Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene or their pharmaceutically acceptable salts and the composition having cardiovascular activity

 

(57) Abstract:

Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene 1, where R1and R2- different and mean hydrogen or OY'; Y and Y' are the same or different and mean hydrogen or acyl ethylcarbamate acid; R3is hydrogen, alkyl; R4and R5- same or different and mean hydrogen, halogen, alkyl or alkoxy; m = 1-2; n = 3-7, and their pharmaceutically acceptable salts. Pharmaceutical composition containing as an active ingredient the compound I exhibits cardiovascular activity. The compounds I are agonists of dopaminergic receptors that are active also when administered orally, are characterized by long term, resulting applicable for the treatment of cardiovascular diseases. 2 s and 5 C.p. f-crystals, 2 tab. I

The present invention relates to new compounds that have effects on the cardiovascular system, in particular to derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene with the properties of the dopaminergic agonist receptors, and pharmaceutical compositions based on them.

It is known that various gidroksilirovanii derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene yavlyaetsya dependencies: activity-structure, in order to identify structures with the best dopaminergic activity and eliminating this undesirable action of dopamine.

Interesting review of such studies is given in work published by H. E. Katerinopoulos, and D. T. Schuster in "Drugs of the Future", so 12(3), pp. 223-253 (1987).

However, despite studies the topology of dopaminergic receptors is still not clear, although in the last ten years and was offered several models of the receptor.

Among the compounds that are closely related to dopamine and/or 2-amino-1,2,3,4-tetrahydronaphthalene, the authors found that the presence of C3- C4is an alkyl substituent in the amino group is one of the conditions for the appearance of dopaminergic activity, but the remainder of the second substituent of the amino group was not found.

However, in the literature there are several examples showing that the structure of these two substituents of the amino group may vary within wide limits, and in practice, small changes in a molecule can affect both quantitatively and qualitatively, on the pharmacological activity is very noticeable.

The following are the most important examples.

In EPA 0072061 (Fisons) revealed that among PROCHILE

< / BR>
in which

X is - (CH2)ngroup, possibly substituted by a hydroxy-group; n = 1-7; R1and R2the same or different and mean hydrogen, alkyl or phenyl; D2means hydrogen, alkyl, phenyl, alkyl, substituted phenyl, in turn substituted with halogen, alkyl, amino, alkoxygroup or nitrogroup, or D2can mean phenylethylene the rest of dopamine or hydroxy-1,2,3,4-tetrahydronaphtalene the rest.

Among the compounds disclosed in EPA 0072061, the connection formula

< / BR>
internationally trivial name dopexamine (The Merk Index, XI ed., N 3418, page 538) and the only connection that, as far as known at present obtained and used in medicine for the treatment of acute heart failure.

It is important that dopexamine, despite given him the preference among several of the compounds disclosed and are shown as examples in EPA 0072061, is less active than dopamine, dopaminergic agonist receptors, and dopamine, is not absorbed when administered orally [A. Fitton and P. Benfield, Drugs, 39(2), 308-330 (1990)].

In EPA 0142283 (Fisons) discloses a class of compounds, which EN is the temperature describes several examples of the compounds with the structure of catecholamine preserving the beneficial effect of dopexamine and also entered through the mouth, or increasing the selective action in relation to both dopaminergic receptors. However, as far as is known, none of these compounds does not show all the required properties.

For specific treatment of hypertension and congestive heart failure in medicine there is still a need for drugs that are more potent than dopamine, dopaminergic agonists, but not showing selective actions on specific subtype of receptor (D1or D2), which do not interact with other receptor systems, and especially , 5-HT2receptors and which at the same time do not have any side effects or adverse therapeutic effects of dopamine, such as the absence of absorption by oral administration and short term actions (Goodman and Gilmans, VII ed., pages 161-163).

In this regard, it is worth noting EPA 0321968 (Simes Societa Italiana Medicinali e Sintetici S. p.A., currently, Zambon Group S. p.A.), where are disclosed compounds of the formula:

< / BR>
where

R and R1are the same or different and mean Boesky carboxylic acids or perhaps substituted karbinovykh or coal acid or phosphoric acid; n and p = 0-1; m = 1, 2, 3, and 4; n+p = 1, m+n = 2, 3 or 4; R2and R3that are the same or different, signify hydrogen, halogen atom, alkyl or alkoxygroup;

and pharmacopoiea based on them.

Compounds described in EPA 321968, are agonists of the D1and D2dopaminergic receptors at the same time have a1- antagonistic action, do not interact with other receptor systems and due to their activity when administered orally can be turned into acceptable prodrugs.

Currently found agonists of dopaminergic receptors with higher than dopamine activity, essentially do not interact with other receptor systems and, most importantly, which are absorbed when administered orally and have a prolonged action.

Such compounds according to the present invention are derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene General formula I:

< / BR>
in which

R1and R2which are different, represent a hydrogen atom or a group OY';

Y and Y', the same or different, represent a hydrogen atom or acyl, which is the remainder of normal or branched C1- C is a hydrogen atom or a C1- C4-alkyl;

R4and R5the same or different and mean a hydrogen atom or halogen, C1- C3-alkyl or alkoxygroup;

and their pharmaceutically acceptable salts.

Compounds of the present invention are agonists of dopaminergic receptors that are active also when administered orally and which are characterized by long term, resulting applicable for the treatment of cardiovascular diseases, in particular for the treatment of hypertension, congestive heart failure, renal failure, for the treatment of peripheral arteriopathy and insufficiency of blood vessels of the brain.

Preferred compounds of formula I, where R1mean group OY'; R2Y, Y' denote a hydrogen atom; n = 5, 6, 7.

In particular, preferred compounds of formula I, where R1mean group OY', R2, Y, Y' denote a hydrogen atom, n = 6, m = 1, R4and R5the same or different and mean a hydrogen atom, methyl, methoxy group or chlorine.

Of the compounds of formula I, preferred are also the compounds of formula I, where Y and Y' are identical or different and denote acyl, which is a remnant of the criminal code of the n asymmetric carbon atom, consequently exist as stereoisomers.

The compounds of formula I may be in the form of stereoisomeric mixtures, and as individual stereoisomers.

While it is desirable that the compounds of formula I were in optically active form.

Typical values of the alkyl or alkoxygroup in the definitions of R3, R4, R5and R6include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, methoxy, ethoxy-, n-propoxy and isopropoxy.

The atoms of halogen is fluorine, bromine, chlorine and iodine.

The term "acyl, which is the residue of an aliphatic carboxylic acid" means an acyl radical derived from a normal or branched aliphatic carboxylic acid with 1-6 carbon atoms, possibly substituted by phenyl, halogen or alkoxycarbonyl; a typical example of such a group is the acyl group of the following acids: formic, acetic, propionic, butyric, isoalkanes, valerianic and pavlinovic.

According to the General concepts of derivatives of catechol compounds of formula I where at least one of the groups Y and Y' is other than hydrogen, are Pro-drugs of the corresponding connection of the relevant compounds I, in which Y and Y' are different and are represented by acyl derived acetic, propionic, butyric, somaclonal and allylcarbamate acid.

Pharmaceutically acceptable salts of compounds of formula I include salts with organic or inorganic acids such as, for example, hydrochloric, Hydrobromic, uudistoodetena, nitric, sulfuric, phosphoric, acetic, aspartic, methansulfonate acid and 3,7-decret.-butylnaphthalene-1,5-disulfonate (debolina acid).

