Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene with activity in relation to cardiovascular system, and pharmaceutical composition

 

(57) Abstract:

Describes new compounds, representing derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene formula I

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intended for the treatment of hypertension, myocardial insufficiency, renal insufficiency, peripheral arteriopathy or cerebrovascular nedostatochnosty. These compounds have high activity and prolonged action, as well as the ability to be absorbed with oral administration. 2 S. and 4 C.p. f-crystals, 4 PL.

The invention relates to compounds having activity in relation to cardiovascular system, in particular to derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene, and to their use in therapy.

It is known that some gidroksilirovanii 2-amino-1,2,3,4-tetrahydronaphthalene are agonists of dopaminergic receptors, and there have been several studies examining the dependence of their activity from the structure in order to identify structural characteristics that define the most high dopaminergic activity and at the same time not having adverse effects characteristic of dopamine.

Representing in the. 23-253 (1987).

However, despite various studies, the topology of dopaminergic receptors is still not fully clarified, and in the last ten years there has been proposed a number of models of these receptors.

Among the compounds, which are structurally similar to dopamine and/or 2-amino-1,2,3,4-tetrahydronaphthalenes, some researchers have found that the presence of C3-C4is an alkyl group on the functional amino group is one of the necessary requirements for the manifestation of dopaminergic activity, while the structural requirements for the second Deputy to the amino group is not installed.

However, from the literature there are several examples showing that the structural features of the two deputies in practice can greatly vary and that small changes in the molecule can both quantitatively and qualitatively accordingly affect the pharmacological activity.

Below are some of the most important of these examples.

In the application for the European patent 72061 (Fisons PLC) provides, among other things, dopamine and aminotetrahydrofuran with mono - or disubstituted by part formula

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where X of the1and R2have identical or different meanings and represent hydrogen, alkyl or phenyl; D2denotes hydrogen, alkyl, phenyl; alkyl substituted by one or more hydroxy groups, pyridium, phenyl; alkyl substituted by phenyl, which in turn substituted with halogen, alkyl, amino-, alkoxy - or nitro-group; or D2can be phenylethylene or tetrahydronaphthalene fragment, optionally mono - or disubstituted by hydroxy-group.

Among the compounds represented in the application for the European patent 72061, the connection formula

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international unregistered name which dopexamine (The Merck Index, ed. XI, No. 3418, page 538), is the only connection, as far as known to the authors of the present invention, which was developed and applied for emergency treatment failure.

It is important that dopexamine, despite the fact that he was chosen out of several of the compounds described and shown as an example in the application for the European patent 72061, is less active dopaminergic agonist receptors than dopamine, and similar to the dopamine it is not absorbed in the introduction oral route [A. Fitton and P. Hope are analogues dopexamine and in which, however, the amino fragment of dopamine is secondary.

From the literature there are several compounds with the structure of catecholamine, which are characterized by the preservation of favorable properties dopexamine, including with the introduction oral route, or increasing the selectivity towards dopaminergic receptors.

Among the compounds listed in the application for the European patent 321968 (SIMES Societa Italiana Medicinali e Sintetici S. p.A.), of particular interest are compounds having the following General formula:

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where R and R1have the same or different values and denote hydrogen or acyl radical, which is derived from aliphatic, aromatic or heteroaromatic carboxylic acid, coal or carbamino acid or phosphoric acid; n and p represent integers selected from 0 and 1; m represents an integer selected from 1, 2, 3 and 4, and these values are chosen so that the sum n + p is equal to 1, and the sum of m + n is equal to 2, 3 or 4; R2and R3have identical or different meanings and represent hydrogen, halogen, alkyl or alkoxy. These compounds are agonists of the D1and D2-dopaminergic receptors, they at the same time the possession is that they can be active in oral introduction, must be converted into the corresponding prodrug.

Compounds described in the international application WO 93/19036 (Zambon Group S. R. A.), which are more active dopaminergic agonists than dopamine, and does not have selectivity with respect to any specific subtype of receptor, which do not interact with other receptor systems and which at the same time do not have any side effects or therapeutically adverse properties of dopamine, are of even more interest.

Compounds described in the above international application, have the following General formula:

< / BR>
where R1and R2have the same or different values and denote hydrogen atoms or OY'-group;

Y and Y' are equal or different values and denote hydrogen atoms or acyl groups derived from aliphatic, aromatic or heteroaromatic carboxylic acid, coal or carbamino acid or phosphoric acid; m is 1 or 2; n represents an integer of 3 or 7; R3denotes hydrogen or C1-C4-alkyl; R4and R5have identical or different meanings and represent hydrogen, halogen, C1, and having a priority in Italy MA September 14, 1993, describes dopaminergic agonists formula

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where R denotes a hydrogen atom or an OY group; R1denotes a hydrogen atom or OY'-group; R2denotes a hydrogen atom or an OY group; provided that at least one of R, R1and R2denotes hydrogen, but R, R1and R2simultaneously denote hydrogen atoms and R1and R2at the same time not indicate OY' or OY group, respectively; Y, Y' and Y" are identical or different meanings and represent a hydrogen atom or acyl group which is derived from optionally substituted aliphatic, aromatic or heteroaromatic carboxylic acid, optionally substituted coal or carbamino acid or phosphoric acid; m is 1 or 2; n represents an integer of 3 or 8; p represents the integer 2 or 4; R3denotes hydrogen or C1-C4-alkyl; R4denotes phenyl, optionally substituted with halogen, C1-C3the alkyl or alkoxygroup, or represents 5 - or 6-membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and sulfur, and optionally substituted with halogen, hydrox is and R4denotes a 5 - or 6-membered heteroaryl, X can also represent a simple bond; provided that when X is O, R4has a value other than phenyl or pyridyl.

According to the present invention were found agonists of dopaminergic receptors, which are more active in comparison with dopamine and other above-described known compounds, which practically do not interact with other receptor systems, which can be absorbed through oral route of administration and have a long lasting effect.

Thus, the object of the present invention are the compounds of formula

< / BR>
where m is an integer selected from 4, 5, 6, 7 and 8;

R, R' and R" represent hydrogen atoms or OH group, provided that at least one of the radicals R, R' and R" denotes a hydrogen atom, but all the radicals R, R' and R" are not simultaneously denote hydrogen atoms and R' and R" are both not simultaneously represent OH groups; or

one of R' and R" denotes NHCHO, NHCH3, NHSO2CH3CH2HE or CH3group and the other represents hydrogen;

R1and R2have the same or different values and denote hydrogen atoms, C1-C
p is an integer selected from 0 and 1;

R3denotes a hydrogen atom or a C1-C4is an alkyl group;

Y represents S, O, N(R7)CO, CO(R7)N or N(R7);

X is N(R8), O, S, SO, SO2, CO or a simple bond;

R4, R5and R6have the same or different values and denote hydrogen, HE, halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, C1-C4-alkylthio, NH2mono - or di-C1-C4-alkylamino, SH, C1-C4-alkylsulfonyl, C1-C4-alkoxycarbonyl, NHCHO, C1-C4-alkylcarboxylic, NHCONH2C1-C4-alkylsulfonyl, C1-C4-alkylaminocarbonyl, SO2NH2, NHSO2NH2, COOH, SO3H, CONH2CH2HE or phenyl; or

R4and R5in anthopology to one another together form an optionally unsaturated chain consisting of three or four groups selected from CR"'RIV, CO, S, O and NRVwhere R' denotes a hydrogen atom or a C1-C4is an alkyl group, RIVdenotes a hydrogen atom, a C1-C4is an alkyl group, or amino group, and RVmeans at the second link, or RVtogether with the adjacent R"' or RVforms a simple link;

R7denotes a hydrogen atom or a C1-C4is an alkyl group;

R8denotes a hydrogen atom; or

R7and R8together form-CH2- or chain-CH2-CH2-; or

R4when it is in anthopology respect to X, forms with R7simple bond or-CH2any chain-CH2-CH2-; or,

when X is O, then

R4when it is in anthopology respect to X, forms with R3chain-CH2-O-;

the asterisk * indicates an asymmetric carbon atom;

provided that when p is 1, X denotes the group N(R8); and provided that when R and R' or R" represent an OH group, R1and R2denote hydrogen atoms and

a) when Y represents N(R7), R7denotes hydrogen or alkyl and R3denotes hydrogen, then at least one of R4, R5and R6does not denote hydrogen, halogen, C1-C4-alkyl and C1-C4-alkoxy;

b) when Y represents N(R7), R7denotes hydrogen or alkyl, R3represents hydrogen and X represents a simple bond, at least one of R
b) when Y represents N(R7), R7denotes hydrogen or alkyl, n is 1, R3represents hydrogen and X represents a simple bond, at least one of R4, R5and R6does not denote hydrogen and OH-group;

and their pharmaceutically acceptable salts.

Condition (a) excludes from the formula I compounds falling under the scope of the above international applications WO 93/19036 and WO 95/07885.

Conditions b) and C) exclude from formula I compounds falling under the scope of the above application for a European patent 72061.

The compounds of formula I have at least one asymmetric centre, marked with an asterisk, and they can exist as stereoisomers. The object of the present invention are the compounds of formula I in the form of mixtures of stereoisomers, as well as individual stereoisomers.

The compounds of formula I are agonists of dopaminergic receptors, active also during oral route of administration and with prolonged action, and they are suitable in the field of cardiovascular therapy, in particular for the treatment of hypertension and congestive heart failure, renal failure, for the treatment of peripheral arringo of the invention, the term halogen denotes fluorine atom, chlorine, bromine or iodine.

Specific examples of alkyl or alkoxygroup include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy.

Specific examples of optionally unsaturated chain comprising 3 or 4 groups selected from CR"'RIV, CO, S, O and NRVare the following groups: -O-CHR"'-O-, -S-CO-NRV-, -CHR"'-CO-NRV-, -S-CRIV=N-, -O-CO-NRV-, -CO-NRV-NRV-, -NRV-CO-NRV-.

Preferred compounds of formula I are compounds in which R' denotes a hydrogen atom, R and R" represent an OH group, and the carbon atom marked with * has the S-configuration.

Even more preferred are compounds in which R', R1and R2denote hydrogen atoms, R and R" represent an OH group, m is 6 and the carbon atom marked with * has the S-configuration.

Among the meanings of the substituents R4, R5and R6preferred are hydrogen, HE, methoxy, methyl, nitro, chlorine, methylsulphonyl, NH2, SO2NH2methylsulfonylamino, NHCONH2methoxycarbonyl, acetylamino, CONH2CH2HE, SO3H and metaly-S-CO - NRV- where RVdenotes a hydrogen atom.

Specific examples of compounds of formula I are:

(S)-N-propyl-N-[6-[(1,4 - benzodioxan-2-yl)methylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

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

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

(S)-N-propyl-N-(5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphthyl)-N'-methyl-N'-[2-(2-oxo-3H-1,3-benzothiazol-6 - yl)ethyl]-1,6-hexanediamine,

(S)-N-propyl-N-[6-[4-(2- methoxyphenyl)piperazine-1-yl] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(R)-N-propyl-N-[6-[2-(2-oxo-3H-1,3 - benzothiazol-6-yl)ethylamino] hexyl] -6-hydroxy-7-formylamino - 1,2,3,4-tetrahydro-2-naphtylamine,

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

(R)-N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino]hexyl]-6-hydroxy-7-formylamino - 1,2,3,4-tetrahydro-2-naphtylamine,

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

(R)-N-propyl-N-[6-(2 - phenylethylamine)hexyl]-6-hydroxy-7-formylamino-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(4- meta wltnylfj)ethylamino]hexyl]-6-hydroxy-7 - formylamino-1,2,3,4-tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[7-[2-(2-oxo - 3H-1,3-benzothiazol-6-yl)ethylamino] heptyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[5-[2-(2-oxo-3H-1,3 - benzothiazol-6-yl)ethylamino] pentyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[3-(4- hydroxyphenyl)propylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[6-(6,7-dihydroxy - 1,2,3,4-tetrahydroisoquinoline-2-yl)hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[5-[2-(2,3-dihydro-2 - oxo-3-methyl-1,3-benzothiazol-6-yl)ethylamino]hexyl]-5,6 - dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6- [2-(3-chloro-4-hydroxyphenyl)ethylamino]hexyl]-5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-oxo-6-[2- (2-oxo-3H-1,3-benzothiazol-6-yl)ethylamino] hexyl]-5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3- the nitro-4-hydroxyphenyl)ethylamino]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(R)-N-PR is-N-[6-[3-(3,4- dihydroxyphenyl)propylamino]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(2,3-dihydro-3-oxo - 1H-indazol-5-yl)ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-methyl-4 - hydroxyphenyl)ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(2,3-dihydro-2 - oxo-1H-benzimidazole-5-yl)ethylamino]hexyl]-5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[4-(4- hydroxyphenylethyl)piperazine-1-yl] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(2,3- dihydro-2-oxo-3H-benzoxazol-6-yl)ethylamino] hexyl]-5,6 - dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[3-(2-hydroxyphenyl)propylamino]hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

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

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

(S)-N-propyl-N-[6-(2-phenylethylamine)hexyl] -6 - hydroxy-5-hydroxymethyl-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(2-oxo-3H-1,3-benzothiazol-6-yl)ethylamino] hexyl] - 5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-(2-phenylethylamine)hexyl] -5-formylamino-6-hydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(2-unilateralism)hexyl] -6-hydroxy-5-methylsulfonylamino-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(2-oxo-3H-1,3 - benzothiazol-6-yl)ethylamino] hexyl] -5-hydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-(2 - phenylethylamine)hexyl] -5,6-dihydroxy-4-methyl-1,2,3,4-tetrahydro - 2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-chloro-5 - hydroxyphenyl)ethylamino]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-(2-phenylethylamine)hexyl] -6-hydroxy-5-methyl - 1,2,3,4-tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[6-(2 - phenylethylamine)hexyl] -6-hydroxy-5-methylamino-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-(2,3-dihydroindol-1 - yl)hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-chloro-4-hydroxyphenyl)ethylamino]hexyl]- 6-hydroxy-5-hydroxymethyl-1,2,3,4-tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[6-[2-(3-chloro-4-hydroxyphenyl)ethylamino]hexyl] -5-formylamino-6-hydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3,4-dihydroxyphenyl)ethoxy]hexyl]-5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino] hexyl]-5-hydroxy-6 - methyl is - 5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-chloro-4-hydroxyphenyl)ethylamino] hexyl] -5,6-dihydroxy-4-methyl-1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2- (3-hydroxy-4-methoxyphenyl)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino] hexyl]-6-hydroxy-5-methyl-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3,4- dihydroxyphenyl)ethylthio] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino]hexyl]-6-hydroxy-5-methylamino - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(3- amino-4-hydroxyphenyl)ethylamino] hexyl]-5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino] hexyl] -6-hydroxy-5-hydroxymethyl - 1,2,3,4-tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino] hexyl] -5-formylamino-6 - hydroxy-1,2,3,4-tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[6-[2-(4-methylsulfinylphenyl)ethylamino] hexyl] -6-hydroxy-5-methylsulfonylamino-1,2,3,4-those whom etrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino] hexyl]-5,6-dihydroxy-4-methyl - 1,2,3,4-tetrahydro-2-naphtylamine,

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

(S)-N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino] hexyl] -6-hydroxy-5-methyl - 1,2,3,4-tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[(3,4 - dihydroxyphenyl)acetylamino]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine,

(S)-N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino] hexyl] -6-hydroxy-5-methylamino - 1,2,3,4-tetrahydro-2-naphtylamine,

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

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

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

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

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

(S)-N-propyl-N-[6-[2-(2-amino-1,3-benzothiazol-6 - yl)ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine.

Pharmaceutically acceptable salt, Hydrobromic, iodine, hydrogen, nitric, sulfuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic, methansulfonate and 3,7-di-tert-butylnaphthalene-1,5 - disulfonate acid (debolina acid).

The compounds of formula I can be obtained in accordance with the method of synthesis described below in this specification.

This method involves reacting the compounds of formula

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where R1and R2have the above values;

R9, R10and R11denote hydrogen atoms or OZ-group, where Z denotes a hydrogen atom or a protective group selected from, for example, methyl, benzyl, benzoyl and 4-methoxybenzoyl, provided that at least one of R9, R10and R11denotes the hydrogen atom, but R9, R10and R11all are not simultaneously denote hydrogen atoms and R10and R11both are not simultaneously denote OZ-group; or

one of R10and R11refers to a group NHCHO, NHCH3, NHSO2CH3CH2HE or CH3and the other denotes hydrogen;

acid formula

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where m, p, R4, R5, R6X and Y have the above meanings; W denoted by the has the above values, when n is 1, 2, 3 or 4; or Q represents a group CHR3or CO, where R3has the above values, when n is 0;

or its reactive derivative, such as allalone or a mixed anhydride, which may not necessarily be obtained in situ, in an inert solvent and in the presence of a base such as a carbonate or bicarbonate of an alkali metal or tertiary amine,

to obtain the intermediate compounds of formula

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where m, p, W, Y, Q, X, R1, R2, R4, R5, R6, R9, R10and R11have the above meanings; and the recovery of the compounds obtained before or after optional removal hydroxyamine groups with obtaining the compounds of formula I.

The recovery of the compounds of formula IV can be carried out using electrophilic reducing agents, in particular of DIBORANE, not necessarily used in the form of a complex with dimethyl sulfide, tetrahydrofuran, aliphatic amines, such as triethylamine, or aromatic amines such as N,N-diethylaniline or pyridine.

Alternatively, recovery may be effected via a nucleophilic reducing agents such as hydrides meta is like, for example, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane.

Optional removal hydroxyamine groups is carried out in accordance with standard methods, such as hydrolysis or hydrogenolysis.

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

The compounds of formula III are known or can easily be obtained in accordance with standard methods.

Alternatively, the compounds of formula I in which Y represents N(R7), can be obtained using a different method.

First carry out the condensation reaction between the compound of formula II and a suitable reactive derivative of the acid of the formula

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where Y denotes the group N (R7); m and R7have the above values; with subsequent optional recovery using the above method, to obtain the intermediate product of the formula

< / BR>
where Y denotes the group N(R7); m, W, R1, R2, R7, R9, R10and R11have the above values.

Then the intermediate product is ormula

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where n, p, R3, R4, R5, R6and X have the values indicated above; r is 0 or 1; the corresponding intermediates of formula IV.

Subsequent recovery before or after optional removal hydroxyamine groups leads to the formation of compounds of formula I in which Y denotes the group N(R7), which is the subject of the present invention.

Another alternative option for obtaining compounds of formula I in which Y denotes the group N(R7), consists primarily in the interaction of compounds of formula II with a suitable reactive derivative bicarbonate acid formula

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where m has the above meanings;

obtaining an intermediate product of the formula

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where m, R1, R2, R9, R10and R11have the above values.

Subsequent condensation with an amine of the formula

< / BR>
where Y denotes the group N(R7); n, p, X, R3, R4, R5, R6and R7have the above values; results of the corresponding intermediates of formula IV.

Subsequent recovery before or after optional removal of gidroksidami is the subject of the present invention.

Some compounds of formula I, which are not necessarily protected, can also be used as intermediate products for the synthesis of other compounds of formula I by transformation of certain functional groups present in the molecule.

For example, the compounds of formula I in which one or more radicals R4, R5and R6denote the nitrogroup or alkoxycarbonyl group can be converted into the corresponding compounds of formula I in which one or more radicals R4, R5and R6indicate the amino - or carboxyl group, respectively by reduction or hydrolysis. In turn, the compounds of formula I in which one or more radicals R4, R5and R6denote the amino group or carboxyl group can be converted into the corresponding compounds of formula I in which one or more radicals R4, R5and R6denote alkylcarboxylic - or CH2group, respectively by acylation or recovery.

Similarly can be made the same transformation intermediates of formula IV.

The compounds of formula I Electives synthesis.

Obtaining salts of the formula I is carried out in accordance with standard methods.

The compounds of formula I are agonists of the D1and D2-dopaminergic receptors with greater affinity than dopamine and than dopexamine, as it was found in experiments on binding in vitro (example 98).

In addition, their activity at least comparable to those identified for compounds described in the international application WO 93/19036.

The results obtained in experiments in vitro, were also confirmed by functional studies in selected tissues, which are the models to detect activity in vivo, such as the test using the carotid artery of the rabbit (NAO) and the test using the ear artery of the rabbit (UAC) (example 99).

The activity in vivo of the compounds of formula I, which are the subject of the present invention, was evaluated by intravenous and oral administration to rats (example 100).

Experiments on interaction with other receptor systems have shown that the compounds of formula I show significant interaction with them and, therefore, have a high specificity.

It was found that the compounds of formula I are also not niceley positive characteristic, usually not typical of other compounds with the same structure as the catecholamine.

It is obvious that these characteristics of selectivity and receptor specificity along with the absence of effects on the Central nervous system making the compounds of formula I are especially suitable for the treatment of cardiovascular diseases and especially for antihypertensive therapy and heart failure, renal failure, for the treatment of peripheral arteriopathy, cerebrovascular nedostatochnosty and ischemic cardiopathy.

In addition to the above pharmacological activity another feature characteristic of the compounds of formula I, which are the object of the invention is their ability to be absorbed in oral introduction and prolonged activity.

Consequently, in practical application in the field of therapy, the compounds of formula I may be introduced parenterally, as well as interline that distinguishes them from dopamine and dopexamine.

Therapeutic doses usually range from 5 mg to 1 g per day, and from 1 to 300 mg in oral introduction for each single administration.

In addition, the us is on the compounds of the formula I or their pharmaceutically acceptable salts in mixture with a suitable carrier.

Pharmaceutical compositions that are the subject of the invention may be liquid, suitable for enteral or parenteral administration, and preferably a solid, for example in the form of tablets, capsules, granules, suitable for oral administration.

Obtaining pharmaceutical compositions that are the subject of the invention may be carried out in accordance with standard methods.

Although the compounds of formula I are also active in oral introduction, with the aim to satisfy certain therapeutic or pharmaceutical requirements, it may be appropriate to transform them into the appropriate prodrugs.

In accordance with the methods used in the field of chemistry derivatives of phenol and catechol, appropriate prodrugs are obtained by the esterification of one or two hydroxyl groups with pharmaceutically acceptable salts.

Specific examples of prodrugs of the compounds of formula I are acetoxy-derivatives in which a hydroxyl group atrificial acetic acid, and mono - or diphosphonates, in which one or both hydroxyl groups atrificial phosphoric acid.

Extract the of, obtained by the esterification of hydroxyl groups of the phenol or one or both hydroxyl groups of the catechol pharmaceutically acceptable acids, as well as pharmaceutical compositions containing the compound of formula I in the form of the corresponding prodrugs and primarily contains compound of formula I in which the hydroxyl group of the phenol or one or both hydroxyl groups of the catechol tarifitsirovana pharmaceutically acceptable acids.

Below the present invention is illustrated in the examples.

Chromatographic purification was performed on a column of silica gel (230-400 mesh mesh).

Mass spectrometry, unless otherwise specified, was carried out under the following conditions: chemical ionization, isobutane, positive ions.

Used the following abbreviations: DMF for N,N-dimethylformamide, THF for tetrahydrofuran, DMSO for dimethyl sulfoxide.

Example 1

Obtain 6-[(4-methoxybenzylthio)acetylamino]Caproic acid (intermediate 1)

To a solution containing (4-methoxybenzylthio)acetic acid (2 g, 10.1 mmole), obtained according to J. Org. Chem., 56 (18), 5346-8 (1991), in CH2Cl2(20 ml), under stirring and at room temperature add the resulting oil was dissolved in CH2Cl2(3 ml). The resulting solution and the solution of 4 N. NaOH (3 ml) were simultaneously added dropwise with vigorous stirring to a solution containing 6-aminocaproic acid (1.3 g; a 9.9 mmole) and NaOH (0.4 g; 10 mmol) in water (5 ml). The reaction mixture was kept under stirring and at room temperature for 2 hours. After separation of the phases the aqueous phase was washed CH2Cl2(5 ml), acidified with 37% HCl to pH 1 and then extracted with CH2Cl2(20 ml). The organic phase was dried over Na2SO4. After cooling to 0oC and filtration of the resulting solid substance was obtained intermediate product 1 (2.4 g).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,15-of 1.62 (m, 6H); of 2.15 (t, 2H); 3,00 (m, 2H); of 3.56 (s, 2H); to 3.73 (s, 3H); 6,85-to 7.18 (m, 4H); 7,95 (bt, 1H).

MS: 312 [M+1].

Similarly, the method described above were obtained the following compounds.

6-[(4-phenylmethoxy)acetylamino] hexanoic acid (intermediate 2) using as the source of the product (4-phenylmethoxy)acetic acid obtained according to J. Med. Chem., 15(9), 940-4 (1972).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,10-of 1.56 (m, 6H); 2,17 (t, 2H); of 3.07 (m, 2H); 4,36 (s, 2H); 5,02 (s, 2H); 6,82-6,98 (m, 4H); 7.24 to was 7.45 (m, 5H); 8,01 (bt, 1H); 12,00 (bs, 1H).

1H-NMR (200 MHz; CDCl3): (part./million): 1,15-to 1.67 (m, 6H); 2,30 (t, 2H); to 2.41 (t, 2H); 2,87 (t, 2H); 3,18 (m, 2H); 3,76 (s, 3H); 5,43 (bt, 1H); 6.75 in-7,14 (m, 4H).

MS: 294 [M+1].

6-[(3,4-methylenedioxyphenyl)acetylamino]hexanoic acid (intermediate 4) using as starting product (3,4-methylenedioxyphenyl)acetic acid (Aldrich company).

