Substituted amino compounds and method of production thereof

 

(57) Abstract:

The invention relates to new substituted the amino compounds of the formula I, their pharmaceutically acceptable salts and method of production thereof. These compounds exhibit analgesic activity and can be used to produce medicines, which represents an analgesic. In the compounds of the formula I R1means H, HE, O-C1-6alkyl, and R1is not N if R2and R7represent H or in position 7 OCH3group substituted; R2means N (if R1is not H, HE, C1-6alkyl, O-aryl, C2-6alkynylaryl, Cl, F, C1-6alkoxy, aryl, C1-6alkylaryl, 5,6 - or 6,7-benzo, unsubstituted, single or disubstituted Cl, F, CF3WITH1-6the alkyl, O-C1-6the alkyl, HE (and, if R1and R2or R7are H, R2or R7can't imagine a CF3group, and R2or R7in position 7 can't be a co3group), or R2and R7both together represent-O-(CH2)(1-2)-O- (in position 5,6 or 6,7); R3means N; R4means1-6alkyl, or R3and R4both together made the B>1-6alkyl, C1-6alkylaryl, -CH2-CH= C(R8)2, -CH2-(C3-7)cycloalkyl,3-7cycloalkyl; C1-6alkylglycerol; R7means N (if R1is not H, HE, C1-6alkyl, O-aryl, C2-6-alkynylaryl,1-6alkoxy, Cl, F, aryl, C1-6alkylaryl, 5,6 - or 6,7-benzo, unsubstituted, single or disubstituted Cl, F, CF3WITH1-6the alkyl, O-C1-6the alkyl, HE (and, if R1and R2or R7are H, R2or R7can't imagine a CF3group, and R2or R7in position 7 cannot represent OCH3group), and R8means N or CH3when that "heterocyclyl" denotes a 5 - or 6-membered unsaturated or saturated, optionally condensed with aryl heterocyclic system containing 1 or 2 heteroatoms from the group comprising nitrogen, oxygen and/or sulfur. The method of obtaining the amino compounds of the formula I is that the tertiary alcohol of the formula II, where R1-R7have the meanings indicated in formula I, is subjected to the interaction with inorganic or organic acids in the temperature range from 0 to 100oWith a tertiary alcohol of General formula II get usaimage and R10identical to R7with the exception of cases, when the hydroxy-group is protected and is benzyloxy or silyloxy, with an ORGANOMETALLIC compound of the formula IV, in which Z denotes MgCl, MgBr, MgI or Li, a R11represents hydrogen, O-C1-6alkyl or a protected hydroxyl group, as described above, to obtain compounds of formula IIA, which is then transferred to the connection II. 2 S. and 6 C.p. f-crystals, 1 PL.

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The invention relates to substituted the amino compounds of General formula I

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or their pharmaceutically applicable salts, method for their production and to their use as pharmaceuticals.

Classical opioids (synthetic drugs, the effects similar to opiates, but not their derivatives), such as morphine, highly effective in the treatment of strong and very strong pain. However, their use is limited because of side effects they cause, such as respiratory depression, vomiting, sedation and constipation, as well as the development of addiction. In addition, they are ineffective in neuropathic or incidenceand pain, which are the first to suffer cancer patients.

what Ptolemy, belonging to the family of so-called associated with G-protein receptors. Biochemical and pharmacological properties of the subtypes of these receptors suggest that specific opioids these subtypes have a different mechanism of action, including the calling side effects, compared to, for example, morphine. If morphine binds selectively with the so-called receptors, endogenous enkephalins are characterized as selective peptides. Further pharmacological studies suggest that there are a number of these subtypes of opioid receptors (1,2,1,2,3,1and2).

Information about the physiological value-receptore-selective substances were significantly expanded with the opening ones of antagonist naltrindole. Today it is obvious that agonists have their own antinociceptive potential. Along with the data obtained by conducting numerous experiments on animals, there are also the results of research conducted with peptide agonist DADL on patients, cancer patients, have more morphine did not show analgesic actions. When intrathecal is tov from-agonists is evident in their interaction with the endogenous opioid antagonist" cholecystokinin (FCS). Along with this difference in the range agonists may are believed to be different from the agonist and the mechanism of action of causing side effects, which is manifested, in particular, in the reduction of respiratory depression.

Based on the foregoing, the invention was based on the task to get possessing analgesic action of the substance, the biological effectiveness of which is partially or predominantly mediated through opioid receptors.

It was found that the specified requirements are met by the amino compounds of General formula I.

The subject of the invention in accordance with this are the substituted amino compounds of General formula I

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where R1means H, HE, O-C1-6alkyl, O-C3-7cycloalkyl, (and R1is not N if R2and R7represent H or in position 7 och3group substituted);

R2means N (if R1is not H, HE, C1-6alkyl, O-aryl, C2-6alkynylaryl, O-C3-7cycloalkyl, Cl, F, C1-6alkoxy, aryl, heterocyclyl,1-6alkylglycerol,1-6alkylaryl, 5,6 - or 6,7-benzo, unsubstituted, single or disubstituted Cl, F, CF3WITH1-6the alkyl, O-C1-63group, and R2or R7in position 7 can't be a co3group, or R2and R7both together represent-O-(CH2)(1-2)-O- (in position 5,6 or 6,7);

R3means N;

R4means1-6alkyl or

R3and R4both together represent -(CH2)(1-4)-;

R5means1-6alkyl, C3-7cycloalkyl;

R6means1-6alkyl, C1-6alkylaryl,1-6alkylglycerol, -CH2-(CH= C(R8)2, -CH2-(C3-7)cycloalkyl,3-7cycloalkyl;