The compounds of formula I can be obtained below way.

The method consists in the reaction between the compound of the formula

< / BR>
where

R7means a hydrogen atom or a protective group selected from, for example, methyl, benzyl, benzoyl and 4-methoxybenzoyl;

R8and R9differ from each other and denote a hydrogen atom or a group-OR7;

m has the values specified above for formula I;

and the acid of General formula

< / BR>
in which

n, R3, R4and R5have the meanings indicated above for formula I; or its reactive derivative, such as allalone or a mixed anhydride, probably formed in situ, in an inert Rast obtain the intermediate compounds of the formula

< / BR>
where

m, n, R3, R4, R5, R7, R8, R9take the values specified for formulas II and III.

The compounds of formula IV restore before or after, if necessary, the release of hydroxyl groups, to obtain the compounds of formula I.

The recovery of the compounds of formula IV can be carried out using electrophilic reducing agents, in particular, DIBORANE, possibly in the form of a complex with dimethyl sulfoxide, tetrahydrofuran, aliphatic amines, such as triethylamine or aromatic amines, such as N,N-diethylaniline or pyridine.

Or restoration can be carried out by nucleophilic reducing agents such as metal hydrides, for example, sociallyengaged.

The reaction of recovery are in an acceptable solvent such as, for example, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane.

The release of hydroxyl groups, when necessary, conduct a usual method, for example, by hydrolysis or hydrogenolysis.

The compounds of formula II are known or can be easily obtained by known methods (patent UK 1509454, The Wellcome Foundation Ltd.).

Connection fosinoprilat formula

< / BR>
in which

R3and n take the values specified for formula I, with allelochemical formula

< / BR>
in which

R4and R5have the meanings indicated above for formula I and X represents a chlorine atom or bromine.

The method of obtaining compounds of formula I may comprise a different sequence of stages.

Thus, the compound of formula II may initially interact with the amino acid of formula V or its reactive derivative to obtain the intermediate compounds of formula

< / BR>
in which

m, n, R3, R7AND R9take the values specified for formula I or II,

then acelerou allelochemical formula VI to obtain the intermediate compound of formula IV. Subsequent restoration of the above ways to get the compounds of formula I.

The compounds of formula I in optically active form can be obtained by the optical separation or stereospecific or stereoselective synthesis using optically active starting compound of formula II. Obtaining compounds of formula I can be carried out by esterification of one or both of the hydroxy groups by conventional methods.

3when R3= H), for example, in the form of benzyloxycarbonyl derived.

Such protective group after the esterification can be easily removed, for example, by hydrogenolysis.

Obtaining salts of compounds of the formula I is carried out by conventional methods.

The compounds of formula I are agonists of the D1and D2dopaminergic receptors, which at least 2-10 times more active than dopamine, which is shown in in vitro tests for binding (example 11).

In addition, these compounds are more active than dopexamine, and compared with the compounds disclosed wyrezyserowany EPA 0321968.

Tests conducted to determine the interaction with other receptor systems, showed that the compounds of formula I with other systems do not interact, i.e. compounds have high specificity.

The compounds of formula I do not have actions on the Central nervous system, and this is another valuable property, not in other compounds having the structure of catecholamine.

The selectivity and specificity of action of the receptor in combination with the lack of action on the Central nervous system does hipertenzivni therapy, in the treatment of congestive heart failure, renal failure, for the treatment of peripheral arteriopathy and insufficiency of blood vessels of the brain.

In addition to the above higher pharmacological activity feature of the compounds that are the subject of the present invention that distinguish them from previously known compounds is the ability of the compounds to be absorbed when administered orally, and the duration of their validity (example 12).

Therefore, for practical application in medicine, the compounds of formula I can be introduced by infusion and parenteral way that distinguishes them from dopamine and dopexamine.

Therapeutic dosages of the compounds will generally be in the range from 10 mg to 1 g per day è5-300 mg with each dose.

The present invention also relates to pharmaceutical compositions having cardiovasculatory activity comprising as an active ingredient derived amino-1,2,3,4-tetrahydronaphthalene and conventional additives. As derived amino-1,2,3,4-tetrahydronaphthalene it contains a compound of formula I or its pharmaceutically acceptable salt in effektivnosti for parenteral, and for oral administration. Examples of such pharmaceutical compositions are tablets, pills, coated with sugar or film, as well as syrups and capsules, for oral and intramuscular, subcutaneous or intravenous injection. However, any compound of formula I in the composition of this song is used as the current (active) start. Thus, the claimed pharmaceutical composition comprises at least one of the above compounds of formula I, as well as the well-known pharmaceutically acceptable excipients. Examples of fillers suitable for preparation of oral pharmaceutical compositions are glycerin, starch, Ragi (glycols), resin tragakant and gum Arabic, silicon dioxide, lactose, polyvinylpyrrolidone, sucrose, glucose, sorbitol, magnesium stearate and calcium, talc, sodium lauryl sulfate, carboxymethylcellulose. Examples of fillers suitable for preparation of parenteral pharmaceutical compositions are bidistilled water, propylene glycol, etiloleat.

The pharmaceutical preparation can be carried out according to traditional methods.

In some cases, for dactyloides invention more convenient may be the use of prodrugs of formula I.

For example, the use of prodrugs may improve properties of the drug or compatibility with other active ingredients.

The choice of compounds of formula I in the form of catechin (Y=Y'=H) or a corresponding prodrug is defined by the technical expertise of a specialist.

The following examples are given to better illustrate the present invention.

Example 1

Obtain (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2 - naphtylamine, hydrochloride

Method AND

To a solution of (S)-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (50 g, 241 mmol) and Propionaldehyde (14.8 g, 255 mmol) in ethanol (95o, 300 ml) is added 10% palladium on coal (50% in water).

The reaction mixture is stirred for 7 hours at 35oC under hydrogen pressure of 2.7 ATM.

The catalyst is filtered off and the solvent evaporated under reduced pressure. The residue is dissolved in absolute ethanol (300 ml) and add a solution of hydrochloric acid in ethyl ether (15% of the mass/about) to strongly acidic pH values.

The precipitate is filtered and dried in vacuum at 40oC.

The connection specified in the header, get back in the white matter of 57.6 g) so pl. 257 - 262oC.

1H-is,77 (s, 3H), 6,83 (d, 1H), 6.89 in (d, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 250 (M+1).

By the same method, but using Butyraldehyde instead of Propionaldehyde and Hydrobromic acid instead of hydrochloric acid, receive the following connection:

the hydrobromide (S)-N-butyl-5,6-dimethoxy-1,2,3,4-tetrahydro - 2-naphtylamine

So pl. 226 - 228oC.

1H-NMR (200 MHz, CDCl3) (free base) (ppm): of 0.9 (t, 3H), 1,26 - of 1.62 (m, 5H), was 2.05 (m, 1H), and 2.6 (m, 2H), 2,69 (m, 2H), 2,81 was 3.05 (m, 3H), of 3.77 (s, 3H), 3,81 (s, 3H), 6,7 (d, 1H), 6.87 in (d, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 264 (M+1).

Method B

To a solution of (S)-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (31 g, 150 mmol) and triethylamine (23 ml, 165 mmol) in dimethylformamide (310 ml) at room temperature under nitrogen atmosphere add propionate (14,3 ml, 165 mmol).