1H-NMR (200 MHz; CDCl3): (part./million): 1,17 by 1.68 (m, 6H); 2,31 (t, 2H); 3,19 (m, 2H); 3.46 in (s, 2H); 5,47 (bt, 1H); 5,95 (s, 2H); 6,62-to 6.80 (m, 3H).

MS: 294 [M+1].

6-[(1,4-benzodioxan-2-yl)carbylamine]hexanoic acid (intermediate 5) using as starting product 2-carboxy-1,4-benzodioxane obtained according to J. Am. Chem. Soc., 77, 5373 (1955).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,21 was 1.69 (m, 6H); 2,32 (t, 2H); and 3.31 (m, 2H); to 4.16 (dd, 1H); of 4.49 (dd, 1H); of 4.66 (dd, 1H); 6,57 (bt, 1H); for 6.81-6,98 (m, 4H).

MS: 294 [M+1].

6-[3-(2-methoxyphenyl)propionamido] hexanoic acid (intermediate 6) using as starting product 3-(2-methoxyphenyl)propionic acid (Aldrich company).

1H-NMR (300 MHz; CDCl3): (part./million): 1,15-to 1.67 (m, 6H); 2,30 (t, 2H); to 2.46 (t, 2H); 2.91 in (t, 2H); 3,18 (m, 2H); 3,81 (s, 3H); 5,55 (bt, 1H); 6,79-7,25 (m, 4H).

MS: 294 [M+1].

6-[(2-nitrophenoxy)acetylamino]nylon items obtained according to J. Med. Chem., 27, 967-78 (1984).

1H-NMR (200 MHz; CDCl3): (part./million): 1,30-of 1.74 (m, 6H); of 2.33 (t, 2H); 3,30-of 3.42 (m, 2H); to 4.62 (s, 2H); 7,27 (bt, 1H); 7,00 - of 8.04 (m, 4H).

MS: 311 [M+1].

6-[(4-nitrophenoxy)acetylamino] hexanoic acid (intermediate 8) using as the source of the product (4-nitrophenoxy)acetic acid obtained according to J. Med. Chem., 27, 967-78 (1984).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,10-of 1.55 (m, 6H); of 2.16 (t, 2H); to 3.09 (m, 2H); to 4.62 (s, 2H); 7,13 (m, 2H); 8,14 compared to 8.26 (m, 3H).

MS: 311 [M+1].

6-[(4-methylsulfinylphenyl)acetylamino] hexanoic acid (intermediate 9) using as the source of the product (4-methylsulfinylphenyl) acetic acid obtained according to J. Med. Chem., 27, 967-78 (1984).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,12-of 1.56 (m, 6H); 2,17 (t, 2H); to 3.02-3.15 in (m, 2H); 3,14 (s, 3H); 4,59 (s, 2H); 7,13 (m, 2H); a 7.85 (m, 2H); 8,16 (bt, 1H); 12,01 (bs, 1H).

MS: 344 [M+1].

6-[(4-nitrophenyl)acetylamino] hexanoic acid (intermediate 10) using as the source of the product (4-nitrophenyl)acetic acid (Aldrich company).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,12-of 1.57 (m, 6H); 2,17 (t, 2H); 2,96-3,10 (m, 2H); 3,55 (s, 2H); 7,47-EUR 7.57 (m, 2H); 8.07 - a to 8.20 (m, 3H).

MS: 295 [M+1].


The solution nanometrology ether carboxylic hexandiol acid (3.6 g; a 20.2 mmole) in CH2Cl2(10 ml) was added at room temperature and under stirring to the solution containing the hydrochloride of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3.1 g; 13.5 mmole) (Aldrich company) and triethylamine (3.7 g; 37,1 mmole) in CH2Cl2(50 ml). After 2 hours was added water (50 ml) and separated phases. The organic phase was washed with an aqueous solution of 0.2 N. HCl and then saturated NaCl solution2. After drying over Na2SO4and evaporation to dryness under reduced pressure the residue was dissolved in methanol (10 ml). To the resulting solution dropwise at room temperature and with stirring was added a solution of NaOH (1.1 g; of 27.5 mmole) in water (5 ml) and the reaction mixture was kept under stirring for 2 hours. After evaporation of methanol under reduced pressure was added water (10 ml), CH2Cl2(20 ml) and 37% HCl to pH 1. After separation of the phases the aqueous phase was again extracted with CH2Cl2(20 ml). The combined organic phases were dried over Na2SO4getting after evaporation of the solvent, the intermediate product 11 (3.6 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 1,54-of 1.80 (m, 4H); and 2.27-2.49 USD (m, 4H); 2,69-2,85 m, is yodice were obtained the following compounds.

6-[4-(2-methoxyphenyl)piperazine-1 - yl]-6-Okakarara acid (intermediate 12) using as the source of the product 4-(2-methoxyphenyl)piperazine (Aldrich company).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,42-to 1.59 (m, 4H); 2,13-to 2.40 (m, 4H); 2,81-3,00 (m, 4H); 3,50-3,61 (m, 4H); of 3.78 (s. 3H); 6,82-7,01 (m, 4H).

MS (chemical ionization, methane, positive ions): 321 [M+1].

6-(2,3-dihydroindol-1-yl)-6-Okakarara acid (intermediate 13) using as starting product 2,3-dihydroindole (company Aldrich).

1H-NMR (200 MHz; CDCl3): (part./million): 1,69-2,00 (m, 4H); 2,32-of 2.66 (m, 4H); 3,23 (t, 2H); 4,10 (t, 2H); 6,97-8,31 (m, 4H).

MS: 248 [M+1].

Example 3

Obtain 6-[2-[3,4-di(phenylmethoxy)phenyl] ethoxy] Caproic acid (intermediate 14)

To a solution containing 2-[3,4-di(phenylmethoxy)phenyl]ethanol (9 g, 26.9 mmole), obtained according to J. Med. Chem., 28(9), 1269-73 (1985), and 1,5-dibromethane (12.4 g; 53,9 mmole) in THF (200 ml) and DMF (20 ml), under nitrogen atmosphere at room temperature was added NaH (0.7 g; 29,2 mmole). The reaction mixture is boiled under reflux with stirring for 5 hours and then poured into an aqueous solution of 1 N. HCl (500 ml). After extraction with ethyl ether (CH ml) the organic phase is CT was purified by chromatography (eluent petroleum ether:ethyl acetate = 75:25), getting ethyl ester 5-bromopentyl-2- [3,4-di(phenylmethoxy)phenyl] (4 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 1,37-of 1.65 (m, 4H); 1,76-of 1.92 (m, 2H); 2,77 (t, 2H); to 3.38 (t, 2H); 3,39 (t, 2H); 3,55 (t, 2H); 5,12 (s, 2H); to 5.13 (s, 2H); 6,68-to 6.88 (m, 3H); 7.23 percent-7,49 (m, 10H).

MS: 483, and 485 [M+1].

To a suspension of magnesium turnings (0.2 g, 8.3 mmole) in THF (5 ml) under nitrogen atmosphere at room temperature was added iodine (20 mg) and ten minutes dropwise a solution of ethyl ester 5-bromopentyl-2-[3,4 - di(phenylmethoxy)phenyl] (3.8 g; of 7.9 mmole) in THF (25 ml). The reaction mixture is boiled under reflux with stirring for 5 hours, then cooled to room temperature and poured into a flask containing dry ice. After heating to room temperature, was added ethyl ether and the aqueous solution 1 N. HCl. The phases were separated and the organic phase was dried over Na2SO4. After evaporation to dryness under reduced pressure the crude product was purified using chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 95:5:0.5), the receiving intermediate product 14 (2 g) as a white solid.

1H-NMR (200 MHz; CDCl3): (part./million): 1,24-1,71 (m, 6H); 2,32 (t, 2H); 2,77 (t, 2H); 3,35-3,66 (m, 4H); 5,12 (s, 2H); to 5.13 (s, 2H); 6,68-6,89 (m, 3H); 7,22-7,49 (m, 10H).

MS: 449 [M+1].

2SO4and was evaporated to dryness under reduced pressure. The crude product was purified using chromatography (eluent CH2Cl2:CH3OH:30% ammonia = 90:10:1) to give intermediate product 15 (4.4 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 1,74 (s, 1H); of 2.36 (m, 4H); 2,84 (m, 4H); 3.40 in (s, 2H); of 3.77 (s, 3H); PC 6.82 (m, 2H); 7,20 (m, 2H).

MS: 207 [M+1].

Example 5

Obtain tert-butyldimethylsilyl ether (3-chloro-4-tert - butyldimethylsilyloxy)phenylacetic acid (intermediate 16)

To a solution containing (3-chloro-4-hydroxy)phenylacetic acid (1 g, 5.3 mmole) of (company Aldrich) and tert-butyldimethylsilyl (2 g, 13.3 mmole) in DMF (6 ml), under nitrogen atmosphere at room temperature was added imidazole (1.8 g; 26,4 mmole). The reaction mixture withstand crashes-auto St is 2CO3(25 ml) and was extracted with hexane (h ml). The organic phase was dried over Na2SO4and the solvent evaporated under reduced pressure, obtaining the intermediate product 16 (2.2 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 0,19 (s, 6H); of 0.21 (s, 6H); of 0.85 (s, 9H); and 1.00 (s, 9H); 3,50 (s, 2H); for 6.81 (d, 1H); 6,99 (dd, 1H), 7,24 (d, 1H).

MS: 415 [M+1].

Similarly, the method described above were obtained the following compounds.

tert-Butyldimethylsilyloxy ether (3-nitro-4-tert-butyldimethylsilyloxy) phenylacetic acid (intermediate 17) using as starting product (3-nitro-4-hydroxy) phenylacetic acid (Aldrich company).

1H-NMR (200 MHz; CDCl3): (part./million): 0,22 (s, 6H); to 0.23 (s, 6H); of 0.85 (s, 9H); 0,99 (s, 9H); 3,59 (s, 2H); 6,91 (d, 1H), 7,32 (dd, 1H), of 7.70 (d, 1H).

MS: 426 [M+1].

tert-Butyldimethylsilyloxy ether (3-methoxy-4-tert-butyldimethylsilyloxy)phenylacetic acid (intermediate 18)using as starting product (3-methoxy-4-hydroxy)phenylacetic acid (Aldrich company).

1H-NMR (200 MHz; CDCl3): (part./million): 0,11 (s, 6H); 0,20 (s, 6H); of 0.82 (s, 9H); to 0.96 (s, 9H); 3,50 ('s.2H); of 3.77 (s, 3H), 6,64-6,79 (m, 3H).

MS: 411 [M+1].

Example 6

Obtain 6-[2-[3,4-di) in anhydrous DMF (50 ml) was added dropwise with stirring to a solution of 2-[3,4-di(phenylmethoxy)phenyl]ethanol (20,0 g; 59,8 mmole) and triphenylphosphine (17,2 g; 65.6 mmole) in anhydrous DMF (200 ml), soaking in the atmosphere of nitrogen at 0oC. the Reaction mixture was heated to room temperature and was stirred for 1.5 h, then was poured into water and ice and was extracted twice with ethyl ether. The combined organic phases were dried over Na2SO4and the solvent was removed under reduced pressure. The residue was purified by chromatography (eluent petroleum ether:ethyl acetate = 95:5) to give 2-[3,4-di(phenylmethoxy)phenyl]-1-bromatan (16.3 g) as a white solid.

1H-NMR (200 MHz; CDCl3): (part./million): 3.04 from (t, 2H); 3,47 (t, 2H); to 5.13 (s, 2H); 5,14 (s, 2H); 6,70 (dd, 1H); is 6.78 (d, 1H), 6.87 in (d, 1H), 7,25-of 7.48 (m, 10H).

MS: 397, 399 [M+1].

A solution of 2-[3,4-di(phenylmethoxy)phenyl]-1 - brometea (13,9 g; 35,0 mmol) and thiourea (3.5 g; 46,0 mmol) in absolute ethanol (50 ml) was heated with stirring under reflux for 16 hours under nitrogen atmosphere. The solvent was removed under reduced pressure and added an aqueous solution of 1,4 N. NaOH (50 ml). The mixture was boiled under reflux for 1.5 h, then was poured into water and ice. Added concentrated HCl to pH 1 and the mixture was extracted twice with ethyl ether. The combined organic phases were washed Vodokanal]ethanethiol (12.0 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 1,29 (t, 1H); 2,61-of 2.86 (m, 4H); 5,12 (s, 3H); 5,14 (s, 2H); 6,69 (dd, 1H); 6,77 (d, 1H), 6,85 (d, 1H), 7,25-of 7.48 (m, 10H).

MS: 351 [M+1].

To a solution of 2-[3,4-di(phenylmethoxy)phenyl]ethanethiol (12.2 g; to 34.8 mmole) and ethyl-6-Bromhexine (15.5 g; 69 mmol) in benzene (140 ml) at room temperature and with stirring was added water (90 ml), Aliquat 336(trioctyltrimellitate) (0.28 g; 0.7 mmole) and dropwise a solution of NaOH (1.7 g; 42,5 mmole) in water (20 ml). The mixture was stirred for 1.5 h at room temperature. The organic phase is washed with water, dried over Na2SO4and the solvent was removed under reduced pressure. The residue was dissolved in ethanol (110 ml) and was added dropwise a solution of NaOH (4.1 g; 102,5 mmole) in water (20 ml). The mixture was stirred for 1 hour at room temperature. The solvents were removed under reduced pressure, then was added ethyl ether (100 ml), water (50 ml) and concentrated HCl to pH 1. The aqueous phase was extracted twice with ethyl ether (100 ml), the organic phases were combined, washed with water and dried over Na2SO4. After removal of the solvent under reduced pressure was obtained intermediate product 19 (15.5 g) as a white solid.

1H-NMR (200 MHz; CDCl3 MS: 465 [M+1].

Example 7

Getting hydrochloride 5-(2-amino-ethyl)-1,3 - benzothiazol-2(3H)-she (intermediate 20)

Triperoxonane anhydride (45,9 g; 218,7 mmole) was added dropwise at room temperature and under stirring to a suspension of tiramina (10.0 g; 72.9 mmole) in ethyl ether (100 ml). The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in methanol (150 ml) and the solvent was removed under reduced pressure. The obtained 4-(2-triptoreline)phenol (16.7 g; 71.6 mmole) was dissolved in ethyl ether (350 ml) and was slowly added at room temperature and with vigorous stirring to a solution of sodium nitrate (6,1 g; 71.7 mmole) and uranyl nitrate cerium (0.3 g; 0.7 mmole) in 6 BC HCl (120 ml). The reaction mixture was stirred for 5 hours at room temperature, then added CH2Cl2(350 ml) and separated phases. The organic phase was dried over Na2SO4and the solvents were removed under reduced pressure. Obtained 2-(4-hydroxy-3-nitrophenyl)-N - cryptanalytically (19,1 g; 68,6 mmole) was dissolved in pyridine (200 ml). At room temperature was added N,N-dimethylthiocarbamate (16,9 g; 137,3 mmole), and then the reaction mixture napravlenii, added chloroform (200 ml) and again the solvent was removed. The residue was dissolved in CH2Cl2(200 ml) and the solution washed with 1 N. HCl (100 ml) and then water (50 ml). The organic phase was dried over Na2SO4and the solvent was removed under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH = 99:1) to give O-[2-nitro-4-(2 - triptoreline)phenyl]-N,N-dimethylthiocarbamate (19,8 g) as a yellow solid.

1H-NMR (200 MHz; CDCl3): (part./million): to 2.99 (t, 2H); to 3.38 (s, 3H); of 3.45 (s, 3H); 3,59-3,61 (m, 2H); 6,41-6,59 (bs, 1H); 7,21 (d, 1H), of 7.48 (dd, 1H), 7,94 (d, 1H).

MS: 366 [M+1].

Clean O-[2-nitro-4-(2 - triptoreline)phenyl]-N,N-dimethylthiocarbamate (19,8 g; 54,2 mmole) kept at 205oC for 0.5 h After cooling to room temperature was added CH2Cl2(200 ml), the insoluble part was filtered and evaporated the solvent under reduced pressure, resulting in the formed residue, which was purified by chromatography (eluent CH2Cl2: CH3OH = 98:2) to give S-[2-nitro-4-(2-triptoreline)phenyl] -N, N-dimethylthiocarbamate (17.5 g) as a pale yellow solid.

1H-NMR (200 MHz; CDCl3): (part./million): 2,89 (t, 2H); is spengiu S-[2-nitro-4-(2 - triptorelin-ethyl)phenyl] -N, N-dimethylthiocarbamate (13,2 g; 36,1 mmole) in water (85 ml) and acetic acid (3.5 ml) was boiled under reflux. Within 30 minutes of the portions was added iron powder (14.0 g) and then the reaction mixture was intensively stirred for 2 hours at the temperature of reflux distilled. After cooling, was added methanol (50 ml), the mixture was filtered to remove the insoluble part and the solvents evaporated under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH = 98:2). The obtained solid substance was dissolved in methanol and the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% in the ratio of the mass to volume (wt. /about. )). Thus was obtained the hydrochloride of S-[2-amino-4-(2 - triptoreline)phenyl] -N,N-dimethylthiocarbamate (7,1 g) as a pale yellow solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): to 2.75 (t, 2H); 2.91 in and 3.05 (2bs, 6H); 3,30-of 3.48 (m, 2H); of 4.77 (bs, 3H); of 6.71 (dd, 1H); to 6.88 (d, 1H), 7,21 (d, 1H), 9,58 (bt, 1H).

MS: 336 [M+1].

Under stirring, the suspension of the hydrochloride of S-[2-amino-4-(2-triptoreline)phenyl]-N,N-dimethylthiocarbamate (3.5 g; 9.5 mmole) in water (118 ml) was boiled under reflux for 4 hours. After filtration of the cooled reaction mixture and the prom is Dogo product, 5-(2-triptoreline)-1,3-benzothiazol-2(3H)-he (1.7 g) was dissolved in ethanol (17 ml) and 6 N. HCl (17 ml). The reaction mixture is boiled under reflux for 5 hours and the solvent was removed under reduced pressure, obtaining the intermediate product 20 (1.3 g) as a pale gray solid.

1H-NMR (200 MHz; D2O): (a frequent. /million): of 2.83 (t, 2H); to 3.09 (t, 2H); 6.89 in-6,97 (m, 2H); 7,29 (d, 1H).

MS: 195 [M+1].

Example 8

Getting hydrobromide 6-(2-amino-ethyl)-1,3-benzothiazol-2(3H)- she (intermediate 21)

Triperoxonane anhydride (21.8 g; 103,6 mmole) was added dropwise at room temperature and under stirring to a suspension of the hydrochloride of 2-(4-nitrophenyl)ethylamine (10,5 g; 51.8 mmole) (Aldrich company) in CH2Cl2(100 ml). The reaction mixture was kept under stirring for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in methanol (150 ml) and the solvent was removed under reduced pressure. Obtained 2-(4-nitrophenyl)-N-cryptanalytically (13.3 g) was dissolved in ethanol (250 ml) and concentrated HCl (5,1 ml). Was added 10% Pd on charcoal (50% water) (1.3 g) and the reaction mixture was kept under stirring under hydrogen pressure (2.7 ATM) at room temperature in triptoreline)ethylaniline (13,4 g). With stirring, a solution of the hydrochloride of 4-(2-triptoreline)ethylaniline (13,1 g; and 48.8 mmole) and potassium thiocyanate (11.9 g, 122,4 mmole) in chlorobenzene (150 ml) was kept at 110oC for 7 hours, after cooling, the reaction mixture was stirred at room temperature for 16 hours and then under reduced pressure, the solvent was removed. To the residue was added ethyl ether (100 ml) and the suspension was stirred at room temperature for 30 minutes. After filtration, the solid product is suspended with stirring in water (100 ml) and 50oC for 10 minutes, then filtered and added CH2Cl2(40 ml). The suspension was kept under stirring at room temperature for 15 minutes, after receiving filter 4-(2-triptoreline) phenyltoloxamine (11.5g) as a light brown solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): was 2.76 (t, 2H); 3,32-3,47 (m, 2H); 7,11-7,35 (m, 4H); 7,02 to 7.75 (bs, 2H); 9,49 (bt, 1H); 9,63 (s, 1H).

MS: 292 [M+1].

Under stirring to a suspension of 4-(2-triptoreline)phenyltoloxamine (11.1 g; 38,1 mmole) in chloroform (150 ml) dropwise at 10oC was added bromine (12.9 g; 80,7 mmole). The reaction mixture was kept under stirring at komnatnoi and filtering received a yellow solid product, which was washed with a small amount of acetone and suspended in water (200 ml). Was added a saturated solution of NaHCO3to complete alkalizing. By filtering received 2-amino-6-[(2-triptoreline)ethyl] -1,3-benzothiazol (8.6 g) as a white solid product.

1H-NMR (200 MHz; DMSO-d6): (part./million): to 2.79 (t, 2H); 3.30 is is-3.45 (m, 2H); 7,02 (dd, 1H); from 7.24 (d, 1H); 7,38 (bs, 2H); of 7.48 (d, 1H); 9,49 (bs, 1H).

MS: 290 [M+1].

With stirring to a solution of 2-amino-6-[(2 - triptoreline)ethyl]-1,3-benzothiazole (4.1 g; 14.2 mmole) in 85% phosphoric acid (94 ml) dropwise within 2 hours at -5oC was added a solution of sodium nitrite (2.9 g; and 42.7 mmole) in water (4.6 ml). After stirring for a further 40 minutes, the mixture for 40 minutes at -5oC and with stirring was added to a solution of the pentahydrate of copper sulfate (28.4 g; 113,7 mmole) and sodium chloride (35.5 g; 607,5 mmole) in water (124 ml). The reaction mixture was stirred at -5oC for 1 hour, and then during the night was allowed to warm to room temperature. The suspension was extracted twice CH2Cl2(G ml), the organic phase is then washed with water, saturated NaHCO3and with brine, then dried over Na2SO4and the solvent was removed when the I 2-chloro-6-[(2 - triptoreline)ethyl]-1,3-benzothiazol (2.7 g) as a white solid product.

1H-NMR (200 MHz; CDCl3): (part./million): 3,00 (t, 2H); 3,59 - 3,61 (m, 2H); 6,35-6,63 (bs, 1H); 7,28 (dd, 1H); to 7.59 (d, 1H); to 7.84 (d, 1H).

MS: 309 [M+1].

With stirring to a solution of 2-chloro-6-[(2 - triptoreline)ethyl]-1,3-benzothiazole (2.1 g; 6.8 mmole) in methanol (24 ml) at room temperature was added a solution of 5.4 M of sodium methoxide in methanol (2.7 ml). The reaction mixture was stirred at 80oC for 5 hours, then added water (3.5 ml) and heating was continued for 2 hours. The solvents are evaporated under reduced pressure and then the residue was added water and CH2Cl2. The phases were separated and the organic phase was washed with brine, dried over Na2SO4and the solvent was removed under reduced pressure. The obtained 6-(2-amino-ethyl)-2-methoxy-1,3-benzothiazol (1.3 g) was dissolved in 48% HBr (9 ml) and the reaction mixture was stirred at the temperature of reflux distilled for 1 hour. After cooling to 0oC and filter the received intermediate product 21 (1.3 g) as a light brown solid.

1H-NMR (200 MHz; D2O): (part./million): 2,82 (t, 2H); 3,10 (t. 2H); 6,94 (d, 1H); 7,05 (dd, 1H); 7,21 (d, 1H).

MS: 195 [M+1].

Example 9

Getting dihydrochloride of 2-amino-6-(2-amino-ethyl)-1,3-benzothiazole (promezhutochnya), obtained according to example 8, in absolute ethanol (20 ml) was added at room temperature 6 N. HCl (20 ml). The reaction mixture is boiled under reflux for 24 hours, then the solvents evaporated under reduced pressure, obtaining the intermediate product 22 (0.84 g) as a white solid.

1H-NMR (200 MHz; DMSO-d6+ D2O): (part./million): 2,86-to 3.09 (m, 4H); to 7.32 (dd, 1H); was 7.45 (d, 1H); of 7.75 (d, 1H).

MS: 194 [M+1].

Example 10

Getting 2-(3-chloro-5-methoxyphenyl)ethylamine (intermediate 23)

A solution of 3-chloro-5-methoxybenzamido alcohol (3.4 g; 19.7 mmole), obtained according to J. Chem. Soc., Perkin Trans. 1, 4, 1095-8 (1982), and DMF (76 ml) in CH2Cl2(20 ml) was added dropwise under nitrogen atmosphere at room temperature and under stirring to a solution of thionyl chloride (2.5 g; 21,0 mmole) in CH2Cl2(30 ml). The reaction mixture is boiled under reflux for 4 hours, after which was added formic acid (50 μl) and the mixture was stirred for another 30 minutes. Then added water (30 ml) and the separated phases, the organic phase is washed with 10% KHCO3then water and dried over Na2SO4. By evaporation of the solvent under reduced pressure was obtained 3 - chloro-5-methoxy who rija (1.5 g; 30,6 mmole) and the reaction mixture was stirred at room temperature for 1 hour and then was poured into water and ice and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4and the solvent was removed under reduced pressure. The obtained 3-chloro-5-methoxyphenylacetonitrile (3.2 g; and 17.6 mmole) was dissolved in anhydrous THF (100 ml) under nitrogen atmosphere. Slowly under stirring and at room temperature was added a complex of borane-dimethyl sulfide (2.6 g; 33,7 mmole). The reaction mixture is boiled under reflux for 3 hours. After cooling to 5oC was slowly added a solution of concentrated HCl (2 ml) in methanol (20 ml). The reaction mixture is boiled under reflux for 2 hours, after which the solvents evaporated under reduced pressure. To the residue were added water and ethyl acetate and separated phases. The aqueous phase was podslushivaet 30% NH4OH and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4and the solvent was removed under reduced pressure, obtaining the intermediate product 23 (2.6 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 1,51 (bs, 2H); in 2.68 (t, 2H); to 2.94 (t, 2H); of 3.77 (s, 3H); 6,60-6,79 (m, 3H).

