be administered in smaller doses, which reduces the possibility of non-specific side effects. In addition, thanks to a stronger analgesic effect can also open other applications in the field of analgesics that do not overlap with the average of its opioid effectiveness of action of tramadol, for example, balanced anesthesia or to reduce the strong and very strong pain in the preoperative period.

The subject of the invention in accordance with this are 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I

< / BR>
in which

X represents O or allogenically C1-C6alkyl, grouping

< / BR>
does

< / BR>
< / BR>
or

< / BR>
R2means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, in the form of their bases or salts of physiologically acceptable acids.

Preferred 1-phenyl-2-dimethylaminomethylene-1-Ola are compounds of the formula I, in which

R1means H, C1-C4alkyl, 2'-methyl-2'- propenyl, cyclopentyl or foretel, provided that R1is C1-C4the alkyl when X is S, and R2means C1-C4alkyl, C2-C4alkenyl, cyclopentylmethyl, phenyl, C1-C4alkoxyphenyl, benzyl, C1-C4alkylbenzene, one - or twofold halogenated phenyl, or mono - or doubly halogenated benzyl.

The compounds of formula I, in which

R1denotes H, methyl, ethyl, isopropyl, 2'-methyl-2'-propenyl, cyclopentyl or foretel, provided that R1is stands, if X is S, and

R2means methyl, propyl, 2'-methylpropyl, allyl, 2'-methyl-2'-propenyl, cyclopentylmethyl, phenyl, 3-methoxide occhialini 1-phenyl-2-dimethylaminoethoxy-1-elovich connections.

The most preferred 1-phenyl-2-dimethylaminomethylene-1-Ola formula I, in which

R1denotes H, methyl or cyclopentyl, provided that R1is stands, if X is S,

group

< / BR>
does

< / BR>
or

and

R2is cyclopentylmethyl, benzyl and 4-chlorbenzyl.

Among 1-phenyl-2-dimethylaminomethylene-1-elovich connections necessary to emphasize the compounds of formula I, in which

X is OH,

R1means H or methyl,

group

< / BR>
does

< / BR>
or

and

R2is benzyl.

1-phenyl-2-dimethylaminomethylene-1-olavie connection in the form of their diastereomers preferably have a configuration according to formula Ia

< / BR>
in which the phenyl ring and dimethylaminomethylene group are in the TRANS position relative to each other.

Another object of the invention is a method of obtaining a 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I in which X represents O or S,

R1means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkyl, halogenated C1SUP>2means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,

characterized in that chetyrehkolenny cyclohexane-1-it formula IIa

< / BR>
get in due to the fact that either the compound of formula IV

< / BR>
in which A represents a branched or unbranched balance CnH2nand n means an integer in the range from 2 to 6, first alkylate compound of formula III

R2-G

in which G represents Cl, Br, I or toluensulfonate, and then deacetylated by proton catalysis, or a compound of the formula V

< / BR>
where A has the above values, first alkylate using alcoholate derived from an alcohol of formula VI

R2-OH

and then through proton catalysis deacetylases to the compounds of formula IIA, then the obtained compound of the formula IIa interaction either with dimethylamine in the reaction of manniche or methylene chloride, dimethylamine transform in the compound of formula VIIa

< / BR>
which is using the ORGANOMETALLIC compound of formula VIII

< / BR>
where Q denotes MgCl, MgBr, MgI or Li, perevodjat adding in an inert, polar solvent, e.g. dimethylformamide, hydride, such as NaH or alcoholate, such as tert-butyl potassium, and subsequent introduction of additives the compounds of formula IV and mixing at temperatures in the range of 20oC to 60oC. Next add the compound of the formula III and alkylate at temperatures in the range of 20oC to 120oC. To obtain a ketone of formula IIa alkilirovanie compound of formula IV is dissolved in a simple ether, e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or hydrocarbons, and under stirring deacetylases using acids such as HCl, HBr, H2SO4(see Gray and others, Journ. Org. Chem. 35 (1970), 1525; Krepcho, etc., Journ. Org. Chem. 36 (1971), 146).

Another possibility of obtaining a ketone of formula IIA is the alkylation of the anion derived alcohol of the formula VI, in a polar, inert solvent, for example dimethylformamide, using the compounds of formula V and subsequent azetilirovanie. The reaction deacetylase also carried out in the above-described conditions. The alcoholate of the alcohol of formula VI is produced by interaction, for example, NaH, alcoholate, NaOH or KOH.

With the compound of the formula IIA at temperatures in the range 40oC to 1201-C4alcohols or acetic acid. Formaldehyde can be used in the form of a solution of formaldehyde or para-formaldehyde (see J. R. Hwu, etc., Journ. Chem. Soc., Chem. Commun. 1984, 721).

The ketone of formula VIIa as hydrochloride can also be obtained, if the ketone of formula IIa to expose interactions with the methylene chloride dimethylamine in an aprotic solvent, e.g. acetonitrile, at temperatures in the range of 20oC to 40oC.

The reaction between the ketone of formula VIIa and connection Grignard reagent of the formula VIII or organolithium compound of the formula VIII can be done in simple aliphatic esters, for example, diethyl ether and/or tetrahydrofuran, at temperatures from 30oC to 80oC. Organolithium compounds of the formula VIII, which can be used when carrying out the above reaction, can be obtained by the coupling of compounds of formula VIII, in which G denotes Cl, Br or I, for example, with a solution of n-utility/hexane due to the exchange of the halogen/lithium.

The subject invention is further a method of obtaining a 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I, in whichcycloalkyl, halogenated C1-C6alkyl, benzyl, diarylethylenes or trialkylsilyl, grouping

< / BR>
does

< / BR>
R2means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein chetyrehkolenny cyclohexane-1-it formula IIb

< / BR>
get in due to the fact that either the connection of the Grignard reagent of the formula IX

R2-CH2-Mg-Hal

in which Hal denotes Cl, Br or I, with the help of a ketone of the formula X

< / BR>
in which A represents a branched or unbranched balance CnH2nand n means an integer in the range from 2 to 6, transforming the compound of formula XI

< / BR>
and then from this compound by prothonotaries deacetylase get catasetinae formula XII

< / BR>
then the subsequent dehydration obtain the connection formula IIb, or a ketone of formula X using phosphorane formula XIII

R3P=CH-R2< / BR>
in which R is aryl, through reaction of the Wittig transform in the compound of formula XIV

< / BR>
then by proton transfer catalysis or by using the methylene chloride dimethylammonio transform in the compound of formula VIIb

< / BR>
which is using the ORGANOMETALLIC compound of the formula VIII, in which Q denotes MgCl, MgBr, MgI or Li, is transferred to the compound of formula I.

Another object of the invention is a method of obtaining a 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula 1, in which

X represents O or S,

R1means C2-C6alkyl, C2-C6alkenyl, C5-C7cycloalkyl, halogenated C1-C6alkyl, benzyl, diarylethylenes or trialkylsilyl, grouping

< / BR>
does

< / BR>
R2means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, wherein the compound of formula IIb, obtained similarly to the above method, in the presence of Pd - or Pt - catalyst hydronaut to get chetyrehjadernogo cyclohexane-1-it formula IIc.

< / BR>
then, the obtained compound of the formula IIc interaction either with dimethylamine in the reaction of manniche or methylene chloride, dimethylamine transform in the compound of formula VIIc

< / BR>
which is using the ORGANOMETALLIC compound of formula VIII is to alocate the interaction of the compounds of formula IX with the compound of the formula X in simple aliphatic or cyclic ethers, for example, in diethyl ether or tetrahydrofuran, at temperatures in the range from 30oC to 100oC. To enhance the yield of compound XI can be added, for example, 1,2-dibromethane. The removal acetamino group of the compounds of formula XI then get the corresponding compound of formula XII. Using formic acid, acetanhydride or chloride inorganic acid compound of formula XII at temperatures in the range of 20oC to 120oC transform in the olefin mixture. From this olefin mixture of the compound of formula IIb can be isolated by known methods of separation, for example by column chromatography.

If necessary, the entire olefin mixture in the presence of Pt or Pd catalyst can gidrirovanii in acetic acid or in pravarasena or branched C1-C4alcohol when 1-100 ATM and in the temperature range of 20oC to 100oC to obtain the compounds of formula IIc (see Shiotani, etc., Chem. Pharm. Bull., 20, (1972), 277).

Another possibility of obtaining the compounds of formula IIb or IIc is conversion of the ketone of formula X by reaction of the Wittig using phosphorane formula XIII, in which R is aryl, such as phenyl, the compound of formula XIV. Aprimer, toluene in the temperature range from 50oC to 110oC. the resulting compound of formula XIV deacetylases and dehydration as described above. The compound obtained of the formula IIb if necessary, you can gidrirovanii to the compounds of formula IIc.