The reaction mixture is stirred for 1 hour, then transferred into water (1.5 l), the precipitate filtered and washed with water.

After drying in vacuum at 50oC get (S)-N-propionyl 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (32,8 g), so pl. 149 - 151oC.

1H-NMR (300 MHz, CDCl3) (free base) (, H).

Mass spectrum (chemical ionization, isobutane, positive ions): 264 (M+1), 190.

To a solution of (S)-N-propionyl 5,6-dimethoxy-1,2,3,4-tetrahydro - 2-naphtylamine (22,5 g, 85.4 mmol) obtained in the aforementioned manner, in anhydrous tetrahydrofuran (900 ml) at room temperature in nitrogen atmosphere are added dropwise complex, borane-dimethyl sulfide (82 ml, 854,4 mmole). The reaction mixture is boiled for 1.5 hours. After cooling to 15oC carefully added dropwise a solution of 36% hydrochloric acid (9.5 ml) in methanol (247 ml). The reaction mixture is boiled for 2 hours, then the solvent (approximately 500 ml) is distilled off at atmospheric pressure and the residue is evaporated to dryness in a vacuum. The resulting crude product is dissolved in absolute ethanol and the solution is heated to boiling with obtaining after cooling and filtration the title compound (23 g), with the same physico-chemical and spectral characteristics as the product obtained by method A.

By the same method obtained the following link:

the hydrobromide (S)-N-butyl-5,6-dimethoxy-1,2,3,4-tetrahydro - 2-naphtylamine with the same physico-chemical and spectral characteristics as the product obtained by method A.

Example 2

Received-5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (22 g, 76,9 mmole) obtained by the method of example 1, in 48% Hydrobromic acid (220 ml) boil (about 130oC) 3 hours.

The solvent is evaporated to dryness in vacuo, the residue is dissolved in toluene and the solvent evaporated to dryness. The resulting crude product is suspended in ethyl acetate and after filtration receive the connection specified in the header, so pl. 219 - 222oC.

1H-NMR (300 MHz, DMSO-d6) (ppm): 0,93 (t, 3H), by 1.68 (m, 3H), of 2.25 (m, 1H), 2,4 - by 2.55 (m, 1H), 2,7 - 3,1 (m, 5H), and 3.31 (m, 1H), 6,40 (d, 1H), is 6.61 (d, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 222 (M+1).

A similar method receives the following link:

the hydrobromide (S)-N-butyl-5,6-dihydroxy-1,2,3,4-tetrahydro - 2-naphtylamine

So pl. 240 - 242oC.

1H-NMR (200 MHz, DMSO-d6) (ppm): of 0.9 (t, 3H), of 1.35 (m, 2H), 1,62 (m, 3H), 2,13 - 3,11 (m, 7H), to 3.38 (m, 1H), to 6.39 (d, 1H), and 6.6 (d, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 236 (M+1).

Example 3

Obtaining hydrochloride (R)-N-propyl-6,7-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine

To a solution of (R)-6,7-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (5 g, 19 mmol) and Propionaldehyde (1.1 g, 19 mmol) in ethanol (95o150 ml) is added 10% of pologoroda 2.7 ATM.

The catalyst is filtered off and the solvent evaporated under reduced pressure. The residue is dissolved in absolute ethanol (100 ml) and add a solution of hydrochloric acid in ethyl ether (15% wt./about.) to strongly acidic pH values.

The solvent is evaporated and the crude product is purified by chromatography on a column of silica gel (230 - 400 mesh) by elution with a mixture of methylene chloride/methanol/acetic acid (90 : 10 : 1).

The connection specified in the header (3.8 g) was obtained as a white substance with so pl. 201 - 203oC.

1H-NMR (200 MHz, DMSO-d6) (ppm): 0,93 (t, 3H), 1.56 to of 1.78 (m, 3H), 2,19 (m, 1H), 2,53 - to 3.02 (m, 6H), 3,30 (m, 1H), 6,46 (s, 2H).

Mass spectrum (chemical ionization, isobutane, positive ions): 222 (M+1).

A similar technique obtained the following link:

hydrochloride (R)-N-butyl-6,7-dihydroxy-1,2,3,4-tetrahydro - 2-naphtylamine

So pl. 126 - 128oC.

1H-NMR (200 MHz, DMSO-d6) (ppm): to 0.89 (t, 3H), of 1.34 (m, 2H), 1,54 and 1.80 (m, 3H), 2,19 (m, 1H), 2,67 - 2,78 (m, 3H), 2,85 - 3,10 (m, 3H), 3,42 (m, 1H), 6,45 (s, 2H).

Mass spectrum (chemical ionization, isobutane, positive ions): 236 (M+1).

Example 4

Obtain 6-[(2-methoxyphenoxy)acetylamino]hexanoic acid

To a solution offering dropwise simultaneously added solution (2 methoxyphenoxy)acetylchloride (24 g, 0.12 moles) in methylene chloride (26 ml) and sodium hydroxide solution (4.8 g, 0.12 moles) in water (26 ml).

After 1 hour, the phases are separated, the aqueous phase is washed with methylene chloride, acidified with hydrochloric acid and extracted with methylene chloride. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated. Purification of the obtained crude product column chromatography on silica gel (230 - 400 mesh) by elution with a mixture of methylene chloride/methanol (9 : 1) get the connection specified in the header (20 g), so pl. 69 - 70oC (ethyl acetate).

1H-NMR (300 MHz, CDCl3) (ppm): to 1.37 (m, 2H), 1.5 and 1.7 (m, 4H), of 2.33 (t, 2H), 3.33 and (m, 2H), 3,88 (s, 3H), 4,55 (s, 2H), 6,9 - 7,05 (m, 4H), and 7.1 (br.t., 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 296 (M+1).

According to the same method the following compounds:

6-[(2-chlorophenoxy)acetylamino]hexanoic acid

So pl. 87 - 88oC,

1H-NMR (200 MHz, DMSO-d6) (h/m): 1,12 - of 1.33 (m, 2H), 1,35 - of 1.56 (m, 4H), to 2.18 (t, 2H), 3,12 (m, 2H), 4,58 (s, 2H), 6,98 (m, 2H), 7,31 (dd, 1H), 7,43 (dd, 1H), to 7.93 (br.t., 1H), 11,98 (br.s., 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 300 (M+1).

6-[[(2-chloro-4-methyl)phenoxy]acetylamino]hexanoic acid), 3,1 (m, 2H), 4,51 (s, 2H), 6.89 in (d, 1H), 7,18 (dd, 1H), 7,26 (dd, 1H), 7,89 (br.t., 1H), 12,02 (br.s., 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 318 (M+1).

6-[[(2-methoxy-4-methyl)phenoxy]acetylamino]hexanoic acid

oil,

1H-NMR (200 MHz, CDCl3) (ppm): 1,24 - of 1.42 (m, 2H), 1,45 to 1.7 (m, 4H), to 2.29 (s, 3H), 2,31 (t, 2H), and 3.31 (m, 2H), of 3.84 (s, 3H), of 4.49 (s, 2H), 6,65 - to 6.80 (m, 3H), 7,08 (br.t., 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 310 (M+1).