R7means N (if R1is not H, HE, C1-6alkyl, O-aryl, C2-6alkynylaryl, O-C3-7cycloalkyl,1-6alkoxy, Cl, F, aryl, heterocyclyl,1-6alkylglycerol,1-6alkylaryl, 5,6 - or 6,7-benzo, unsubstituted, single or disubstituted Cl, F, CF3WITH1-6the alkyl, O-C1-6the alkyl, HE (and, if R1and R2or R7are H, R2or R7can't imagine a CF3group, and R2or R7in position 7 can't be a co3group) and

R8means N or CH3,

or pharmaceutically applicable to the E. of them, in which

R2, R6and R7mean1-6alkylaryl or1-6alkylglycerol, a R1, R3-R5and R8have the above meaning according to the General formula I or

R2, R7means aryl or heterocyclyl, and R1, R3-R6and R8have the above meaning according to the General formula I or

R1means HE or-O-C1-6alkyl, R5and R6mean1-6alkyl, a R2-R4and R7have the above meaning.

Especially preferred compounds in which R1IT means, R5and R6means methyl, a R2-R4and R7have values according to the General formula I.

The concept of "1-6alkyl" in the context of the present invention means remotemachine or branched hydrocarbons with 1 to 6 carbon atoms. As examples of such can be called methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.

The concept of "1-6alkoxy" in the present invention means remotemachine or branched hydrocarbons with 1 to 6 carbon atoms, as defined above, linked through an oxygen atom.

on IT, F, Cl, CF3WITH1-6the alkyl, C1-6alkoxygroup,1-7cycloalexie,3-7cycloalkyl,2-6alkylene, heterocyclyl or phenyl. Heterocyclyl or phenyl residues may be optionally attached by a condensation reaction. This concept may not necessarily be included naphthyl.

The term "heterocyclyl" in the framework of the present invention are meant 5 - or 6-membered saturated or unsaturated, optionally provided with a condensed aryl system of heterocyclic compounds containing 1 or 2 heteroatoms from the group comprising nitrogen, oxygen and/or sulfur.

As examples of saturated heterocyclyl can result in 1,4-dioxane, tetrahydrofuran and 1,4-dioxan.

From the group of unsaturated heterocyclyl can be called, for example, furan, thiophene, pyridine, pyrimidine, thiazole, oxazole, isoxazol, pyridazine, pyrazin, quinoline, isoquinoline, phthalazine and hinzelin.

The concept of "1-6alkylaryl", respectively "C1-6alkylglycerol" in the framework of the present invention means that arily", respectively "heterocyclyl" in the above deciphering their meanings are related through WITH1-6alkyl gr is Il - or triallelic, dialkylanilines or diarylethylenes, which is used as a protective group for the hydroxyl function. Examples thereof can serve triethylsilyl, Tripropylene, dimethylphenylsilane, di-tert-butylphenylmethyl, triisopropylsilyl, dimethylazobenzene, diethylenediamine, dimethylhexylamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-silisili, triphenylsilane, diphenylmethylene or propertyresolver.

The subject of the invention is also a method of obtaining substituted amino compounds of General formula I, characterized in that the tertiary alcohol of General formula II

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where R1-R7have the same meanings as in formula I,

subjected to interaction with polyetherdiamine or strong organic or inorganic acids, especially formic acid or hydrochloric acid in a temperature range from 0 to 100oWith, and tertiary alcohols of General formula II are due to the fact that first-aminoketone General formula III

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where R3-R6have the same meanings as in formula I, R9identical to R2, a R10identical to R7except in those cases where hydroxylate interaction with the ORGANOMETALLIC compound of the formula IV

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in which Z denotes MgCl, MgBr, MgI or Li, a R11has the same meaning as R1except in those cases where the hydroxyl function is represented in a protected form as benzyloxy or silyloxy, such as tert-butyldiphenylsilyl,

obtaining the compounds of formula IIA

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which is then transferred to the compound of formula II.

The reaction with compounds of formulas III and IV is carried out in a simple aliphatic ether, for example diethyl ether and/or tetrahydrofuran, in a temperature range from -70 to 60oC. the compounds of formula IV in which Z is a lithium atom, with compounds of the formula IV, in which Z denotes Br or I, through exchange of halogen and lithium implemented, for example, in a solution of n-utility/n-hexane.

To perform the reaction with the compound of the formula IIA with obtaining the compounds of formula II, depending on the values of9, R10accordingly, R11there are a number of methods.

So, if R9, R10and/or R11represent benzyloxy, it is advisable to use the method of restorative dibenzylamine with catalytically activated hydrogen, etc which the Reaction is carried out in a solvent, such as acetic acid, or in1-4Akilova alcohol at a pressure in the range from 1 to 100 bar and in the temperature range from 20 to 100oC, and the compound IIA is used preferably in the form of one of its salts.

If R9, R10and/or R11represent a silyl group, the cleavage of the protective groups are due to the fact that the corresponding compound of formula IIA at 20oWith the subject in an inert solvent, such as tetrahydrofuran, dioxane or diethyl ether, interaction with fluoride, Tetra-n-butylamine or treated with a methanol solution of hydrogen chloride.

If R9, R10and/or R11in the compound of formula IIA are metaxylene radical, the interaction with the hydride diisobutylaluminum in an aromatic hydrocarbon, such as toluene or xylene, at temperatures in the range from 60 to 130oSince it is possible to obtain the compound of formula II in which R1represents a hydroxyl group. It is also possible to directly obtain the analogous compounds of formula I is carried out by heating under reflux compound IIA with a solution of hydrogen bromide in glacial s R1, R2and/or R7are metaxylene group, can be obtained by the method described above interaction with the hydride diisobutylaluminum the compounds of formula I, where R1, R2and/or R7represent IT.