Another object of the invention is a method of obtaining a 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I, in which

X represents O or S,

R1represents H,

group

< / BR>
does

< / BR>
< / BR>
or

< / BR>
R2means C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, and the method is characterized by the fact that either the compound of formula I, in which R1is stands, is subjected to the interaction with the hydride diisobutylaluminum, or a compound of the formula I, in which R1is benzyl, hydronaut in the presence of Pt - or Pd-catalyst, or a compound of the formula I, in which R1is diarylethylenes or trialkylsilyl, hydrolyzing or subjected to interaction with fluoride, Tetra-n-butylamine.

The reaction between the compound of formula I, in kotoroy solvents, for example, in toluene, in the temperature range from 60oC to 130oC.

Hydrogenation of the compounds of formula I in which R1is benzyl, and X is Oh, carry out usually in the presence of Pt - or Pd-catalyst in acetic acid or in a branched or non-branched C1-C4alcohol when 1-100 atmospheres and temperatures in the range of 20oC to 50oC.

If the starting compound is used as a compound of the formula I, in which R1is diarylethylenes or trialkylsilyl residue, preferably tert-butyldimethylsilyl or tert-butyldiphenylsilyl, using acids, for example, diluted hydrochloric acid or fluoride, Tetra-n-butylamine, otscheplaut silyl group.

The subject invention is further a method of obtaining a 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I, in which

X represents O or S,

R1means H, C1-C6alkyl, C2-C6alkenyl, C5-C7cycloalkyl, halogenated C1-C6alkyl, benzyl, diarylethylenes or trialkylsilyl, grouping

< / BR>
does

< / BR>
< / BR>
or

< / BR>
R2means C1-C6 is substituted or unsubstituted benzyl, characterized in that a ketone of formula XV

< / BR>
in which A represents a branched or unbranched balance CnH2nand n means an integer in the range from 2 to 6, the interaction with the methylene chloride dimethylammonio transform-dimetilaminometil formula XVI

< / BR>
from which then, using ORGANOMETALLIC compound of the formula VIII, in which Q denotes MgCl, MgBr, MgI or Li, obtain the connection formula XVII

< / BR>
then driving through catalysis deacetylases to the compounds of formula XVIII

< / BR>
and then either the resulting compound of formula XVIII to restore 4-hydroxy formula XIX

< / BR>
from which subsequent formation of the alcoholate and the interaction with the compound of the formula III in which G represents Cl, Br, I or toluensulfonate receive compound of the formula I, in which groups

< / BR>
does

< / BR>
either the compound obtained of the formula XVIII interaction with the compound of the formula XX

< / BR>
in which n denotes an integer from 1 to 3, transforming the compound of formula I, in which groups

< / BR>
does

< / BR>
which if necessary hydronaut to obtain compounds of the Fort is tylenchida dimethylammonio obtaining - dimetilaminokhalkona with spiritlessly acetaldol structure of formula XVI is carried out usually in acetonitrile at acetylchloride catalysis. Then, the resulting compound of formula XVI interaction with the ORGANOMETALLIC compound of formula VIII in simple aliphatic or cyclic ethers, e.g. diethyl ether or tetrahydrofuran, at temperatures in the range from 30oC to 80oC transform in the compound of formula XVII. To enhance the yield of the compounds of formula XVII can be added, for example, 1,2-dibromethane.

The resulting compound of formula XVII is dissolved in a simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or hydrocarbons. Then, using acids such as HCl, HBr or H2SO4, spirocycles acatalog group under stirring otscheplaut, obtaining in this way a compound of formula XVIII. Subsequent recovery of the compounds of formula XVIII to the 4-hydroxy of the formula XIX can be carried out using a complex hydride of an alkali metal, preferably sodium borohydride or lithium aluminum hydride, in an organic solvent, for example tetrahydrofuran, diethyl ether and/or C2-C4Akilova sitiawan ether, using an alkali metal hydride, e.g. sodium hydride, can be obtained 4-alcoholate compound of formula XIX, which subsequent interaction with the compound of the formula III at temperatures in the range 40oC to 100oC transform in the compound of the formula I, in which groups

< / BR>
does

< / BR>
Another possibility of obtaining from compounds of formula XIX compounds of formula I in which the grouping.

< / BR>
does

< / BR>
is the reaction Horner-Emmons with the compound of the formula XX, in which n means preferably the number 2, in a solvent, such as dimethylformamide, at temperatures in the range of 0oC to 20oC.

Carried out, if necessary, subsequent reaction of the hydrogenation of the compounds of formula I, in which groups

< / BR>
does

< / BR>
obtaining the compounds of formula I, in which groups

< / BR>
does

< / BR>
carried out in the presence of Pt - or Pd-catalyst in acetic acid or in pravarasena or branched C1-C4alcohol when 1-100 atmospheres and temperatures in the range of 20oC to 100oC.

The compounds of formula I according to the present invention is syshestvyut by known methods.

Proposed according to the invention compounds with physiologically acceptable acids, 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 and/or aspartic acid, can be translated by well-known methods in their salts. The salt formation reaction carried out preferably in a solvent, e.g. diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone and/or 2-butanone. To obtain hydrochloride can be used, in addition, trimethylchlorosilane in the presence of water in one of the above solvents.

Proposed according to the invention compounds have a pronounced analgesic effect and toxicologically safe. You can apply them so as pharmaceutical active substances. The subject invention accordingly is also the use of 1-phenyl-2-dimethylaminomethylene-1-elovich compounds of the formula I as active ingredients in the re with one 1-phenyl-2-dimethylaminomethylene-1-alowyn compound of formula I of the medicinal product according to the invention also contain media fillers, solvents, diluents, dyes and/or binders. The choice of these auxiliary substances, as well as the used amount depend on the route of administration of the medicinal product, i.e., designate whether its for oral, intravenous, intraperitoneal, intradermal, intramuscular, vnutripuzarnogo, buccal or topical administration, for example, skin infections, mucous membranes and eyes. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, medicines and syrups; for parenteral, local, and inhalation can be applied solutions, suspensions, easily reconstructed dry compositions, as well as aerosols. As examples preparative forms designed for percutaneous introduction, you can call connection according to the invention in a depot in a soluble form or in a plaster, optionally with the addition of tools to facilitate skin penetration. From the insertion oral route or through the skin preparative form release compounds according to the invention may be gradual. The preferred form of use of medicines according to the invention is intravenous.

Naenia, from the evidence and the severity of the disease. Usually prescribed dosage from 1 to 200 mg of at least one 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I.

Examples

If not specified, the used petroleum ether with a boiling point of 50 to 70oC. the Term "simple ether" means diethyl ether.

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

Ratio in mixtures of eluents for all chromatographic methods indicated in all cases in volume (volume/volume).

The racemate separation was performed on a column Chiracel OD company Daicel Chemical Industries, LTD.

CT means room temperature, tPLmeans melting point.

Example 1

(1RS,2RS,4SR)-4-benzyloxy-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (1)

2,42 g magnesium turnings (100 mmol) was stirred in 25 ml of tetrahydrofuran and was added dropwise to 12.7 ml (100 mmol) of 1-bromo-3-methoxybenzene dissolved in 64 ml of tetrahydrofuran. Then for 1 h was boiled under reflux, then cooled to 5-10oC. Then, at this temperature for Kaplan-723), dissolved in 65 ml of tetrahydrofuran. Then for 1 h, stirred at room temperature, cooled to 5 to 10oC and a solution of Grignard reagent was decomposed by addition of 110 ml of 20% aqueous solution of ammonium chloride. The reaction mixture was diluted with 180 ml of a simple ester, after which the phases were separated. The aqueous phase was twice extracted with 180 ml of simple ether, dried over sodium sulfate and the solvent was removed by distillation. The residue (25 g) was applied on the column h cm, filled with silica gel, and was first suirable simple ether-n-hexane in the ratio of 1:1, and then a simple ether-n-hexane in a ratio of 3: 1. In this way got to 10.9 g of pure base, which was dissolved in a mixture of simple ether-2-butanone and mixed with water trimethylchlorosilane. The result was obtained 10.6 g of crystalline hydrochloride (1).

Yield: 53% of theory.

Melting point: 156-158oC.

Example 2

Enantiomers hydrochloride (1):

(1S,2S,4R)-4-benzyloxy-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride [(-)1] and

(1R,2R,4S)-4-benzyloxy-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride [(+)1]

From the compound (1) using a mixture of dichloromethane-caustic soda released base, the solution was dried and donovania compounds [(-)1] and [(+)1], which was dissolved in 2-butanone and mixed with water trimethylchlorosilane. In this way received hydrochloride.

[(-)1]: Exit: 42.8% of theory

Melting point: 212-214oC

[]KDT= 20.5 andC (water=1)

[(+)1]: Yield: 40% of theory

Melting point: 213-215oC

[]KDT= 21,8(water=1).

Example 3

(1RS,2RS,4SR)-4-benzyloxy-2-dimethylaminomethyl-1-(methoxyphenyl)cyclohexanol, hydrochloride (2)

1-bromo-3-ethoxybenzoyl were subjected to interaction with 4-benzyloxy-2-dimethylaminomethylene under the conditions described in example 1. The resulting base was purified on silicagel column simple ether-methanol 6:1; and then was dissolved in 2-butanone and mixed with water trimethylchlorosilane. Thus obtained compound (2) with a yield of 43% of theory.