3-[(2-methoxyphenoxy]acetylamino]propionic acid

So pl. 95 - 97oC,

1H-NMR (300 MHz, DMSO-d6) (ppm): to 2.42 (t, 2H), 3,34 (m, 2H), of 3.77 and with 3.79 (2s, 3H), 4,42, and to 4.62 (2s, 2H), 6,8 - 7,03 (m, 4H), of 7.96 (br.t., 1H), 12,42 (br.s., 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 254 (M+1).

3-[(2-chlorophenoxy)acetylamino]propionic acid

So pl. 143 - 144oC,

1H-NMR (200 MHz, DMSO-d6) (ppm): 2,43 (t, 2H), 3,36 (m, 2H), 4,57 (s, 2H), 6,99 (m, 2H), 7,27 (m, 1H), 7,42 (dd, 1H), 7,98 (br.t., 1H), 12,3 (br.s, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 258 (M+1).

3-[[(2-methoxy-4-methyl)phenoxy]acetylamino]propionic acid oil

1H-NMR (200 MHz, CDCl3) (ppm): 2,28 (s, 3H), of 2.72 (t, 2H), 3,69 (m, 2H), 3,82 (s, 3H), and 4.5 (s, 2H), 6,63 - of 6.78 (m, 3H)>/P>Example 5

Obtain 6-[N-methyl-N-[(2-methoxyphenoxy)acetyl] amino]hexanoic acid

To a solution prepared by propulsiveness for 20 minutes at - 10oC in toluene (150 ml) gaseous metalina, with stirring 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) (12.8 g, 84 mmole) and ethyl ester of 6-Bromhexine acid (12.3 g, 55 mmol). Then the temperature was raised to 20oC and the reaction mixture is stirred for 1 hour. The excess methylamine is removed propulsiveness nitrogen under reduced pressure until a neutral pH value.

To stir the reaction mixture is added a solution of (2-methoxyphenoxy)acetylchloride (5,4 g, 27 mmol) in toluene (10 ml). After an hour, add a saturated solution of sodium chloride and the phases are separated.

The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure.

The resulting crude product was then purified by chromatography on a column of silica gel (230 - 400 mesh) by elution with petroleum ether (so Kip. 40 - 70oC)/ethyl acetate (1:1).

Obtain 2.6 g of ethyl ester of 6-[N-methyl-N-[(2-methoxyphenoxy)acetyl] amino]hexanoic acid.

1H-NMR (200 Mghz, CDCl3) (ppm): of 1.23 (t, 3H), 1.30 and of 1.74 (m, 4H), of 1.84 (m, 1H is isace, isobutane, positive ions): 338 (M+1).

To a stirred solution of ethyl ester of 6-[N-methyl-N-[(2-methoxyphenoxy)acetyl] amino] hexanoic acid (2.5 g, 7.4 mmole) in methanol (5 ml) at room temperature add the potassium hydroxide solution of 1.1 g of 19.4 mmole) in water (5 ml).

The reaction mixture is stirred for 30 minutes, acidified with 1 N. hydrochloric acid to pH 1 and the solvent is evaporated to dryness under reduced pressure. The residue is treated with a mixture of methylene chloride with water. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure.

The resulting crude product was then purified column chromatography on silica gel (230 - 400 mesh) by elution with a mixture of methylene chloride/methanol/acetic acid (95:5:1).

Obtain 1.8 g of the compound indicated in the title, in the form of butter.

1H-NMR (200 MHz, CDCl3) (h/m): 1,30 (m, 2H), 1,42 was 1.69 (m, 4H), 2,28 (m, 2H), 2.91 in and 3.04 (2s, 3H), 3,30 - to 3.41 (m, 2H), of 3.84 (s, 3H), 4.72 in (s, 2H), 6,8 - 6,98 (m, 4H).

Mass spectrum (chemical ionisation, ammonia, positive ions): 310 (M+1).

According to the same method the following compounds:

6-[N-methyl-N-[[(2-chloro-4-methyl)phenoxy]acetyl]amino]hexanoic acid

1P CLASS="ptx2">

Mass spectrum (chemical ionizaciya, isobutane, positive ions): 328 (M+1).

3-[N-methyl-N-[(2-methoxyphenoxy)acetyl]amino]propionic acid

So pl. 71 - 73oC,

1H-NMR (200 SMC, DMSO-d6) (ppm): 2.41 and 2,6 (2t, 2H), 2,79 and 3,00 (2s, 3H), 3,50 (m, 2H, in), 3.75 (s, 3H), 4.72, and to 4.81 (2s, 2H), 6,76 - 6,99 (m, 4H).

Mass spectrum (chemical mononitate, isobutane, positive ions)% 268 (M+1).

3-[N-methyl-N-[[(2-chloro-4-methyl)phenoxy]acetyl]amino]propionic acid

so pl. 143 - 145oC,

1H-NMR (200 MHz, CDCl3) (ppm): 2,24 (s, 3H), 2,62, and 2,69 (2t, 2H), 2,93 3.14 (2s, 3H), 3,62 and 3.76 (2t, 2H), 4,71 and 4,80 (2s, 2H), 6,85 (t, 1H), of 6.96 (dd, 1H), 7,16 (dd, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 286 (M+1).

Example 6

Getting dihydrochloride (S)-(-)-N-propyl-N- [6-[2-(2-methoxyphenoxy] ethylamino]hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 1)

How A

a) To a solution of 6-[(2-methoxyphenoxy)acetylamino]hexanoic acid (63.5 g, 215 mmol) obtained by the method of example 4, in methylene chloride (420 ml) is added chloride thionyl (68,2 g, 573 mmole). After incubation for 2 hours at room temperature, the reaction mixture is evaporated to dryness under reduced pressure. Polucen is the target hydrobromide (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (50 g, 165 mmol) obtained by the method of example 2, in water (1000 ml) under nitrogen atmosphere add sodium borate (66.6 g) 331 mmol). The mixture is heated at 70oC until complete dissolution, then cooled to room temperature and add methylene chloride (100 ml), potassium carbonate (178,3 g, 1,290 mole) and with vigorous stirring a solution of yellow residue (obtained by the method of the above paragraph (a) in methylene chloride (400 ml). After incubation for 1 hour at room temperature, add toluene (500 ml).

After acidification with concentrated hydrochloric acid, the phases are separated. The aqueous phase is again extracted with methylene chloride (500 ml).

The collected organic phases are dried over anhydrous sodium sulfate, filtered and the solvent evaporated to dryness. The resulting residue is dissolved in tetrahydrofuran (334 ml) and the solution slowly with stirring complex, borane-dimethyl sulfide (172 g, 2,143 mol). The temperature spontaneously rises to 35oC, the reaction mixture was kept at this temperature for 30 minutes, then boil for 1.5 hours.

After cooling to 5oC for one hour add a solution of 37% hydrochloric acid (to 85.2 g, 0,864 mmole) in methanol (643 ml).

AI and then under reduced pressure to dryness. The residue is dissolved in methanol (830 ml), the solvent is distilled off under reduced pressure, add absolute ethanol (830 ml) and the solvent is again distilled off. Again add absolute ethanol (830 ml) then a solution of hydrochloric acid in ethyl ether (10 ml, 15% wt./vol.).

After evaporation of the solvent the residue is dissolved in absolute ethanol (660 ml), add ethyl acetate (1170 ml) and the mixture is cooled for 24 hours at 0 to 5oC. the Crystalline product is filtered off and after drying in vacuum at 30oC get the connection 1 in the form of a white substance with so pl. 193 - 194oC.