The compounds of formula I 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 may be converted by known methods into their salts. Preferably the process of salt formation in the solvent, such as diethyl ether, diisopropyl ether, alkilany ether acetic acid, acetone and/or 2-butanone. To obtain hydrochloride especially suitable trimethylchlorosilane in aqueous solution.

The subject invention is also the application of the proposed substituted amino compounds of General formula I as medicines. Possessing analgesic effect of the composition together with at least one sectorial, diluents, dyes and binders. The choice of these auxiliary substances, as well as their applicable amount, depend on whether the drug for oral, intravenous, intraperitoneal, intradermal, intramuscular, buccal or local injection. For oral administration suitable compositions in the form of tablets, chewable tablets, pills, capsules, granules, drops, mixtures or syrups; for parenteral, local and inhalation suitable solutions, suspensions, easily reconstructed dry compositions, as well as aerosols. The proposed connection to the depot in dissolved form, printed on foil-based or put in a plaster, optionally with the addition of means contributing to the permeability through the skin, are examples of forms that are suitable for transdermal administration. Used for oral or percutaneous administration of compositions of the compounds according to the invention can be released gradually, with a certain slowdown. Assign the patient a dose of active substances vary depending on the weight of the patient, method of administration, the indication and the severity of the disease.

The method according to the invention is explained more in digislide-0,063 mm) of the firm E. Merck, Darmstadt.

Research by thin-layer chromatography was performed using ready TSHUR-plates, silica gel 60 F 254, company E. Merck, Darmstadt.

The ratio of components in eluent for all chromatographic studies indicated in all cases in relation to volume/volume.

Example 1

3-(2-Dimethylaminomethyl-3,4-dihydronaphtho-1-yl)phenol hydrochloride

Stage 1

(RS)-2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalene-1-he

A solution of 21 ml of 3,4-dihydro-2H-naphthalene-1-it 200 ml of ice-cold vinegar consistently mixed from 8.2 g of dimethylamine, hydrochloride, 3.0 g of paraformaldehyde. The mixture was heated for 2 h to 100oWith, then under vacuum, the solvent evaporated and the residue was dissolved in 200 ml of water. Then was extracted three times respectively with 100 ml of diethyl ether. The aqueous phase with vigorous stirring due to additives portions of potassium carbonate was adjusted at pH 10. Then was extracted three times respectively in portions of 150 ml ethyl ester of acetic acid. The extracts were washed with a saturated solution of sodium chloride and dried over sodium sulfate. After filtration and evaporation of the filtrate under vacuum got to 15.4 g (75.6% of theory) of (RS)-2--2-Dimethylaminomethyl-l-(3-methoxyphenyl)-1,2,3,4-tetrahydronaphtyl-1-ol

A solution of 7.5 g of 1-bromo-3-methoxybenzene in 15 ml of dry tetrahydrofuran at -50oWith under stirring and in an atmosphere of protective gas N2mixed dropwise with 25 ml of a 1.6 molar solution of n-utility in n-hexane. Stirring is continued for another 30 min at -30oWith, then at -50oC was added dropwise a solution of 6.1 g of the product from stage 1 in 120 ml of dry tetrahydrofuran. The mixture is stirred first for 3 h at -50oC and then for 12 h at -20oC. After adding 100 ml of hydrochloric acid (10%) was twice extracted with respectively 100 ml of ethyl ether acetic acid. Hydrochloric acid phase due to the additives of potassium carbonate was adjusted at a pH of about 10 and was extracted three times respectively with 50 ml dichloromethane. The extracts were dried over sodium sulfate, the solvent is evaporated under vacuum and the residue was purified by column chromatography with ethyl ether acetic acid/methanol = 3/1 as eluent. In this way got to 5.3 g (56.5% of theory) of (1RS,2RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-1,2,3,4-tetrahydronaphtyl-1-ol in the form of a viscous oil.

Stage 3

3-(2-Dimethylaminomethyl-3,4-dihydronaphtho-1-yl)phenol hydrochloride

to 5.2 g of the product Ease (33% NVG). Then was evaporated under vacuum and the residue was dissolved in 150 ml of water. Further podslushivaet sodium carbonate and was extracted three times respectively with 50 ml dichloromethane. After washing the extracts with a saturated solution of sodium chloride and drying over sodium sulfate, evaporated and the residue was purified by column chromatography with ethyl ether acetic acid/methanol (5/1) as the eluent. Thus obtained base of the connection specified in the header translated with help of trimethylchlorosilane/water in 2-butanone in hydrochloride.

Yield 2.3 g (43.8% of theory), so pl. 197-199oC.