MS: 186 [M+1].


The triethylamine (12.7 g; 126,1 mmole) and then a solution of acid chloride 6-phthalimidopropyl acid (15.5 g; of 55.5 mmole) in CH2Cl2(120 ml) was added to a suspension of the hydrochloride of (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (14.4 g; of 50.4 mmole) in CH2Cl2(150 ml), which was kept under stirring at room temperature. The reaction mixture was kept under stirring and at room temperature for 1.5 hours After adding water (250 ml) and separation of the phases the organic phase was washed with water (150 ml), dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified by chromatography (eluent petroleum ether:ethyl acetate = 6:4) to give (S)-N-propyl-N-[(6 - phthalimido-1-oxo)hexyl] -5,6-dimethoxy-1,2,3,4-tetrahydro-2 - naphtylamine (24,1 g).

1H-NMR (200 MHz; CDCl3): (part./million): 0,80-0,94 (2t, 3H); 1.30 and 2,02 (m, 10H); and 2.26-of 2.38 (m, 2H); 2,59 - up 3.22 (m, 6H); 3,60-and 3.72 (m, 2H); 3.75 to 3,84 (4s, 6H), 3,85-of 4.66 (m, 1H); 6,66-PC 6.82 (m, 2H); to 7.64-a 7.85 (m, 4H).

MS: 493 [M+1].

A solution of (S)-N-propyl-N-[(6-phthalimido-1-oxo)hexyl] -5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphtylamine (24,1 g; 48,9 mmole) in 33% solution of methylamine in ethanol (240 ml) was kept under stirring and at room temperature for 20 hours. The reaction mixture was dried on the 30% ammonia = 90:10:1), receiving the intermediate product 24 (11.9 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 0,80-0,93 (2t, 3H); 1,20-2,04 (m, 10H); 2,25-2,48 (m, 2H); 2,58-is 3.21 (m, 8H); 3,72-3,81 (4s, 6H); 3,82 with 4.64 (m, 1H); 6,66-to 6.80 (m, 2H).

MS: 363 [M+1].

Example 12

Getting dihydrochloride (S)-N-propyl-N-[(6-amino)hexyl]-5,6 - dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 25)

Borane-dimethylsulfide complex (3 g, 37 mmol) was slowly added at room temperature and under stirring in nitrogen atmosphere to a solution of intermediate 24 (2.3 g; 6,34 mmole), obtained according to example 11, in THF (40 ml). After the addition was finished the reaction mixture is boiled under reflux for 2 hours. After cooling to 5oC solution was added 37% HCl (1.5 ml) in methanol (12 ml). The reaction mixture is again boiled under reflux for 1 hour and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml) and the solvent drove away under reduced pressure, the newly added methanol (30 ml) and the solvent evaporated to dryness. The crude product was purified using chromatography (eluent CH2Cl2:CH3OH:afire (15% wt. /about. ) to markedly acidic pH values. By evaporation of the solvent under reduced pressure was obtained intermediate product 25 (1.9 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,19-of 1.32 (m, 4H); 1,40-of 2.20 (m, 8H); 2,44-3,17 (m, 10H); 3.46 in-3,63 (m, 1H); 3,59 (s, 3H); 3,68 (s, 3H); 6,76-6,85 (2d, 2H).

MS: 349 [M+1].

Example 13

Getting dihydrobromide (S)-N-propyl-N-[(6-amino)hexyl]-5,6 - dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 26)

A solution of intermediate 25 (1.2 g; 2,87 mmole), obtained according to example 12, in 48% HBr (10 ml) was boiled under reflux in nitrogen atmosphere for 5 hours. Then the reaction mixture was dried to dryness under reduced pressure and the resulting residue was added absolute ethanol (20 ml). After evaporation of the solvent was added ethyl acetate (20 ml) and again evaporated solvent. The crude product was purified by crystallization from a mixture of absolute ethanol/ethyl acetate, obtaining the intermediate product 26 (1.2 g) as a white solid.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,21-2,19 (m, 12H); 2,39-3,11 (m, 10H); 3,44-of 3.60 (m, 1H); 6,50 (d, 1H); 6,62 (d, 1H).

MS: 321 [M+1].

Example 14

< / BR>
A solution of di-tert-BUTYLCARBAMATE (14.5 g; 66,2 mmole) in DMF (28 ml) was added under stirring and at room temperature in a nitrogen atmosphere to a solution of dihydrobromide (S)-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (20 g, 66 mmol) and triethylamine (6.7 g; 66 mmol) in DMF (160 ml). The reaction mixture was kept under stirring for 3 hours, then was poured into a mixture of water, ice and ethyl ether. After adding 1 N. HCl to obtain a markedly acidic pH values are of the same phase. The organic phase is twice washed with water, dried over Na2SO4and was evaporated to dryness under reduced pressure. The residue was dissolved in DMF (250 ml) and the resulting solution was added under stirring and at room temperature potassium carbonate (34.4 g; 248,9 mmole) and benzylbromide (26,6 g; 155,5 mmole). The reaction mixture was stirred at 60oC for 7 hours, then kept at room temperature and under stirring for 16 hours and finally poured into a mixture of water and ethyl ether. After phase separation the organic phase is washed with water, dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified by chromatography (eluent petroleum ether: ethyl acetate = 93:7) to give (S)-UP>1H-NMR (200 MHz; CDCl3): (part./million): 0,86 (t, 3H); of 1.46 (s, 9H); 1,49-to 1.98 (m, 4H); 2,52-and 3.16 (m, 6H); 3,80-4,32 (bs, 1H); 4,99 (s, 2H); 5,10 (s, 2H); 6,74 (d, 1H); for 6.81 (d, 1H); 7,25-7,47 (m, 10H).

MS: 502 [M+1].

A solution of HCl in ethyl acetate (13% wt./about.) (250 ml) was added under stirring and at room temperature to a solution of (S)-N-tert-butoxycarbonyl-N-propyl-5,6-di(phenylmethoxy)- 1,2,3,4-tetrahydro-2-naphtylamine (23 g; 45.8 mmole) in ethyl acetate (100 ml). After 30 minutes the precipitate was filtered, washed with ethyl acetate and dried under vacuum at 50oC for 10 hours, receiving the intermediate product 27 (16.4 g) as a white solid.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 (t, 3H); 1,71-of 2.54 (m, 4H); 2,28 is 3.23 (m, 7H); is 4.85 (s, 2H); of 4.95 (s, 2H); 6,60 (d, 1H); of 6.68 (d, 1H); 7,12-7,33 (m, 10H).

MS: 402 [M+1].

Example 15

Obtain (S)-N-propyl-N-[(6-amino-1-oxo)hexyl]-5,6-di(phenyl-methoxy)- 1,2,3,4-tetrahydro-2-naphtylamine (intermediate 28)

The solution of acid chloride 6-phthalimidopropyl acid (11.2 g; 40.2 mmole) in CH2Cl2(60 ml) was added under stirring and at room temperature to a solution containing the intermediate product 27 (16 g; of 36.5 mmole), obtained according to example 14, and triethylamine (9.2 grams; 91,3 mmole) in CH2Cl2(130 ml). The reaction mixture was stirred for Eskow phase was washed with water (100 ml), dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was dissolved in 33% solution of methylamine in ethanol (240 ml) and the reaction mixture was kept under stirring and at room temperature for 6 hours. After evaporation of the solvent under reduced pressure the residue was purified by chromatography (eluent CH2Cl2: CH3OH: 30% ammonia = 90:10:1) to give intermediate 28 (10,9 g).

1H-NMR (200 MHz; CDCl3): (part./million): 0,81-of 0.95 (2t, 3H); 1,23-2,02 (m, 10H); and 2.26-to 3.38 (m, 2H); of 2.51 3.21-in (m, 8H); 3,80-br4.61 (m, 1H); 4,99 (2s, 2H); 5,09 (2s, 2H); 6,69-6,87 (m, 2H); 7,25-7,47 (m, 10H).

MS: 515 [M+1].

Example 16

Obtain (S)-N-propyl-N-(5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphthyl)-5-carboxypentyl (intermediate 29)

The solution nanometrology ether carboxylic hexandiol acid (5.9 g; a 33.3 mmole) in CH2Cl2(10 ml) was added under stirring and at room temperature to a solution containing hydrogen bromide (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (10 g; 30,3 mmole) and triethylamine (7.6 g; 75,3 mmole) in CH2Cl2(80 ml). After 2 hours was added water (100 ml) and separated phases. The organic phase was washed with an aqueous solution of 0.2 N. HCl, then with water, dried over Na2SO2Cl2(100 ml). After drying the organic phase over Na2SO4and evaporation of the solvent was obtained intermediate product 29 (11.4 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 0,91 0,87 and (2t, 3H); 1,48-2,07 (m, 8H); 2,29 is 2.46 (m, 4H); 2,60-of 3.27 (m, 6H); of 3.77 and 3.80, and 3,82, 3,83 (4s, 6H); 3,84-of 4.05 and 4,48-4,67 (2m, 1H); 6,69 (d, 1H); 6,79 (d, 1H).

MS: 378 [M+1].

Similarly, the method described above were obtained the following compounds.

(S)-N-propyl-N-[5,6-di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl] -5 - carboxypentyl (intermediate 30) using as the starting material, intermediate product 27, obtained according to example 14.

1H-NMR (200 MHz; CDCl3): (part./million): 0,91 0,87 and (2t, 3H); 1,47-to 2.06 (m, 8H); 2,28 is 2.46 (m, 4H); of 2.51-of 3.27 (m, 6H); 3,82-4,01 and 4,46 with 4.65 (2m, 1H); 4,98 and 5,01 (2s, 2H); 5,09 and 5,11 (2s, 2H); 6,69-to 6.88 (m, 2H); 7,25-of 7.48 (m, 10H).

MS: 530 [M+1].

(S)-N-propyl-N-[5 - methoxy-1,2,3,4-tetrahydro-2-naphthyl] -5-carboxypentyl (intermediate 31) with ispano J. Med. Chem. 29, 912 (1986).

1H-NMR (200 MHz; CDCl3): (part./million): of 0.91 0.88 and (2t, 3H); 1,49 is 2.10 (m, 8H); 2,28 is 2.46 (m, 4H); 2,48-of 3.31 (m, 6H); 3,78 and of 3.80 (2s, 3H); a 3.87-4,07 and 4,49-4,69 (2m, 1H); 6,60-7,17 (m, 3H).

MS: 348 [M+1].

Example 17

Getting 4-nitrophenyl-(S)-N-propyl-N- [5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]-6-amino-6-oxohexanoate (intermediate 32)

With stirring to a solution of intermediate 30 (3.4 g; 6.4 mmole), obtained according to example 16, CH2Cl2(18 ml) under nitrogen atmosphere at room temperature was added DMF (25 μl) and thionyl chloride (1.2 g; 10.1 mmole). After soaking for 30 minutes at room temperature the reaction mixture was evaporated to dryness under reduced pressure. The resulting residue was dissolved in CH2Cl2(10 ml) and this solution is added dropwise under nitrogen atmosphere was added under stirring to a solution of 4-NITROPHENOL (0,82 g, 5.9 mmole) and triethylamine (1.2 g; 11.9 mmole) in CH2Cl2(16 ml) and DMF (1 ml). The mixture was stirred at room temperature for 2.5 h, and then added water (30 ml) and CH2Cl2(50 ml). The organic phase is washed with water, dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified by chromatography (eluent CHC; CDCl3): (part./million): of 0.91 0.88 and (2t, 3H); 1,45-2,02 (m, 8H); and 2.26-2.49 USD (m, 2H); 2.50 each-of 3.32 (m, 8H); 3,81-of 4.44 4.00 and with 4.65 (2m, 1H); 4.99 and 5,01 (2s, 2H); 5,09 and 5,11 (2s, 2H); 6,68-to 6.88 (m, 2H); 7,19-of 7.48 (m, 12H); 8,18-8,30 (m, 2H).

MS: 651 [M+1].

Example 18

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4- methoxybenzylthio)ethylamino] hexyl] -5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 33)

Thionyl chloride (1.4 g; an 11.7 mmole) was added under stirring and at room temperature to a suspension of intermediate 1 (2.4 g; 7.7 mmole), obtained according to example 1, CH2Cl2(20 ml). After 1 h the solvent evaporated under reduced pressure to obtain oil, which was dissolved in CH2Cl2(10 ml). The solution was added dropwise under stirring and at room temperature to a suspension obtained after the addition of triethylamine (2.1 g; 21 mmol) to a suspension hydrobromide (S)-N-propyl-5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphtylamine (2.3 g; 7 mmol) in CH2Cl2(30 ml). The reaction mixture was kept under stirring and at room temperature for 1 hour. After adding water (40 ml) and separation of the phases the organic phase is washed with acidified water, dried over Na2SO4and was evaporated to dryness under reduced pressure. The remainder rastvorennoi the temperature of the complex of borane-dimethyl sulfide (3.2 g; of 40.8 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added 37% hydrochloric acid (1.3 ml) in methanol (11 ml). The reaction mixture is again boiled under reflux for 1 hour, then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (20 ml) and the solvent evaporated under reduced pressure. After further addition of methanol (20 ml) and the solvent is evaporated to dryness the resulting crude product was purified by chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 90:10:1). The obtained product was dissolved in absolute ethanol (20 ml). After adding a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and evaporation of the solvents under reduced pressure was obtained intermediate product 33 (2.1 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,08-of 2.21 (m, 12H); 2,42-is 3.21 (m, 14H); 3,41-of 3.60 (m, 1H); to 3.58 (s, 3H); 3,63 (s, 3H); 3,68 (s, 3H); 6,76-7,34 (m, 6H).

MS: 515 [M+1].

Similarly, the method described above were obtained from shadowseeker-2-naphtylamine (intermediate 34) using as the starting material, intermediate product 3.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,12-2,22 (m, 14H); 2,44 of 3.56 (m, 15H); 3,59 (s, 3H); the 3.65 (s, 3H); of 3.69 (s, 3H); 6,76 for 7.12 (m, 6H).

MS (thermospray): 497 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-(6,7-dimethoxy-1,2,3,4 - tetrahydroisoquinoline-2-yl)hexyl] -5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 35), using as the starting material, intermediate product 11.

1H-NMR (200 MHz; CDCl3): (part./million): to 0.98 (t, 3H); 1,33-to 2.57 (m, 12H); 2,58-3,71 (m, 15H); 3,76 (s, 3H); 3,81 (s, 3H); is 3.82 (s, 3H); 3,83 ('s. 3H): 4,11-4,43 (m, 2H); to 6.58 (s, 1H); 6,70 (s, 1H); 6,74 (d, 1H); PC 6.82 (d, 1H).

MS: 525 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-(2,3-dihydroindol-1-yl)hexyl] -5,6 - dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate product 36) using as the starting material, intermediate product 13.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.93 (t, 3H); 1,15-2,31 (m, 12H); 2,41-of 3.94 (m, 15H); is 3.82 (s, 3H); 3,86 (s, 3H); to 6.43-7,16 (m, 6H).

MS: 451 [M+1].

Example 19

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4-nitrophenyl)ethylamino] hexyl]-5,6 - di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 37)

Working according to the method similar to that described in example 18, but using instead hydrobromide (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro the ERU 14, and the intermediate product 10, obtained according to example 1 was obtained intermediate product 37.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.91 (t, 3H); 1,20-to 2.41 (m, 12H); 2,53 - of 3.25 (m, 14H); 3,40-3,51 (m, 1H); is 4.93 (s, 2H); 5,14 (s, 2H); 6,85 (d, 1H); 7,01 (d, 1H); 7,27-to 7.50 (m, 10H); 7,51-to 7.61 (m, 2H); 8,16 is 8.25 (m, 2H).

MS: 650 [M+1].

Example 20

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4-phenylmethoxy) ethylamino]hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (intermediate 38)

Thionyl chloride (3 g, 25.2 mmole) was added under nitrogen atmosphere at room temperature to a suspension of intermediate 2 (6.4 g; 17.2 mmole), obtained according to example 1, CH2Cl2(52 ml). After 1 h the solvent evaporated under reduced pressure to obtain oil, which was dissolved in CH2Cl2(17 ml). Sodium tetraborate (5.3g; to 26.3 mmole) was added under nitrogen atmosphere to a solution of the hydrobromide (S)-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (4 g, 13.2 mmole) in water (80 ml). After heating to 70oC for complete dissolution and cooling to room temperature was added CH2Cl2(10 ml), potassium carbonate (14.2 g; 102,7 mmole) and with vigorous stirring the above solution in CH2Cl2. After soaking in techenie was extracted with CH2Cl2(50 ml). The combined organic phases were washed with brine, slightly acidified with HCl, dried over Na2SO4and was evaporated to dryness under reduced pressure. The resulting residue was dissolved in a nitrogen atmosphere at room temperature in THF (40 ml). To the resulting solution was slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (6.2 g; 78,9 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added 37% hydrochloric acid (3 ml) in methanol (27 ml). The reaction mixture is again boiled under reflux for 1 hour, then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (50 ml) and the solvent evaporated under reduced pressure. After adding methanol (50 ml) and the solvent is evaporated to dryness the resulting residue was dissolved in absolute ethanol (50 ml). After adding a solution of HCl in ethyl ether (15% wt. /about.) and evaporation of the solvents under reduced pressure the crude product was purified using chromatography (eluent ) and after adding a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and evaporation of the solvents under reduced pressure was obtained intermediate product 38 (4 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,15-of 2.20 (m, 12H); 2,34 is 3.15 (m, 10H); 3,25-of 3.32 (m, 2H); 3,39-3,59 (m, 1H); 4,05 is 4.13 (m, 2H); 4,91 (s, 2H); of 6.49 (d, 1H); 6,63 (d, 1H); of 6.71-6.89 in (m, 4H); 7,21-7,33 (m, 5H).

MS: 547 [M+1].

Similarly, the method described above were obtained the following compounds.

Hydrochloride (S)-N-propyl-N-[6-[2- [3,4-di(phenylmethoxy)phenyl] ethoxy] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (intermediate 39) using as the starting material, intermediate product 14.

MS: 638 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[3- (2-methoxyphenyl)propylamino]hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 40) using as the starting material, intermediate product 6.

1H-NMR (300 MHz; D2O): (part./million): 0,78 (t, 3H); 1,16-2,17 (m, 14H); 2,52 (t, 2H); 2,37-3,18 (m, 12H); 3,43-to 3.58 (m, 1H); 3,66 (s, 3H): 6.48 in (d, 1H); is 6.61 (d, 1H); 6,76-7,16 (m, 4H).

MS: 469 [M+1].

Hydrochloride (S)-N-propyl-N-[6-[2-[3,4- di(phenylmethoxy)phenyl] ethylthio] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 41) using as the starting material, intermediate product 19.

1H-NMR (200 MHz; CDCl3+ D2O): (part./million): of 0.95 (t, 3H); 1,15-of 2.56 (m, 16H); 2.57 m-3,47 (m, 11H); 5,07 )-N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino] hexyl] -5,6-dimethoxy-1,2,3,4-tetrahydro - 2-naphtylamine (intermediate 42)

DMF (2 drops) and oxacillin (0.8 g; 6.3 mmole) was added under nitrogen atmosphere at 0oC to a solution of intermediate 16 (2.2 g; 5.3 mmole), obtained according to example 5, CH2Cl2(4 ml). The reaction mixture was stirred at 0oC with stirring for 1.5 h, then was given the opportunity to spontaneously warm to room temperature. After evaporation of the solvent under reduced pressure the resulting residue was dissolved in CH2Cl2(5 ml). The solution was added dropwise in a nitrogen atmosphere at room temperature to a solution of intermediate 24 (of 1.9 g, 5.3 mmole), obtained according to example 11, and triethylamine (1.6 g; 16 mmol) in CH2Cl2(5 ml). After 3 hours was added water (10 ml), the phases were separated and the aqueous phase was extracted with CH2Cl2(10 ml). The combined organic phases were dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was dissolved in ethyl ether (20 ml) and to the solution was added trihydrate of tetrabutylammonium (3.4 g; 10.8 mmole). After exposure for 2 h under stirring and at room temperature the solvent is evaporated under reduced pressure and the residue was distributed between water and CH2Cl2. , which the crude product was purified using chromatography (eluent CH2Cl2:CH3OH = 98: 2) to give (S)-N-propyl-N-[6-[(3-chloro-4-hydroxyphenyl)acetylamino]-1 - oxohexyl] -5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (1.7 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 0,86 and 0,91 (2t, 3H); 1,17-2,07 (m, 10H); 2,24-to 2.42 (m, 2H); 2,58-3,30 (m, 8H); of 3.42 (s, 2H); 3,76 and 3.80, and 3,81, and 3,82 (4s, 6H); 3,83-4,04 and 4,46-4,66 (2m, 1H); of 5.89 (bt, 1H); to 6.43 (bs, 1H); 6,70 (d, 1H); to 6.80 (d, 1H); 6,88-7,26 (m, 3H).

MS: 531 [M+1].

Similarly, the method described above using intermediate product 17 as a starting substance was obtained (S)-N-propyl-N-[6-[(3 - nitro-4-hydroxyphenyl)acetylamino] -1-oxohexyl] -5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphtylamine.

1H-NMR (200 MHz; CDCl3): (part./million): 0,91 0,87 and (2t, 3H); 1,21-of 2.08 (m, 10H); 2,27-to 2.41 (m, 2H); 2.57 m-to 3.35 (m, 8H); of 3.48 and 3.49 points (2s, 2H); 3,76 and with 3.79 and 3.80, and 3,82 (4s, 6H); 3,85-of 4.05 and 4,43-4,65 (2m, 1H); 6,37 and 6.42 per (2bt, 1H); 6,70 (d, 1H); to 6.80 (d, 1H); 7,02-8,02 (m, 3H); of 10.47 (bs, 1H).

MS: 542 [M+1].

The complex of borane-dimethyl sulfide (1.6 g; a 20.3 mmole) was slowly added under stirring in nitrogen atmosphere to a solution of (S)-N-propyl-N-[6- [(3-chloro-4-hydroxyphenyl)acetylamino] -1-oxohexyl] -5,6 - dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (1.7 g; 3.2 mmole) in THF (10 ml). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5the IR for 1 hour, then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (15 ml) and the solvent evaporated under reduced pressure. After further addition of methanol (15 ml) and the solvent is evaporated to dryness the resulting residue was dissolved in absolute ethanol (15 ml). After adding a solution of HCl in ethyl ether (15% wt./about.) (0.5 ml) and evaporation of the solvents under reduced pressure the crude product was purified using chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 85:15:1). The obtained solid product was dissolved in absolute ethanol (20 ml) and after adding a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and evaporation of the solvents under reduced pressure was obtained intermediate product 42 (1.4 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,17-of 1.32 (m, 4H); 1,39-of 2.24 (m, 8H); 2,46-3,18 (m, 14H); 3.46 in-the 3.65 (m, 1H); 3,61 (s, 3H); 3,70 (s, 3H); 6,79-to 7.18 (m, 5H).

MS: 503 [M+1].

Similarly, the method described above were obtained the following compounds.

The dihydrochloride (S)-N-propyl-N-[6-[2-(3- the nitro-4-hydroxyphenyl)ethylamino] hexyl]-5 the product (S)-N-propyl-N-[6- [(3-nitro-4-hydroxyphenyl)acetylamino] -1-oxohexyl] -5,6 - dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,17-of 2.23 (m, 12H); 2,47-3,24 (m, 14H); 3,47-3,66 (m, 1H); of 3.60 (s, 3H); of 3.69 (s, 3H); for 6.81-7,06 (m, 5H).

MS: 514 [M+1].

Example 22

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(3-methoxy-4 - hydroxyphenyl)ethylamino] hexyl] -5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 44)

DMF (2 drops) and oxacillin (0.7 g; 5.5 mmole) was added under nitrogen atmosphere at 0oC to a solution of intermediate 18 (1.8 g; 4.4 mmole), obtained according to example 5, CH2Cl2(3 ml). The reaction mixture was stirred at 0oC with stirring for 1.5 h, then was given the opportunity to spontaneously warm to room temperature. After evaporation of the solvent under reduced pressure the resulting residue was dissolved in CH2Cl2(3 ml). The solution was added dropwise in a nitrogen atmosphere at room temperature to a solution of intermediate 28 (2.3 g; 4.4 mmole), obtained according to example 15, and triethylamine (1.3 g; 13.1 mmole) in CH2Cl2(3 ml). After 4 hours was added water (10 ml), the phases were separated and the aqueous phase was extracted with CH2Cl2(10 ml). The combined organic phases were dried over Na2SO4and the solvent evaporated of premonitory (2.8 g; 8.9 mmole). After exposure for 2 h under stirring and at room temperature the solvent is evaporated under reduced pressure and the residue was distributed between water and CH2Cl2. The organic phase was dried over Na2SO4and the solvent evaporated under reduced pressure. The resulting crude product was purified by chromatography (eluent CH2Cl2:CH3OH = 98: 2) to give (S)-N-propyl-N-[6-[(3 - methoxy-4-hydroxyphenyl)acetylamino] -1-oxohexyl]-5,6 - di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphtylamine (2.8 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 0,86 and 0,91 (2t, 3H); 1,16-2,00 (m, 10H); 2,22-of 2.36 (m, 2H); of 2.51-of 3.27 (m, 8H); of 3.45 and 3.46 (2s, 2H); 3,85 and 3,86 (2s, 3H); 3.75 to 3,98 and to 4.41-4,63 (2m, 1H); 4,98 and 5,01 (2s, 2H); 5,09 and 5,11 (2s, 2H); 5,61 (bt, 1H); 6,67-to 6.88 (m, 5H); 7,24-of 7.48 (m, 10H).