[]D= -32,5o(1% in methanol).

1H-NMR (300 MHz, DMSO-d6) (ppm): to 0.92 (t, 3H), of 1.34 (br.s, 4H), to 1.70 (m, 7H), 2,28 (m, 1H), 2,4 - 2,6 (m, 1H), 2,8 - 3,2 (m, 9H), 3,30 (t, 2H), 3,5 (m, 1H), 3,76 (s, 3H), 4,25 (t, 2H), 6,41 (d, 1H), 6,62 (d, 1H), 6,85 - 7,05 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 472 (M+1).

According to the same method the following compounds:

the dihydrochloride of (R)-N-propyl-N-[6-[2- (2-methoxyphenoxy)ethylamino]hexyl] -6,7-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 2)

1H-NMR (200 MHZ, D2O) (ppm): 0.78 (t,3H), 1,19-to 2.06 (m, 12H), 2,45-3,13 (m, 10H), 3,3 (m, 2H), 3,38-of 3.53 (m, 1H), 3,67 (s, 1H), 4,12 (m, 2H), 6,46 (s, 2H), 6,77-6,92 (m, 4H).

M is Teal-N-[6-[2- (2-methoxyphenoxy)ethylamino]hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 3)

1H-NMR (200 MHz, D2O) (ppm): 0.75 in (t, 3H), 1,11-to 1.67 (m, 12H), 2,16 is 2.46 (m, 2H), a 2.36-3.15 in (m, 10H), 3,29-to 3.34 (m, 2H), 3,41 is 3.57 (m, 1H), 3,69 (s, 3H), 4,11-4,16 (m, 2H), 6.48 in (d, 1H), is 6.61 (d, 1H), for 6.81-6,93 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 485 (M+1).

the dihydrochloride (S)-N-butyl-N-[6-[2- (2-chlorophenoxy)ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro - 2-naphtylamine (compound 4)

1H-NMR (200 MHz, D2O) (h/m): to 0.74 (t,3H), 1,11-to 1.77 (m, 13H), 2,05-2,17 (m, 1H), 2,35 is 3.57 (m, 13H), 4,17-4,22 (m, 2H), 6,47 (d, 1H), and 6.6 (d, 1H), 6,8-7,26 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 489 (M+1).

the dihydrochloride (S)-N-propyl-N-[6-[2-[(2-chloro-4-methyl)phenoxy]ethyl - amino] hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 5)

1H-NMR (200 MHz, D2O) (h/m): 0,79 (t,3H), 1,24 is 1.75 (m, 11H), 2,04 (s, 3H), 2,03-of 2.15 (m, 1H), 3.33 and (m, 2H), 2,34-of 3.53 (m, 11H), to 4.15 (m, 2H), 6,46 (d, 1H), 6,59 (d, 1H), for 6.81 (dd, 1H), 6,94 (dd, 1H),? 7.04 baby mortality (d, 1H).

Mass spectrum (chemical ionization, isobutane, positive ions): 489 (M+1). the dihydrochloride of (R)-N-propyl-N-[6-[2-[(2-chloro-4-methyl)phenoxy] ethyl - amino]hexyl]-6,7-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 6)

1H-NMR (200 MHz, D2O) (h/m): 0,79 (t, 3H), 1,20 was 1.69 (m, 10H), 1,47-to 2.06 (m, 2H), 2,09 (s, 3H), 2,53-is 3.08 (m, 10H), 3,26-of 3.31 (m, 2H), 3,4-3,55 (m, 1H), 3,66 (s, 3H), 4,06-4,11 (m, 2).

the dihydrochloride (S)-N-propyl-N-[3-[2-(2-methoxyphenoxy)ethylamino]- propyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 7)

1H-NMR (200 MHz, D2O) (h/m): 0.8 in (t, 3H), 1,50-to 2.18 (m, 6H), 2,36 is 3.23 (m, 10H), 3,35 is 3.40 (m, 2H), 3,47-of 3.60 (m, 1H), to 3.67 (s, 3H), 4,14-4,19 (m, 2H), 6.48 in (d, 1H), is 6.61 (d, 1H), 6,83-6,91 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 429 (M+1).

the dihydrochloride of (R)-N-propyl-N-[3-[2- (2-chlorophenoxy)ethylamino]propyl]-6,7-dihydroxy-1,2,3,4-tetrahydro - 2-naphtylamine (compound 8)

1H-NMR (200 MHz, D2O) (h/m): 0,79 (t, 3H), 1,48 with 2.14 (m, 6H), 2,46-3,20 (m, 10H), 3,37 is 3.57 (m, 3H), 4,19-4,24 (m, 2H), 6,44 (s, 1H), 6,46 (s, 1H), 6,8-7,25 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 433 (M+1).

the dihydrochloride (S)-N-butyl-N-[3-[2- [(2-methoxy-4-methyl)phenoxy] ethylamino]propyl]-5,6 - dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 9)

1H-NMR (200 MHz, D2O) (ppm): 0.75 in (t, 3H), 1,11-of 1.30 (m, 2H), 1,46-of 1.62 (m, 2H), 2,08 (s, 3H), 1.60-to of 2.15 (m, 2H), 1,97-of 2.15 (m, 2H), 2,34-up 3.22 (m, 10H), 3,31-to 3.36 (m, 2H), 3,44 is 3.57 (m, 1H), to 3.64 (s, 3H), of 4.12 (m, 2H), 6,46 (d, 1H), is 6.61 (d, 1H), 6,6-of 6.78 (m, 3H).

Mass spectrum (chemical ionization, isobutane, positive ions): 457 (M+1).

the dihydrochloride (S)-N-[2-(5,6-dihydroxy-1,2,3,4 - tetrahydro)naphthyl]-N-propyl-N'-methyl-N'-[2-(2-methoxyphenoxy,54 (m, 13H), 3,63 (s, 3H), 4,15 (m, 2H), 6,41 (d, 1H), to 6.57 (d, 1H), 6,74-6,86 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 485 (M+1).

the dihydrochloride of (R)-N-butyl-N-[2-(6,7-dihydroxy-1,2,3,4 - tetrahydro)naphthyl] -N'-methyl-N'-[2-(2-methoxyphenoxy)ethyl] -1,6 - hexanediamine (compound 11)

1H-NMR (200 MHz, D2O) (h/m): to 0.74 (t, 3H), 1,14-1,71 (m, 12H), 1,48-2,04 (m, 2H), 2,77 (s, 3H), 2,54-of 3.53 (m, 13H), to 3.67 (s, 3H), 4,2 (m, 2H), of 6.49 (s, 2H), 6,76-6,93 (m, 4H).

Mass spectrum (chemical ionization, isobutane, positive ions): 499 (M+1).

the dihydrochloride (S)-N-[2-(5,6-dihydroxy-1,2,3,4 - tetrahydro)naphthyl]-N-propyl-N'-methyl-N'-[2- [(2-chloro-4-methyl)phenoxy] ethyl] -1,6-hexanediamine (compound 12)

1H-NMR (200 MHz, D2O) (h/m): 0,79 (t, 3H), 1,22-of 1.30 (m, 4H), 1,47-1,71 (m, 7H), 2,02 (s, 3H), 2,02 and 2.13 (m, 1H), 2,80 (s, 3H), 2,32-3,18 (m, 10H), 3,35-to 3.50 (m, 3H), 4,20 (m, 2H), 6,44 (d, 1H), return of 6.58 (d, 1H), 6,77-of 6.99 (m, 3H).