Melting point: 205-207oC.

Example 4

(1RS, 2RS, 4SR)-4-benzyloxy-2-dimethylaminomethyl-1-(3-isopropoxyphenyl)cyclohexanol, hydrochloride (3)

1-bromo-3-isopropoxybenzoic were subjected to interaction with 4-benzyloxy-2-dimethylaminomethylene under the conditions described in example 1. The resulting base was purified on silicagel to what methylchlorosilanes. Thus obtained compound (3) with the release of 35% of theory.

Melting point: 166-167oC.

Example 5

(1RS, 2RS, 4SR)-4-benzyloxy-2-dimethylaminomethyl-1-[3-(2-methylacrylate)phenyl] cyclohexanol, hydrochloride (4)

1-bromo-3-(2-methylacrylate)benzene obtained by alkylation of 1-bromo-3-hydroxybenzoyl 3-chloro-2-methyl-1-propene were subjected to interaction with 4-benzyloxy-2-dimethylaminomethylene in conditions described in example 1. The resulting base was purified on silicagel column simple ether-methanol 9:1) which was dissolved in simple ether and mixed with water trimethylchlorosilane. Thus obtained compound (4).

Yield: 33% of theory.

Melting point: 166-167oC.

Example 6

(1RS, 2RS, 4SR)-3-(4-benzyloxy-2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol hydrochloride (5)

(3 bromophenoxy)tert-butyldimethylsilyl were subjected to interaction with 4-benzyloxy-2-dimethylaminomethylene in conditions described in example 1. The resulting base was purified on silicagel column acetic ether. Then silyl protective group was tsalala with diluted hydrochloric acid and then it is carbonated is hydrofuran and was mixed with concentrated hydrochloric acid. Thus obtained compound (5) with a total yield of 47% of theory.

Melting point: 245-247oC.

Example 7

(1RS, 2RS, 4SR)-4-benzyloxy-2-dimethylaminomethyl-1-(3-methylsulfinylphenyl)cyclohexanol, hydrochloride (6)

1-bromo-3-methylsulfonylbenzoyl were subjected to interaction with 4-benzyloxy-2-dimethylaminomethylene in conditions described in example 1, but differs in that the solvent used here is a simple ether, and to enhance the yield in the reaction mixture was added 1,2-dibromethane. The resulting base was purified on silicagel column, n-hexane, diisopropyl ether and simple ether, then dissolved in a mixture of 2-butanone is a simple ether and mixed with water trimethylchlorosilane. In this way received a crystalline compound (6) with a yield of 43% of theory.

Melting point: 194-198oC (decomposition).

Example 8

The enantiomers of the compound (6):

(1S, 2S, 4R)-4-benzyloxy-2-[(dimethylamino)methyl]-1-(3-methylsulfinylphenyl)cyclohexanol, hydrochloride [(-)6]

and

(1R, 2R, 4S)-4-benzyloxy-2-[(dimethylamino)methyl]-1-(3-methylsulfinylphenyl)cyclohexanol, hydrochloride [(+)6]

From the compound (6) using methylene chloride/in which the cosmology vacuum then the racemate was separated by chiral ghud - hand column. The result has been the Foundation of the compounds [(-)6] and [(+)6], which was dissolved in 2-butanone and small amounts of diisopropyl ether and mixed with water trimethylchlorosilane. In this way received hydrochloride.

[(-)6]: Exit: 57% of theory.

Melting point: 195-196oC

[]KDT= -19(water=1)

[(+) 6]: Output: 50% of theory.

Melting point: 194-194,5oC

[]KDT= 20(water=1).

Example 9

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-(3-methoxybenzyloxy)-1-(3-methoxyphenyl)cyclohexanol) hydrochloride (7)

Stage 1

4-(3-methoxybenzyloxy) cyclohexanone (8)

4.4 g of 60% sodium hydride in mineral oil (of 0.11 mol) was stirred in 35 ml of absolute dimethylformamide under nitrogen atmosphere. Then was dissolved to 15.7 g (0.1 mole) of 1,4-dioxaspiro [4.5] Decan-8-ol in 65 ml of dimethylformamide. This solution was added dropwise to a suspension of sodium hydride. Then was added 16 ml of 1-chloromethyl-3-methoxybenzene (of 0.11 mole) dissolved in 25 ml of dimethylformamide. Within 30 min was stirred at 60oC, was poured on ice, extracted with simple ether and dried the Ala was stirred for 1 h with a mixture of 190 ml of tetrahydrofuran and 50 ml of concentrated hydrochloric acid. Next was diluted with a saturated solution of sodium chloride, the phases were separated, was extracted with simple ether and dried. After removal by distillation of the solvent the obtained compound (8) was purified on silicagel column diisopropyl ether.

Yield: 14 g (60% of theory).

Stage 2

2-dimethylaminomethyl-4-(3-methoxybenzyloxy)cyclohexanone (9)

of 11.8 g (50 mmol) of the compound (8), 0.84 g (28 mmol) of paraformaldehyde and 2.26 g (28 mmol) of dimethylamine, hydrochloride, was dissolved in 20 ml of acetic acid for 15 min was stirred in a bath at a temperature of 105oC. After evaporation of the solvent was determined using a sodium hydroxide alkaline pH value and the basis of mannia was extracted with dichloromethane. The solution was dried and the solvent drove away. In this way got to 12.1 g of 80% of theory, of the compound (9).

Stage 3

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-(3-methoxybenzyloxy)-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (7)

The connection manniche (9) were subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The mixture of bases (the substituent in position 4 of the CIS and TRANS with respect to IT) was filed on silicagel column and sequentially swirling column simple ether-methanol 7:1, was dissolved in 2-butanone and mixed with water trimethylchlorosilane, adding if necessary a simple ether. The result obtained CIS-form compound (7) with the release of 7.5% and a melting point of 151-153oC and TRANS-form compound (7) with a yield of 20% from theory and the melting point of 133-135oC.

Example 10

(1RS,2RS,4SR)-4-allyloxy-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (10)

Stage 1

8 allyloxy-1,4-dioxaspiro [4.5] decane (11)

23.7 g (150 mmol) of 1,4-dioxaspiro [4.5] Decan-8-ol was dissolved in 120 ml of absolute dimethylformamide under nitrogen atmosphere. After you have added 7.9 g of 50% sodium hydride in mineral oil (165 mmol) was stirred at 20oC for 1 h After addition of 14.3 ml allylbromide (165 mmol) was heated to 70oC and was stirred for 1 h Then was mixed with 160 ml of water and 10-15oC was extracted three times with simple ether, washed once with water and once with saturated sodium chloride solution and dried over sodium sulfate. After removal by distillation of the solvent was obtained 24 g of the crude product (81% of theory).

Stage 2

4-aryloxyalkanoic (12)

of 19.8 g (0.1 mol) of the compound (11 ) was mixed with 120 ml of simple ether and 40 ml 6H which was extracted with simple ether and the ether solution was dried over sodium sulfate. After removal by distillation of the solvent was obtained 15.2 g of the crude product, which was purified on silicagel column diisopropyl ether-n-hexane 3:1.

Yield: 12.8 g (83% of theory).

Stage 3

4 allyloxy-2-dimethylaminomethylene, hydrochloride (13)

15.5 g (100 mmol) of the compound (12), 1.5 g (50 mmol) of paraformaldehyde and 4.1 g (50 mmol) of dimethylamine, hydrochloride, stirred in 30 ml of acetic acid for 25 min in a bath at a temperature of 105oC. Acetic acid is kept under vacuum and the residue was dissolved in 110 ml of 2-butanone. In the received connection (13) yield 77% of theory and the melting point 125-127oC.

Stage 4

(1RS,2RS,4SR)-4-allyloxy-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (10)

The base (13) were subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column simple ether-diisopropyl ether 1:4 and was dissolved in a mixture of 2-butanone is a simple ether 1:1. After adding water trimethylchlorosilane received the compound (10) with the release of 37% of theory.

Melting point: 88-94oC.

Example 11

(1RS, 2RSBR> 8-(2-methylacrylate)-1,4-dioxaspiro [4.5] decane (15)

In conditions described in example 1 to obtain compound (15) was carried out by the interaction between 1,4-dioxaspiro [4.5] decane-8-I and 2-methylacrylamide. The obtained compound (15) was purified on silicagel column diisopropyl ether-n-hexane 1:2. In the received connection (15) in the form of a light oil with a yield of 81% of theory.

Stage 2

4-(2-methylacrylate) cyclohexane (16)

Cleavage of the acetal compound (15) was carried out in conditions described in example 10, step 2. The obtained compound (16) was purified on silicagel column diisopropyl ether-n-hexane 2: 1. In the received connection (16) in the form of an oil with a yield of 62% of theory.

Stage 3

2-dimethylaminomethyl-4-(2-methyl-2-allyloxy) cyclohexanone, hydrochloride (17)

In conditions described in example 10, step 3, was carried out by reaction of manniche connection between (16) and dimethylamine, hydrochloride. 2-butanone received the compound (17) with 38% of theory. Melting point: 111-112oC.