Example 2

Using indan-1-he, 3,4-dihydro-2H-phenanthrene-1-he, 6,7,8,9-tetrahydrobenzaldehyde-5-he, 7,8,9,10-tetrahydro-6N-benzocycloheptene-5 he, 5-phenyl-3,4-dihydro-2H-naphthalene-1-he, 6-phenyl-3,4-dihydro-2H-naphthalene-1-he, 6-(3-chlorophenyl)-3,4-dihydro-2H-naphthalene-1-he, 8,9,10,11-tetrahydrocyclopent[] naphthalene-1-he, 3,4-dihydro-2H-anthracene-1-he-or 6-(4-chlorophenyl)-3,4-dihydro-2H-naphthalene-1-he instead of 3,4-dihydro-2H-naphthalene-1-it, as well as optional other amines in stage 1, according to the method similar to that described in example 1, there are obtained the following compounds:

2A: 3-(6-dimethylaminomethyl-8,9-dihydro-7H-benzocycloheptene-5-yl)phenol, guided, so pl. 208-211oWITH,

2B: 3-(6-di-n-propylaminoethyl-8,9-dihydro-7H-benzocycloheptene-5-yl)phenol, hydrochloride, T. pl. 199-201oWITH,

2: 3-{6-[(methylphenethylamino)methyl]-8,9-dihydro-7H-benzocycloheptene-5-yl}phenol hydrochloride, T. pl. decomposition from 117oWITH,

2D: 3-{6-[(benzylmethylamine]-8,9-dihydro-7H-benzocycloheptene-5-yl} phenol hydrochloride, T. pl. decomposition 80oWITH,

2nd: 3-(6-dimethylaminomethyl-7,8,9,10-tetrahydrobenzaldehyde-5-yl)phenol, hydrochloride, T. pl. 251-253,5oWITH,

2ZH: 3-{ 6-[(cyclopropanemethylamine)methyl]-8,9-dihydro-7H-benzocycloheptene-5-yl}phenol hydrochloride, T. pl. 200-202oWITH,

2H: 3-(6-{ [methyl-(2-pyridin-2-retil)amino]methyl}-8,9-dihydro-7H-benzocycloheptene-5-yl)phenol, dihydrochloride, so pl. 100-105oWITH,

2i: 3-(2-dimethylaminomethyl-3H-inden-1-yl)phenol, hydrochloride, T. pl. 210-212oWITH,

2K: 3-(2-dimethylaminomethyl-3,4-dihydrogenated-1-yl)phenol, hydrochloride, T. pl. 253-254oWITH,

2: 3-(2-dimethylaminomethyl)-5-phenyl-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 250-263,5oWITH,

2m: 3-(2-dimethylaminomethyl-6-phenyl)-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 242-243oWITH,

2n: 3-[6-(3-chlorophenyl)-2-dimethylaminomethyl-3,4-dihydronaphtho-1-yl] phenol hydrochloride, T. pl. decomposition from 152o

2P: 3-(2-dimethylaminomethyl-3,4-dihydroanthracene-1-yl)phenol, hydrochloride, T. pl. 220-222oWITH,

2P: 3-[6-(4-chlorophenyl)-2-dimethylaminomethyl-3,4-dihydronaphtho-1-yl] phenol hydrochloride, T. pl. 245-247oWITH,

2C: 2-{ 6-[(furan-3-ylmethylamino)methyl] -8,9-dihydro-7H-benzocycloheptene-5-yl}phenol hydrochloride.

Example 3

(6-Methoxy-1-phenyl-3,4-dihydronaphtho-2-ylmethyl)dimethylamine, hydrochloride

Stage 1

A solution of 50 g of 6-methoxy-3,4-dihydro-2H-naphthalene-1-it in 500 ml of acetonitrile were mixed from 26.6 g of chloride N,N-dimethylmethyleneammonium and two drops of acetylchloride and the mixture was stirred for 30 h at 20oC. Then the crystalline product was isolated, washed with acetone and dried under vacuum at 40oC. in This way got to 70.9 g (92,5% of theory) of hydrochloride of the compound indicated in the title (so pl. 180-182o(C) from which using diluted sodium liquor was allocated by the base, which was extracted with dichloromethane. After drying the extracts over sodium sulfate and evaporation of the solvent under vacuum received 56,3 g of (RS)-2-dimethylaminomethyl-6-methoxy-3,4-dihydro-2H-naphthalene-1-it is in the form of a yellowish oil.

Stage 2

(1RS, 2RS)-2-Dimethylaminomethyl-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphtyl-1-and the supply of dry nitrogen was mixed dropwise with 50 ml of 2-molar solution finelite in cyclohexane/diethyl ether (70/30). Stirring was continued for another 2 h at -60oWith, and then was dissolved 150 ml of saturated solution of ammonium chloride. The organic phase was separated, and the aqueous phase was extracted twice more with ethyl ether acetic acid. The combined organic phases were washed with a saturated solution of sodium chloride and dried over sodium sulfate. Remaining after evaporation under vacuum of the solvent an oil was purified by column chromatography diisopropyl ether as eluent. The result was 21,3 g (78,0% of theory) of (1RS, 2RS)-2-dimethylaminomethyl-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphtyl-1-ol in the form of butter.

Stage 3

(6-Methoxy-1-phenyl-3,4-dihydronaphtho-2-ylmethyl)dimethylamine, hydrochloride

A solution of 6.3 g of the product from stage 2 in 100 ml of hydrochloric acid (10%) was stirred for 12 h at 20oC. Then podslushivaet 1 N. sodium lye and was extracted three times with dichloromethane. The extracts were washed with a saturated solution of sodium chloride and dried over sodium sulfate. Obtained after evaporation under vacuum of the solvent the crude product was purified by column chromatography with ethyl ether acetic acid/methanol (3/1) as eluent. Then the substrate using chartr the Example 4

(5-Methoxy-1-phenyl-3,4-dihydronaphtho-2-ylmethyl)dimethylamine, hydrochloride

Using 5-methoxy-3,4-dihydro-2H-naphthalene-1-initial connection stage mechanism and the procedure described in example 3 has been specified in the title compound as white crystals, so pl. 205-206oC.