Mass spectrum (chemical ionization, isobutane, positive ions): 503 (M+1).

the dihydrochloride (S)-N-propyl-N-[2-(5,6-dihydroxy-1,2,3,4 - tetrahydro)naphthyl] -N'-methyl-N'-[2-(2-methoxyphenoxy)ethyl] -1,3 - propandiamine (compound 13)

1H-NMR (200 MHz, D2O) (h/m): 0,78 (t, 3H), 1,46-of 2.15 (m, 6H), 2,82 (s, 3H), 2,27-3,51 (m, 13H), 3,61 (s, 3H), 4,22 (m, 2H), 6.42 per (d, 1H), 6,60 (d, 1H), 6,74-6,91 (m, 4H).

Mass spectrum (chemical ionization, isobut the yl] -N'-methyl-N'-[2-[(2-chloro-4-methyl)phenoxy]ethyl]- 1,3-propandiamine (compound 14)

1H-NMR (200 MHz, D2O) (h/m): to 0.74 (t, 3H), 1,09 of 1.28 (m, 2H), 1,44 is 1.60 (m, 2H), a 2.01 (s, 3H), 1,45-of 2.20 (m, 2H), 1,91-of 2.20 (m, 2H), 2,88 (s, 3H), 2.40 a-3,48 (m, 11H), of 3.54 (m, 2H), 4,25 (m, 2H), 6,41 (s, 1H), 6,44 (s, 1H), 6,8-6,97 (m, 3H).

Mass spectrum (chemical ionization, isobutane, positive ions): 475 (M+1).

Method B

a) To a solution of the hydrobromide (S)-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthalamine (7 g, of 23.2 mmole) obtained by the method of example 2, in triperoxonane acid (80 ml) at 20oC in nitrogen atmosphere add a solution of 4-methoxybenzylamine (11.8 g, 69,5 mmole) in triperoxonane acid (24 ml). The reaction mixture is stirred for 2 hours at room temperature, after which the solvent is evaporated to dryness. The residue is dissolved in ethyl acetate (20 ml) and add a solution of hydrochloric acid in diethyl ether to strongly acidic pH values.

Filtration of the resulting precipitate receive hydrochloride (S)-N-propyl-5,6-dihydroxy-5,6-di(4-methoxybenzyloxy)-1,2,3,4 - tetrahydro-2-naphtylamine (12.5 g), so pl. 114-117oC []D= -42,64 (1% in methanol).

1H-NMR (300 MHz, DMSO-d6) (ppm): of 0.95 (t, 3H), 1,60-1,80 (m, 3H), by 2.55 (m, 1H), 2,60 (m, 1H), 2,75 was 3.05 (m, 4H), and 3.31 (dd, 1H), 3,47 (m, 1H), 3,76 (s, 3H), of 3.78 (s, 3H), 6,94 (d, 2H), 7,00 (d, 2H), 7,21 (d, 1H), 7,25 (d, 1H), 7, 84 (d, 2H), 7,92 (d, 2H).

Mass spectrum (chem is Ino]hexanoic acid (8 g, a 27.4 mmole) obtained by the method of example 4, and triethylamine (2.8 ml, a 27.4 mmole) in anhydrous dimethylformamide (240 ml) at -12oC in an atmosphere of nitrogen was added dropwise ethylchloride (2,9 ml, a 27.4 mmole).

The reaction mixture is stirred for 30 minutes at a temperature of from -10oC to -12oC, then add a solution of the hydrochloride of (S)-N-propyl-5,6-di(4-methoxybenzyloxy)-1,2,3,4-tetrahydro-2 - naphtylamine (12 g, of 22.8 mmole) obtained by the above method of paragraph (a), and triethylamine (2.3 ml, of 22.8 mmole) in anhydrous dimethylformamide (200 ml). The reaction mixture is stirred for about a day at room temperature.

After evaporation to dryness the residue is dissolved in methylene chloride (100 ml) and washed with water (3 x 50 ml).

The organic phase is dried over anhydrous sodium sulfate and after evaporation of the solvent under reduced pressure to obtain (S)-N-propyl-N-[6-[[(2-methoxyphenoxy)acetyl] amino] hexanoyl] -5,6 - di(4-methoxybenzyloxy)-1,2,3,4-tetrahydro-2-naphtylamine in the form of crude oil (19 g), which are used directly in the next stage.

1H-NMR (300 MHz, DMSO-d6) (ppm): 0,86 (tt, 3H), 1,15-1,35 (m, 2H), 1,35-of 1.65 (m, 6H), 1,75-2,05 (m, 2H), 2,20-2,40 (m, 2H), 2.70 height is 3.25 (m, 8H), of 3.77 (s, 3H), of 3.78 (S, 3H), of 3.80 (s, 3H), Android 4.04 (m, 1H), 4,43 (d, 2H), of 6.96 (d, 2H)s): 767 (M-1), 337, 296.

C) a Solution of crude (S)-N-propyl-N-[6- [[(2-methoxyphenoxy)acetyl]amino] hexanoyl] -5,6 - di(4-methoxybenzyloxy)-1,2,3,4-tetrahydro-2-naphtylamine (18.5 g, 24,15 mmole) obtained by the method of the above paragraph (b), and butylamine (7,16 ml, 72.5 mmole) in absolute ethanol (510 ml) is boiled under nitrogen atmosphere for 17 hours.

After evaporation to dryness the resulting crude product was then purified column chromatography on silica gel (230-400 mesh mesh) by elution methylene chloride and then with a mixture of methylene chloride-methanol (95:5) and obtain (S)-N-propyl-N-[6- [[(2-methoxyphenoxy)acetyl] amino] hexanoyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (6.3 g) which was directly used in the next stage.

To a solution of the obtained compound, (6 g, 12,1 mmole) in anhydrous tetrahydrofuran (240 ml) at room temperature in nitrogen atmosphere are added dropwise complex, borane-dimethyl sulfide (16 ml, 168,5 mmole).

The reaction mixture is boiled for 1.5 hours. After cooling to 15oC carefully added dropwise 36% hydrochloric acid (3,25 ml) in methanol. The reaction mixture is boiled for 1 hour, the solvent (approximately 120-150 ml) is distilled off at atmospheric pressure and then vacuum evaporated to dryness. The crude product dwai what xanam and after recrystallization from absolute ethanol compound 1 (4.5 g) with the same physico-chemical and spectral characteristics, that of the product obtained by method A.

Example 7

Getting debuginfo (S)-N-propyl-N-[6-[2-(2-methoxyphenoxy)ethyl - amino] hexyl]-5,6-diacetoxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 15)

To a solution of compound 1 (0.9 g, 1.6 mmole), obtained by the method of example 6, in triperoxonane acid (7 ml) at room temperature and stirring acetylchloride (0.4 g, 5.1 mmole). After aging for 15 hours under these conditions, the solvent is evaporated under reduced pressure and the resulting residue is purified column chromatography on silica gel (230-400 mesh mesh) by elution with a mixture of methylene chloride/methanol (88:12).

The obtained product is dissolved in water (3 ml) add a solution of debuginfo sodium (0.5 g, 1,1, mmole) in water (4 ml) and then methylene chloride (5 ml) and the phases are separated. The aqueous phase is again extracted with methylene chloride (3 ml).