MS: 679 [M+1].

The complex of borane-dimethyl sulfide (1.9 grams; and 24.2 mmole) was slowly added under stirring in nitrogen atmosphere to a solution of (S)-N-propyl-N-[6-[(3 - methoxy-4-hydroxyphenyl)acetylamino] -1-oxohexyl] -5,6 - di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphtylamine (2.8 g; 4.1 mmole) in THF (25 ml). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added 37% HCl (0.9 ml) in methanol (8 ml). Reacts is Stroiteley at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (20 ml) and the solvent evaporated under reduced pressure. After further addition of methanol (20 ml) and the solvent is evaporated to dryness the resulting residue was dissolved in absolute ethanol (20 ml). After adding a solution of HCl in ethyl ether (15% wt./about.) (0.5 ml) and evaporation of the solvents under reduced pressure the crude product was purified using chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 90:10:1). The obtained solid product was dissolved in absolute ethanol (20 ml) and after adding a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and evaporation of the solvents under reduced pressure was obtained intermediate product 44 (1.5 g) as an amorphous white solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.91 (t, 3H); 1.18 to 2,39 (m, 12H); of 2.51-of 3.65 (m, 15H); of 3.75 (s, 3H); is 4.93 (s, 2H); 5,16 (s, 2H); 6,58? 7.04 baby mortality (m, 5H); 7,26-to 7.50 (m, 10H); 8,88 (bs, 1H); remaining 9.08 (bs, 2H); of 10.47 (bs, 1H).

MS: 651 [M+1].

Example 23

Getting dihydrochloride (S)-N-propyl-N-[6-[3- (3,4-acid), propylamino] hexyl] -5,6 - dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 45)

DMF (2 drops) and thionyl chloride (1.2 g; 10.1 mmole) was added in a nitrogen atmosphere at on the>(10 ml). After 1 hour, the solvent evaporated under reduced pressure to obtain oil, which was dissolved in CH2Cl2(5 ml). The triethylamine (0.8 g; of 7.9 mmole) and the solution obtained above in CH2Cl2was added at room temperature and under stirring to a solution of intermediate 24 (2 g, 5.5 mmole), obtained according to example 11, CH2Cl2(15 ml). The reaction mixture was kept under stirring and at room temperature for 3 hours. After adding water (30 ml) and separation of the phases the organic phase was dried over Na2SO4and the solvent evaporated under reduced pressure. The resulting residue was dissolved in THF (15 ml). To the resulting solution under stirring in nitrogen atmosphere and at room temperature was slowly added a complex of borane-dimethyl sulfide (2.6 g; 32,5 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added 37% HCl (1 ml) in methanol (7.5 ml). The reaction mixture is again boiled under reflux for 1 hour, then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The remainder of the solution is of anola (30 ml) and the solvent is evaporated to dryness the resulting residue was dissolved in absolute ethanol (30 ml). After adding a solution of HCl in ethyl ether (15% wt./about.) (1 ml) and evaporation of the solvents under reduced pressure the crude product was purified using chromatography (eluent CH2Cl2: CH3HE: 50% HCOOH = 90: 10:1). The obtained solid product was dissolved in absolute ethanol and after adding a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and evaporation of the solvents under reduced pressure was obtained intermediate product 45 (1.3 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,15-of 2.21 (m, 14H); of 2.50 (t, 2H); 2,47-3,20 (m, 12H); 3,43-3,61 (m, 1H); 3,59 (s, 3H); 3,66 (s, 3H); 3,68 (s, 3H); of 3.69 (s, 3H); 6,65-6,86 (m, 5H).

MS: 527 [M+1].

Similarly, the method described above were obtained the following compounds.

The dihydrochloride (S)-N-propyl-N-[6-[2-(3-methyl-4 - methoxyphenyl)ethylamino] hexyl]-5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 46) using as the starting material (3-methyl-4 - methoxyphenyl)acetic acid obtained according to Chem. Pharm. Bull., 30(7), 2440-6 (1982).

1H-NMR (200 MHz; D2O): (part./million): or 0.83 (t, 3H); 1,13-of 2.25 (m, 12H); 2,04 (s, 3H); 2,48-up 3.22 (m,14H); 3,45-the 3.65 (m, 1H); 3,62 (s, 3H); of 3.69 (s, 3H); 3,71 (s, 3H); to 6.80-7.03 is (m, 5H).

MS: 497 is trihydro-2-naphtylamine (intermediate 47) using as initial substances (3,5-dimethoxy-4-were)acetic acid, obtained according to J. Chem. Res. Synop., (5), 149 (1981).

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,13-of 2.20 (m, 12H); to 1.82 (s, 3H); 2,42-3,19 (m,14H); to 3.52 (m, 1H); of 3.57 (s, 3H); the 3.65 (s, 6H); to 3.67 (s, 3H); 6.48 in (s, 2H); 6.75 in (d, 1H); for 6.81 (d, 1H).

MS: 527 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(4- methoxy-3-phenylmethanesulfonyl)ethylamino]hexyl]-5,6 - di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 48) using as starting substances intermediate 28 and (4-methoxy-3-phenylmethanesulfonyl) acetic acid obtained according to J. Org. Chem., 49(26), 5243-6 (1984).

1H-NMR (200 MHz; DMSO-d6): (part./million): to 0.92 (t, 3H); 1,20-to 2.42 (m, 12H); 2,52-the 3.65 (m, 15H); and 3.72 (s, 3H); is 4.93 (s, 2H); of 5.06 (s, 2H); further 5.15 (s, 2H); 6,74? 7.04 baby mortality (m, 5H); 7,27-7,51 (m, 15H): 9,10-a 9.35 (bs, 2H); 10,50-10,71 (bs, 1H).

MS: (thermospray) 741 [M+1].

Example 24

Getting trihydrochloride (S)-N-propyl-N-[6-[4-(4-methoxyphenethyl)piperazine-1-yl] hexyl]-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 49)

Thionyl chloride (1.1 g; 9.2 mmole) was added under nitrogen atmosphere at room temperature to a solution of intermediate 29 (2.3 g; 6.1 mmole), obtained according to example 16, CH2Cl2(15 ml). After 1 hour, the solvent evaporated under reduced pressure to obtain oil that Rast is ur and under stirring to a solution of intermediate 15 (1.2 g; 5.8 mmole), obtained according to example 4, and triethylamine (0.8 g; of 7.9 mmole) in CH2Cl2(15 ml). The reaction mixture was kept under stirring and at room temperature for 2 hours. After adding water (30 ml) and separation of the phases the aqueous phase was extracted with CH2Cl2(20 ml). The combined organic phases are washed with water, dried over Na2SO4and the solvent evaporated under reduced pressure. The resulting residue was dissolved in THF (15 ml). To the resulting solution under stirring in nitrogen atmosphere and at room temperature was slowly added a complex of borane-dimethyl sulfide (3,3 g, 42 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added 37% HCl (1.4 ml) in methanol (12 ml). The reaction mixture is again boiled under reflux for 1 hour, then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml) and the solvent evaporated under reduced pressure. After adding methanol (30 ml) and the solvent is evaporated to dryness the resulting residue was dissolved Eli, receiving intermediate 49 (2.5 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1.18 to 2,24 (m, 12H); 2,46 is 3.23 (m, 10H); 3,31-the 3.65 (m, 9H); 3,61 (s, 3H); 3,70 (s, 6H); 4,24 (s, 2H); at 6.84 (s, 2H); 6.90 to and 7.36 (m, 4H).

MS: 538 [M+1].

Similarly, the method described above were obtained the following compounds.

The dihydrochloride (S)-N-propyl-N-[6-[2-(2- oxo-3H-1,3-benzothiazol-6-yl)ethylamino] hexyl] -5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphtylamine (intermediate 50) using as the starting material, intermediate product 21.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,13-of 2.20 (m, 12H); 2,40-3,20 (m, 14H); 3,42-3,61 (m, 1H); of 3.57 (s, 3H); 3,66 (s, 3H); 6,74 (d, 1H); is 6.78 (d, 1H); 6,95-7,26 (m, 3H).

MS: 526 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2- (2-oxo-3H-1,3-benzothiazol-5-yl)ethylamino] hexyl] -5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphtylamine (intermediate 51) using as the starting material, intermediate product 20.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.93 (t, 3H); 1,15-to 2.42 (m, 12H); 2,52-the 3.65 (m, 15H); 3,68 (s, 3H); 3,76 (s, 3H); 6,83 (d, 1H); 6.90 to (d, 1H); 7,00-was 7.08 (m, 2H); 7,52 (d, 1H); 9,02-of 9.30 (bs, 2H); 10,34-10,54 (bs, 1H); 12,04 (s, 1H).

MS: 526 [M+1].

Trihydrochloride (S)-N-propyl-N-[6-[2-(2-amino-1,3-benzothiazol-6 - yl)ethylamine is one substance intermediate product 22.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,14-2,22 (m, 12H); 2,41-up 3.22 (m, 14H); 3,44-to 3.64 (m, 1H); of 3.57 (s, 3H); to 3.67 (s, 3H); to 6.80 (s, 2H); 7.23 percent (dd, 1H); 7,30 (d, 1H); 7,50 (d, 1H).

MS (thermospray): 525 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(3- chloro-5-methoxyphenyl)ethylamino]hexyl] -5,6-dimethoxy-1,2,3 - tetrahydro-2-naphtylamine (intermediate 53) using as the starting material, intermediate product 23.

1H-NMR (200 MHz; CDCl3): (part./million): 0,86 (t, 3H); 1.18 to 2,09 (m, 12H); 2,38-3,13 (m, 15H); 3,76 (s, 3H); of 3.77 (s, 3H); 3,81 (s, 3H); 6,60-PC 6.82 (m, 5H).

MS: 517 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(2-oxo-3H-1,3-benzothiazol-6 - yl)ethylamino]hexyl]-5-methoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 54) using as starting substances intermediate product 21 and the intermediate product 31.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.93 (t, 3H); 1,19-of 2.45 (m, 12H); 2,68-of 3.32 (m, 14H); 3,50-3,68 (m, 1H); 3,76 (s, 3H); 6,67-7,51 (m, 6H); a 9.25 (bs, 2H); or 10.60 (bs, 1H).

MS: 496 [M+1].

Example 25

Obtain (S)-N-propyl-N-[6-[(3,4 - acid)acetylamino]hexyl]-5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 55)

DMF (2 drops) and thionyl chloride (0.8 g; 6.7 mmole) was added under nitrogen atmosphere at room temperature to a solution of the ü evaporated under reduced pressure to obtain oil, which was dissolved in CH2Cl2(5 ml). The above solution in CH2Cl2was added at room temperature and under stirring to a solution of intermediate 25 (1.4 g; 3.3 mmole), obtained according to example 12, and triethylamine (1.2 g; 11.9 mmole) in CH2Cl2(14 ml). The reaction mixture was kept under stirring and at room temperature for 3 hours and then was poured into water (25 ml). After separation of the phases the aqueous phase was extracted with CH2Cl2(25 ml) and the combined organic phases are washed with water, dried over Na2SO4and the solvent evaporated under reduced pressure. The resulting crude product was purified by chromatography (eluent CH2Cl2:CH3OH:30% ammonia = 95: 5:0.5), the receiving intermediate 55 (0.6 g) as oil.

1H-NMR (200 MHz; CDCl3): (part./million): 0,86 (t, 3H); 1,14-2,12 (m, 12H); 2,38 is 3.23 (m, 10H); to 3.49 (s, 2H); 3,76 (s, 3H); 3,81 (s, 3H); 3,85 (s, 6H); 5,44 (bs, 1H); 6,68-6,86 (m, 5H).

MS: 527 [M+1].

Example 26

Obtain (S)-N-propyl-N-[5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]-N'-[2-(4-ethoxycarbonylphenyl)ethyl]-1,6 - hexanediamine (intermediate 56)

Thionyl chloride (1.25 g; 10.5 mmole) was added under nitrogen atmosphere to a solution of intermediate temperature for 2 hours the reaction mixture was evaporated to dryness under reduced pressure. The resulting residue was dissolved in CH2Cl2(5 ml) and the solution was added dropwise in a nitrogen atmosphere with stirring to a solution of methyl-4-(2 - amino-ethyl)benzoate (1.5 g, 7.0 mmol), obtained according Berichte, 71, 59 (1938), and triethylamine (1.8 g; of 17.5 mmole) in CH2Cl2(40 ml). After holding at room temperature for 2 hours was added water (30 ml) and separated phases. The aqueous phase was extracted with CH2Cl2(20 ml) and the combined organic phases are washed with water, dried over Na2SO4was filtered and the solvent was removed under reduced pressure. The resulting crude product was purified by chromatography (eluent CH2Cl2:CH3OH = 95:5) to give intermediate product 56 (4.0 g) as amorphous solids.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 and 0.90 (2t, 3H); 1,44-2,03 (m, 8H); 2,09-2,39 (m, 4H); of 2.51 is 3.23 (m, 8H); 3,44-to 3.58 (m, 2H); 3,79-3,99 and to 4.41-4,60 (2m, 1H); a 3.87 (s, 3H); 4,98 and 5,01 (2s, 2H); 5,09 and 5,10 (2s, 2H); 6,15-of 6.29 (m, 1H); 6,70-6,87 (m, 2H); 7,20-7,47 (m, 12H); to 7.95 (dd, 1H).

MS: 691 [M+1].

Example 27

Obtain (S)-N-propyl-N-[6-[2-(4-ethoxycarbonylphenyl)ethylamino] hexyl] -5,6-di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 57)

The complex of borane-dimethyl sulfide (2.0 g; of 25.6 mmole) slowly dabaw g; 6.4 mmole), obtained according to example 26, in THF (100 ml). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC was slowly added a solution of concentrated HCl (1.4 ml) in methanol (10 ml). The reaction mixture is again boiled under reflux for 2 hours and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml) and the solvent evaporated under reduced pressure. Was added methanol (30 ml) and the solvent again evaporated. Added ethyl acetate (50 ml), water (30 ml) and 30% aqueous NH4OH, to obtain a pH value of 14. The aqueous phase was extracted with ethyl acetate (30 ml), and then the organic phases were combined, washed with water and dried over Na2SO4. After evaporation of the solvents under reduced pressure was obtained the crude product, which was purified by chromatography (eluent CH2Cl2:CH3OH:30% NH4HE = 90:10:0.5), the receiving intermediate 57 (3.0 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): 0,86 (t, 3H); 1.18 to to 2.06 (m, 13H); 2,38-and 3.16 (m, 15H); the 3.89 (s, 3H); to 4.98 (s, 2H); 5,09 (s, 2H); 6,76 (d, 1H); for 6.81 (d, 1H); 7.23 percent-of 7.48 (m, 12H); to $ 7.91-7:99 (m, 2H). the ftil] -N'-[2-(4-carboxyphenyl)ethyl] -1,6 - hexanediamine (intermediate 58)

An aqueous solution of 4 N. NaOH (2 ml) was added dropwise at room temperature and under stirring to a solution of intermediate 56 (2.0 g; 2.9 mmole), obtained according to example 26, in methanol (10 ml). The reaction mixture is boiled under reflux with stirring for 2 hours. The solvents were removed under reduced pressure, and then added CH2Cl2(20 ml), water (20 ml) and concentrated HCl to obtain a pH value of 1. The aqueous phase was extracted with CH2Cl2(20 ml) then the combined organic phases were washed with water and dried over Na2SO4. After removal of the solvent under reduced pressure was obtained intermediate product 58 (1.9 g) as a white amorphous solid.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 and 0.90 (2t, 3H); 1,45 e 2.06 (m, 8H); 2,10-2,47 (m, 4H); 2.50 each-of 3.32 (m, 8H); 3,43-3,59 (m, 2H); of 3.80-4.00 and to 4.41-br4.61 (2m, 1H); 4,98 and 5,00 (2s, 2H); 5,09 and 5,10 (2s, 2H); 6,27-of 6.45 (m, 1H); 6,68-6,87 (m, 2H); 7,21-7,47 (m, 12H); 7,94 (d, 1H).

MS: 677 [M+1].

Example 29

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4- sulfophenyl)ethylamino] hexyl]-5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 59)

A solution of 4-(2-amino-ethyl)benzylmalonate acid (1.7 g; 8.5 mmole) (Aldrich company) in water (51 ml) was added kinnego according to example 17, in pyridine (210 ml). The reaction mixture was heated to 70oC and kept under stirring for 2 hours. The solvents were removed under reduced pressure, was added methanol (30 ml) and then delete it under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 85:15:1). The purified product was dissolved under nitrogen atmosphere in anhydrous THF (30 ml) and then slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (1.5 g, 19.0 mmol). The reaction mixture is boiled under reflux for 2 hours. After cooling to 5oC was slowly added a solution of concentrated HCl (0.7 ml) in methanol (7 ml). The mixture was boiled under reflux for 2 hours, concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (20 ml), the solvent is kept under reduced pressure, was added methanol (20 ml) and the solvent was removed again. Added absolute ethanol (20 ml) and a solution of HCl in ethyl ether (15% wt./about.) (1 ml). After evaporation of the solvents under reduced pressure was obtained the crude product, which was purified by chromatograph using the Ohm ethanol, the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% wt./vol.), and the solvents were removed under reduced pressure. Using crystallization from methanol was obtained intermediate product 59 (1.4 g) as a white solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.91 (t, 3H); 1,20-of 2.34 (m, 12H); of 2.51-3,30 (m, 14H).; 3,42-to 3.67 (m, 1H); is 4.93 (s, 2H): 5,16 (s, 2H); 6,86 (d, 1H); 7,02 (d, 1H); 7,17-of 7.23 (m, 2H); 7,25 is 7.50 (m, 10H); 7,51-to 7.59 (m, 2H) 8,69-of 8.90 (bs, 2H); 9,81-9,98 (bs, 1H).

MS (thermospray): 685 [M+1].

Example 30

Obtain (S)-N-propyl-N-[5,6 - di(phenylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl] -N'- phenylmethanesulfonyl-N'-[2-(4-ethoxycarbonylphenyl)ethyl] -1,6 - hexanediamine (intermediate 60)

Benzylchloride (0.8 g; 4.7 mmole) was added dropwise at room temperature and under stirring to a solution of intermediate 57 (2.7 g; 4.1 mmole), obtained according to example 27, and triethylamine (0.5 g; 5.0 mmol) in CH2Cl2(70 ml). The mixture was stirred at room temperature for 1 hour and then added an aqueous solution of 1 N. HCl (20 ml). The phases were separated and the organic phase is washed with 10% aqueous solution of KHCO3(20 ml), dried over Na2SO4and the solvent was removed under reduced pressure. The intermediate product 60 (3.1 g) was obtained in the form(m, 15H); the 3.89 (s, 3H); 4,99 (s, 2H); 5,09 (s, 2H); to 5.08 and 5.12 (2s, 2H); 6,77 (d, 1H); for 6.81 (d, 1H); 7,08-of 7.48 (m, 17H); of 7.90-7,98 (m, 2H).

MS (thermospray): 797 [M+1].

Similarly, the method described above were obtained the following compounds.

(S)-N-propyl-N-[5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]-N'-phenylmethanesulfonyl-N'-[2-(4 - nitrophenyl)ethyl]-1,6-hexanediamine (intermediate 61) using as the starting material, intermediate product 37.

1H-NMR (200 MHz; CDCl3; 60oC): (part./million): of 0.87 (t, 3H); 1,21-2,22 (m, 12H); 2,38 is 3.23 (m, 13H); of 3.48 (t, 2H); 5,00 (s, 2H); 5,09 (2s, 4H); 6.73 x (d, 1H); for 6.81 (d, 1H); 7,19 was 7.45 (m, 17H); 8,02-8,11 (m, 2H).

MS: 784 [M+1].

(S)-N-propyl-N-[5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]-N'-phenylmethanesulfonyl-N'-[2-(4 - sulfophenyl)ethyl]-1,6-hexanediamine (intermediate 62) using as the starting material, intermediate product 59.

1H-NMR (200 MHz; CDCl3; 60oC): (a frequent. /million): 0,32-2,02 (m, 15H); 2,20-of 3.75 (m, 15H); free 5.01 (s, 2H); 5,09 (s, 2H); to 5.17 (s, 2H); 6.75 in-6,91 (m, 2H); 7,00-7,11 (m, 2H); 7.24 to 7,46 (m, 15H); 7,72-7,83 (m, 2H); of 10.25-of 10.50 (bs, 1H).

MS (thermospray): 819 [M+1].

Example 31

Obtain (S)-N-propyl-[5,6-di(phenylmethoxy)-1,2,3,4-tetrahydro-2 - naphthyl]-N'-phenylmethanesulfonyl-N'-[2-(4-carbamoylphenoxy)ethyl]-1,6 - hexanediamine (intermediate the NII to a solution of intermediate 60 (3.1 g; 3.9 mmole), obtained according to example 30, in dioxane (30 ml) and methanol (3 ml). The reaction mixture was heated to 80oC and kept under stirring for 1 hour. The solvents were removed under reduced pressure and then added ethyl acetate (50 ml), water (30 ml) and concentrated HCl to obtain a pH value of 1. The aqueous phase was extracted with ethyl acetate (20 ml) then the combined organic phases were washed with water and dried over Na2SO4. After removal of the solvent under reduced pressure, the obtained residue, which was dissolved in CH2Cl2(40 ml). In nitrogen atmosphere under stirring and at room temperature was added thionyl chloride (0.6 g; 5.0 mmol). After exposure for 1 hour at room temperature the reaction mixture was evaporated to dryness under reduced pressure. The resulting residue was dissolved in CH2Cl2(10 ml) and the solution was added dropwise in a nitrogen atmosphere to a stirred solution of ammonia in 0.65 M THF (80 ml). The solvents were removed under reduced pressure, and then added CH2Cl2(40 ml) and water (20 ml). The organic phase is washed with water and dried over Na2SO4. The residue was purified by chromatography (eluent CH2Cl2: CH3OH: 30% NH4OH = 90:10DCl3): (part./million) as 0.96 (t, 3H); 1,15-2,07 (m, 12H); 2,36-3,51 (m, 15H); 4,99 (s, 2H); 5,09 (s, 2H); 5.08 to and 5,11 (2s, 2H); 5,56-6,28 (bs, 2H); 6,77 (d, 1H); for 6.81 (d, 1H); 7,08-7,47 (m, 17H); to 7.61-to 7.77 (m, 2H).

MS: 782 [M+1].

Example 32

Obtain (S)-N-propyl-[5,6-di(phenylmethoxy)-1,2,3,4 - tetrahydro-2-naphthyl]-N'-phenylmethanesulfonyl-N'-[2-(4 - AMINOPHENYL)ethyl]-1,6-hexanediamine (intermediate 64)

Iron powder (0.65 g) was added during 30 minutes under stirring to a suspension of intermediate 61 (1.1 g; 1.4 mmole), obtained according to example 30, in water (6 ml) and acetic acid (0.3 ml) at the temperature of reflux distilled. The reaction mixture is boiled under reflux for 6 hours and then added water (10 ml) and ethyl acetate (30 ml). The mixture was filtered through Celiteand separated phases. The organic phase is washed with water and then aqueous solution KHCO3, dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2: CH3OH = 9:1) to give intermediate product 64 (0.7 g) as oil.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 (t, 3H); 1,12-2,07 (m, 12H); 2,37-of 3.46 (m, 17H); 4,99 (s, 2H); 5,09 (s, 2H); 5,10 (bs, 2H); 6,52-only 6.64 (m, 2H); 6,77 (d, 1H); for 6.81 (d, 1H); 6,82-7,03 (m, 2H); 7,26-of 7.48 (m, 15H).

MS: 754 [M+1].

P is ceilometer)ethyl] -1,6 - hexanediamine (intermediate 65)

To a solution of intermediate 64 (0.7 g; 0.9 mmole), obtained according to example 32, and triethylamine (0.14 g; 1.4 mmol) in CH2Cl2(7 ml) dropwise at room temperature in a nitrogen atmosphere and with stirring was added acetylchloride (0.08 g; 1.0 mmol). After 2 hours was added water (10 ml) and CH2Cl2(10 ml), separated phase and the organic phase was dried over

Na2SO4. The solvent is evaporated under reduced pressure, obtaining the intermediate product 65 (0.7 g) as oil.

1H-NMR (200 MHz; CDCl3): (part./million): to 0.89 (t, 3H); 1,13-2,12 (m, 12H); 2,02 and is 2.09 (2s, 3H); 2,36-of 3.53 (m, 15H); free 5.01 (s, 2H); 5,10 (s, 2H); 5,11 and 5,15 (2s, 2H); 6,79 (d, 1H); 6,83 (d, 1H); 6,97-7,20 (m, 2H); 7.23 percent-7,49 (m, 17H); 7,95-of 8.09 (bs, 1H).

MS: 796 [M+1].

Example 34

Obtain (S)-N-propyl-[5,6-di(phenylmethoxy)- 1,2,3,4-tetrahydro-2-naphthyl] -N'-phenylmethanesulfonyl-N'-[2-(4 - methylsulfonylamino)ethyl]-1,6-hexanediamine (intermediate 66)

To a solution of intermediate 64 (3.0 g; 4.0 mmole), obtained according to example 32, and triethylamine (0.4 g; 4.0 mmole) in CH2Cl2(50 ml) dropwise at 0oC in nitrogen atmosphere and with stirring was added methanesulfonyl anhydride (0.7 g; 4.0 mmole). The reaction mixture was heated to 40oC and kept at pereless). The reaction mixture was heated to 40oC and kept under stirring for 2 hours, was added water (25 ml) and the phases were separated. The organic phase was dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH:30% NH4OH = 95:5:0.5), the receiving intermediate 66 (3.1 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 (t, 3H); 1,11-of 2.08 (m, 12H); 2,33-to 3.49 (m, 15H); of 2.93 (s, 3H); 4,99 (s, 2H); 5,10 (s, 2H); at 5.10 and 5.12 (2s, 2H); 6,76 (d, 1H); for 6.81 (d, 1H); 7,00-7,21 (m, 4H); 7,25-7,47 (m, 15H).