Stage 4

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-4-(2-methyl-2-allyloxy)cyclohexanol, hydrochloride (14)oxybenzone. The resulting base was purified on silicagel column acetic ether-methanol 1:1 and dissolved in a simple ether. After adding water trimethylchlorosilane received the compound (14) with the release of 36% of theory.

Melting point: 112-114oC.

Example 12

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-(2-methyl-2-allyloxy)-1-[3-(2-methyl-2-allyloxy)phenyl]cyclohexanol, hydrochloride (18)

The ground connection (17) and 1-bromo-3-(2-methylacrylate) benzene was subjected to interaction in the conditions corresponding to the one described in example 1. The crude product was applied on silicagel column and suirable diisopropyl ether-simple ether. The obtained relative position 1 epimeno the mixture was divided by jhud on CIS - and TRANS-diastereoisomers and then was dissolved in a mixture of 2-butanone/diisopropyl ether. After adding water trimethylchlorosilane received the compound (18) with the release of 18% of theory.

Melting point: 151-152,5oC.

Example 13

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-(2-methyl-2-allyloxy)-1-(3-methylsulfinylphenyl)cyclohexanol, hydrochloride (19)

The ground connection (17) and 1-bromo-3-methylsulfonylbenzoyl were subjected to interact under conditions that meet the and to enhance the yield in the reaction mixture was added 1,2-dibromethane. The crude product was purified on silicagel column diisopropyl ether-simple ether 1:1 and dissolved in acetic ether. After adding water trimethylchlorosilane received connection (19)to yield 40% of theory.

Melting point: 146-150oC.

Example 14

(1RS,2RS,4SR)-2-dimethylaminomethyl-4-isobutoxy-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (20)

Stage 1

4-isobutoxyethanol (21)

of 16.9 g (0.1 mole) of the compound (16) was dissolved in 90 ml of methanol. After adding 1.8 g of palladium on coal (Pd content 10%) carried out the hydrogenation at room temperature and normal pressure. Then the catalyst was removed and the solvent is kept under vacuum. Received 15 g of the crude product was stirred with 60 ml of simple ether and 30 ml 4H hydrochloric acid for 1 h at room temperature. Then was neutralized with sodium hydrogen carbonate, the ether phase was separated and was extracted twice with simple ether. The ether solution was dried over sodium sulfate and the ether drove away. Received of 10.5 g of oil was purified on silicagel column diisopropyl ether-hexane 1:1. The result has been 6,85 g of compound (21) to yield 40% of theory.

Stage 2

2-dimethylamine is nom, the hydrochloride, in the conditions corresponding to the one described in example 10, step 3. 2-butanone received the compound of formula (22) to yield 53% of theory.

Melting point: 113-115oC.

Stage 3

(1RS,2RS,4SR)-2-dimethylaminomethyl-4-isobutoxy-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (20)

The basis of the compound (22) was subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column acetic ether-methanol 1:1 and dissolved in a simple ether. After adding water trimethylchlorosilane received connection (20) with 38% of theory.

Melting point: wing 112-116oC.

Example 15

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-isobutoxy-(3-methylsulfinylphenyl)cyclohexanol, hydrochloride (23)

Compound (22) was subjected to interaction with 1-bromo-3-methylsulfonylbenzoyl in conditions described in example 1. In contrast to the conditions specified in the solvent used here is a simple ether, and to enhance the yield was added 1,2-dibromethane. The crude product was purified on silicagel column diisopropyl ether and dissolved in a mixture of tetrahydrofuran-Sosnovo ether. Thus obtained compound (23) with the release of 32% of theory.

Melting point: 120-122oC.

Example 16

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-4-phenoxethanol, hydrochloride (24)

Stage 1

8 phenoxy-1,4-lexapro [4.5] decane (25)

440 mg of 60% sodium hydride in mineral oil (0.12 mmole) was stirred in 9 ml of absolute dimethylformamide under nitrogen atmosphere. First was added 1.1 g (0.12 mmole) of phenol, and then 3.1 g (10 mmol) of 1,4-dioxaspiro [4.5] Dec-8-silt ester toluene-4-sulfonic acid (see Gray and others, Journ. Org. Chem., 35 (1970), 1525-1533), dissolved in 6 ml of dimethylformamide. Within 2 h, stirred at a temperature in the range from 80oC to 85oC. After cooling, the reaction mixture was poured on ice, extracted with simple ether, the solution washed with dilute sodium hydroxide and dried with sodium sulfate. After evaporation of the solvent the crude product was purified on silicagel column diisopropyl ether. The result obtained 1.27 g (54% of theory) of the compound (25) in the form of butter.

Stage 2

4-penicillamine (26)

of 11.7 g (50 mmol) of 8-phenoxy-1,4-dioxaspiro [4.5] decane (25) was dissolved in 250 ml of a simple ester. Under stirring was added at night. After then a phase separation was extracted with simple ether, washed with saturated sodium chloride solution, dried over sodium sulfate and drove the solvent. The result obtained 9 g (91% of theory) of the compound (26).

Stage 3

2-dimethylaminomethyl-4-penicillamine, hydrochloride (27)

9.5 g (50 mmol) 4-penicillamine (26), 0,765 g (25 mmol) of paraformaldehyde and of 2.08 g (25 mmol) of dimethylamine, hydrochloride was heated in 17 ml of acetic acid for 20 min in an oil bath at a temperature of 105oC. the solvent is Then kept under vacuum, the residue was twice mixed with 2-butanone, followed by a 2-butanone was removed by distillation under vacuum. The obtained salt was dissolved in 30 ml of 2 - butanone. The result has received 2.85 g of the compound (27) to yield 40% of theory.

Melting point: 104-106oC.

Stage 4

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-4-phenoxethanol, hydrochloride (24)

The basis of the compound (27) was subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column acetic ether-methanol 6:1 and dissolved in 2-butanone. After adding aq is SUP>oC.

Example 17

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-ethoxyphenyl)-4-phenoxethanol, hydrochloride (28)

The basis of the compound (27) was subjected to interaction with 1-bromo-3-ethoxybenzyl in conditions described in example 1. The resulting base was purified on silicagel column acetic ether-methanol 6:1 and dissolved in 2-butanone. After adding water trimethylchlorosilane received the compound (28) with the release of 49% of theory. Melting point: 237-239oC.

Example 18

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-isopropoxyphenyl)-4-phenoxethanol, hydrochloride (29)

The basis of the compound (27) was subjected to interaction with 1-bromo-3-propoxybenzene in conditions described in example 1. The resulting base was purified on silicagel column acetic ether-methanol 6:1 and dissolved in 2-butanone. After adding water trimethylchlorosilane received the compound (29) with 38% of theory.

Melting point: 200-202oC.

Example 19

(1RS, 2RS, 4SR)-3-(2-dimethylaminomethyl)-1-hydroxy-4-phenoxytoluene) phenol hydrochloride (30)

The basis of the compound (27) was subjected to interaction with 1-bromo-3-benzyloxybenzyl in terms coatetelco 50% of theory (crude product). Then was dissolved in methanol was added palladium on coal (Pd content 10%) and benzyl group was tsalala by hydrogenation at room temperature under normal pressure. The resulting base was purified on silicagel column acetic ether-methanol 6:1 and dissolved in 2-butanone. After adding water trimethylchlorosilane received the connection (30) to yield 50% of theory.

Melting point: 220-222oC.

Example 20

(1RS,2RS,4SR)-2-dimethylaminomethyl-1- [3-(2-methylacrylate)phenyl]-4-phenoxethanol, hydrochloride (31)

The basis of the compound (27) was subjected to interaction with 1-bromo-3-(2-methylacrylate) benzene in conditions described in example 1. The resulting base was purified on silicagel simple column with ether, and dissolved in 2-butanone. After adding water trimethylchlorosilane received the compound (31) in 51% yield from theory.

Melting point: 193-195oC.

Example 21

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-(3-methoxyphenoxy)-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (32)

Stage 1

4-(3-methoxyphenoxy)cyclohexanone (33)

3-methoxyphenol were subjected to interaction with 1,4-dioxaspiro [4.5] Dec-8-silt ester toluene-4-sulfonatophenyl acetal under conditions described in example 16, step 2. The resulting ketone was purified on silicagel column diisopropyl ether. The result obtained compound (33) with a yield of 57% of theory.

Stage 2

2-dimethylaminomethyl-4-(3-methoxyphenoxy)cyclohexanone (34)

The compound (33) was subjected to interaction with diethylamino, hydrochloride, in the conditions corresponding to the one described in example 16, step 3. For further processing acetic acid drove away, the residue was dissolved in water and was extracted with simple ether. Using caustic soda has established an alkaline pH value of the aqueous phase and the product was extracted with dichloromethane. The solvent was removed by distillation and the obtained compound (34)in the form of a CIS-TRANS mixture to yield 50% of theory.