The collected organic phases are dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure.

Get the connection 15 (0.8 g) as a white substance with so pl. 165-167oC (decomp.).

1H-NMR (200 MHz, D2O) (h/m): 0,60 (br.s, 2H), 0,36-0,61 (br.s, 3H), of 0.89 (t, 3H), of 1.16 (s, 18H), 1,6 (br.s, 3H), 2,24 (s, 6H), 2,08-3,4 (m, 17H), of 3.75 (s, 3H), 4.26 deaths (br.s, 2H), 6,77-7,10 (m.

Example 8

Obtain (S)-N-propyl-N-[2-(5,6-dihydroxy-1,2,3,4 - tetrahydro)naphthyl] -N'-benzyloxycarbonyl-N'-[2- (2-methoxyphenoxy)ethyl]-1,6-hexanediamine

In a nitrogen atmosphere to a solution of compound 1 (4 g, 7.3 mmole) obtained by the method of example 6, in methylene chloride (200 ml) and dimethylformamide (20 ml) is added potassium carbonate (3.4 g, of 24.6 mmole), water (20 ml) and benzylchloride (1.3 g, 7.7 mmole). After 1 hour the reaction mixture is washed twice with a saturated aqueous solution of sodium chloride.

The organic phase is dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. Purification of the residue column chromatography on silica gel (230-400 mesh mesh) by elution with a mixture of methylene chloride/methanol/toluene/formic acid (90: 10: 15: 0,5) get the connection specified in the header, in the form of a white solid (3,6).

1H-NMR (200 MHz, CDCl3) (ppm): 0,99 (t, 3H), 1,20 is 1.96 (m, 12H), 2,12-of 2.20 (m, 1H), 2,75-to 3.35 (m, 8H), to 3.38 (m, 2H), 3,65 (m, 2H), 3,81 (s, 3H), 4,03-4,20 (m, 2H), 5,11 (s, 2H), 6,21 (d, 1H), 6,77 (d, 1H), 6.73 x-7,38 (m, 9H).

Mass spectrum (chemical ionisation, ammonia, positive ions): 605 (M+1).

Example 9

Obtain (S)-N-propyl-N-[2-(5,6-di(ethylcarbonate)-1,2,3,4 - tetrahydro)naphthyl] -N'-benzyloxycarbonyl-N'-[2-(silexcolor-N'-[2-(2-methoxyphenoxy)ethyl] -1,6-hexanediamine (3.6 g, 6 mmol), obtained according to the method of example 8, in utilizationa (20 ml) is boiled with stirring in a nitrogen atmosphere for 24 hours.

Excess utilizationof evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The resulting solution was washed with water. The organic phase is dried over anhydrous sodium sulfate and the solvent is then evaporated under reduced pressure. Purification of the residue column chromatography on silica gel (230-400 mesh mesh) by elution with a mixture of methylene chloride/methanol/toluene (90:5: 5) get the connection specified in the header (2.2 g).

1H-NMR (200 MHz, CDCl3) / (h/m): to 0.88 (t, 3H), of 1.18 (t, 3H), 1,19 (t, 3H), 1,10-of 1.80 (m, 12H), 1,96-to 2.18 (m, 1H), 2,40-3,10 (m, 8H), 3,1-to 3.41 (m, 6H), of 3.65 (m, 2H), 3,81 (s, 3H), 4,03-is 4.21 (m, 2H), 5,02-5,17 (m, 2H), of 5.11 (s, 2H), 6,72 and 7.36 (m, 11H).

Example 10

Obtain (S)-N-propyl-N-[6-[2- (2-methoxyphenoxy)ethylamino] hexyl]-5,6-di(ethylcarbonate)- 1,2,3,4-tetrahydro-2-naphtylamine (compound 16)

To a solution of (S)-N-propyl-N-[2-[5,6-di(ethylcarbonate)-1,2,3,4 - tetrahydro] naphthyl] -N'-benzyloxycarbonyl-N'-[2-(2-methoxyphenoxy)ethyl] -1,6-hexanediamine (2 g, 2.7 mmole), obtained by the method of example 9, in absolute ethanol (80 ml) was added 37% hydrochloric acid (0.6 ml) and 10% palladium on charcoal (0.2 g).

Reactivat and the solvent evaporated under reduced pressure.

Purification of the residue column chromatography on silica gel (230-400 mesh mesh) by elution with a mixture of methylene chloride/methanol/toluene/ammonia (80:10:10:0.5) with the gain of 0.6 g of compound 16.

1H NMR (200 MHz, D2) / (ppm): of 0.79 (t, 3H), of 0.96 (t, 3H), of 0.97 (t, 3H), 1,23-to 1.63 (m, 10H), 1,58 and 2.13 (m, 2H), 2,37 is 3.15 (m, 14H), 3,30 (m, 2H), 3,48-the 3.65 (m, 1H), 3,68 (s, 3H), of 4.12 (m, 2H), 6,77-6,97 (m, 6H).

Mass spectrum (chemical ionization, isobutane, positive ions): 611 (M-1)

Example 11

Identification of affinity with D1and D2receptors

A) receptor Binding

In male rats farm sprag-doli (200-250 g) remove the brain, and the membrane of the veins fabric prepared according to the method specified Billard et al., Life Sciences, 35, 1885 (1984).

The tissue is homogenized in 40 mm Tris-HCl buffer, pH 7,4 (1:100 weight/volume).

The homogenate was centrifuged, the precipitate is again suspended, again centrifuged and re-suspended in 50 mm Tris-HCl buffer (pH of 7.4) containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 1 mm MgCl2.

Affinity with D1receptor and D2the receptor is determined by use as labeled ligands, respectively [3H] -SCH23390 and [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl - 1H-3-benzazepin-7-ol hydrochloride] and [3H] domperidone (Merc Index, XI ed., N se with the use of [3H]-SCH23390 was used following standard conditions of incubation (volume 1000 ml): 50 mm Tris-HCl buffer (pH of 7.4), 0.2 nm [3H]-SCH23390, the preparation of membranes from 130-140 µg protein/ml

The mixture is incubated for 15 minutes at 37oC with test compounds at various concentrations, filtered under vacuum through GF/C filters firm Whatman paper and then washed 4 times with 5 ml ice 50 mm Tris-HCl buffer (pH 7,4).

In the analysis of the binding of D2-receptor [3H]-domperidone (0.3 nm) incubated in a volume of 1000 μl containing buffer and the preparation of the membranes of the above composition. In addition, added 0.01% bovine serum albumin (BSA).

The mixture is incubated for 30 minutes at 37oC for each concentration of the tested compounds.

These values, expressed as Ki (nm) compound 1, dopamine and dopexamine shown in table 1, where given the affinity /Ki (nm) with D1and D2receptors of compounds 1, dopamine and dopexamine, certain analyses on binding with veins membranes of rats.

Compound 1 showed high affinity for both receptors subtypes. The activity of compounds 1 to 10 times the activity of dopamine and dopexamine to D1re-agonistic activity

Analyses of the binding of the receptor to identify affinity with D1and D2receptors reproduce the methodology described above in paragraph A, but using as the labeled ligand for D2receptor [3H]-spiperone (Merc Index, XI ed., N 8707, page 1380).