MS: 832 [M+1].

Example 35

Obtain (S)-N-propyl-[5,6-di(phenylmethoxy)- 1,2,3,4-tetrahydro-2-naphthyl] -N'-phenylmethanesulfonyl-N'-[2-(4 - aminocarbonylmethyl)ethyl] -1,6-hexanediamine (intermediate 67)

Concentrated HCl (0.7 g; 7.1 mmole) and sodium cyanate (0,38 g, 5.8 mmole) was added at room temperature in a nitrogen atmosphere and with stirring to a solution of intermediate 64 (2.2 g; 2.9 mmole), obtained according to example 32, in chlorobenzene (20 ml). The reaction mixture was heated to 110oC and kept under stirring for 1 hour. The solvents are evaporated under reduced pressure, and then added water (30 ml) and ethyl acetate (50 ml). The phases were separated, is whether using chromatography (eluent CH2Cl2:CH3OH:30% NH4OH = 90:10:0.5), the receiving intermediate 67 (1.9 grams) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.91 (t, 3H); 1,01-2,22 (m, 12H); 2,44-of 3.48 (m, 15H); 4,99 (s, 2H); of 5.06 (bs, 2H); 5,10 (2s, 4H); 6,76 (d, 1H); for 6.81 (d, 1H); 6.89 in-7,11 (m, 2H); 7,20-7,46 (m, 17H); 7,81-8,08 (bs, 1H).

MS: 797 [M+1].

Example 36

Getting dihydrochloride (S)-N-propyl-[6-[2-(4- methylsulfinylphenyl) ethylamino]hexyl]-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 68)

1,1'-carbonyldiimidazole (0,76 g, 4.7 mmole) was added under stirring to a suspension of (4-methylsulphonyl)phenylacetic acid (1.0 g; 4.7 mmole), obtained according to J. Chem. Soc., 1501-6 (1948), CH2Cl2(25 ml). The mixture was kept under stirring for 1.5 h at room temperature, and then was added triethylamine (0,48 g, 4.7 mmole) and a solution of intermediate 24 (1.7 g; 4.7 mmole), obtained according to example 11, CH2Cl2(20 ml). After 1 hour, was added water (30 ml) and CH2Cl2(30 ml), the phases were separated and the organic phase was dried over Na2SO4. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (25 ml) under nitrogen atmosphere. Under stirring and at room temperature was slowly added borane complex-DIMET is up to 5oC was slowly added a solution of concentrated HCl (1.1 ml) in methanol (11 ml). The reaction mixture is boiled under reflux for 1 hour, concentrated by distillation of the solvents under atmospheric pressure and then dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml), the solvent is kept under reduced pressure, was added methanol (30 ml) and the solvent was again removed. Added absolute ethanol (30 ml) and a solution of HCl in ethyl ether (15% wt./about.) (1 ml), and then under reduced pressure, evaporated the solvent, obtaining the crude product, which was purified by chromatography (eluent CH2Cl2:CH3OH:30% HCOOH = 85:15:1). The resulting solid was dissolved in absolute ethanol and the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% wt./vol.). After evaporation of the solvents under reduced pressure was obtained intermediate product 68 (2.3 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): or 0.83 (t, 3H); 1,16-of 2.25 (m, 12H); 2,47 of 3.28 (m, 14H); 3,11 (s, 3H); 3,49-3,68 (m, 1H); 3,61 (s. 3H); 3,70 (s, 3H); at 6.84 (s, 2H); 7,40-of 7.48 (m, 2H); 7,75-7,83 (m, 2H).

MS (thermospray): 531 [M+1].

Example 37

Obtain (S)-N-propyl-[5,6 - di(phenylmethoxy)-1,2,3,4-t is CT 69)

DMF (15 μl) and thionyl chloride (0.65 g; 5.5 mmole) was added at room temperature in a nitrogen atmosphere and with stirring to a solution of intermediate 59 (3.0 g; 3.7 mmole), obtained according to example 29 in toluene (60 ml). The reaction mixture was heated to 80oC and kept under stirring for 4 hours and then under reduced pressure, the solvent was removed. The residue was dissolved in THF (30 ml) and the solution was added dropwise at 0oC in nitrogen atmosphere to a 0.65 M solution of ammonia in THF (28 ml). The reaction mixture gave the opportunity to spontaneously warm to room temperature overnight, and then under reduced pressure, the solvent was removed and to the residue was added water (30 ml) and CH2Cl2(50 ml). The phases were separated, the organic phase was dried over Na2SO4and solvent was removed under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH = 95:5) to give intermediate product 69 (1.6 g) in the form of butter.

1H-NMR (200 MHz; CDCl3): (part./million): to 0.89 (t, 3H); 1,08-2,12 (m, 14H); 2,33-of 3.53 (m, 15H); 4,99 (s, 2H); 5,09 (2s, 4H); 6,76 (d, 1H); for 6.81 (d, 1H); 7,11-of 7.23 (m, 2H); 7,25-of 7.48 (m, 15H); 7,71-a 7.85 (m, 2H).

MS (thermospray): 818 [M+1].

Example 38

Getting dihydrochloride (S)-N-propyl-N-[6-[who I according to the method similar to that described in example 20, but using intermediate product 5 instead of the intermediate product 2 got connection 1.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1.18 to its 1.68 (m, 10H); 1,63-of 2.20 (m, 2H); 2,38-of 3.27 (m, 12H); 3,42-of 3.60 (m, 1H); 3,95 (dd, 1H); 4,18 (dd, 1H); of 4.44-of 4.54 (m, 1H); 6,50 (d, 1H); 6,62 (d, 1H); 6.75 in-6,85 (m, 4H).

MS (chemical ionisation, ammonia, positive ions): 469 [M+1].

In a similar manner there were obtained the following compounds.

The dihydrochloride (S)-N-propyl-N-[6- [2-(3,4-methylenedioxyphenyl)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 2) using as the starting material of the intermediate product 4.

1H-NMR (200 MHz; D2O): (part./million): or 0.83 (t, 3H); 1,21-2,19 (m, 12H); 2,40-3,15 (m, 14H); 3,43-of 3.60 (m, 1H); 5,79 (s, 2H); of 6.49-of 6.73 (m, 5H).

MS: 469 [M+1].

Trihydrochloride (S)-N-propyl-N-[6- [4-(2-methoxyphenyl)piperazine-1-yl]hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 3) using as the starting material of the intermediate product 12.

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1,22-of 1.78 (m, 10H); 1,52-to 2.18 (m, 2H); 2,37-to 3.64 (m, 19H); of 3.69 (s, 3H); 6.48 in (d, 1H); 6,60 (d, 1H); 6,80-to 7.09 (m, 4H).

MS (thermospray): 496 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(2- nitrophenoxy the underwater substance intermediate product 7.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,23-2,19 (m, 12H); 2,36-3,11 (m, 10H); 3,33-to 3.58 (m, 3H); 4,29-4,34 (m, 2H); 6,46 (d, 1H); 6.58 (d, 1H); of 6.96-7,74 (m, 4H).

MS: 486 [M+1].

The dihydrochloride (S)-N - propyl-N-[6-[2-(4-nitrophenoxy)ethylamino]hexyl]-5,6 - dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 5) using as the starting material of the intermediate product 8.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,21 by 1.68 (m, 10H); 1,62-of 2.15 (m, 2H); 2,34-is 3.08 (m, 10H); 3,33-to 3.38 (m, 2H); 3,40 of 3.56 (m, 1H); 4,23-4,27 (m, 2H); of 6.45 (d, 1H); to 6.58 (d, 1H); 6,88-of 8.06 (m, 4H).

MS: 486 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(4-methylsulfinylphenyl) ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 6), using as the starting material, intermediate product 9.

1H-NMR (200 MHz; D2O): (part./million): 0,84 (t, 3H); 1.30 and of 2.21 (m, 12H); 2,42-and 3.16 (m, 10H); 3,10 (s, 3H); 3,38-of 3.42 (m, 2H); 3,47-3,63 (m, 1H); 4.26 deaths-or 4.31 (m, 2H); 6,53 (d, 1H); 6,66 (d, 1H); 7,05-7,80 (m, 4H).

MS (chemical ionisation, ammonia, positive ions): 519 [M+1].

Example 39

Obtaining hydrochloride (S)-N-propyl-N-[6-[2-(2- methoxyphenoxy)acetylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 7)

DMF (2 drops) and thionyl chloride (0.6 g; 5 mmol) was added in a nitrogen atmosphere at room 17(1), 28-33 (Chemical Abstracts 69:67041g), CH2Cl2(10 ml). After 3 hours, the solvent evaporated under reduced pressure to obtain oil, which was dissolved in CH2Cl2(5 ml). Sodium tetraborate (1 g; 5 mmol) was added under nitrogen atmosphere to a solution of intermediate 26 (1.2 g; 2.5 mmole), obtained according to example 13, in water (15 ml). After heating to 70oC until complete dissolution and cooling to room temperature was added CH2Cl2(2 ml), potassium carbonate (2.7 g; 19.5 mmole) and with vigorous stirring the above solution in CH2Cl2. After exposure for 1 hour at room temperature the reaction mixture was acidified with 37% HCl to pH 1 and separated phases. The aqueous phase was extracted with CH2Cl2(15 ml). The combined organic phases were washed with brine, slightly acidified with HCl, dried over Na2SO4and was evaporated to dryness under reduced pressure. The resulting residue was purified using chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 85:15:1). The obtained solid product was dissolved in absolute ethanol. After adding a solution of HCl in ethyl ether (15% wt./about.) before receiving the degree to which the acidic pH of the solvents evaporated under reduced; 2O): (part./million): of 0.79 (t, 3H); 0,96-of 2.09 (m, 12H); 2,28-3,10 (m, 10H); 3,26-of 3.42 (m, 1H); 3,63 (m, 3H); 4.35 the 4,36 and (2s, 2H); to 6.43 (d, 1H); to 6.58 (d, 1H); 6,64-to 6.80 (m, 4H).

MS: 485 [M+1].

Example 40

Getting dihydrobromide (S)-N-propyl-N-[6-[2-(4-hydroxyphenyl) ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (compound 8)

A solution of intermediate 33 (1.9 g; 3.2 mmole), obtained according to example 18, in 48% HBr (19 ml) was boiled under reflux in nitrogen atmosphere for 5 hours. Then the reaction mixture was evaporated to dryness under reduced pressure and the resulting residue was added absolute ethanol (40 ml). After evaporation of the solvent and addition of ethyl acetate (40 ml), the solvent evaporated again. The resulting residue was purified using chromatography (eluent CH2Cl2: CH3HE:50% HCOOH = 85:15:1) to give compound 8 (0.8 g) as an amorphous white solid product.

1H-NMR (200 MHz; D2O): (part./million): 0,78 (t, 3H); 1,17 with 2.14 (m, 12H); 2,35-of 3.06 (m, 14H); 3,38 of 3.56 (m, 1H); 6,46 (d, 1H); to 6.58 (d, 1H); 6,65-7,26 (m, 4H).

MS: 473 [M+1].

Similarly, the method described above were obtained the following compounds.

Dihydrobromide (S)-N-propyl-N-[6- [3-(4-hydroxyphenyl)propylamino]hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-h

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,15-of 2.15 (m, 14H); 2,33-3,11 (m. 14H); 3,34-3,51 (m, 1H); of 6.45 (d, 1H); 6,59 (d, 1H); 6,63-6,98 (m, 4H).

MS: 455 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-(6,7-dihydroxy-1,2,3,4 - tetrahydroisoquinoline-2-yl)hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (compound 10) using as the starting material, intermediate product 35.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,28-of 2.16 (m, 12H); 2,38-3,59 (m, 15H); 4,08 (bs, 2H); of 6.49 and 6.57 (2s, 2H); of 6.49 (d, 1H); is 6.61 (d, 1H).

MS (thermospray): 469 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(3-chloro-4-hydroxyphenyl) ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 11), using as the starting material, intermediate product 42.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,19-2,19 (m, 12H); 2,38-3,14 (m, 14H); 3,42 is 3.57 (m, 1H); of 6.49 (d, 1H); 6,62 (d, 1H); to 6.80 (d, 1H); 6,94 (dd, 1H): to 7.15 (d, 1H).

MS: 475 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(3- the nitro-4-hydroxyphenyl)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 12), using as the starting material, intermediate product 43.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,17 was 2.25 (m, 12H); 2,40 is 3.23 (m, 14H); 3,47-the 3.65 (m, 1H); of 6.52 (d, 1H); only 6.64 (d, 1H); 6,,4-tetrahydro-2-naphtylamine (compound 13), using as the starting material, intermediate product 45.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,17-2,17 (m, 14H); to 2.42 (t, 2H); 2,37-3,10 (m, 12H); 3,44-of 3.60 (m, 1H); 6.48 in - of 6.71 (m, 5H).

MS (thermospray): 471 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(3-methyl-4-hydroxyphenyl) ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 14), using as the starting material, intermediate product 46.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,20-2,19 (m, 12H); 2,02 (s, 3H); 2.40 a-3,13 (m, 14H); 3,44-of 3.60 (m, 1H); 6,51 (d, 1H); only 6.64 (d, 1H); 6,67-to 6.95 (m, 3H).

MS (thermospray): 455 [M+1].

Trihydrobromide (S)-N-propyl-N-[6-[4-(4- hydroxyphenylethyl)piperazine-1-yl] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 15), using as the starting material, intermediate product 49.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,20-2,20 (m, 12H); 2,39 is 3.15 (m, 10H); 3,35-3,59 (m, 9H); 4,19 (s, 2H); 6,50 (d, 1H); 6,62 (d, 1H); 6,76-7,25 (m, 4H).

MS (chemical ionisation, ammonia, positive ions): 496 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[3-(2- hydroxy(phenyl)propylamino]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 16), using as the starting material, intermediate product 40.

1H-NMR (200 MHz; D2O): (part./million): 0,79 (t, is rebraid (S)-N-propyl-N-[6-[2-(3,5-dihydroxy-4-were) ethylamino]hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (compound 17), using as the starting material, intermediate product 47.

1H-NMR (200 MHz; D2O): (part./million): of 0.85 (t, 3H); 1,20-of 2.24 (m, 12H); 1,90 (s, 3H); 2,44-3,17 (m, 14H); 3,48-3,63 (m, 1H); 6,29 (s, 2H); 6,55 (d, 1H); to 6.67 (d, 1H).

MS: 471 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2- (2-oxo-3H-1,3-benzothiazol-6-yl)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 18), using as the starting material, intermediate product 50.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,17-2,17 (m, 12H); 2,34-3,18 (m, 14H); 3,38-of 3.54 (m, 1H); of 6.45 (d, 1H); to 6.58 (d, 1H); of 6.96-7,24 (m, 3H).

MS: 498 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(2-oxo-3H-1,3-benzothiazol-5-yl) ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 19), using as the starting material, intermediate product 51.

1H-NMR (200 MHz; D2O; 60oC): (part./million): of 1.20 (t, 3H); 1.60-to of 2.56 (m, 12H); 2,78-3,61 (m, 14H); 3,83-of 3.96 (m, 1H); 6.90 (d, 1H); 7,02 (d, 1H); 7,35-7,40 (m, 2H); of 7.75 (d, 1H).

MS: 498 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(2-oxo-3H-1.3 - benzothiazol-6-yl)ethylamino]hexyl]-5-hydroxy-1,2,3,4-tetrahydro - 2-naphtylamine (compound 20), using as the starting material, intermediate product 54.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.93 (t, 3H); 1,20-2,31 (m, 12H); 2,84-of 3.25 (m, 14H); 3,56-3,71 (m, 1H); 6,55-of 7.48 (m, 6H); and 8.50 (bs, 2H) who Ino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 21), using as the starting material, intermediate product 53.

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1.18 to 2,17 (m, 12H); 2,38 is 3.15 (m, 14H); 3,44-3,59 (m, 1H); 6.48 in (d, 1H); is 6.61 (d, 1H); 6,54-6,72 (m, 3H).

Dihydrobromide (S)-N-propyl-N-[6- [2-(4-methylsulfinylphenyl)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 22), using as the starting material, intermediate product 68.

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1,11-2,14 (m, 12H); 2,36-is 3.21 (m, 14H); of 3.07 (s, 2H); 3.39-of 3.56 (m, 1H); 6.48 in (d, 1H); 6,60 (d, 1H); of 7.36-to 7.77 (m, 4H).

MS (thermospray): 503 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-(2,3-dihydroindol-1 - yl)hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 23), using as the starting material, intermediate product 36.

1H-NMR (200 MHz; D2O): (part./million): of 0.85 (t, 3H); 1,27-2,22 (m, 12H); 2,43-3,61 (m, 13H); a 3.83 (t, 2H); is 6.54 (d, 1H); to 6.67 (d, 1H); 7,33-7,39 (m, 4H).

MS: 423 [M+1].

Example 41

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4- hydroxyphenoxy)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 24)

To a solution of intermediate 38 (3.4 g; 5.5 mmole), obtained according to example 20, in absolute ethanol (100 ml) was added 37% HCl (1 ml) and 10% Pd on coal (50% in water) (0.7 g). The mixture was first made in the apparatus Parra (2,7 antibody is purified using chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 85:15:2). The formed solid product was dissolved in absolute ethanol (40 ml). After adding a solution of HCl in ethyl ether (15% wt./about.) to markedly acidic pH and evaporation of the solvents under reduced pressure received connection 24 (2.5 g) as an amorphous white solid product.

1H-NMR (200 MHz; D2O): (part./million): or 0.83 (t, 3H); 1,22-of 2.16 (m, 12H); 2,39-3,13 (m, 10H); 3.27 to of 3.32 (m, 2H); 3,42 is 3.57 (m, 1H); 4,06-4,11 (m, 2H); 6,50 (d, 1H); only 6.64 (d, 1H); 6,65-to 6.80 (m, 4H).

MS (thermospray): 457 [M+1].

Similarly, the method described above were obtained the following compounds.

Hydrochloride (S)-N-propyl-N-[6-[2-(3,4- dihydroxyphenyl)ethoxy]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 25), using as the starting material, intermediate product 39.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.91 (t, 3H); 1,29 of-2.32 (m, 12H); 2,60 (t, 2H); 2,42-3,20 (m, 8H); at 3.35 (t, 2H); of 3.45 (t, 2H); 3,40-of 3.60 (m, 1H); 6,38-6,63 (m, 5H); 8,31 and 8,67 and 8,73 and 9.08 (4s, 4H); of 10.05 (bs, 1H).

MS (thermospray): 458 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(3-methoxy-4-hydroxyphenyl) ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (compound 26), using as the starting material, intermediate product 44.).

MS: 471 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(3- hydroxy-4-methoxyphenyl)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 27), using as the starting material, intermediate product 48.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,16-to 2.18 (m, 12H); 2,38-3,11 (m, 14H); 3,43-3,59 (m, 1H); 3,66 (s, 3H); of 6.49 (d. 1H); 6,62 (d, 1H); 6,64-6,86 (m, 3H).

MS: 471 [M+1].

Hydrochloride (S)-N-propyl-N-[6-[2-(3,4-dihydroxyphenyl)ethylthio] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 28), using as the starting material, intermediate product 41.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.91 (t, 3H); 1.26 in-to 2.29 (m, 12H); 2,45-up 3.22 (m, 14H); 3.46 in-3,62 (m, 1H); 6,38-6,63 (m, 5H); of 8.28 (s, 1H); 8,68 (s, 1H); 8,72 (s, 1H); 9,06 (s, 1H); 9,44 (bs, 1H).

Trihydrochloride (S)-N-propyl-N-[6-[2-(3-amino-4 - hydroxyphenyl)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 29), using as the starting material of the intermediate product 12.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,20-2,20 (m, 12H); 2,39 is 3.15 (m, 14H); 3,45-3,61 (m, 1H); 6.50 (d, 1H); 6,62 (d, 1H); 6,82-7,05 (m, 3H).

MS (thermospray): 456 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(4-sulfamoylbenzoyl)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 KTA 69.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,22-of 2.16 (m, 12H); 2,38-is 3.21 (m, 14H); 3,44 is 3.57 (m, 1H); of 6.49 (d, 1H); is 6.61 (d, 1H); 7,32-7,72 (m, 4H).

MS: 504 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(4- methylsulfonylamino)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 31), using as the starting material, intermediate product 66.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,23-2,17 (m (12H); only 2.91 (s, 3H); 2,38-3,17 (m, 14H); 3,44-3,59 (m, 1H); 6,50 (d, 1H); 6,63 (d, 1H); 7,07-7,20 (m, 4H).

MS (thermospray): 518 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(4- aminocarbonylmethyl)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 32), using as the starting material, intermediate product 67.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,21-of 2.15 (m, 12H); a 2.36-3.15 in (m, 14H); 3,40-3,55 (m, 1H); 6.48 in (d, 1H); is 6.61 (d, 1H); to 7.09 (s, 4H).

MS (thermospray): 483 [M+1].

The dihydrochloride (S)-N-propyl-N-[6-[2-(4-acetylaminophenol) ethylamino]hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 33), using as the starting material, intermediate product 65.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,21-2,17 (m, 12H); to 1.98 (s, 3H); 2,38-3,17 (m, 14H); 3,43-of 3.60 (m, 1H); of 6.49 (d,propyl-N-[6- [(3,4-dihydroxyphenyl)acetylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 34)

1 M solution of tribromide boron in CH2Cl2(4,7 ml) was added under nitrogen atmosphere at 0oC to a solution of intermediate 55 (0.6 g; 1.1 mmole), obtained according to example 25, CH2Cl2(8 ml). The reaction mixture gave spontaneously warm to room temperature. After holding at room temperature for 3 hours was added methanol (5 ml) and the resulting solution was evaporated to dryness under reduced pressure. The crude product was purified using chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 85:15: 1) to give compound 34 (0.6 g) as a white amorphous solid product.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,10-2,14 (m, 12H); 2,38-of 3.07 (m, 10H); 3,24 (s, 2H); 3,38-of 3.53 (m, 1H); 6.48 in of 6.68 (m, 5H).

MS (thermospray): 471 [M+1].

Example 43

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4- ethoxycarbonylphenyl)ethylamino] hexyl] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 35)

To a solution of intermediate 56 (1,9 g, 2.7 mmole), obtained according to example 26, in methanol (50 ml) was added 10% Pd on coal (50% in water) (0.4 g). The mixture was kept under stirring and under 40oC under hydrogen pressure (2.7 almasteral in THF (50 ml) under nitrogen atmosphere and slowly added with stirring and at room temperature the complex of borane-dimethyl sulfide (1.1 g; 13.7 mmole). The reaction mixture is boiled under reflux for 2 hours. After cooling to 5oC was slowly added a solution of concentrated HCl (0.5 ml) in methanol (4 ml). The reaction mixture is boiled under reflux for 2 hours, then concentrated by distillation of the solvent at atmospheric pressure, and then dried to dryness under reduced pressure. The residue was dissolved in methanol (20 ml), the solvent is kept under reduced pressure, was added methanol (20 ml) and the solvent was again removed. Added absolute ethanol (20 ml) and a solution of HCl in ethyl ether (15% wt./about.) (1 ml) and under reduced pressure, evaporated the solvent, obtaining the crude product, which was purified by chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 85:15:2). The formed solid product was dissolved in absolute ethanol and the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% wt./vol.). After evaporation of the solvents under reduced pressure received connection 35 (0.6 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,19-2,19 (m, 12H); 2,39-up 3.22 (m, 14H); 3,43-3,59 (m, 1H); of 3.75 (s, 3H); of 6.49 (d, 1H); 6,62 (d, 1H); 7.24 to a 7.85 (m, 4H).

MS: 483 [M+1].

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1,19-2,19 (m, 12H); 2,40-3,18 (m, 14H); 3,45-of 3.60 (m, 1H); of 4.44 (s, 2H); 6,50 (d, 1H); 6,63 (d, 1H); 7,13-7,24 (m, 4H).

MS: 455 [M+1].

Example 44

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4- carbamoylphenoxy)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 37)

To a solution of intermediate 63 (2.4 g; 3.1 mmole), obtained according to example 31, in ethanol (70 ml) was added concentrated HCl (0.7 ml) and 10% Pd on coal (0.50 g). The mixture was kept under stirring and at room temperature under hydrogen pressure (2.7 ATM) within 36 hours. The catalyst was filtered and the solvents evaporated under reduced pressure. The crude product was purified using chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 80:20:2). The formed solid product was dissolved in absolute ethanol and the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% wt. /about.). After evaporation of the solvents under reduced pressure received connection 37 (0.7 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1.18 to 2,17 (m, 12H); 2,38-3,20 (m, 14H); 3,43-3,59 (m, 1H); of 6.49 (d, 1H); is 6.61 (d, 1H); 7.23 percent-7,63 (m, 4H).

MS (thermospray): 468 [M+1].