Stage 3

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-4-(3-methoxyphenoxy)-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (32)

Compound (34) was subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. Epimeno mixture in relation to the position 1 of the reasons was sequentially purified on silicagel column diisopropyl ether and acetic ether. Then the fraction enriched in CIS-form was purified on silicagel simple column e is connected (32) (position 4 CIS relative to IT)with the release of 10% of theory.

Melting point: 208-210oC.

Example 22 (1RS,2RS,4SR)-4-benzyl-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol, hydrochloride (35)

Stage 1

4-benzyl-2-dimethylaminomethylene, hydrochloride (36)

4-benzylchloride were subjected to interaction with dimethylamine, hydrochloride, in the conditions corresponding to the one described in example 10, step 3. Thus obtained compound (36) in crystalline form with the release of 50% of theory.

Melting point: 136-138oC.

Stage 2

(1RS, 2RS, 4SR)-4-benzyl-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol, hydrochloride (35)

The ground connection (36) were subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column simple ether-methanol 7:1 and dissolved in a simple ether. After adding water trimethylchlorosilane received the compound (35) with the yield 55% of theory.

Melting point: 138-142oC.

Example 23

(1RS, 2RS, 4SR)-3-(4-benzyl-2-dimethylaminomethyl-1-hydroxycyclohexyl)phenol hydrochloride (37)

Stage 1

4-benzyl-1-(3-benzyloxyphenyl)-2-dimethylaminomethylphenol (38)

Asianam in example 1. The resulting base was purified on silicagel column simple ether-methanol 7:1, resulting in the connection (38) yield 76% of theory.

Stage 2

(1RS,2RS,4RS)-3-(4-benzyl-2-dimethylaminomethyl-1-hydroxycyclohexyl) phenol hydrochloride (37)

Compound (38) was dissolved in methanol. After addition of palladium on coal (Pd content 10%) carried out the hydrogenation at room temperature and normal pressure. After filtering off the catalyst and removal by distillation of the solvent was dissolved in a simple ether. The subsequent addition of water trimethylchlorosilane received hydrochloride. After recrystallization from aqueous 2-butanone received the compound (37) with a yield of 61% of theory.

Melting point: 187-192oC.

Example 24

(1RS,2RS,4SR)-3-[2-dimethylaminomethyl-1-hydroxy-4-(4-methylbenzyl)cyclohexyl]phenol hydrochloride (39)

Stage 1

4-hydroxy-4-(4-methylbenzyl)cyclohexanone (40)

To 2.9 g (120 mmol) of magnesium turnings was added dropwise a small amount of the solution of 22.2 g (120 mmol) of 1-bromacil-4-methylbenzene in 80 ml of a simple ester. After start of the reaction of the Grignard reagent was added to the residual solution and within 30 min boiled under reflux. The ZAT she dissolved in 35 ml of tetrahydrofuran and 70 ml of a simple ester. Then within 2 hours and boiled under reflux. After cooling to 0 to 10oC was added 80 ml of a 20% aqueous solution of ammonium chloride and the phases were separated. Then was extracted with simple ether, dried over sodium sulfate and the solvent was removed by distillation. The result has been 27.5 g of the crude product, which was dissolved in 300 ml of simple ether was mixed with 200 ml policecontributing hydrochloric acid and was stirred for 3 h at room temperature. Then was diluted with a saturated solution of salt. After separation of the phases was extracted with simple ether and dried over sodium sulfate. In the end drove the solvent and purified on silicagel column simple ether-hexane 2:1.

The yield of compound (40) was 11.5 g (53% of theory).

Stage 2

4-(4-methylbenzyl)cyclohexanone (41)

of 10.9 g (50 mmol) of the compound (40) was dissolved in 250 ml of formic acid for 3 h and boiled under reflux. The result has been olefinic mixture. Formic acid is kept under vacuum and olefins was purified on silicagel column simple ether-hexane 1:1. The result was obtained 7.5 g of olefin mixtures which races and normal pressure. After filtering off the catalyst and removal by distillation of the solvent was obtained 7.8 g of the ketone. Cleavage of the acetal and subsequent processing was performed under the conditions described in the implementation stage 1. In this way received 6.7 g of the ketone, which was purified on silicagel column simple ether-hexane 1:2.

The yield of compound (41) was 5.15 g (51% of theory).

Stage 3

2-dimethylaminomethyl-4-(4-methylbenzyl)cyclohexanone, hydrochloride (42)

Compound (41) was subjected to interaction with dimethylamine, hydrochloride, in the conditions corresponding to the one described in example 10, step 3. Thus obtained compound (42) in crystalline form with a yield of 46% of theory.

Melting point: 124-127oC.

Stage 4

1-(3-benzyloxyphenyl)-2-dimethylaminomethyl-4-(4-methylbenzyl) cyclohexanol (43)

1-bromo-3-benzyloxybenzyl and the base of compound (42) was subjected to interaction in the conditions corresponding to the one described in example 1. The obtained product was dissolved in a mixture of simple ether/hexane and the base was extracted with 10% acetic acid. After the establishment of the alkaline pH of the compound (43) was extracted with simple ether and dried over sodium sulfate. After udaljenim 1:1, receiving the connection (43) yield 65% of theory.

Stage 5

(1RS,2RS,4SR)-3-[2-dimethylaminomethyl-1-hydroxy-4-(4-methylbenzyl)cyclohexyl]phenol hydrochloride (39)

Compound (43) was first made in the conditions described in example 23, step 2. Then was dissolved in a mixture of dichloromethane-simple ether 1:1 and added water trimethylchlorosilane. After recrystallization from aqueous 2-butanol was obtained compound (39) with a yield of 56% of theory.

Melting point: 188-191oC.

Example 25

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-4-(4-methylbenzyl)cyclohexanol, hydrochloride (44)

The basis of the compound (42) was subjected to interaction with 1-bromo-Z - methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column simple ether-methanol 7:1 and dissolved in a simple ether. After adding water trimethylchlorosilane received the compound (44) with the release of 39% of theory.

Melting point: 116-122oC.

Example 26

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-4-phenylethylamines, hydrochloride (45)

Stage 1

4-hydroxy-4-phenylethylamine (46)

(2-chloroethyl)benzene is tadia 1. The obtained product was purified on silicagel column simple ether-n-hexane 5: 1. In the received connection (46) yield 71% of theory.

Stage 2

4-(phenylethyl)cyclohexanone (47)

Compound (46) in the conditions corresponding to the one described in example 24, step 2, dehydrational and was first made. After dehydration of the obtained olefin mixture was purified on silicagel column diisopropyl ether-n-hexane 3:1. Obtained after hydrogenation of the compound of formula (47) was purified on silicagel column diisopropyl ether-n-hexane 1:1. The compound (47) was obtained with the yield 54% of theory.

Stage 3

2-dimethylaminomethyl-4-(phenethyl)cyclohexanone, hydrochloride (48)

of 20.2 g (0.1 mol) of the compound (47), and 1.5 g (0.05 mole) of paraformaldehyde and 4,07 g (0.05 mole) of dimethylamine, hydrochloride, was dissolved in 40 ml of acetic acid and with stirring, they were heated for 20 min in a bath at 105oC. Then acetic acid is kept under vacuum, the residue was dissolved in 100 ml of water and was extracted with simple ether. The aqueous phase using sodium hydroxide was adjusted at pH 11 and the base of mannia was extracted with dichloromethane. After drying and removal by distillation of the solvent was obtained 17.5 g base soedinenii of 17.2 g of compound (48) with the yield 58% of theory.

Melting point: 159-160oC.

Stage 4

(1RS, 2RS, 4SR)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-4-phenylethylamines, hydrochloride (45)

The basis of the compound (48) was subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column simple ether-methanol 7:1) which was purified by Ehud. Then was dissolved in 2-butanone was added water trimethylchlorosilane, if necessary with the addition of a simple ester. The compound (45) was obtained with the yield 40% of theory.

Melting point: 170-173oC.

Example 27

(1RS, 2RS, 4SR)-3-(2-dimethylaminomethyl-1-hydroxy-4-penitenziagite)phenol hydrochloride (49)

Stage 1

1-(3-benzyloxyphenyl)-2-dimethylaminomethyl-4-fenetylline (50)

The basis of the compound (48) was subjected to interaction with 1-bromo-3-benzyloxybenzyl in conditions described in example 1. The resulting base was purified on silicagel column simple ether-methanol 6:1. The compound (50) was obtained with the yield 87% of theory.

Stage 2

(1RS, 2RS, 4SR)-3-(2-dimethylaminomethyl-1-hydroxy-4-penitenziagite) phenol hydrochloride (49)

Connect the Yu water trimethylchlorosilane transformed into the hydrochloride. Compound (49) was obtained with the yield 63% of theory.

Melting point: 254-256oC.

Example 28

(1RS, 2RS,4SR)-2-dimethylaminomethyl-1-(3-methylsulfinylphenyl)-4-phenethyl-1-cyclohexanol, hydrochloride (51)

The basis of the compound (48) was subjected to interaction with 1-bromo-3-methylsulfonylbenzoyl in conditions described in example 1. In contrast to the conditions specified in the solvent used here is a simple ether, and to enhance the yield in the reaction mixture was added 1,2-dibromethane. The crude product was purified on silicagel column diisopropyl ether and dissolved in 2-butanone. After adding water trimethylchlorosilane received the compound (51) with the release of 23% of theory.