Example 5

5A: 6-Dimethylaminomethyl-5-phenyl-7,8-dihydronaphtho-2-ol, hydrochloride

3.5 g of the product from example 3, similarly to that described in example 1, stage 3, were subjected to interaction with 100 ml of a solution of hydrogen bromide in glacial vinegar (33% NVG). After appropriate processing, purification by column chromatography and interaction with trimethylchlorosilane/water received 2.4 g (63,7% of theory) of the compound indicated in the title, in the form of white crystals, so pl. 189-191oC.

5B: 6-Dimethylaminomethyl-5-phenyl-7,8-dihydronaphtho-1-ol, hydrochloride.

According to the method described in example 5A, of the product of example 4 in a similar way has been specified in the header of the connection, so pl. 245-247oC.

Example 6

6-Dimethylaminomethyl-5-(3-hydroxyphenyl)-7,8-dihydronaphtho-2-ol, hydrochloride

Stage 1

(1RS, 2RS)-2-Dimethylaminomethyl-6-methoxy-1-(3-methoxyphenyl)-1,2,3,4-tetri light boil received the appropriate Grignard reagent, which then in 5-10oWith was added dropwise a solution of 46.7 g of (RS)-2-dimethylaminomethyl-6-methoxy-3,4-dihydro-2H-naphthalene-1-it (the product from example 3, step 1) in 100 ml dry tetrahydrofuran. Stirring was continued for 16 h at 22oFrom and after cooling to about 10oWith was dissolved 100 ml of saturated solution of ammonium chloride. Then the reaction mixture was diluted with 100 ml of water and 200 ml of diethyl ether, the phases were separated and the aqueous phase was extracted twice more, respectively 100 ml of diethyl ether. The combined organic phases were dried over sodium sulfate and vacuum remove volatile components. The oily residue was purified by column chromatography with ethyl ether acetic acid as eluent to obtain the result for 43.9 g (64,3% of theory) of (1RS, 2RS)-2-dimethylaminomethyl-6-methoxy-1-(3-methoxyphenyl)-1,2,3,4-tetrahydronaphtyl-1-ol.

Stage 2

6-Dimethylaminomethyl-5-(3-hydroxyphenyl)-7,8-dihydronaphtho-2-ol, hydrochloride

of 34.2 g of the product from stage 1 was mixed with 350 ml of a solution of hydrogen bromide in glacial vinegar (33% Nug) for 20 h at a temperature of 100-110oC. and Then was evaporated under vacuum and the residue was dissolved in 500 ml of water. After processing, anal the om acetic acid/methanol (3/1) as eluent. Thus obtained base of the connection specified in the header, using trimethylchlorosilane/water in 2-butanone was transferred into the hydrochloride.

Yield 12.2 g (41.2% of theory), so pl. 210-212oC.

Example 7

Isomeric with respect to the product in example 6 compounds 7a and 7b were obtained by applying appropriate raw substances, according to the method described in example 6:

7a: 6-dimethylaminomethyl-5-(3-hydroxyphenyl)-7,8-dihydronaphtho-1-ol, hydrochloride, T. pl. 260-262oWITH,

7b: 7-dimethylaminomethyl-8-(3-hydroxyphenyl)-5,6-dihydronaphtho-2-ol, hydrochloride, T. pl. 239-242oC.

Replacing (RS)-2-dimethylaminomethyl-6-methoxy-3,4-dihydro-2H-naphthalene-1-he in example 6, step 1, at (RS)-6-dimethylaminomethyl-2-methoxy-6,7,8,9-tetrahydrobenzaldehyde-5-he (7b), respectively (RS)-2-dimethylaminomethyl-6-(3-methoxyphenyl)-3,4-dihydro-2H-naphthalene-1-he (7 g) and carried out further reaction according to the method described in example 6, got:

7b: 6-dimethylaminomethyl-5-(3-hydroxyphenyl)-8,9-dihydro-7H-benzocycloheptene-2-ol, hydrochloride, T. pl. decomposition from 110oWITH,

7G: 3-[2-dimethylaminomethyl-6-(3-hydroxyphenyl)-3,4-dihydronaphtho-1-yl]phenol hydrochloride.

Example 8

3-(2-Dimethylaminomethyl-7-phenoxy-3,4-dihydronaphtho-1 is and potassium in 300 ml of dry pyridine was mixed with 35.7 g of 7-hydroxy-3,4-dihydro-2H-naphthalene-1-she and the mixture was heated to 40oC. then with stirring was added first to 19.9 g of copper oxide (II), and then dropwise to 39.6 g of bromine benzol. The reaction mixture was heated for 4 days under reflux. After almost complete evaporation under vacuum of the pyridine, the residue is thoroughly stirred with 200 ml of ethyl ether, acetic acid and filtered through silica gel. Then the filtrate was washed with saturated solution of ammonium chloride and sodium chloride, dried over sodium sulfate and evaporated under vacuum. The residue was purified by column chromatography with n-hexane/ethyl ether acetic acid as eluent to obtain the result 41,2 g (78.6% of theory) of 7-phenoxy-3,4-dihydro-2H-naphthalene-1-it.

Stage 2

2-Dimethylaminomethyl-7-phenoxy-3,4-dihydro-2H-naphthalene-1-he

Analogously to example 3, stage 1, of 40.5 g of the product from stage 1 in 500 ml of acetonitrile was subjected to interaction with 16.0 g of chloride N,N-dimethylmethyleneammonium. After appropriate processing of the received 45,8 g (91.3% of theory) 2-dimethylaminomethyl-7-phenoxy-3,4-dihydro-2H-naphthalene-1-it is in the form of butter.