4-tetrahydro-2-naphtylamine (compound 38)

A solution of compound 35 (1.0 g; 1.8 mmole), obtained according to example 43, in dioxane (10 ml) and concentrated HCl (5 ml) was boiled under reflux with stirring for 6 hours. The solvents were removed under reduced pressure and the residue was purified by chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 80: 20: 2). The formed solid product was dissolved in absolute ethanol and the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% wt./vol.). After evaporation of the solvents under reduced pressure, the obtained compound 38 (0.6 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,20-2,20 (m, 12H); 2,40 is 3.23 (m, 14H); 3,44-of 3.60 (m, 1H); 6,50 (d, 1H); 6,63 (d, 1H); 7,25-to 7.84 (m, 4H).

MS: 469 [M+1].

Example 46

Getting dihydrochloride (S)-N-propyl-N-[6-[2-(4- sulfophenyl)ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro - 2-naphtylamine (compound 39)

To a suspension of intermediate 59 (0.9 g; 1.2 mmole), obtained according to example 29, in 95% ethanol (240 ml) was added concentrated HCl (2 ml) and 10% Pd on coal (50% in water) (0.6 g). The mixture was kept under stirring and at room temperature under hydrogen pressure (2.7 ATM) for 16 hours, and then on igenom pressure, receiving a connection 39 (0.6 g) as an amorphous white solid.

1H-NMR (200 MHz; D2O): (part./million): 0,78 (t, 3H); 1,14-of 2.16 (m, 12H); 2,34-3,17 (m, 14H); 3,39-of 3.54 (m, 1H); 6,46 (d, 1H); 6,59 (d, 1H); 7,20-7,58 (m, 4H).

MS (thermospray): 505 [M+1].

Example 47

Getting trihydrochloride (S)-N-propyl-N-[6-[2-(2-amino-1,3 - benzothiazol-6-yl)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2 - naphtylamine (compound 40)

To a solution of intermediate 52 (0.9 g; 1.4 mmole), obtained according to example 24, in chloroform (44 ml) was added dropwise at -35oC in nitrogen atmosphere and with stirring, 1 M solution trichloride boron in CH2Cl2(27 ml). The reaction mixture was kept under stirring at -30oC for 15 minutes, then was heated to 50oC and kept under stirring for 4 hours. Was added methanol (30 ml) and the solvents were removed under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH: 50% HCOOH = 80:20:1). The formed solid product was dissolved in absolute ethanol and the solution was acidified to pH 1 by adding a solution of HCl in ethyl ether (15% wt./vol.). After evaporation of the solvents under reduced pressure received connection 40 (0.54 g) as a white amorphous (m, 1H); 6,47 (d, 1H); 6,60 (d, 1H); 7,20-of 7.48 (m, 3H).

MS: 497 [M+1].

Example 48

Getting 4-(2,3-acid)-2-oxopentanoic acid

To a mixture of copper iodide (7,62 g; 40 mmol) in anhydrous ethyl ether (76 ml) at 0oC in nitrogen atmosphere for 10 minutes under stirring was added 1,6 N. ether solution (37.5 ml) metallyte (60 mmol). The solution was kept under stirring for 5 minutes, and then was slowly added a solution of 4-(2,3-acid)-2-oxo-3-butenova acid (4.72 in g; 20 mmol), obtained in accordance with the method described in the application for the European patent 0534536 (Zambon Group S. p.A.), in anhydrous THF (40 ml). The mixture was stirred over night at 0oC in nitrogen atmosphere and then at 0oC was poured into rapidly stirred with 1.2 HCl solution (0.5 l). The mixture was extracted with ethyl acetate (4x100 ml). The organic layers were dried and evaporated under reduced pressure, obtaining a brown oil (5 g). By purification using chromatography (eluent CH2Cl2: CH3OH:CH3COOH = 95:5:0.5) with the received 4-(2,3-acid)-2-oxopentanoic acid (3,84 g; yield 76%) as a yellow oil, which was hardened after treatment with n-hexane.

1H-NMR (200 MHz; CDCl3): (part./million): to 1.31 (d, 3H); 3,66-3,82 (m, 1H); 3,80 3,82 and (2s, 6H); phenyl)pentanol acid

To a solution of 4-(2,3-acid)-2-oxopentanoic acid (0.5 g; 2 mmole), obtained according to example 48, in anhydrous ethanol (20 ml) under stirring and at room temperature in a nitrogen atmosphere was added anhydrous pyridine (0,52 ml). The two portions were added hydroxylamine hydrochloride (0.17 g; 2.4 mmole), keeping the temperature below 10oC. the Solution was stirred for 2 hours at room temperature, was poured into a mixture of water-ice (100 ml), acidified with concentrated hydrochloric acid (pH 1) and was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried and concentrated under vacuum, obtaining 2-hydroxyimino-4-(2,3 - acid)pentane acid (0.52 g; yield 97%) as a colourless oil, which was hardened during maturation.

1H-NMR (200 MHz; CDCl3): (part./million): 1,22 (d, 3H); 2,86-3,03 (m, 2H); 3,80 3,82 and (2s, 6H); 3,66-of 3.85 (m, 1H); 6,72-7,05 (m, 3H).

MS (methyl ester from the reaction with diazomethane): 281 [M].

Example 50

Obtaining 2-amino-4-(2,3-acid)pentanol acid

A solution of mercury chloride (92,3 g; 0,34 mmole) in water (1850 ml), cooled to 0oC, with stirring, was treated with aluminum foil (45,9 g, 1.7 mmole). After holding at room temperature stirring solution was added 2-hydroxyimino-4-(2,3 - acid)pentanol acid (34,63 g; of 0.13 mol), obtained according to example 49, in methanol (300 ml), maintaining the temperature below 25oC. After stirring overnight at room temperature, the mixture was stirred at 45oC for 5 hours, acidified with concentrated HCl until complete dissolution, and then was purified by chromatography on ion-exchange resin Amberlite IR-120(300 g), elwira a mixture of H2O:CH3OH = 1:1, water and then a 2.5% ammonium hydroxide. Combined fractions were evaporated in vacuum, obtaining 2-amino-4-(2,3-acid)pentane acid (17.5 g; yield 53%) as a white solid product.

tPL> 200oC.

1H-NMR (200 MHz; DCl 1H): (part./million): of 1.40-1.50 (m, 3H); 2,20-of 2.50 (m, 2H); 3.45 points-of 3.60 (m, 1H); 3,95 of 4.05 and (2s, 6H); 3,80-4,20 (m, 1H); 7,08-7,41 (m, 3H).

MS: 254 [M+1]

Example 51

Obtaining N-(1,2,3,4-tetrahydro-5,6-dimethoxy-4 - methyl-1-oxo-2-naphthyl)trifurcated

To a solution of 2-amino-4-(2,3 - acid)pentanol acid (17.5 g; 69 mmol), obtained according to example 50, in triperoxonane acid (200 ml), cooled to -5oC, under stirring was added in nitrogen atmosphere triperoxonane anhydride (36,33 g; 173 mmole). The solution was kept under stirring for 1 hour at 0oC and during the night pratte. The organic layer, washed with aqueous sodium bicarbonate and water, dried and evaporated to dryness, obtaining a brown oil. The crude product was purified using fast chromatography (eluent n-hexane:ethyl acetate = 9:1) to give N-(1,2,3,4-tetrahydro - 5,6-dimethoxy-4-methyl-1-oxo-2-naphthyl)triptorelin (18 g; yield 79%) as a pale orange solid product.

tPL83-85oC.

1H-NMR (200 MHz; CDCl3): (part./million): 1,45-of 1.52 (m, 3H); 2,00-2,70 (m, 2H); 3,40-of 3.60 (m, 1H); of 3.85 and 3.95 (2s, 6H); 4,80-of 4.95 (m, 1H); 6.90 to (d, 1H); 7,40 (bs, 1H); of 7.82 (d, 1H).

MS: 332 [M+1].

Example 52

Obtain 1,2,3,4-tetrahydro-5,6-dimethoxy-4-methyl-2 - naphtylamine

A solution of N-(1,2,3,4-tetrahydro-5,6-dimethoxy-4-methyl - 1-oxo-2-naphthyl)trifurcated (6.2 g; to 18.7 mmole), obtained analogously to example 51, in ethanol (250 ml), acidified 70% perchloro acid (0,37 ml), was first made in a Parr shaker overnight (4,08 ATM) at 60oC in the presence of 10% Pd on coal (0.6 g) as a catalyst. Upon completion of the hydrogenation the catalyst was filtered and washed with ethanol. The organic phase half was evaporated in vacuum and the remaining solution was stirred over night at 50oC with 32% aqueous NaOH solution (5,25 ml; 56,1 mmole). The mixture was concentrated, the one phase podslushivaet NaOH and was extracted with ethyl acetate. The organic extracts were dried and evaporated to dryness, obtaining 1,2,3,4-tetrahydro-5,6-dimethoxy-4-methyl-2-naphtylamine (3,44 g; yield 83%) as a yellow oil, which was used in subsequent reactions without further purification.

1H-NMR (200 MHz; CDCl3): (part./million): of 1.23 and 1.32 to (2d, 3H); to 1.48 (bs, 2H); 1,50-to 3.35 (m, 6H); of 3.77-3,83 (3s, 6H); 6,68-to 6.80 (m, 2H).

MS: 222 [M+1].

Example 53

Obtain 1,2,3,4-tetrahydro-5,6-dimethoxy-4 - methyl-2-naphtylpropionate

To a solution of 1,2,3,4-tetrahydro-5,6 - dimethoxy-4-methyl-2-naphtylamine (3.7 g; 16.7 mmole), obtained according to example 52, in anhydrous CH2Cl2cooled to 0oC, was added in an atmosphere of nitrogen triethylamine (2.8 ml; a 20.2 mmole) and slowly added propionate (1,64 ml; of 18.4 mmole) dissolved in CH2Cl2(10 ml). The solution was kept under stirring and at room temperature under nitrogen atmosphere overnight and then was evaporated to dryness under reduced pressure, dissolved in ethyl acetate and washed with saturated aqueous NaHCO3with 5% HCl and with brine. The organic phase was dried over Na2SO4and focused, getting 1,2,3,4-tetrahydro-5,6 - dimethoxy-4-methyl-2-naphtylpropionate (4,58 g; quantitative yield) as a white solid produk (3s, 6H); 3,00-4,43 (m, 1H); lower than the 5.37-of 5.48 (m, 1H); 6,68-6,77 (m, 2H).

MS: 276 [M+1].

Example 54

Getting hydrochloride N-propyl-1,2,3,4-tetrahydro-5,6-dimethoxy-4 - methyl-2-naphtylamine

Working according to the method similar to that described in example 12, but using as starting product of 1,2,3,4-tetrahydro-5,6-dimethoxy-4 - methyl-2-naphtylpropionate obtained according to example 53, received hydrochloride N-propyl-1,2,3,4-tetrahydro-5,6-dimethoxy-4-methyl-2-naphtylamine in the form of a white solid in quantitative yield.

1H-NMR (200 MHz; D2O): (part./million): 0,83 0,82 and (2t, 3H); 1.04 million and 1.15 (2d, 3H); 1,23-2,00 (m, 4H); 2,25-3,55 (m, 6H); 3,61 and of 3.64 and 3,68 (3s, 6H); for 6.81 (bs, 2H).

MS: 300 [M+1].

Example 55

Working according to the method similar to that described in example 18, were obtained the following compounds.

The dihydrochloride of N-propyl-N-[6-(2 - phenylethylamine)hexyl]-4-methyl-5,6-dimethoxy-1,2,3,4-tetrahydro - 2-naphtylamine (intermediate 70) as an amorphous solid (yield 93%).

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,02 is 2.33 (m, 15H); 2,71-of 3.77 (m, 20H); to 6.80 (bs, 2H); 7,14-7,28 (m, 5H).

MS: 467 [M+1].

The dihydrochloride of N-propyl-N- [6-[2-(4-methylsulfinylphenyl)ethylamino]hexyl] -4-methyl - 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (probiotech; D2O-CDCl3): (part./million): 0,95-of 1.03 (m, 3H); 1,21-to 2.55 (m, 15H); a 3.01 (s, 3H); 2,81-of 3.48 (m, 13H); 3,59-3,70 (m, 1H); 3,79 and 3,81 3,83 and (3s, 6H); 6,70-6,84 (m, 2H); 7,42-7,86 (m, 4H).

MS: 545 [M+1].

The dihydrochloride of N-propyl-N-[6-[2-(3-chloro-4 - methoxyphenyl)ethylamino]hexyl] -4-methyl-5,6-dimethoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 72) as a white foam (yield 97%).

1H-NMR (200 MHz; DMSO-d6): (part./million): from 0.88 to 0.96 (m, 3H); 1,16-to 2.18 (m, 15H); 2,77-of 3.80 (m, 14H); 3,70-3,82 (4s, 9H); 6,80-to 7.35 (m, 5H); 9,26 (bs, 2H); 10,70 (bs, 1H).

MS: 532 [M+1].

The dihydrochloride of N-propyl-N-[6-[2-(3-chloro-4 - methoxyphenyl)ethylamino]hexyl] -4-methyl-5-methoxy-1,2,3,4 - tetrahydro-2-naphtylamine (intermediate 73) in the form of a white amorphous solid (yield 100%).

1H-NMR (200 MHz; CDCl3): (part./million): 0,98-1,05 (m, 3H); 1,42-2,69 (m, 12H); 2,88-to 3.33 (m, 14H); 3,50 at 3.69 (m, 1H); of 3.77 and a 3.83 (2s, 6H); 6,62-7,26 (m, 6H); 9,78 (bs, 2H); of 10.93 (bs, 1H).

MS: 561 [M+1].

The dihydrochloride of N-propyl-N- [6-[2-(4-methylsulfinylphenyl)ethylamino]hexyl] -4-methyl-5 - methoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate product 74) in the form of a white amorphous solid (yield 100%).

1H-NMR (200 MHz; CDCl3): (part./million): 0,98 was 1.06 (m, 3H); 1,44-of 2.64 (m, 12H); a 3.01 (s, 3H); 2,90-3,47 (m, 14H); 3,54 at 3.69 (m, 1H); of 3.78 (s, 3H); 6,44-7,14 (m, 3H); 7,47-a 7.85 (m, 4H); 9,87 (bs, 2H); a 10.74 (bs, 1H).

the e connection.

Dihydrobromide N-propyl-N-[6-(2-phenylethylamine)hexyl] -4-methyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 41) in the form of a pink solid (yield 62%).

1H-NMR (200 MHz; D2O): (part./million): 0,77 is 0.86 (m, 3H); 1.07 and 1.18 to (2d, 3H); 1,15-of 2.36 (m, 12H); 2,67-to 3.33 (m, 13H); 3,60-of 3.77 (m, 1H); 6,47-of 6.65 (m, 2H); 7,12-7,29 (m, 5H).

MS: 439 [M+1].

Dihydrobromide N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino]hexyl] -4-methyl-5,6 - dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 42) as a pink solid (yield 42%).

1H-NMR (200 MHz; D2O): (part./million): 0,77 is 0.86 (m, 3H); 1.07 and 1.18 to (2d, 3H); 1,21-of 1.97 (m, 12H); is 3.08 (s, 3H); 2,69-to 3.33 (m, 13H); 3,61-of 3.78 (m, 1H); of 6.49 (d, 1H); 6,59-of 6.65 (m, 1H); 7,40 for 7.78 (m, 4H).

MS: 517 [M+1].

Dihydrobromide N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino]hexyl] -4-methyl-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 43) in the form of a beige solid (yield 48%).

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.89 to 0.97 (m, 3H); 1,17-of 2.08 (m, 15H); 2,77-of 3.42 (m, 13H); 3,63-of 3.80 (m, 1H); 6,38-only 6.64 (m, 2H); 6,88-7,25 (m, 3H).

MS: 490 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(3-chloro-4 - hydroxyphenyl)ethylamino] hexyl] -5-hydroxy-1,2,3,4-tetrahydro - 2-naphtylamine (compound 44) in the form of solid ivory (yield 69%).

MS: 459 [M+1].

Dihydrobromide (S)-N-propyl-N-[6-[2-(4-methylsulfinylphenyl) ethylamino] hexyl] -5-hydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 45) in the form of solid ivory (yield 67%).

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,21-of 2.21 (m, 12H); to 3.09 (s, 3H); 2,36-3,24 (m, 14H); 3,48-to 3.64 (m, 1H); 6,58-of 6.99 (m, 3H); 7,40-7,79 (m, 4H).

MS: 487 [M+1].

Example 57

Obtain (S)-N-(5-hydroxy-6-methoxy-1,2,3,4 - tetrahydro-2-naphthyl)propanamide

To a solution of (S)-N-(5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphthyl)propanamide (79 g; 0,3 mol), obtained in accordance with the method described in international application WO 93/19036 (Zambon Group S. p.A.), in CHCl3(800 ml) in a dry nitrogen atmosphere was added attributively (143 ml of 1.05 mol). The solution was left overnight, washed with 10% aqueous sodium thiosulfate solution and evaporated to dryness. By crystallization from isopropanol was obtained (S)-N-(5-hydroxy-6 - methoxy-1,2,3,4-tetrahydro-2-naphthyl)propanamide (72.4 g; output 96,8%) as a white solid.

tPL163-165oC.

1H-NMR (200 MHz; CDCl3): (part./million): of 1.12 (t, 3H); 1,67-of 2.08 (m, 2H); 2,17 (q, 2H); 2,50-3,10 (m, 4H); of 3.84 (s, 3H); 4,18 is 4.36 (m, 1H); 5,38-5,49 (m, 1H); 5,70 (s, 1H); to 6.57 (d, 1H); 6,69 (d, 1H).

MS: 250 [M+1].

Primes, contains (S)-N-(5-hydroxy-6 - methoxy-1,2,3,4-tetrahydro-2-naphthyl)propanamide (60,8 g; 0,24 mol), obtained according to example 57, K2CO3(67,5 g; of 0.48 mole) and N-phenylbis(triftormetilfullerenov) (95,9 g; 0,264 mol) in THF (750 ml) was stirred over night. After evaporation the residue was dissolved in water and CH2Cl2, the organic phase was evaporated and was led from ethyl acetate/petroleum ether, obtaining (S)-N-(5-tripterocalyx-6-methoxy-1,2,3,4-tetrahydro-2-naphthyl)propanamide (81,7 g; yield of 89.2%) as a white solid.

tPL126-127oC.

1H-NMR (200 MHz; CDCl3): (part./million): to 1.14 (t, 3H); 1,65 is 2.10 (m, 2H); 2,19 (q, 2H); of 2.51-and 3.16 (m, 4H); of 3.84 (s, 3H); 4,16-4,34 (m, 1H); 5,33-of 5.45 (m, 1H); 6,72 (d, 1H); 7,02 (d, 1H).

MS: 382 [M+1].

Example 59

Obtaining methyl ester (S)-2-methoxy-6-(1-oxopropyl)amino - 5,6,7,8-tetrahydronaphthyl-1-carboxylic acid

A solution of (S)-N-(5-tripterocalyx-6-methoxy-1,2,3,4-tetrahydro-2-naphthyl)propanamide (22 g; 0,058 mol), obtained according to example 58, triethylamine (17,7 ml; 0,128 mol), methanol (30 ml), palladium acetate (0.5 g; of 2.23 mmole) and 1,3-bis(diphenylphosphino)propane (1 g; 2,42 mmole) in DMSO (50 ml) was stirred at room temperature for 15 minutes. Through the solution for 4-5 min is whether to 75oC. After 24 hours the reaction mixture was allowed to cool to room temperature. Was added water (400 ml) and the mixture was extracted with CH2Cl2. After evaporation the residue was led from acetonitrile, receiving the methyl ester of (S)-2-methoxy-6-(1-oxopropyl)amino-5,6,7,8-tetrahydronaphthyl-1 - carboxylic acid (10 g) as a white solid. An additional amount of product (4.7 g) were obtained from mother solutions using chromatography (eluent CH2Cl2:CH3OH = 98:2).

Total yield: 87.3 per cent.

tPL151-152oC.

1H-NMR (200 MHz; CDCl3): (part./million): of 1.12 (t, 3H); 1,64-2,05 (m, 2H); of 2.15 (q, 2H); 2,48-to 3.09 (m, 4H); 3,78 and 3,88 (2s, 6H); 4,16-to 4.33 (m, 1H); 5,45 (bd, 1H); 6,72 (d, 1H); 7.03 is (d, 1H).

MS: 292 [M+1].

Example 60

Obtain (S)-2-methoxy-6-(1-oxopropyl)amino-5,6,7,8 - tetrahydro-naphthyl-1-carboxylic acid

A solution of methyl ester (S)-2-methoxy-6-(1-oxopropyl)amino-5,6,7,8-tetrahydronaphthyl-1 - carboxylic acid (9 g; 0,031 mol), obtained according to example 59, in methanol (90 ml) and 40% NaOH (13,8 ml) kept at 65oC for 72 hours and then was evaporated. The residue was dissolved in water, was extracted with simple ether and acidified with HCl. The acid precipitate was extracted with hot ethyl acetate. After paride white solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.95 (t, 3H); 1,43-to 1.98 (m, 2H); 2,07 (q, 2H); 2,43-of 2.97 (m, 4H); to 3.73 (s, 3H); 3,78-of 3.96 (m, 1H); at 6.84 (d, 1H); 7,07 (d, 1H); of 7.82 (d, 1H); 12,90 (bs, 1H).

MS: 278 [M+1].

Example 61

Obtaining methyl ester (S)-2-methoxy-6-(1 - oxopropyl)amino-5,6,7,8-tetrahydronaphthyl-1-carbamino acid

A mixture containing (S)-2-methoxy-6-(1-oxopropyl)amino-5,6,7,8 - tetrahydronaphthyl-1-carboxylic acid (7.7 g; 0,0278 mol), obtained according to example 60, diphenylphosphoryl (6,6 ml; 0,0306 mol) and triethylamine (5.8 ml; 0,0417 mol) in dioxane (75 ml) was boiled under reflux overnight. Was added methanol (18.5 ml) and boiling under reflux was continued for 2 hours. After evaporation the residue was dissolved in CHCl3, washed with water, hydrochloric acid, sodium bicarbonate and finally dried over Na2SO4. After evaporation of chloroform were obtained crude product (7.7 g), which was led from acetonitrile, receiving the methyl ester of (S)-2-methoxy-6-(1-oxopropyl) amino-5,6,7,8-tetrahydronaphthyl-1-carbamino acid (6.5 g; yield 76%) as a white solid.

tPL226-227 of theoC.

1H-NMR (200 MHz; CDCl3): (part./million): of 1.12 (t, 3H); 1,62-2,04 (m, 2H); 2,17 (q, 2H); 2,48-3,10 (m, 4H); 3,82 and 3,88 (2s, 6H); 4,orida methyl ester (S)-2-methoxy-6-propylamino-5,6,7,8-tetrahydronaphthyl-1-carboxylic acid

The complex of borane-dimethyl sulfide (5,73 ml; 0,0605 mol) was added dropwise under nitrogen atmosphere to a solution of methyl ester (S)-2-methoxy-6-(1 - oxopropyl)amino-5,6,7,8-tetrahydronaphthyl-1-carboxylic acid (8 g; 0,0275 mol), obtained according to example 59, in THF (65 ml). The mixture was boiled under reflux for 1 hour and evaporated. Caution was added methanol (50 ml) and concentrated HCl (2.5 ml) and the solution boiled under reflux for 2 hours. After evaporation was added methanol and evaporated again, getting hydrochloride methyl ester (S)-2-methoxy-6-propylamino-5,6,7,8-tetrahydronaphthyl - 1-carboxylic acid (8.5 g; yield of 98.5%) as amorphous solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.93 (t, 3H); 1,58-to 2.29 (m, 4H); 2,61-up 3.22 (m, 6H); 3,31-of 3.46 (m, 1H); to 3.73 and of 3.78 (2s, 6H); 6,93 (d, 1H); 7.18 in (d, 1H); 9,06-9,29 (bm, 2H).

MS: 278 [M+1].

Similarly, the method described above was obtained the following compound.

Methyl ester of (S)-2-methoxy-6-propylamino-5,6,7,8 - tetrahydronaphthyl-1-carbamino acid as white solids (yield of 49.3%).

1H-NMR (200 MHz; CDCl3): (part./million): to 0.92 (t, 3H); 1,42-2,07 (m, 4H); 2,45-to 3.02 (m, 7H); 3,72 and of 3.77 (2s, 6H); 6,05 (bs, 1H); 6,70 (d, 1H); of 6.96 (d, 1H).

MS: 293 [M+1].

Example 63
after-1-carbamino acid (intermediate 75)

To a mixture containing methyl ester (S)-2-methoxy-6-propylamino - 5,6,7,8-tetrahydronaphthyl-1-carbamino acid (731 mg, 2.5 mmole), obtained according to example 62, CH2Cl2(10 ml) was added triethylamine (0.7 ml, 5 mmol), and then a solution of acid chloride of 6-(phenylacetylamino)Caproic acid (736 g; a 2.75 mmole) in CH2Cl2(10 ml). The reaction mixture was kept under stirring and at room temperature for 2 hours, washed with diluted HCl, sodium bicarbonate, water and dried over Na2SO4. After evaporation under reduced pressure was obtained intermediate product 75 (1,25 g; output 95,5%) as amorphous solid.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.82 to 0.92 (m, 3H); 1,16-of 1.95 (m, 10H); 2,23 is 2.33 (m, 2H); 2,72-of 3.25 (m, 8H); 3,52 and 3,54 (2s, 2H); 3,71 and 3.74, and of 3.77, and 3,79 (4s, 6H); 3,88-of 4.57 (m, 1H); 5,58-5,70 (m, 1H); 6,04-to 6.19 (m, 1H); 6,66-6,98 (m, 2H); 7,21 was 7.36 (m, 5H).

MS: 524 [M+1].

Similarly, the method described above was obtained the following compound.