Melting point: 161-163oC.

Example 29

(1RS, 2RS, 4SR)-4-(cyclopentylmethyl)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (52)

Stage 1

Bromide (cyclopentadienylmanganese) (53)

of 17.7 g (100 mmol) (2-bromacil)cyclopentane, with 32.5 g (124 mmole) of triphenylphosphine and 100 ml of toluene was boiled for 56 h under reflux. Then during the night was stirred at room temperature. The resulting crystals were aspirated, washed simple EPE is 210-213oC.

Stage 2

8-(2-cyclopentylacetyl)-1,4-dioxaspiro[4.5] decane (53)

The reaction was carried out in nitrogen atmosphere, eliminating the presence of moisture. To 5.6 g (50 mmol) of potassium tert-butylate in 400 ml of toluene was added to 21.9 g (50 mmol) of the compound (52). First was stirred for 30 min at room temperature and then for 1 h at 80oC, and then cooled to 60oC. was Then added to 7.8 g (50 mmol) of 1,4-dioxaspiro[4.5] decane-8 - it. Then was stirred for 18 h at 60oC and cooled. After this was added dropwise 100 ml of water. The organic phase was separated, the aqueous phase was twice extracted with toluene, dried with sodium sulfate and removed by distillation of the solvent. The result obtained 29 g of oil which was purified on silicagel column diisopropyl ether-n-hexane 1:4.

The output was 6.8 g (58% of theory) of the compound (54).

Stage 3

(2-cyclopentylmethyl) cyclohexanone (55) of 9.45 g (40 mmol) of the compound (54) was dissolved in 50 ml of methanol, mixed with 1.3 g of palladium on coal (Pd content 10%) and was first made at normal pressure at room temperature. The catalyst was separated, the solvent was removed by distillation and the residue was mixed with 10 parts of tetrahydrofuran and what was regionali simple ether, was dried over sodium sulfate and the solvent drove away. The resulting oil was purified on silicagel column simple ether-n-hexane 1:9. Compound (55) was obtained with the yield of 5.9 g (76% of theory).

Stage 4

4-(2-cyclopentylmethyl)-2-dimethylaminomethylene, hydrochloride (56)

Compound (55) was subjected to interaction with dimethylamine, hydrochloride, in the conditions corresponding to the one described in example 26, step 3.

Compound (56) was obtained with the yield 76% of theory.

Melting point: 127-128oC.

Stage 5

(1RS, 2RS, 4SR)-4-(cyclopentylmethyl)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (52)

The basis of the compound (56) was subjected to interaction with 1-bromo-3-methoxybenzoate in conditions described in example 1. The resulting base was purified on silicagel column diisopropyl ether and dissolved in a simple ether. After adding water trimethylchlorosilane received connection (52) to yield 54% of theory.

Melting point: 154-156oC.

Example 30

(1RS, 2RS, 4SR)-3-[4-(2-cyclopentylmethyl)-2-dimethylaminomethyl-1-hydroxycyclohexyl]phenol hydrochloride (57)

The reaction was carried out in nitrogen atmosphere, the claim is and was added dropwise 25 ml of 20% aqueous hydride diisobutylaluminum in toluene (35 mmol). Then for 6.5 h boiled under reflux and cooled. At a temperature in the range of 0oC to 10oC was added dropwise at first, 5 ml of ethanol, and then 5 ml of aqueous ethanol 1:1 and 35 ml of toluene. After stirring for 1 h the obtained salt was aspirated and the solvent drove away. The resulting oil was dissolved in acetic ether. After adding water trimethylchlorosilane received the compound (57) with a yield of 0.35 g, which accounted for 23% of theory. Melting point: 226-228oC.

Example 31

(1RS, 2RS, 4SR)-4-cyclopentylmethyl-2-dimethylaminomethyl-1-(3-ethoxyphenyl)cyclohexanol, hydrochloride (58)

The basis of the compound (56) was subjected to interaction with 1-bromo-3-ethoxybenzyl in conditions described in example 1. The resulting base was purified on silicagel column diisopropyl ether and dissolved in 2-butanone-simple ether. After adding water trimethylchlorosilane received connection (58) yield 52% of theory.

Melting point: 152-152,5oC.

Example 32

(1RS, 2RS, 4SR)-4-(2-cyclopentylmethyl)-1-(3-cyclopentyloxy)-2-dimethylaminomethylphenol, hydrochloride (59)

The basis of the compound (56) was subjected to interaction with 1-bromo-3-CEC is nagelneu column diisopropyl ether and dissolved in a mixture of acetic ether/diisopropyl ether. After adding water trimethylchlorosilane received connection (59) yield 67% of theory.

Melting point: 140-143oC.

Example 33

(1RS, 2RS, 4SR)-4-cyclopentyloxy-1-(3-cyclopentyloxy)-2-dimethylaminomethylphenol, hydrochloride (60)

Stage 1

4-(cyclopentyloxy)cyclohexanone (61)

23.7 g (150 mmol) of 1,4-dioxaspiro[4.5] Decan-8-ol was dissolved in 120 ml of dimethylformamide in a nitrogen atmosphere for 1 h at room temperature was mixed with 7.2 g (159 mmol) of 50% sodium hydride in mineral oil. Then added 38 g (150 mmol) cyclopentylmethyl ester toluene-4-sulfonic acid (see Krapcho, Johnson, Journ. Org. Chem., 36, 146, (1971)). Stirring was continued at room temperature, then cooled to a temperature in the range of 5oC to 10oC. Then was added dropwise 125 ml of water. Then was extracted with simple ether, dried over sodium sulfate and removed by distillation of the solvent. The resulting product (32 g) was dissolved in diisopropyl ether and within 20 h was mixed with 65 ml of water and 95 ml of concentrated hydrochloric acid. Then was neutralized with sodium hydrogen carbonate, was extracted with simple ether and dried over sodium sulfate. The floor is and 17.5 g of compound (61), that was 60% of theory.

Stage 2

4-(cyclopentyloxy)-2-dimethylaminomethylene (62)

Connection (61) transformed under the conditions as described in example 26, step 3. Compound (62) was obtained with the yield 90% of theory.

Stage 3

(1RS, 2RS, 4SR)-4-cyclopentyloxy-1-(3-cyclopentyloxy)-2-dimethylaminomethylphenol, hydrochloride (60)

Compound (62) was subjected to interaction with 1-bromo-3-cyclopentylacetyl in conditions described in example 1. Which resulted in formation of a mixture of CIS - and TRANS-isomers, which were separated and purified on silicagel column simple ether-methanol 20:1. Then CIS-isomer was dissolved in 2-butanone was added water trimethylchlorosilane. After recrystallization from 2-butanone received connection (60) with the release of 12% of theory.

Melting point: 181-182,5oC.

Example 34

(E)-(1RS,2RS)-4-benzylidene-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride [E(63)]

and

(Z)-(1RS,2RS)-4-benzylidene-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride [Z(63)]

Stage 1

7-dimethylaminomethyl-1,4-dioxaspiro[4.5]decane-8-he hydrochloride (64)

130 g (0,83 mole) of 1,4-dioxaspiro[mperature. After adding 1 ml of acetylchloride continued stirring for 3 h at room temperature and formed a colorless, transparent solution. Then the reaction mixture was added dropwise to 1 l of simple ether. As a result received 203 g (98% of theory) 7-dimethylaminomethyl-1,4-dioxaspiro[4.5] decane-8-she hydrochloride (64), in crystalline form.

Stage 2

7-dimethylaminomethyl-8-(3-methoxyphenyl)-1,4-dioxaspiro [4.5] Decan-8-ol (65)

To 16,4 g (of 0.68 mole) of magnesium turnings in 50 ml of tetrahydrofuran was added dropwise 85 ml of 0.68 mole) of 1-bromo-3-methoxybenzene dissolved in 350 ml of tetrahydrofuran. Later in the course of 1 h was heated under reflux and cooled to a temperature of 5-10oC. 7 - dimethylaminomethyl-1,4-dioxaspiro [4.5] decane-8-she hydrochloride (64), using a mixture of dichloromethane-caustic soda released the substrate and after drying, the solution was removed by distillation of dichloromethane. 95 g (of 0.45 mol) of the obtained base was dissolved in 150 ml of tetrahydrofuran and added to a solution of the Grignard reagent. The solution was left overnight and then cooled to a temperature of 5-10oC. by Addition of 600 ml of 20% aqueous solution of ammonium chloride solution of Grignard reagent was decomposed. It was further diluted with 500 ml of tetrahydrofuran, organic futurehome solvent residue (156 g) was filed on silicagel column and suirable first n-hexane-diisopropyl ether 4: 1, and then ethyl acetate-methanol 1:1. As a result received 137 g (94% of theory) connecting the base (65) in the form of a light yellow, viscous oil.