Stage 3

(1RS, 2RS)-1-[3-(tert-butyldiphenylsilyl)phenyl] -2-dimethylaminomethyl-7-phenoxy-1,2,3,4-tetrahydronaphtyl-1-ol

The solution of 41,2 g (3-bro is ohoho nitrogen was mixed dropwise with 62.5 ml of a 1.6 M solution of n-utility in n-hexane. Stirring is continued for another 30 min, then was added dropwise a solution of 25.1 g of the product from stage 2 in 75 ml of dry tetrahydrofuran. The reaction mixture gave for 12 h to reach the 20oAnd then was dissolved by adding 100 ml of saturated solution of ammonium chloride. After dilution, respectively, portions of 200 ml of water and ethyl ester acetic acid, the organic phase was separated, and the aqueous phase was twice extracted with 100 ml ethyl ester of acetic acid. The combined organic phases were washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under vacuum. The residue was purified by column chromatography with ethyl ether acetic acid as eluent and received in this way to 32.9 g (61,6% of theory) of (1RS,2RS)-1-[3-(tert-butyldiphenylsilyl)phenyl]-2-dimethylaminomethyl-7-phenoxy-1,2,3,4-tetrahydronaphtyl-1-ol in the form of an almost colorless viscous oil.

Stage 4

(1RS, 2RS)-2-Dimethylaminomethyl-1-(3-hydroxyphenyl)-7-phenoxy-1,2,3,4-tetrahydronaphtyl-1-ol

A solution of 31.4 g of the product from stage 3 in 360 ml of dry tetrahydrofuran at a temperature in the range from 5 to +10oWith stirring and mixed dropwise 57.5 ml of 1-molar calc at 20oC, was mixed with 150 ml of saturated sodium chloride solution and was extracted three times respectively in portions of 150 ml ethyl ester of acetic acid. The extracts were dried over sodium sulfate and evaporated under vacuum. The residue was purified by column chromatography with ethyl ether acetic acid/methanol (5/1) as the eluent and thus received 17.3 g (88.7% of theory) of (1RS,2RS)-2-dimethylaminomethyl-1-(3-hydroxyphenyl)-7-phenoxy-1,2,3,4-tetrahydronaphtyl-1-ol in the form of a viscous oil, lightly colored in yellow.

Stage 5

3-(2-Dimethylaminomethyl-7-phenoxy-3,4-dihydronaphtho-1-yl)phenol hydrochloride

15.6 g of the product from stage 4 is similar to that described in example 3, stage 3, were subjected to interaction with 150 ml of 6 N. hydrochloric acid. After similar processing, and translation hydrochloride obtained by 12.1 g (73.8% of theory) 3-(2-dimethylaminomethyl-7-phenoxy-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, in the form of white crystals, so pl. 210-212oC.

Example 9

Replacing 7-phenoxy-3,4-dihydro-2H-naphthalene-1-he from example 8, step 2, to the corresponding derivatives of 5-methoxy (9a), 7-phenyl (9b), 7-Venetia (9g), 5-phenoxy (9D), 6-phenoxy (9F) and 7-n-butyl (9b), respectively, 2-phenoxy-6,7,8,9-tetrahydrobenzoic>/BR>9a: 3-(2-dimethylaminomethyl-5-methoxy-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 245-247oWITH,

9b: 3-(2-dimethylaminomethyl-7-phenyl-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 232-233oWITH,

9b: 3-(7-n-butyl-2-dimethylaminomethyl-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 202-205 areoWITH,

9g: 3-(2-dimethylaminomethyl-7-phenethyl-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 233-237oWITH,

9D: 3-(2-dimethylaminomethyl-5-phenoxy-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. 197-198oWITH,

9F: 3-(2-dimethylaminomethyl-6-phenoxy-3,4-dihydronaphtho-1-yl)phenol, hydrochloride, T. pl. of 224.5-226oWITH,

G: 3-(6-dimethylaminomethyl-2-phenoxy-8,9-dihydro-7H-benzocycloheptene-5-yl)phenol, hydrochloride, T. pl. 245-247oC.

Example 10

3-{ 6-[Allylmethylamine]-8,9-dihydro-7H-benzocycloheptene-5-yl}phenol hydrochloride

Stage 1

6-[(allylmethylamine]-6,7,8,9-tetrahydrobenzaldehyde-5-he

to 5.2 g of 6,7,8,9-tetrahydrobenzaldehyde-5-it, 0.96 g of paraformaldehyde and 10.0 g of allylmethylamine, hydrochloride in 60 ml of ice-cold vinegar subjected interaction is similar to that described in example 1, stage 1. After a similar treatment has received 6.7 g (84,8% of theory) of 6-[(allylmethylamine] -6,7,8,9-tetrahydrobenzaldehyde-7H-benzocycloheptene-5-yl}phenol hydrochloride

The product from stage 1 by the method described in example 8, stages 3-5, subjected to further processing. The result was 3-{6-[allylmethylamine]-8,9-dihydro-7H-benzocycloheptene-5-yl}phenol hydrochloride as white crystals, so pl. 156-159oC (decomposition).