Analysis, in which the use of [2H]-SCH23390, conducted in the following standard conditions (volume 1 ml): 50 mm Tris-HCl buffer (pH of 7.4), 0.2 nm [3H]-SCH23390, the preparation of membranes 3 mg/ml, which corresponds to 130-150 µg protein/ml), incubation temperature 37oC and incubation time of 15 minutes.

Analysis, in which the use of [3H]-spiperone, conducted in the following standard conditions (volume 2 ml): 50 mm Tris-HCl buffer (pH of 7.4), 0.2 nm [3H]-spiperone, the preparation of membranes (3 mg/ml, which corresponds to 130-150 µg protein/ml), incubation time of 15 minutes and the incubation temperature 37oC.

These values, expressed as Ki (μm), for compounds 1-14, dopamine and dopexamine are shown in table 2.

DA2-agonistic activity is determined as follows.

Transverse sections (2-3 mm) ear artery of the rabbit hung in the bath for isolated organs, containing a solution of Krebs-Henseleit with the addition of coali field every 5 minutes (10 Hz, 1 msec, 30-60, duration 500 MS), left to stabilize for 2 hours.

Build a curve based dose-response for compounds according to the invention, dopamine and dopexamine as comparative compounds and determine the inhibitory effect on the contraction induced by electrical stimulation.

Each drug is used three increasing concentration, allowing to identify the main conditions prior to introduction.

These values, expressed as pD2(-log EC50), for compounds 1-14, dopamine and dopexamine are shown in table 2, where given the affinity /Ki (μm)/ D1and D2receptors (receptor binding) veins on the membranes of rats and DA2-agonistic activity (pD2) on the ear artery of the rabbit for compounds 1-14, dopamine and dopexamine.

Example 12

Identification of antihypertensive activity in vivo

Male rats of the SHR at the age of 3-4 months fixed for 16 hours before the beginning of the experience. Systolic blood pressure (ACS) and heart rate (HR) register method using tail cuff of conscious animals using BP recorder (W+W Basile, Italy). Before each determination of the pressure the ranks periods of up to 7 hours after administration of the test compounds.

Compounds administered orally via a stomach tube in a volume of 10 ml/kg, and the dose 10-160 mg/kg For the introduction of compounds suspended in 0.5% carboxymethylcellulose (CMC) in water with the addition of tween 80 (0.3 ml/10 ml CMC).

The results, expressed as ED30mmHg(mg/kg p. O.), i.e. the dose that causes a drop of 30 mm Hg from the baseline value of CDSS (a decline of about 15%) for compounds 1 have the following meanings:

Connection 1 - ED30mmHg= 22.9 mg/p. O.

The results also show that the effect of compound 1 is prolonged (about 4 hours).

Similar results were obtained for other compounds of formula I.

For typical representatives of the claimed group of compounds strong toxicity was observed at oral and intravenous administration to mice of large doses of compound 1. Final LD50was 358 lhs/kg (oral administration) and 21 lhs/kg (intravenous).

1. Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene formula I

< / BR>
where R1and R2- different and mean a hydrogen atom or a group OY';

Y, Y' are the same or different and mean a hydrogen atom or acyl derived from a normal Il is - the volume of hydrogen, C1-C4-alkyl;

R4, R5- same or different and mean a hydrogen atom or halogen, C1-C3-alkyl or alkoxygroup;

m = 1-2;

n = 3-7;

and their pharmaceutically acceptable salts.

2. Connection on p. 1, where R1mean group OY';

R2, Y, Y' denote a hydrogen atom;

n = 5, 6, 7.

3. Connection on p. 1, where R1mean group OY', R2, Y, Y' denote a hydrogen atom, n = 6, m = 1,

R4, R5the same or different and mean a hydrogen atom, methyl, methoxy group or chlorine.

4. Connection on p. 1, where Y and Y' are identical or different and denote acyl derived from acetic, propionic, butyric, somaclonal acids.

5. Connection on p. 1, in optically active form.

6. Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene formula I under item 1, with the properties of the dopaminergic agonist receptors.

7. Pharmaceutical composition having cardiovascular activity comprising as an active ingredient derived aminotetralin and conventional additives, characterized in that the quality of the derived aminotetraline it contains 2-amino - 1,2,3,4-is

 

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The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

FIELD: medicine, endocrinology.

SUBSTANCE: the present innovation deals with preventing diabetes mellitus and its aftereffects. It is suggested to apply sibutramin and its analogs to decrease non-susceptibility to insulin in diabetes-free patients, prevent decreased tolerance to glucose and decrease the quantity of introduced insulin in diabetes-suffering patients and normalize body weight, as well.

EFFECT: higher efficiency of application.

28 cl, 3 dwg, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzene of the formula (I): wherein A represents a group taking among the following groups: -C≡C-, -CH=CH-, -CH2-CH2; n = 1 or 2; X represents hydrogen, chlorine or fluorine atom or methyl or methoxy-group; Y represents hydrogen, chlorine or fluorine atom; R1 represents cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with methyl group, phenyl group monosubstituted or disubstituted with fluorine or chlorine atom or methoxy-group, cycloheptyl, tert.-butyl, dicyclopropylmethyl, 4-tetrahydropyranyl or 1- or 2-adamantyl, or adamantine-2-ol group; or R1 represents phenyl group and in this case X and Y both represents chlorine atom; R2 represents hydrogen atom or (C1-C4)-alkyl group; R3 represents (C5-C7)-cycloalkyl, and salts of these compounds formed by addition of pharmaceutically acceptable acids, and their solvates and hydrates also. Also, invention relates to methods for preparing compounds of the formula (I) and to pharmaceutical composition able to interact with receptors sigma-2 based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for treatment of autoimmune states, disturbance on heart contraction frequency and control against proliferation of tumor cells.

EFFECT: improved preparing methods, valuable medicinal properties of compositions.

18 cl, 14 tbl, 78 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: medicine.

SUBSTANCE: the suggested transdermal therapeutic system (TTS) is indicated for percutaneous injection of tolterodin for several days. It is, also, described the method for its manufacturing. The suggested TTS is being a self-gluing lamellar matrix structure that contains methacrylate copolymer including ammonium groups, at least, one plastifier and up to 25 weight% tolterodin. TTS is of good tolerance by skin and is of good physical and chemical stability at prolonged storage and application, it, also, has got good adhesive properties and can provide the penetration of maximal quantity of active substance through skin.

EFFECT: higher efficiency of application.

8 cl, 2 dwg, 3 ex, 3 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: method involves applying fractal introduction of 0.2 mg/kg MT calypsol and 0.4 mcg/kg MT fentanyl every 10 min during operation. Additional local spinal cord root irrigation with 2% lidocaine solution at maximum traumatic operation moment.

EFFECT: enhanced effectiveness of treatment; preserved spontaneous patient respiration.

1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

FIELD: obstetrics and gynecology.

SUBSTANCE: over a 2-5 day period, 2.0 ml of Ginipral is administered once a day intravenously in a drop-by-drop manner followed by intravenously drop-by-drop administered 30-40 min later 2.0 ml of Instenone and, in the evening, 1 dragee Instenone orally. Afterwards, Instenone and Ginipral are administered orally: the former in dose of 1 dragee thrice a day with meal and the latter in dose of 1 pellet four times a day after meal until symptoms of the risk of prevention of pregnancy disappear.

EFFECT: prolonged pregnancy and prevented premature birth, which favors reduced irritation, normalized tonus, contractive activity of uterus, and improved psychic and emotional state of women.

2 ex

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