Stage 3

3-dimethylaminomethyl-4-hydroxy-4-(3-methoxyphenyl)cyclohexanone (66)

78 g (0,24 mol) 7-dimethylaminomethyl-8-(3-methoxyphenyl)-1,4-dioxaspiro[4.5] Decan-8-ol (65) was dissolved in 500 ml of tetrahydrofuran and cooled to a temperature of 0-5oC. for 30 min was added 200 ml of aqueous hydrochloric acid (conc. hydrochloric acid/water 2:1). Within 12 h was stirred at room temperature and then cooled to a temperature in the range of 0oC to 5oC. After adding 250 ml of concentrated sodium hydroxide was extracted three times with simple ether and dried over sodium sulfate. After removal by distillation of the solvent the residue (66 g) was filed on silicagel column and consistently suirable diisopropyl ether, diisopropyl ether-simple ether 1:1 and ethyl acetate-methanol 1:1. The result obtained 36 g connecting the base (66) (48% of theory) as a light yellow, viscous oil.

Stage 4

(E)-(1RS,2RS)-4-benzylidene-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride [E(63)]

and

(Z)-(1RS,2RS)-4-benzylidene-2-dimethylaminomethyl-1-(Ty was dissolved in 70 ml of dimethylformamide and cooled with ice bath was mixed with 4,28 g (80 mmol) methanolate sodium. After 30-minute stirring was added dropwise 10 g (36 mmol) of 3-dimethylaminomethyl-4-hydroxy-4-(3-methoxyphenyl)cyclohexanone (66), dissolved in 20 ml of dimethylformamide, while cooling with ice bath. Then was heated to room temperature and for 24 h and was stirred at this temperature. For decomposition during cooling ice bath was added dropwise a mixture of 45 ml of water and 25 ml of methanol. After three simple extraction with ether, washed with water and dried over magnesium sulfate. Then the ether was removed by distillation and the residue (15,8 g) was filed on silicagel column. After elution of diisopropyl ether-methanol 7:1 was obtained 4.9 g [Z(63)] and 3.8 g [E(63)]-connection of which with the help of water trimethylchlorosilane in 2-butanone was obtained hydrochloride.

[Z(63)]: Yield: 5.0 g (35% of theory).

TPL: 191-192oC.

[E(63)]: Exit: 3,9 g (28% of theory).

TPL: 220-221oC.

Example 35

(1RS, 2RS, 4SR)-4-(3,4-dichloraniline)- 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (67)

Stage 1

2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexane-1,4-diol, hydrochloride (68)

10 g (36 mmol) of the compound (66) was dissolved in 80 ml of isopropanol and cooled to whom mperature within 2 hours Upon cooling, the ice bath was added first with 20 ml of diluted hydrochloric acid (conc. HCl:H2About 1:4), and then 10 ml of 20% aqueous sodium hydroxide. Was twice extracted with dichloromethane. After drying and removal by distillation of the solvent the crude product (10.3 g) was dissolved in 2-butanone and for separation of the diastereomers using water trimethylchlorosilane were transferred into the hydrochloride. The result fell in the form of crystals of 10.2 g (90% of theory) of the compound (68).

Stage 2

(1RS, 2RS, 4SR)-4-(3,4-dichloraniline)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride (67)

From the compound (68) using dichloromethane-caustic soda released the substrate and after drying, the solution was removed by distillation of dichloromethane. 2.8 g (10 mmol) of the obtained base was dissolved in 10 ml of dimethylformamide and mixed with 480 mg of sodium hydride (50%). Then within 2 hours and was stirred at 55oC. Then was added dropwise to 1.38 ml (1,95 g, 10 mmol) 1,2-dichloro-4-chloromethylbenzene. After stirring for 2 h at 55oC was cooled to room temperature, poured on ice/water, was extracted three times with simple ether, washed first with caustic soda and then with water and dried over sodium sulfate. After removal Beregovaya diisopropyl ether-methanol 7:1 was obtained 3.0 g of the base, from which with the help of water trimethylchlorosilane in 2-butanone was obtained the compound of the formula (67) (3.1 g, 65% of theory) with a melting point 196-197oC.

Examples 36-61

In the following table 1 presents examples 36-61. The compounds were obtained from the corresponding starting compounds according to the conditions described in examples 1-35.

Pharmacological studies

Tests of analgesia in mice in the test on wince tail. Compounds according to the invention was tested for analgesic efficacy in mice in the test on wince tail using heat 5 radiation by the method of D'amour and Smith (Journ. Pharm. Exp. Ther. 72, 74-79 (1941). For this purpose, the experiments used male mice of NMRI weighing from 20 to 24, the Experimental animals were placed singly in a special cell and the tail hit the focused thermal beam from an electric lamp (analgesiometer type Rhema 3010). The radiation intensity of the lamp was set so that the time from the moment the lamp is switched on until a sudden, convulsive shaking of the tail (pain latency) in untreated animals was 3-5 C. prior To the introduction of one of the compounds according to the invention animals Excitable initial average value before testing. Pain was recorded respectively in 20, 40 and 60 minutes ate intravenous administration of the compounds according to the invention. With increasing pain latency of the maximum exposure time is limited to 12 and with the increase of the latent period of up to 150% of the initial average value before testing took for the value that comes analgesic action. To determine, depending on the dosage corresponding connection according to the invention was administered 3-5 doses in logarithmically growing number, including respectively the threshold and maximum effective dose, and the number analiziropany animals according to the method of Litchfield and Wilcoxon (Journ. Pharm. Exp. Ther. 96, 99-1123 (1949)) determine the values of the ED50. The definition of ED50carried out to the maximum range after 20 min after intravenous injection of substances.

All used compounds according to the invention showed a pronounced analgesic efficacy. The results are presented in the following table.2.

1. 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I

< / BR>
in which X is O and S;

R1means H or hydroxy - or mercaptohexanol group, pregnyl, WITH5-C7cycloalkyl or halogenated1-C6alkyl,

group

< / BR>
does

or

R2means1-C6alkyl, C2-C6alkenyl,5-C7cycloalkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, in the form of their bases or salts of physiologically acceptable acids.

2. 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I on p. 1, wherein R1means H, C1-C4alkyl, 2'-methyl-2'-propenyl, cyclopentyl or foretel provided that R1is1-C4the alkyl when X is S, and R2means1-C4alkyl, C2-C4alkenyl, cyclopentylmethyl, phenyl, C1-C4alkoxyphenyl, benzyl,1-C4alkylbenzene, one - or twofold halogenated phenyl, or mono - or Ducato halogenated benzyl.

3. 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I under item 1 or 2, wherein R1denotes H, methyl, ethyl, isopropyl, 2'-methyl-2'-propenyl, cyclopentyl or foretel provided that R1is stands, if X is S, and R2Osnach the et-butylbenzyl, 4-Chlorobenzyl, 4-terbisil or 3,4-dichlorobenzyl.

4. 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I according to one of paragraphs.1 to 3, wherein R1denotes H, methyl or cyclopentyl provided that R1is stands, if X is S, grouping

< / BR>
does

< / BR>
or

< / BR>
R2is cyclopentylmethyl, benzyl and 4-chlorbenzyl.

5. 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I on p. 1, wherein X is O, R1means H or methyl, grouping

< / BR>
does

< / BR>
or

< / BR>
R2means benzyl.

6. 1-phenyl-2-dimethylaminomethylene-1-olavie the compounds of formula I according to one of paragraphs.1 to 5, characterized in that the compounds have a configuration according to formula Ia

< / BR>
7. The way to obtain 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I

< / BR>
X is O or S, R1means1-C6alkyl, C2-C6alkenyl,5-C7cycloalkyl, halogenated1-C6alkyl or hydroxy - or mercaptohexanol group that represents benzyl, dialkylanilines or trialkylsilyl6alkenyl,5-C7cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,

characterized in that chetyrehkolenny cyclohexane-1-it formula IIa

< / BR>
get in due to the fact that either the compound of formula IV

< / BR>
in which a represents a branched or unbranched balance CnH2nand n means an integer in the range 2 - 6,

first alkylate compound of formula III

R2- G

in which G represents Cl, Br, I or toluensulfonate,

and then deacetylated by proton catalysis, or a compound of the formula V

< / BR>
in which a represents a branched or unbranched balance CnH2nand n means an integer in the range 2 - 6,

first alkylate using alcoholate derived from an alcohol of formula VI

R2HE,

and then through proton catalysis deacetylases to the compounds of formula IIa, then the obtained compound of the formula IIa interaction either with dimethylamine in the reaction of manniche or methylene chloride, dimethylamine transform in the compound of formula VII

< / BR>
which is using the ORGANOMETALLIC connection is 8. The way to obtain 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I

< / BR>
in which X is O or S;

R1means N,

group

< / BR>
does

or

R2means1-C6alkyl, C2-C6alkenyl,5-C7cycloalkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, wherein any compound of formula I, in which R1means methyl, is subjected to the interaction with the hydride diisobutylaluminum, or a compound of the formula I, in which R1means benzyl, hydronaut in the presence of Pt - or Pd-catalyst, or a compound of the formula I, in which R1means diarylethylenes or trialkylsilyl, hydrolyzing or subjected to interaction with fluoride, Tetra-n-butylamine.