Example 11

a) 3-[3-dimethylamino-1-(3-hydroxyphenyl)-2-methylpropenyl]phenol hydrochloride

Stage 1

(2RS)-3-dimethylamino-1,1-bis(3-methoxyphenyl)-2-methylpropan-1-ol, hydrochloride

of 27.0 g of magnesium shavings were mixed in 150 ml of dry tetrahydrofuran. Then was added dropwise 207,6 g of 1-bromo-3-methoxybenzene dissolved in 400 ml of dry tetrahydrofuran, and the addition was carried out in such a way that the reaction mixture while gently boiling. After adding the heating continued for one hour under reflux, then cooled to 5-10oC and at this temperature was added dropwise 166,0 g of (RS)-3-dimethylamino-1-(3-methoxyphenyl)-2-methylpropan-1-she dissolved in 400 ml of tetrahydrofuran. The reaction mixture was stirred overnight, then was re-cooled to 5-10oC. by Adding 300 ml of 20% aqueous solution of ammonium chloride solution of Grignard reagent was decomposed. Then the reaction mixture was diluted with 400 m of the joint organic phases are dried over sodium sulfate and the solvent was removed. The residue (342 g) was dissolved in 4000 ml of 2-butanone and mixed with 81,5 g trimethylchlorosilane and 13.5 ml of water. During the night when 4-5oWith in the form of crystals fell 165.0 g (60% of theory) of 3,3-bis(2-hydroxyphenyl-2-methylprop-2-enyl)dimethylamine, hydrochloride, T. pl. 158-160oC.

Stage 2

3-[3-Dimethylamino-1-(3-hydroxyphenyl)-2-methylpropenyl]phenol hydrochloride

58 g of (2RS)-3-dimethylamino-1,1-bis(3-methoxyphenyl)-2-methylpropan-1-ol, hydrochloride from stage 1 was dissolved in 2000 ml of concentrated Hydrobromic acid (47%) and over 7 h was heated under reflux. After cooling to room temperature the reaction mixture was mixed with 800 ml of water, 2000 ml of dichloromethane and 80 g of sodium bicarbonate. After separation dichloromethane phase the aqueous phase was twice extracted with 1000 ml ethyl ester of acetic acid. The combined organic phases were dried over sodium sulfate and the solvent was removed. The remainder (42 g), dissolved in a mixture consisting of 100 ml of ethyl ester of acetic acid and 100 ml of tetrahydrofuran (THF) was purified by column chromatography. After elution with ethyl ether acetic acid/methanol (4/1) received 22 g of the base, which was dissolved in 500 ml of 2-butanone and was mixed with 8.5 g trim and cleaning was suspiciously in 1000 ml of 2-butanone. The suspension was stirred for 5 h using a reverse refrigerator. After cooling to room temperature was obtained 13.5 g of hydrochloride (26.4% of theory), so pl. 222-224oC.

b) Z-3-(1-Biphenyl-4-yl-3-dimethylamino-2-methylpropyl)phenol, hydrochloride

As described in example 11a methodology and using (RS)-1-biphenyl-4-yl-3-dimethylamino-2-methylpropan-1-he, similarly received by the connection specified in the header, so pl. 192-194oC.

Using the appropriate substituted dimethylaminohigher-1-ones in stage 1 at a similar stage mechanism has received the following connections:

11b: E-3-[1-(3,4-dichlorophenyl)-3-dimethylamino-2-methylpropyl] phenol hydrochloride, T. pl. 176-178oWITH,

11g: Z-3-[1-(4-chlorophenyl)-3-dimethylamino-2-methylpropyl]phenol hydrochloride, T. pl. 144-146oWITH,

11: Z-3-[3-dimethylamino-2-methyl-1-(4-phenoxyphenyl)propenyl]phenol hydrochloride, T. pl. 190-192oWITH,

11th: Z-3-(3-dimethylamino-2-methyl-1-p-tolylpropan)phenol, hydrochloride, T. pl. 200-201oWITH,

G: Z-3-(2-dimethylaminomethyl-1-phenylbut-1-enyl)phenol, hydrochloride, T. pl. 188-190oWITH,

Z: Z-3-[1-(4'-chlorobiphenyl-4-yl)-3-dimethylamino-2-methylpropyl]phenol hydrochloride, T. pl. 156-158oWITH,

11And: Z-3-[3-dimethylamino-2-IU is ylphenyl)propenyl]phenol, hydrochloride, T. pl. 183-185oWITH,

11L: Z-3-[3-dimethylamino-1-(4-hydroxyphenyl)-2-methylpropenyl]phenol hydrochloride,

11m: Z-3-(1-benzo[1,3]dioxol-5-yl-3-dimethylamino-2-methylpropyl)phenol, hydrochloride, T. pl. 121-124oC.

The following studies on the binding of opioid receptor show that the proposed according to the invention the compounds of formula I have an extremely high effectiveness as analgesics.

Research associate-opioid receptor

Research to identify affinity proposed according to the invention compounds of formula I with-opiate receptor were performed on homogenates of the brain membranes of male Wistar rats (homogenate brain without cerebellum, Pons and medulla oblongata).

To this end, respectively svezhepriobretenny the brain of rats under ice cooling homogenized in 50 mmol/l Tris-HCl (pH 7.4) and for 10 min, centrifuged at 5000 g and 4oC. After desantirovaniya and discarding the supernatant re-dissolution and homogenization of the membrane sediment in 50 mmol/l Tris-Hcl (pH 7.4) and the homogenate for 20 min, centrifuged at 20000 g and 4oC. This stage leaching Povera/l Tris-HCl, 20% glycerol (wt./vol.), of 0.01% bacitracin (wt. /about. ) (pH 7.4) and aliquot quantities were frozen prior to testing. For studies on the binding of receptor aliquots were thawed and diluted in appropriate buffer at a ratio of 1:10. As a buffer in these studies used 50 mmol/l Tris-HCl, 5 mmol/l MgCl2(pH 7.4) supplemented with 0.1% (wt./about.) bovine serum albumin, and as a radioactive ligand used 1 nmol/l (3H)-2-D-Ala-deltorphin II. The share of non-specific binding was determined in the presence of 10 mcmole/l of naloxone.