Methyl ester of (S)-2-methoxy-6-[[6- (phenylacetylamino)-1-oxohexyl] propylamino] -5,6,7,8 - tetrahydronaphthyl-1-carboxylic acid (intermediate 76) in the form of a viscous oil (yield 80%).

1H-NMR (200 MHz; CDCl3): (part./million): 0,82-of 0.93 (m, 3H); 1,20-of 1.66 (m, 8H); 1,82 is 1.96 (m, 2H); 2.23 to- MS: 509 [M+1].

Example 64

Obtain (S)-N-[[6-(5-amino-6 - methoxy-1,2,3,4-tetrahydro-2-naphthyl)propylamino]-6-oxohexyl] benzoylacetone (intermediate 77)

A solution of intermediate 75 (2.4 g; 4,58 mmole), obtained according to example 63, in 48% HBr (40 ml) was kept under stirring overnight. After evaporation the residue was dissolved in ethyl acetate and washed with sodium bicarbonate. After evaporation of the organic phase were obtained intermediate product 77 (2.1 g; yield 100%) as a yellow oil.

1H-NMR (200 MHz; CDCl3): (part./million): 0,83-of 0.94 (m, 3H); 1,19-2,04 (m, 10H); 2,24 of-2.32 (m, 2H); 2,44-of 3.25 (m, 8H); 3,52 3,53 and (2s, 2H); 3,59 with 4.65 (m, 6H); 5,67-USD 5.76 (m, 1H); 6.42 per-6,69 (m, 2H); 7,19-to 7.35 (m, 5H).

MS: 466 [M+1].

Example 65

Obtain (S)-N-[[2-methoxy-6-[6-(phenylacetylamino)-1 - oxohexyl]propylamino]-5,6,7,8-tetrahydro-1-naphthyl] methanesulfonamide (intermediate 78)

Intermediate 78 was obtained as amorphous solid (yield 94,4%) is similar to the method described in example 63, using as starting substances intermediate 77 product obtained according to example 64, and methanesulfonanilide.

1H-NMR (200 MHz; CDCl3): (part./million): to 0.80-0.95 (m, 3H); 1,20-is 2.37 (m, 12H); 2,70-to 3.52 (m, 13H); 3,80-4,51 (m, 7H); of 5.05-5,70 (m, 1H); 5,97 (d, 1H); 6,69-7,05 (m, 2H); 7,20-7,, what was alocale the following connections.

(S)-N-propyl-N-[[6-(2 - phenylethyl)amino] hexyl] -5-methyl-6-methoxy-1,2,3,4-tetrahydro-2 - naphtylamine (compound 79) as a yellow oil (yield 54%)using as the starting material, intermediate product 76.

1H-NMR (200 MHz; CDCl3): (part./million): 0,86 (t, 3H); 1,24-to 2.06 (m, 12H); of 2.08 (s, 3H); 2,41-of 2.93 (m, 15H); of 3.77 (s, 3H); to 6.67 (d, 1H); 690 (d, 1H); 7,14-to 7.32 (m, 5H).

MS: 437 [M+1].

Trichloride (S)-2-methoxy-N1N-methyl-N6-[[6-(2 - phenylethyl)amino] hexyl]-N6-propyl-5,6,7,8-tetrahydronaphthyl-1,6 - diamine (intermediate 80) in the form of a white amorphous solid (yield 77%)using as the starting material, intermediate product 75.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,20-of 2.27 (m, 12H); 2,65-3,19 (m, 14H); 3,54-3,68 (m, 1H); of 3.77 (s, 3H); 6,92 (d, 1H); 7,12-7,29 (m, 6H).

MS: 452 [M+1].

(S)-[2-methoxy-6-[[6-(2-phenylethyl)amino]hexyl]propylamino]-5,6,7,8 - tetrahydro-1-naphthyl]methanesulfonamide (intermediate 81) as a pale yellow oil (yield 55%) using as the starting material, intermediate product 78.

1H-NMR (200 MHz; CDCl3): (part./million): 0,84 (t, 3H); 1,22-2,02 (m, 12H); to 2.94 (s, 3H); 2,39 of 3.28 (m, 15H); is 3.82 (s, 3H); of 6.71 (d, 1H); 7,00 (d, 1H); 7,14-7,31 (m, 5H).

is their connection.

Dihydrobromide (S)-N-propyl-N-[[6- (2-phenylethyl)amino]hexyl]-5-methyl-6-hydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 46) in the form of amorphous nut-brown solid (yield 45%) using as the starting material, intermediate product 79.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1.91 a (s, 3H); 1,22 - 2,19 (m, 12H); 2,44-3,18 (m, 14H); 3,44-of 3.77 (m, 1H); 6,60 (d, 1H); 6,77 (d, 1H); 7,13-7,29 (m, 5H).

MS: 423 [M+1].

Trihydrobromide (S)-N-propyl-N-[[6-(2-phenylethyl)amino] hexyl] -5 - methylamino-6-hydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 47) as an orange solid (yield 65%) using as the starting material, intermediate product 80.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,24-of 2.26 (m, 12H); 2,84 (s, 3H); 2,65-3,19 (m, 14H); 3,55-3,68 (m, 1H); 6,77 (d, 1H); 7,02 (d, 1H); 7,13-7,30 (m, 5H).

MS: 438 [M+1].

Example 68

Working according to the method similar to that described in example 42, received the following connection.

Dihydrobromide (S)-[2-hydroxy-6-[[6-(2-phenylethyl)amino] hexyl] propylamino]-5,6,7,8-tetrahydro-1-naphthyl]Amin]methanesulfonamide (compound 48) in the form of nut-brown solid (yield 53%)using as the starting material, intermediate product 81,15-7,30 (m, 5H).

MS: 502 [M+1].

Example 69

Obtaining (R)-N-propionyl 6-methoxy-7-nitro - 1,2,3,4-tetrahydro-2-naphtylamine

A solution of 100% nitric acid (0,81 ml; or 19.3 mmole) in triperoxonane acid (2 ml) was added dropwise with stirring and at 0oC to a solution of (R)-N-propionyl 6-methoxy-1,2,3,4-tetrahydro-2-naphtylamine (4.5 g; or 19.3 mmole) obtained in accordance with the method described in the application for the European patent 74903, triperoxonane acid (20 ml). After 30 minutes the solvent is evaporated under reduced pressure and at room temperature. To the residue was added water (30 ml) and methylene chloride (50 ml), the layers were separated and the organic layer was washed with sodium bicarbonate solution, dried over Na2SO4and was evaporated to dryness under reduced pressure. The residue was purified by chromatography (eluent petroleum ether:ethyl acetate in the ratio, increasing from 1: 1 to 1: 4) to give (R)-N-propionyl 6-methoxy-7-nitro-1,2,3,4-tetrahydro-2-naphtylamine (2.4 g) as a pale yellow solid.

1H-NMR (200 MHz; CDCl3): (part./million): to 1.14 (t, 3H); 1,62-of 2.15 (m, 2H); 2,19 (q, 2H); 2,48-3,13 (m, 4H); 3,90 (s, 3H); 4,15 is 4.35 (m, 1H); 5,39-5,56 (bd, 1H); 6,76 (s, 1H); to 7.59 (s, 1H).

MS: 279 [M+1].

Example 70

Obtaining hydrochloride (R)-N is slowly added under stirring and at room temperature to a solution of (R)-N-propionyl 6-methoxy-7-nitro-1,2,3,4 - tetrahydro-2-naphtylamine (2.2 g; of 7.9 mmole), obtained according to example 69, in THF (30 ml). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added conc. hydrochloric acid (0.8 ml) in methanol (8 ml). The reaction mixture is again boiled under reflux for 1.5 h, and then concentrated at atmospheric pressure. Was added methanol (20 ml), the solvent is kept under reduced pressure, the newly added methanol (20 ml) and the solvent evaporated to dryness. The residue was dissolved in ethyl acetate. After filtration of the solid and drying under vacuum at 50oC received hydrochloride (R)-N-propyl-6-methoxy-7 - nitro-1,2,3,4-tetrahydro-2-naphtylamine (2.3 g) as a beige solid.

1H-NMR (200 MHz; D2O): (part./million): or 0.83 (t, 3H); 1,46-of 2.24 (m, 4H); 2,62-3,18 (m, 6H); 3,33-of 3.53 (m, 1H); of 3.78 (s, 3H); 6,92 (s, 1H); to 7.67 (s, 1H).

MS: 265 [M+1].

Example 71

Getting 4-(2-carboxyethyl)phenyltoloxamine

The potassium thiocyanate (257 g; 2,64 mol) was added under stirring and under 50oC to a solution of 4-aminophenylarsonic acid (200 g; 1,32 mol) in water (1000 ml) and concentrated HCl (130 g; 1,32 mol). The reaction mixture was stirred at 100oC for 16 hours, then ohla ATiM refrigerator for 1 hour. After cooling to 0oC, filtering and drying the solids under vacuum at 60oC was obtained 4-(2-carboxyethyl)phenyltoloxamine (173 g) as a solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): 3,52 ('s. 2H); 7,16-7,35 (m, 4H); 7,20-of 7.70 (bs, 2H); for 9.64 (s, 1H); 12,30 (bs, 1H).

MS: 211 [M+1].

Example 72

Getting 2-chloro-6-(2-carboxyethyl)-1,3-benzothiazole

To a suspension of 4-(2-carboxyethyl)phenyltoloxamine (172 g; of 0.82 mol), obtained according to example 71, in chloroform (1.7 l) was slowly added with stirring and at 0oC bromine (261 g; 1,64 mol). After 30 minutes the reaction mixture is boiled under reflux for 1 hour, then was cooled to 0oC and filtered. The solid is washed with acetone and dissolved in water (2.5 ml), and then under stirring and at room temperature was added to 10.8 N. aqueous NaOH solution (67 ml). After 1 hour the solid was filtered and washed with water. After drying under vacuum at 60oC received 2-amino-6-(2-carboxyethyl)- 1,3-benzothiazol (129 g).

1H-NMR (200 MHz; DMSO-d6): (part./million): 3,55 (s, 2H); was 7.08 (dd, 1H); to 7.25 (d, 1H); 7,41 (bs, 2H); 7,52 (d, 1H); 12,11-12,45 (bs, 1H).

MS: 209 [M+1].

A solution of sodium nitrite (104 g, and 1.5 mol) in water (155 ml) was added capl is Olya) in 85% phosphoric acid (1145 ml). After 1 hour the mixture for 1 hour under stirring and at 0oC was added to a solution of CuSO45H2O (500 g; 2,0 mol) and sodium chloride (584 g; of 10.0 moles) in water (2 l). The reaction mixture was allowed to warm to room temperature over night and after filtration, the solid is washed with water and dried in vacuum at 60oC, receiving 2-chloro-6-(2-carboxyethyl)-1,3-benzothiazole (104 g).

1H-NMR (200 MHz; DMSO-d6): (part./million): to 3.73 (s, 2H); 7,44 (dd, 1H); 7,89 (d, 1H); to 7.99 (d, 1H); 12,42 (bs, 1H).

MS: 228 [M+1].

Example 73

Getting 2-methoxy-6-(2-carboxyethyl)-1,3 - benzothiazole (intermediate 82)

Sodium metal (17.8 g) was added in portions with stirring to methanol (800 ml). After complete dissolution was added 2-chloro-6-(2-carboxyethyl)-1,3-benzothiazol (80 g; 0,35 mol), obtained according to example 72, and the reaction mixture is boiled under reflux for 3 hours. The solvent is evaporated and to the residue was added water (640 ml), methanol (160 ml) and with stirring and at room temperature, concentrated HCl (44 ml). After cooling to 0oC and filtration, the solid was dried in vacuum at 60oC, receiving the intermediate product 82 (71 g) as a beige solid.

Example 74

Obtain 6-(2-methoxy-1,3-benzothiazol-6-yl)atsetilaminokapronovoy acid (intermediate 83)

To a solution of intermediate 82 (2.0 g; 9.0 mmol), obtained according to example 73, N-hydroxysuccinimide (1.0 g; 9.0 mmol) in dioxane (15 ml) under stirring and at room temperature was added N,N'-dicyclohexylcarbodiimide (1.85 g; 9.0 mmol). After 1 hour, was added ethyl ether (15 ml) and the reaction mixture was filtered. The solution was evaporated to dryness and the resulting residue was dissolved in dioxane (10 ml) and DMF (5 ml). The resulting solution under stirring and at room temperature was added to a solution of 6-aminocaproic acid (1.2 g; 9.0 mmol) and dicyclohexylamine (1.6 g; 9.0 mmol) in water (6 ml) and ethanol (6 ml). After 1 hour the solvents evaporated under reduced pressure, was added water (20 ml) and with stirring, a solution of potassium bisulfate (1.3 g; 9.6 mmol) in water (6 ml). After 30 minutes the precipitate was filtered and dried under vacuum at 60oC, receiving the intermediate product 83 (2.8 g) as a white solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,12-of 1.56 (m, 6H); of 2.16 (t, 2H); 2,94-is 3.08 (m, 2H); 3,44 (s, 2H); 4,13 (s, 3H); 7,26 (dd, 1H); 7,58 (d, 1H); 7,71 (d, 1H); 8,03 (t, 1H).

MS: 337 [M+1].

Example 75

the DRO-2-naphtylamine (intermediate 84)

Working according to the method similar to that described in example 36, was obtained intermediate product 84.

1H-NMR (200 MHz; D2O): (part./million): of 0.82 (t, 3H); 1,16-2,22 (m, 12H); 2,45-3,26 (m, 14H); is 3.08 (s, 3H); 3,49-3,68 (m, 1H); 3,59 (s, 3H); 3,68 (s, 3H); for 6.81 (s, 2H); 7,42-7,58 (m, 2H); to 7.64 to 7.75 (m, 2H).

MS: 531 [M+1].

Example 76

Getting dihydrobromide (S)-N-propyl-N-[6-[2- (3-methylsulphonyl-phenyl)ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 49)

Working according to the method similar to that described in example 40 and using as the starting material, the intermediate product 84, obtained according to example 75, received the connection 49.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,20-to 2.18 (m, (12H); 2,38 is 3.23 (m, 14H); to 3.09 (s, 3H); 3,42-3,59 (m, 1H); of 6.49 (d, 1H); 6,62 (d, 1H); 7,44-7,73 (m, 4H).

MS: 503 [M+1].

Example 77

Working according to the method similar to that described in example 16, were obtained the following compounds.

(S)-N-propyl-N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl)- 6-carboxykinase (intermediate 85)

1H-NMR (200 MHz; CDCl3): (part./million): 0,91 0,87 and (2t, 3H); 1,27-of 2.08 (m, 10H); and 2.26-to 2.41 (m, 4H); 2,59-3,30 (m, 6H); of 3.77 and 3,79 and 3,81 3,82 and (4s, 6H); 3,85-4,04 and 4,46-4,68 (2m, 1H); 6,70 (d, 1H); 6,79 (d, 1H).

MS: 392 [M+1].

(S)-N-propyl-N-(5,6-dimethoxy-1,2,3,4 - tetrahydro (2t, 3H); 1,49-of 2.08 (m, 6H); 2,37 of $ 2.53 (m, 4H); 2.57 will be 3.29 (m, 6H); of 3.77 and 3,79 and 3,81 3,82 and (4s, 6H); 3,85-of 4.05 and 4.45-4,65 (2m, 1H); 6,70 (d, 1H); 6,79 (d, 1H).

MS: 364 [M+1].

Example 78

Getting dihydrochloride (S)-N-propyl-N-[(7 - amino)heptyl]-5,6-dimethoxy-1,2,3,4-tetrahydro-2 - naphtylamine (intermediate 87)

To a solution of intermediate 85 (2.6 g; 6.6 mmole), obtained according to example 77, in methylene chloride (40 ml) under stirring and at room temperature was added thionyl chloride (0.87 g; 7.3 mmole). After 2 hours the reaction mixture was evaporated to dryness. The residue was dissolved in methylene chloride (40 ml) and the resulting solution was added dropwise with stirring and at 0oC to a solution of ammonia in 0.65 M THF (40 ml). After 1 hour the solvents evaporated under reduced pressure, was added water and ethyl acetate and separated phases. The organic layer was washed with a solution of potassium bicarbonate, and then water and dried over Na2SO4. After evaporation of the solvent, the resulting residue was dissolved in THF (80 ml). To the solution was slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (3.8 g; 49.2 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC to what rinicom within 1 hour and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml), the solvent is kept under reduced pressure, was added methanol (30 ml) and the solvent again evaporated to dryness. The residue was purified by chromatography (eluent CH2Cl2:CH3OH: 50% HCOOH = 85:15:2) and the resulting product was dissolved in absolute ethanol (20 ml). Was added a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and the solvent evaporated under reduced pressure, obtaining the intermediate product 87 (1.8 g) as an amorphous solid.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,12-of 2.24 (m, 14H); 2,46-of 3.25 (m, 10H); 3,47-to 3.67 (m, 1H); of 3.60 (s, 3H); of 3.69 (s, 3H); PC 6.82 (s, 2H).

MS: 363 [M+1].

Similarly, the method described above were obtained the following compounds.

The dihydrochloride (S)-N-propyl-N-[(5 - amino)pentyl]-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 88) using as the starting material, intermediate product 86.

1H-NMR (200 MHz; D2O): (part./million): or 0.83 (t, 3H); 1,21 was 2.25 (m, 10H); 2,47-3,26 (m, 10H); 3,47-to 3.67 (m, 1H); 3,61 (s, 3H); 3,70 (s, 3H); 6,83 (s, 2H).

MS: 335 [M+is eroticly product 89) using as the starting material intermediate 29 and using methylamine instead of ammonia.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,16-2,22 (m, 12H); 2,52 (s, 3H); 2,45 is 3.23 (m, 10H); 3.46 in-3,66 (m, 1H); 3,59 (s, 3H); 3,68 (s, 3H); for 6.81 (s, 2H).

MS: 363 [M+1].

Example 79

Working according to the method similar to that described in example 23, were obtained the following compounds.

The dihydrochloride (S)-N-propyl-N-[7-[2-(2-oxo-3H-1,3-benzothiazol-6-yl) ethylamino]heptyl]-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 90) using as starting substances intermediate 87, obtained according to example 78, and intermediate 82, obtained according to example 73.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,09-of 2.21 (m, 14H); 2,42-is 3.21 (m, 14H); 3,43-to 3.64 (m, 1H); to 3.58 (s, 3H); to 3.67 (s, 3H); 6,76 (d, 1H); to 6.80 (d, 1H); 7,01 (d, 1H); to 7.09 (dd, 1H); 7,28 (d, 1H).

MS (thermospray): 540 [M+1].

The dihydrochloride (S)-N-propyl-N-[5-[2-(2-oxo-3H-1,3-benzothiazol-6-yl) ethylamino]pentyl]-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 91) using as the starting material intermediate 88, obtained according to example 78.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,17-2,22 (m, 10H); 2,43-is 3.21 (m, 14H); 3,45-to 3.64 (m, 1H); to 3.58 (s, 3H); 3,66 (s, 3H); 6.75 in (d, 1H); 6,79 (d, 1H); 7,01 (d, 1H); was 7.08 (dd, 1H); 7,27 (d, 1H).

MS (thermospray): 512 [M+1].

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1,09-of 2.16 (m, 12H); 2,29-3,63 (m, 15H); of 2.72 (s, 3H); of 3.48 (s, 3H); of 3.57 (s, 3H); 6,55-6,70 (m, 2H); PC 6.82 (dd, 1H); 6,99 (d, 1H); for 7.12 (d, 1H).

MS (thermospray): 540 [M+1].

Example 80

Working according to the method similar to that described in example 40, received the following connections.

Dihydrobromide (S)-N-propyl-N-[7-[2-(2-oxo-3H-1,3-benzothiazol-6-yl)ethylamino] heptyl] -5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 50), using as the starting material of the intermediate product 90, obtained according to example 79.

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1,13-of 2.15 (m, 14H); 2,34 is 3.15 (m, 14H); 3,39-of 3.54 (m, 1H); of 6.45 (d, 1H); to 6.58 (d, 1H); 6,98 (d, 1H); 7,07 (dd, 1H); from 7.24 (d, 1H).

MS: 512 [M+1].

Dihydrobromide (S)-N-propyl-N-[5-[2-(2-oxo-3H-1,3 - benzothiazol-6-yl)ethylamino] pentyl] -5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (compound 51), using as the starting material intermediate 91, obtained according to example 79.

1H-NMR (200 MHz; D2O): (part./million): of 0.79 (t, 3H); 1,20-2,11 (m, 10H); and 2.26-3,18 (m, 14H); 3,33-of 3.48 (m, 1H); 6,35-of 6.52 (m, 2H); 6.89 in (d, 1H); 7,02 (dd, 1H); 7.18 in (d, 1H).

MS (thermospray): 484 [M+1].

Dihydrobromide (S)-N-methyl-N-[2-(2-oxo-3H-1,3 - benzothiazol-6-yl)e is TBE source of matter intermediate 92, obtained according to example 79.

1H-NMR (200 MHz; D2O): frequent./million): 0,81 (t, 3H); 1,16-of 2.16 (m, 12H); to 2.74 (s, 3H); 2,33-to 3.36 (m, 14H); 3,41-3,55 (m, 1H); 6.42 per-6,59 (m, 2H); 6,99 (d, 1H); to 7.09 (dd, 1H); 7,28 (d, 1H).

MS: 512 [M+1].

Example 81

Obtaining hydrochloride (S)-N-propyl-N-(5 - methoxycarbonyl)pentyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2 - naphtylamine (intermediate 93)

The solution nanometrology ether carboxylic hexandiol acid (2.4 g; 13.3 mmole) in CH2Cl2(5 ml) under stirring and at room temperature was added to a solution of the hydrobromide (S)-N-propyl-5,6-dimethoxy - 1,2,3,4-tetrahydro-2-naphtylamine (4.0 g; 12,1 mmole) and triethylamine (3.0 g; 30.0 mmol) in CH2Cl2(40 ml). After 2 hours was added water (50 ml) and separated phases. The organic phase was washed with 0.2 N. aqueous HCl solution and then with water, dried over Na2SO4and was evaporated to dryness under reduced pressure. The residue was dissolved in THF (30 ml). To the solution was slowly added under stirring in nitrogen atmosphere at room temperature the complex of borane-dimethyl sulfide (1.7 g; of 21.7 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 2 hours. After cooling to 5oC solution was added 37% HCl (1.5 ml) in methanol (12 ml). Rea solvents at atmospheric pressure, and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml) and the solvent drove away under reduced pressure, the newly added methanol (30 ml) and the solvent evaporated to dryness. The residue was purified by chromatography (eluent CH2Cl2: CH3OH:50% HCOOH = 90:10:1). The formed solid product was dissolved in absolute ethanol and the solution was added HCl in ethyl ether (15% wt. /about. ) to obtain markedly acidic pH values. By evaporation of the solvent under reduced pressure was obtained intermediate product 93 (2.7 g) as an amorphous solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.91 (t, 3H); 1,20-2,39 (m, 10H); 2,31 (t, 2H); 2,52-of 3.27 (m, 8H); 3,44-the 3.65 (m, 1H); to 3.58 (s, 3H); to 3.67 (s, 3H); 3,76 (s, 3H); 6,83 (d, 1H); to 6.88 (d, 1H); 10,28 (bs, 1H).

MS: 378 [M+1].

Example 82

Obtaining hydrochloride (S)-N-propyl-N-(5-carboxy)pentyl-5,6 - dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 94)

A solution of NaOH (1.1 g; a 2.75 mmole) in water (3 ml) was added dropwise under stirring and at room temperature to a solution of intermediate 93 (2.6 g; 6.3 mmole), obtained according to example 81, in methanol (13 ml). After 2 hours the reaction mixture was evaporated to dryness. The residue was dissolved in water and the solution was acidified with concentrated HCl to pH 1, and then axiana pressure, receiving intermediate 94 (1.8 g) as an amorphous solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): to 0.92 (t, 3H); 1,19-2,39 (m, 10H); 2,22 (t, 2H); of 2.51-of 3.65 (m, 9H); 3,68 (s, 3H); 3,76 (s, 3H); at 6.84 (d, 1H); 6.89 in (d, 1H); 10,12 (bs, 1H); a 12.03 (bs, 1H).

MS: 364 [M+1].

Example 83

Obtain (S)-N-propyl-N- [6-oxo-[6-[2-(2-oxo-3H-1,3-benzothiazol-6-yl)ethylamino] hexyl] ] -5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 95)

1,1'-carbonyldiimidazole (0.73 g; 4.5 mmole) was added under stirring and at room temperature to a solution of intermediate 94 (1.8 g; 4.5 mmole), obtained according to example 82, and triethylamine (and 0.46 g, 4.5 mmole) in THF (10 ml) and DMF (8 ml). After 1 hour, was added a solution of intermediate 21 (1.2 g; 4.5 mmole), obtained according to example 8, and triethylamine (and 0.46 g, 4.5 mmole) in DMF (20 ml). After soaking overnight, the mixture was poured into water and ethyl acetate. The phases were separated and the organic phase was dried over Na2SO4and was evaporated to dryness under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2:CH3OH:ammonia = 90:10:0.5), the receiving intermediate 95 (1.1 g) as amorphous solids.

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 (t, 3H); 1,17-of 2.20 (m, 10H); 2,1].

Example 84

Working according to the method similar to that described in example 42, received the following connection.

The hydrobromide (S)-N-propyl-N-[6-oxo-[6-[2-(2-oxo - 3H-1,3-benzothiazol-6-yl)ethylamino] hexyl] ] -5,6-dihydroxy - 1,2,3,4-tetrahydro-2-naphtylamine (compound 53), using as the starting material intermediate 95, obtained according to example 83.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 0,87 is 2.10 (m, 10H); 1,99 (t, 2H); 2,32-of 3.12 (m, 10H); 3,26-of 3.48 (m, 3H); 6,44 (d, 1H); to 6.58 (d, 1H); 6,91 for 7.12 (m, 3H).