9. The way to obtain 1-phenyl-2-dimethylaminomethylene-1-olowahu the compounds of formula I

< / BR>
in which X is O or S;

R1means H or hydroxy - or mercaptohexanol group that represents benzyl, dialkylanilines or trialkylsilyl,1-C6alkyl, C2-C6alkenyl,5-C7cycloalkyl, halogenated1-C6< the, WITH2-C6alkenyl,5-C7cycloalkenyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl,

characterized in that a ketone of formula XV

< / BR>
in which a represents a branched or unbranched balance CnH2nand n means an integer in the range 2 - 6,

interaction with methylene chloride, dimethylamine transform-dimetilaminometil formula XVI

< / BR>
from which then, using ORGANOMETALLIC compound of formula VIII

< / BR>
in which Q denotes MgCl, MgBr, MgI or Li, obtain the connection formula XVII

< / BR>
then by proton catalysis deacetylases to the compounds of formula XVIII

< / BR>
and then either the resulting compound of formula XVIII to restore 4-hydroxy formula XIX

< / BR>
from which subsequent formation of the alcoholate and the interaction with the compound of the formula III

R2-G

in which G represents Cl, Br, I or toluensulfonate receive compound of the formula I, in which groups

< / BR>
does

< / BR>
either the compound obtained of the formula XVIII interaction with the compound of the formula XX

< / BR>
in which n means the BR> which if necessary hydronaut to obtain the compounds of formula I, in which groups

< / BR>
does

< / BR>
10. Drug with analgesic effect, characterized in that the active ingredient in it is 1-phenyl-2-dimethylaminomethylene-1-olove compound of formula I according to any one of paragraphs.1 - 6.

11. Drug under item 10, characterized in that it is an analgesic.

 

Same patents:

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The invention relates to the field of medicine and relates to a medicinal product on the basis of paracetamol containing antihypoxic drug in therapeutic doses

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-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida

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

Drug // 2163122
The invention relates to medicine, namely to medicines affecting the immune system

The invention relates to the field of pharmacy and relates to a method of receiving funds from vegetable raw materials, which possess anti-inflammatory activity

The invention relates to the field of pharmacy and concerns a method for obtaining tools and plant materials that have choleretic and anti-inflammatory activity

The invention relates to the field of medicine and new therapeutic anti-inflammatory and pain management pharmaceutical compositions containing nimesulide, which is N-(4-nitro, 2-phenoxyphenyl)methanesulfonamide for percutaneous introduction, and method of its manufacture

The invention relates to an anti-inflammatory drug for external use, comprising as active ingredient nimesulide

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

or its pharmaceutically acceptable salt, where m, p, q, Ar, R1 and R2 are as given in the description, as well as a pharmaceutical composition with selective affinity to 5-HT receptors which contains a formula (I) compound.

EFFECT: obtained compounds have selective affinity to 5-HT receptors and can be used, as expected, in treating certain central nervous system disorders.

21 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutical industry and medicine and is intended for treatment of wounds and burns. Agent for treatment of wounds and burns is described, having the following composition, wt %: polyvinylpyrrolidone - 2.0- 10.0, agar - 1.0-3.0, polyethylene oxide - 1.0-3.0, myramistin - 0.01-1.0, lidocaine hydrochloride - 0.01-5.0, aminocapronic acid - 0.01-5.0, water - balance. Agent is produced by linkage of medical-purpose polymers under action of ionising radiation.

EFFECT: agent has elasticity, tensile strength, sorbtion effect relative to wound exudate, transparency, which makes it possible to follow course of wound process, painless removal from wound surface, creates optimal microclimate in wound (humidity, temperature), provides for antimicrobial, analgetic, styptic and wound healing effects.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutical industry and medicine. Antimicrobial, analgetic and wound healing agent intended for treatment of wounds and burns is described, having the following composition, wt %: polyvinylpyrrolidone - 2.0- 10.0, agar - 1.0-3.0, polyethylene oxide - 1.0-3.0, myramistin - 0.01-1.0, lidocaine hydrochloride - 0.01-5.0, water - balance. Agent is produced by linkage of medical-purpose polymers under action of ionising radiation.

EFFECT: agent has elasticity, tensile strength, sorbtion effect relative to wound exudate, transparency, which makes it possible to follow course of wound process, painless removal from wound surface, creates optimal microclimate in wound (humidity, temperature), provides for antimicrobial, analgetic and wound healing effects.

3 ex

FIELD: chemistry.

SUBSTANCE: anhydride is a physiologically active substance and can be used, for example, in chemotherapy as a low-toxic agent for inhibiting growth of carcinoma 755 (breast cancer). The object of the present invention is synthesis of a novel mixed anhydride based on dichloroacetic and aminoacetic acid which, for instance, enables to inhibit growth of carcinoma 755 (breast cancer) in monotherapy. The given task is solved through synthesis of a novel mixed anhydride based on dichloroacetic acid and aminoacetic acid of formula 1, which can be used in medical practice as an anti-tumour agent which enables, for example, to inhibit growth of carcinoma 755. The other objective of the invention is designing a method of producing the mixed anhydride based on dichloroacetic acid and aminoacetic acid. This task is solved using a method which involves successive reaction of aminoacetic acid with an alkali metal hydroxide in an aqueous medium followed by treatment of the reaction mass with dichloroacetyl chloride in a chloroalkane solution, acidation of the reaction medium with aqueous hydrochloric acid solution and extraction of the end product using existing techniques. The disclosed compound can be used in medical practice as an anti-tumour compound.

EFFECT: use of said compound in oncological practice inhibits growth of carcinoma.

2 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is an antimicrobial and wound healing agent of hydrogel polymeric matrix used for wounds, burns and dermatologic disorders. The agent has the following formulation, wt %: polyvinylpyrrolidone - 2-10, agar - 1, polyethylene oxide - 1-3, an antimicrobial pharmaceutical substance selected from gentamycin and miramystine - 0.02-1,0, water - the rest. The agent is prepared by cross-linking medical polymers under ionising radiation. The hydrogel polymeric matrixes of the various area are sterile and ready for application on open wound surfaces.

EFFECT: agent exhibits elasticity, breaking strength, sorption properties in relation to wound exudate, transparency that enables following a course of wound process, painless removal from wound surface, creates an optimum microclimate in a wound (humidity, temperature).

3 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical and cosmetic industry, particularly an agent applied to skin. A vesicle applied to skin containing α,ε-bis(γ-N-(C10-30)acylglutamyl)lysine and/or its salt; ceramide and/or its derivative; and one or more ethers selected from glycerin ether of fatty acid, polyglycerin ether of fatty acid and glycerin ether of pyroglutamic acid taken in certain proportions. The therapeutic agent for external application to skin containing a certain amount of the vesicle.

EFFECT: vesicle and based therapeutic agent are stable, effectively encapsulates an active ingredient that allows it reaching true skin, effectively suppress transepidernal dehydration.

6 cl, 13 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to catalysts of olefin hydroamination, their obtaining and application. Claimed is lithium-ligated hydroamination catalyst, which contains boron-beta-zeolites, molar ratio of boron atoms to lithium atoms constituting from 5:1 to 50:1. Also described is method of obtaining amines by converting ammonium or primary, respectively secondary amines with olefins at higher temperatures and pressure in presence of said hydroamination catalyst. Claimed is method of obtaining raw material for rubber industry: vulcanisation accelerators, methods of plant protection or pharmaceutical preparations with application of tert-butyl amine preliminarily obtained by method described above.

EFFECT: increased amine output.

10 cl, 1 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention describes a method of treating severe acute psychopharmaceutical poisoning in children by conducting a combined therapy: taking infusion detoxification measures including administration of starting colloidal solution in order to recover the volemic status, and conducting a medicinal treatment of progressive dysfunctions in a child's body; for the first hours of the combined therapy, immediately after the administration of starting colloidal solution, before the medicinal treatment, providing the stable volemic status, Reamberin 10 ml/kg of body weight a day at 5 ml a minute, a medication mixture consisting of 5% glucose and Riboxinum 20 mg/kg of patient's body weight are administered one by one during 3 to 5 days.

EFFECT: method is characterised by the high clinical effectiveness; enables correcting the functional insufficiency of the main body systems within a short time, achieving the reliable stabilisation of primary homeostasis parameters and preventing the progression of life-threatening complications, such as toxic encephalopathy and cardiopathy, reducing an asthenisation level; the length of treatment and staying in hospital are also considerably reduced.

2 tbl, 2 ex

FIELD: veterinary medicine.

SUBSTANCE: method involves growing animals under normal feeding and keeping conditions. Additionally, the lithium salt of oxyglycine is administered parenterally in an amount of 2 mg per 1 kg of body weight at the age of 1 and 2 months.

EFFECT: increased non-specific resistance and productivity of animals.

4 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

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