Other mixtures of compounds according to the invention were added sequentially changing concentrations and determined the displacement of the radioactive ligand from its specific bound state. Corresponding mixtures, which are explored in three parallel experiments were incubated for 90 min at 37oWith, and then to identify associated with the homogenate membrane radioactive ligand, the latter was collected by filtering through a glass fiber filter (GF/B). Radioactivity disk glass fiber filter was measured after adding scintillator in the counter beta radiation.

The affinity of compounds for izobreteniya regression. Based on the IC50-values according to the equation of Cheng-Prusoff expected values TOi. These Kivalues are indicated as mean values standard deviations conducted independently from other experiments at number 3.

The data presented in table show that the proposed according to the invention the amino compounds possess analgesic efficacy, and this biological efficacy partially or predominantly mediated via opioid receptors and thus can be confirmed.

As an effective and selective-opioid agonists and antagonists compounds of General formula I according to the invention can be used as tools in pathological conditions for which treatment is usually used agonists and antagonists, opioid receptor. Preferably the compounds of General formula I can be used as analgesics.

1. Substituted amino compounds of General formula I

< / BR>
where R1means H, HE, O-C1-6alkyl, and R1is not N if R2and R7represent H or in position 7 och3group substituted;

R2means N (if R1is not the Bo 6,7-benzo, unsubstituted, single or disubstituted Cl, F, CF3WITH1-6the alkyl, O-C1-6the alkyl, HE (and, if R1and R2or R7are H, R2or R7can't imagine a CF3group, and R2or R7in position 7 can't be a co3group), or R2and R7both together represent-O-(CH2)(1-2)-O- (in position 5,6 or 6,7);

R3means N;

R4means1-6alkyl, or R3and R4both together represent -(CH2)(1-4)-;

R5means1-6alkyl, C3-7cycloalkyl;

R6means1-6alkyl, C1-6alkylaryl, -CH2-CH= C(R8)2, -CH2-(C3-7)cycloalkyl,3-7cycloalkyl,1-6alkylglycerol;

R7means N (if R1is not H, HE, C1-6alcl, O-aryl, C2-6alkynylaryl,1-6alkoxy, Cl, F, aryl, C1-6alkylaryl, 5,6 - or 6,7-benzo, unsubstituted, single or disubstituted Cl, F, CF3WITH1-6the alkyl, O-C1-6the alkyl, HE (and, if R1and R2or R7are H, R2or R7can't imagine a CF3group, and R2or R7the floor is "heterocyclyl" denotes a 5 - or 6-membered unsaturated or saturated, optionally condensed with aryl heterocyclic system containing 1 or 2 heteroatoms from the group comprising nitrogen, oxygen and/or sulfur,

or pharmaceutically applicable salts of these compounds.

2. Substituted amino compounds on p. 1, wherein R6means1-6Alkylglucoside or1-6alkylaryl, R2and R7means1-6alkylaryl, a R1, R3-R5shall have the meaning specified in paragraph 1.

3. Substituted amino compounds on p. 1, wherein R2, R7mean aryl, and R1, R3-R6and R8shall have the meaning specified in paragraph 1.

4. Substituted amino compounds on p. 1, wherein R1means HE or-O-C1-6alkyl, R5means1-6alkyl, R6means1-6alkyl, and R2-R4and R7shall have the meaning specified in paragraph 1.

5. Substituted amino compounds on p. 1, wherein R1IT means, R5means methyl, R6means methyl, and R2-R4and R7shall have the meaning specified in paragraph 1.

6. The method of obtaining the compounds of formula I

< / BR>
where R1-R7shall have the meaning specified in paragraph 1,

about the about and in the formula I,

subjected to interaction with organic or inorganic acids in the temperature range from 0 to 100oC, and the tertiary alcohol of General formula II are due to the fact that first-aminoketone General formula III

< / BR>
where R3-R6have the same meaning as in formula I, R9identical to R2, a R10identical to R7except in those cases where the hydroxyl function is represented in a protected form as benzyloxy or silyloxy,

subjected to interaction with the ORGANOMETALLIC compound of the formula IV

< / BR>
in which Z denotes MgCl, MgBr, MgI or Li, a R11represents hydrogen, O-C1-6alkyl or a protected hydroxyl function, represented as benzyloxy or silyloxy,

obtaining the compounds of formula IIA

< / BR>
which is then transferred to the compound of formula II.

7. Substituted amino compounds of General formula I on p. 1, having analgesic activity.

8. Substituted amino compounds of General formula I according to p. 7 for receiving medicines, representing an analgesic.

 

Same patents:

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The invention relates to a new derivative of 2-(3H)-oxazolone formula I, where R1is an alkyl group or a group-NR4R5where each R4and R5independently are hydrogen, alkyl or benzyl group, R2is naftilos, unsubstituted phenyl or a phenyl group substituted by 1 to 3 halogen atoms, alkyl groups, hydroxy, alkoxy or triptorelin group, R3is hydrogen or alkyl group
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< / BR>
where m is 0 or 1, n is 0,

R1is hydrogen, benzyl, (C1-C2-alkyl)-(C6-C10-aryl), heteroaryl-C1- C2-alkyl,

A represents a group

< / BR>
or

< / BR>
where R6, R7, R8, R9- C1-C6-alkyl, Z1and Z2is hydrogen, represents6-C10aryl that may be substituted for CH3or HE

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