MS: 512 [M+1].

Example 85

Similar to that described in example 1 method was obtained the following compound.

[6-(4-methylsulfinylphenyl)acetylamino] hexanoic acid (intermediate 96) using as the starting material (4-methylsulfinylphenyl)acetic acid obtained according to J. Chem. Soc., 1501-6 (1948).

1H-NMR (200 MHz; DMSO-d6): (part./million): 1,18-of 1.56 (m, 6H); 2,17 (t, 2H); 2,97-is 3.08 (m, 2H); 3,18 (s, 3H); to 3.52 (s, 2H); 7,70-a 7.85 (m, 4H); to 8.14 (t, 1H); 12,00 (bs, 1H).

MS: 328 [M+1].

Example 86

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

To a solution of (R)-6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (2.0 g; 9.6 mmole), obtained according to J. Org. Chem., 50, 3619-22 (is the temperature of propionitrile (1.0 g; 10.8 mmole). After 1 hour the mixture was poured into water, acidified with HCl. The phases were separated and the organic phase is washed with water, dried over Na2SO4and was evaporated to dryness under reduced pressure. The residue was dissolved in THF (75 ml) under nitrogen atmosphere. To the solution was slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (2.9 g; 37,0 mmol). Upon completion of addition the reaction mixture is boiled under reflux for 2 hours. After cooling to 5oC solution was added concentrated HCl (1.7 ml) in methanol (14 ml). The reaction mixture is again boiled under reflux for 2 hours and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml), the solvent is kept under reduced pressure, was added methanol (30 ml) and the solvent again evaporated to dryness, obtaining hydrochloride (R)-N-propyl-6,7-dimethoxy-1,2,3,4-tetrahydro-2 - naphtylamine (2.6 g) as a white solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): to 0.94 (t, 3H); 1.57 in-2,31 (m, 4H); 2,59-3,17 (m, 6H); 3,23-of 3.46 (m, 1H); of 3.69 (s, 6H); 6,66 (s, 2H); 8,93-9,26 (bs, 2H).

MS: 250 [M+1].

Example 87

Working on technique, AI-1,2,3,4-tetrahydro-2-naphtylamine, obtained according to example 86, and an intermediate 96 product obtained according to example 85, received the following connection:

(R)-N-propyl-N-[6-[2-(4-methylsulfinylphenyl)ethylamino] hexyl] - 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 97)

1H-NMR (200 MHz; CDCl3): (part./million): of 0.87 (t, 3H); 1,20-2,04 (m, 13H); 2,38-2,99 (m, 15H); a 3.01 (s, 3H); of 3.80 (s, 6H); is 6.54 (s, 2H); 7,33-7,88 (m, 4H).

MS: 531 [M+1].

Example 88

Working according to the method similar to that described in example 40, but using as the starting material, the intermediate product 97, obtained according to example 87, received the following connection:

dihydrobromide (R)-N-propyl-N-[6-[2-(4-methylsulfinylphenyl)ethylamino] hexyl]-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphtylamine (compound 54).

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,23-2,10 (m, 12H); to 3.09 (s, 3H); 2,58-3,24 (m, 14H); 3,47-3,62 (m, 1H); of 6.52 (s, 2H); 7,40-7,79 (m, 4H).

MS: 503 [M+1].

Example 89

Obtaining (R)-N-propyl-N-[6-[(4 - methylsulfinylphenyl)acetylamino] -1-oxohexyl]-6-methoxy-7 - nitro-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 98)

To a suspension of intermediate 96 (0.84 g; of 2.56 mmole), obtained according to example 85, in methylene chloride (10 ml) was added under stirring and at cognatively under reduced pressure to obtain oil, which was dissolved in methylene chloride (4 ml). The solution was added dropwise under stirring and at room temperature to a suspension of the hydrochloride of (R)-N-propyl-6-methoxy-7-nitro-1,2,3,4-tetrahydro-2-naphtylamine (0.7 g; 2.3 mmole), obtained according to example 70, and triethylamine (0.7 g; 7.0 mmol) in CH2Cl2(10 ml). After 2 hours was added water (10 ml), the phases were separated and the organic phase is washed with water, acidified with HCl, dried over Na2SO4and was evaporated to dryness under reduced pressure. The resulting residue was purified using chromatography (eluent CH2Cl2:CH3OH = 98: 2) to give intermediate product 98 (0,93 g) as amorphous solids.

1H-NMR (200 MHz; CDCl3): (part./million): 0,82-0,97 (2t, 3H); 1,21-1,72 (m, 8H); 1,83 is 2.10 (m, 2H); 2,28-2,39 (m, 2H); 2.71 to to 3.33 (m, 8H); to 3.02 (s, 3H); of 3.60 (s, 2H); 3.90 and 3,91 (2s, 3H); to 3.89-4.09 to and 4,37-4,58 (2m, 1H); 6,06-6,29 (2t, 1H); 6,76 and 6.78 (2s, 1H); 7,42-to $ 7.91 (m, 4H); to 7.59 and 7.62 (2s, 1H).

MS: 574 [M+1].

Example 90

Getting dihydrochloride (R)-N-propyl-N-[6-[2-(4- methylsulphonyl-phenyl)ethylamino] hexyl]-6-methoxy-7 - methylsulfonylamino-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 99)

A solution of intermediate 98 (0.7 g; 1.2 mmole), obtained according to example 89, in absolute ethanol (50 ml) was first made in the devices and evaporation of the solvent under reduced pressure the resulting residue was dissolved in CH2Cl2(6 ml). To the solution was added triethylamine (of 0.13 g, 1.3 mmole) and dropwise with stirring and at room temperature methanesulfonamide (0.15 g; 1.3 mmole). After exposure for 4 hours at room temperature was added water (10 ml), the phases were separated and the organic phase is washed with 10% HCl solution and then the solution of NaHCO3. The organic phase was dried over Na2SO4and the solvent evaporated under reduced pressure. The resulting residue was dissolved in THF (10 ml) under nitrogen atmosphere. To the solution was slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (0,48 g, 6.1 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added concentrated HCl (0.25 ml) in methanol (2.5 ml). The reaction mixture is again boiled under reflux for 1 hour and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (10 ml), the solvent is kept under reduced pressure, was added methanol (10 ml) and the solvent again evaporated to dryness. The residue was purified by chromatography is e (20 ml). Was added a solution of HCl in ethyl ether (15% wt. /about. ) to obtain markedly acidic pH and the solvent evaporated under reduced pressure, obtaining the intermediate product 99 (0.34 g) as amorphous solids.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,13-2,19 (m, 12H); 2,61-of 3.27 (m, 14H); 2,90 (s, 3H); to 3.09 (s, 3H); 3,50-3,71 (m, 1H); of 3.69 (s, 3H); 6,76 (s, 1H); of 6.96 (s, 1H); 7,39-of 7.82 (m, 4H).

MS: 594 [M+1].

Example 91

Getting dihydrochloride (R)-N-propyl-N-[6-[2-(4- methylsulfinylphenyl)ethylamino] hexyl] -6-hydroxy-7 - methylsulfonylamino-1,2,3,4-tetrahydro-2-naphtylamine (compound 55)

To a solution of intermediate 99 (0.27 g; 0.4 mmole), obtained according to example 90, in water (1 ml) was added methylene chloride (2 ml) and to obtain an alkaline pH value of the aqueous solution of K2CO3. The phases were separated and the organic phase was dried over Na2SO4and was evaporated to dryness. The resulting residue was dissolved in CHCl3(5 ml) and to the solution with stirring and at -30oC was added a 1 M solution of BCl3in CH2Cl2(of 2.3 ml, 2.3 mmole). Upon completion of addition the reaction mixture was allowed to warm to room temperature. After holding at room temperature for 15 hours was added methanol (10 ml) and dissolve the3OH:50% HCOOH = 85:15:1) to give the product, which was dissolved in absolute ethanol (5 ml). Was added a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and the solvent evaporated under reduced pressure, obtaining the connection 55 (0,22 g) as amorphous solids.

1H-NMR (200 MHz; D2O): frequent./million): 0,81 (t, 3H); 1,19-to 2.13 (m, 12H); 2,92 (s, 3H); to 3.09 (s, 3H); 2.57 m-3,24 (m, 14H); 3,51-3,68 (m, 1H); 6,63 (s, 1H); 6,94 (s, 1H); 7,40-7,79 (m, 4H).

MS: 580 [M+1].

Example 92

Getting dihydrochloride (R)-N-propyl-N-[6-(2 - phenylethylamine)hexyl]-6-hydroxy-7-nitro-1,2,3,4-tetrahydro-2 - naphtylamine (intermediate 100)

To a solution of 6-(phenylacetylamino)Caproic acid (1.1 g; 4.4 mmole) in CH2Cl2(12 ml) was added under stirring and at room temperature, DMF (20 ml) and thionyl chloride (0,57 g, 4.8 mmole). After 1 hour, the solvent and excess thionyl chloride are evaporated under reduced pressure to obtain oil, which was dissolved in CH2Cl2(5 ml). The solution was added dropwise under stirring and at room temperature to a suspension of the hydrochloride of (R)-N-propyl-6 - methoxy-7-nitro-1,2,3,4-tetrahydro-2-naphtylamine (1.2 g; 4.0 mmole), obtained according to example 70, and triethylamine (1.0 g; 10.0 mmol) in HCl, dried over Na2SO4and was evaporated to dryness under reduced pressure. The resulting residue was dissolved in THF (20 ml) under nitrogen atmosphere. To the solution was slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (1.9 grams; 24,0 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added concentrated HCl (1 ml) in methanol (10 ml). The reaction mixture is again boiled under reflux for 1 hour and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (30 ml), the solvent is kept under reduced pressure, was added methanol (30 ml) and the solvent again evaporated to dryness. The residue was purified by chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 90:10:1) to give the product, which was dissolved in absolute ethanol (20 ml). Was added a solution of HCl in ethyl ether (15% wt. /about. ) to obtain markedly acidic pH and the solvent evaporated under reduced pressure, obtaining the intermediate product 100 (1.8 g) as an amorphous solid.

1H-NMR >/P>MS (thermospray): 467 [M+1].

Example 93

Obtaining (R)-N-propyl-N-[6-(2 - methoxy-1,3-benzothiazol-6-yl)acetyl-amino-1-oxohexyl] -6-methoxy - 7-nitro-1,2,3,4-tetrahydro-2-naphtylamine (intermediate 101)

To a solution of intermediate 83 (2.5 g; 7.4 mmole), obtained according to example 74, and triethylamine (0.75 g; 7.4 mmole) in THF (44 ml) was added under stirring and at -10oC isobutylparaben (1.0 g, 7.4 mmole). After 15 minutes, also at 10oC was added triethylamine (0,69 g, 6.8 mmole) and hydrochloride (R)-N-propyl-6-methoxy-7-nitro-1,2,3,4-tetrahydro-2-naphtylamine (2.0 g; 6.7 mmole), obtained according to example 70. After 1 h the reaction mixture was allowed to warm to room temperature. After 15 hours at room temperature was added ethyl acetate (150 ml) and water (50 ml), the phases were separated and the organic phase was washed with 1% HCl solution, a solution of NaHCO3and then a saturated solution of NaCl. The organic phase was dried over Na2SO4and the solvent evaporated under reduced pressure. The residue was purified by chromatography (eluent CH2Cl2: CH3OH = 97:3) to give intermediate product 101 (3.3 g) as an amorphous solid.

1H-NMR (200 MHz; CDCl3): (part./million): 0,82-0,97 (2t, 3H); 1,19-1,71 (m, 8H)2s, 1H); 7,52-the 7.65 (m, 3H).

MS: 583 [M+1].

Example 94

Getting dihydrochloride (R)-N-propyl-N-[6-[2-(2- oxo-3H-1,3-benzothiazol-6-yl)ethylamino] hexyl] -6-methoxy-7-nitro - 1,2,3,4-tetrahydro-2-naphtylamine (intermediate 102)

To a solution of intermediate 101 (3.2 g; 5.5 mmole), obtained according to example 93, in dioxane (40 ml) under stirring and at room temperature was added concentrated HCl (1 ml). After 4 hours, the solvents evaporated under reduced pressure and to the residue was added water and methylene chloride. The phases were separated and the organic phase is washed with a solution of NaHCO3, dried over Na2SO4and was evaporated to dryness under reduced pressure. The resulting residue was dissolved in THF (30 ml) under nitrogen atmosphere. To the solution was slowly added under stirring and at room temperature the complex of borane-dimethyl sulfide (2.6 g; a 33.2 mmole). Upon completion of addition the reaction mixture is boiled under reflux for 1.5 hours After cooling to 5oC solution was added concentrated HCl (1.4 ml) in methanol (14 ml). The reaction mixture is again boiled under reflux for 1 hour and then concentrated by distillation of the solvent at atmospheric pressure and dried persevering (duration), was added methanol (30 ml) and the solvent again evaporated to dryness. The residue was purified by chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 85:15:1) to give the product, which was dissolved in absolute ethanol (20 ml). Was added a solution of HCl in ethyl ether (15% wt./about.) to obtain markedly acidic pH and the solvent evaporated under reduced pressure, obtaining the intermediate product 102 (2.2 g) as an amorphous solid.

1H-NMR (200 MHz; D2O; 60oC): (part./million): to 1.21 (t, 3H); 1,49-2,61 (m, 12H); 2,91-3,62 (m, 14H); 3,84-4,08 (m, 1H); 4,10 (s, 3H); 7,21 (s, 1H); 7,30-of 7.60 (m, 3H); of 7.90 (s, 1H).

MS: 541 [M+1].

Example 95

Getting dihydrochloride (R)-N-propyl-N-[6-(2 - phenylethylamine)hexyl]-6-hydroxy-7-amino-1,2,3,4-tetrahydro-2 - naphtylamine (intermediate 103)

To a solution of intermediate 100 (1.8 g; 3.3 mmole), obtained according to example 92, in CHCl3(20 ml) was added under stirring and at -50oC 1 M solution BCl3in CH2Cl2with 16.5 ml of 16.5 mmole). Upon completion of addition the reaction mixture was allowed to warm to room temperature and then kept at 50oC for 5 hours. After additional aging at room temperature for 15 hours dobavlyali again evaporated under reduced pressure, was added ethanol (20 ml) and the resulting solution was first made in the apparatus Parra (3.4 ATM) for 1 hour in the presence of Pd on coal (50% in water) (0.7 g). After filtering off the catalyst and evaporating the solvent under reduced pressure was obtained intermediate product 103 (1.6 g) as an amorphous solid.

1H-NMR (200 MHz; CDCl3; free base): (part./million): of 0.85 (t, 3H); 1,16-2,00 (m, 13H); 2,38-2,99 (m, 15H); 3,40-to 3.73 (bs, 3H); 6.73 x (s, 1H); 6.42 per (s, 1H); 7,12-to 7.32 (m, 5H).

MS: 424 [M+1].

Similarly, the method described above was obtained the following compound.

The dihydrochloride of (R)-N-propyl-N-[6-[2-(2-oxo-3H-1,3-benzothiazol-6 - yl)ethylamino] hexyl] -6-hydroxy-7-amino-1,2,3,4-tetrahydro-2 - naphtylamine (intermediate 104) using as the starting material, intermediate product 102.

1H-NMR (200 MHz; D2O): (part./million): to 0.80 (t, 3H); 1.18 to 2,10 (m, 12H); 2.57 m-3,19 (m, 14H); 3,44-3,59 (m, 1H); 6,47 (s, 3H); 6,53 (s, 1H); 7,00-7,28 (m, 3H).

MS: 497 [M+1].

Example 96

Getting monohydrochloride of monotremata (R)-N-propyl-N-[6-(2 - phenylethylamine)hexyl] -6-hydroxy-7-formylamino-1,2,3,4-tetrahydro - 2-naphtylamine (compound 56)

A solution of intermediate 103 (0.9 g; 1.8 mmole), obtained according to example 95, and acetic acid is 30 minutes, and then kept at 50oC for 1 hour. After additional aging at room temperature for 15 hours was added acetic anhydride (0.07 g; 0.7 mmole) and the reaction mixture was again kept at 50oC for 4 hours. Was added ethyl ether (20 ml) and the solvents evaporated under reduced pressure. The resulting residue was purified using chromatography (eluent CH2Cl2:CH3OH:50% HCOOH = 85:15:1) to give compound 56 (0.4 g) as an amorphous solid.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.90 (t, 3H); 1,28 was 2.25 (m, 12H); 2,56-3,50 (m, 15H); is 6.61 (s, 1H); 7,19-7,37 (m, 5H); 7,83 (s, 1H); to 8.14 (s, 1H); by 8.22 (d, 1H); 9,51 (d, 1H).

MS: 452 [M+1].

Similarly, the method described above was obtained the following compound.

Deformat (R)-N-propyl-N-[6-[2-(2-oxo-3H-1,3-benzothiazol-6-yl) ethylamino] hexyl] -6-hydroxy-7-formylamino-1,2,3,4-tetrahydro-2-naphtylamine (compound 57), using as the starting material, intermediate product 104.

1H-NMR (200 MHz; DMSO-d6): (part./million): of 0.90 (t, 3H); 1,29-of 2.24 (m, 12H); 2,62-of 3.60 (m, 15H); 6,60 (s, 1H); 7,05 - 7,47 (m, 3H); 7,88 (s, 1H); to 8.14 (s, 2H); by 8.22 (d, 1H); 9,51 (d, 1H).

MS: 525 [M+1].

Example 97

Getting trihydrochloride (R)-N-propyl-N-[6-(2 - phenylethylamine) the ID (0.11 g; 1.5 mmole) was slowly added under stirring and at room temperature in a nitrogen atmosphere to a suspension of compound 56 (0.2 g; 0,38 mmole), obtained according to example 96, in THF (5 ml). Upon completion of addition the reaction mixture is boiled under reflux for 3.5 hours After cooling to 5oC solution was added concentrated HCl (60 μl) in methanol (0.6 ml). The reaction mixture is again boiled under reflux for 1.5 h, and then concentrated by distillation of the solvent at atmospheric pressure and dried to dryness under reduced pressure. The residue was dissolved in methanol (5 ml), the solvent is kept under reduced pressure, was added methanol (5 ml) and the solvent again evaporated to dryness. The residue was purified by chromatography (eluent CH2Cl2: CH3OH: 50% HCOOH = 85:15:1) to give the product, which was dissolved in absolute ethanol (5 ml). Was added a solution of HCl in ethyl ether (15% wt. /about. ) to obtain markedly acidic pH and the solvent evaporated under reduced pressure, obtaining the connection 58 (0,13 g) as amorphous solids.

1H-NMR (200 MHz; D2O): (part./million): 0,81 (t, 3H); 1,19-2,14 (m, 12H); of 2.86 (s, 3H); 2,70-3,19 (m, 14H); 3,43 at 3.69 (m, 1H); 6,70 (s, 1H); 7,02 (s, 1H); 7,12-7,30 (m, the RAM

Binding to the receptor

Allocated the brain in male rats Sprague-Dawley (weight 200-250 g) and membrane striped fabric prepared in accordance with the method described by Billard and others , in Life Sciences, 35, 1885, (1984). The tissue is homogenized in 50 mm Tris/HCl buffer with a pH of 7.4 (1:100 weight/volume). The homogenate was centrifuged and debris resuspendable, re-centrifuged and resuspendable again in 50 mm Tris/HCl buffer with a pH of 7.4, containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 1 mm MgCl2.

The affinity to the D1-receptor and D2the receptor was evaluated using as labeled ligands [3H]-SCH23390 [hydrochloride R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3 - benzazepin-7-ol] and [3H] domperidone (The Merck Index, ed. XI, N 3412, page 537), respectively.

As control compounds were applied dopamine, dopexamine dihydrochloride and (S)-N-propyl-N-[6-[2-(2- methoxyphenoxy)ethylamino]hexyl]-5,6-dihydroxy-1,2,3,4 - tetrahydro-2-naphtylamine (EUR. (A) described in example 6 of the international application WO 93/19036.

The standard conditions of incubation (volume 1000 ál) for the experiment, which used a [3H]-SCH23390, were as follows: 50 mm Tris/HCl-buffer (pH of 7.4), 0.2 nm [3H] -SCH23390, a preparation of membrane containing 130-140 µg proteaceae 20 minutes was filtered under vacuum through a filter type Whatman GF/C and then washed 4 times with 5 ml chilled on ice in 50 mm Tris/HCl-buffer (pH 7,4).

To study the affinity to the D2the receptor [3H]-domperidone (0.3 nm) were incubated in a volume of 1000 μl containing buffer and the preparation of the membrane, as described above. In addition, added bovine serum albumin (BSA) (0,01%).

For each concentration of the test compounds, the mixture is incubated at 37oC for 30 minutes.

The results, expressed as K1(nm), for compounds 1-10, 13, 15-16, 24-25 and 34, EUR. But, dopamine and dopexamine presented below in table 1.

Compounds that are the subject of the present invention exhibit high affinity for both receptor subtypes with significantly greater affinity towards both D1-, and D2-receptors than dopamine and dopexamine, and at least the same affinity that is comparable to that for EUR. A.

Example 99

Dopaminergic functional studies on selected tissues

Evaluation of D1-like activity in the experience of using the splenic artery of the rabbit (SAK)

Arterial rings were prepared in C9,11 dideoxy - 11,9-epoxytetradecane F2in a submaximal concentration of 0.1 um.

The compounds were administered in a cumulative way.

As a control substance used against. A.

Table 2 shows data on agonistic activity, which was evaluated by the maximum effect was expressed as the ratio of efficiencies (EC50EUR. A/EC50the compounds).

Evaluation of D2-like activity in the test using the ear artery of the rabbit (UAC)

Arterial rings were prepared in accordance with the method described in Steinsland and others, Science, 1978, 443, 199, modified as follows. Male new Zealand rabbits weighing 2.5 to 3 kg were killed by intravenous injection of excessive doses of pentobarbital sodium and was driven away. Cut off both ears and the Central ear artery was cut rings, length 3 mm, These samples were immersed in the bath for bodies with a volume of 25 ml containing Krebs solution (mm/l): NaCl 118, KCl 4.7 In, CaCl22,5, MgSO41,2, NaHCO325, KH2PO41,2, glucose of 11.1, balanced 95% O2/5% CO2, and kept at a temperature of 351oC. the Krebs Solution was saturated add (10 μm) to prevent oxidation of the catecholamine and desipramine (Paraty stimulated by an electric current (10 Hz, 1 MS, 40-80 mA, duration 500 MS) with 5-minute intervals.

The compounds were administered in a cumulative way.

As a control substance used against. A.

Table 2 shows data on agonistic activity, which was evaluated by the maximum effect was expressed as the ratio of efficiencies (EC50EUR. A/EC50the compounds).

These data indicate that the compounds of formula I, which is the subject of the present invention have a very high dopaminergic activity, which for some compounds exceeds that for EUR. And about 100 times.

Example 100

Hypertensive activity in vivo

Used male rats (Charles River) aged over 14 weeks with spontaneous hypertension. Catheters were implanted into the right carotid artery and left yugular vein under anesthesia with barbiturate. Animals were given an opportunity during the night to return to normal.

The compounds were injected into the left yugular vein by rapid intravenous injection of a large volume of the drug. Control animals were injected with the same amount of nosiree (ACS) was in the range of 190-200 mm RT.article.

Data on antihypertensive activity of the compounds 22, expressed in the form of lower ACS, compared with antihypertensive activity EUR. As shown in table 3.

Antihypertensive activity was evaluated after oral administration to rats with spontaneous hypertension.

Data on antihypertensive activity of the compounds 22, which is expressed in the form of lower ACS, compared with antihypertensive activity EUR. As shown in table 4.

For testing has been used pharmaceutical composition which is an aqueous solution of the test compound 22 containing 0.1 wt.% Na2S2O5as a developer.

1. Derivatives tetrahydronaphthalene General formula I

< / BR>
where m is an integer selected from 4, 5, 6, 7 and 8;

R, R' and R" represent hydrogen atoms or OH group, provided that at least one of the radicals R, R' and R" denotes a hydrogen atom, but all the radicals R, R' and R" are not simultaneously denote hydrogen atoms and R' and R" are both not simultaneously represent an OH group, or one of R' and R" denotes NHCHO, NHCH3and NHSO2CH3and the other denotes hydrogen;

R1and R2are the same is an integer, selected from 0, 1, 2, 3, and 4;

p is an integer selected from 0 and 1;

R3denotes a hydrogen atom;

Y represents S, O, N(R7)CO, CO(R7)N or N(R7);

X is N(R8), O, S, SO, SO2, CO or a simple bond;

R4, R5and R6have identical or different meanings and represent hydrogen, OH, halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NH2C1-C4-alkylsulfonyl, C1-C4-alkoxycarbonyl, NHCHO, C1-C4-alkylcarboxylic, NHCONH2C1-C4-alkylsulfonamides, SO2NH2, COOH,

SO3H, CONH2CH2OH or phenyl; or R5and R6in anthopology to one another together form a saturated chain of three or four groups selected from CR"'RIV, CO, S, O and NRVwhere R"' represents a hydrogen atom, RIVdenotes a hydrogen atom or amino group, and RVdenotes a hydrogen atom;

R7denotes a hydrogen atom or a C1-C4is an alkyl group;

R8denotes a hydrogen atom, or R7and R8together form-CH2- or chain-CH2-CH2-;

or when X is O, R4when it is immaturity carbon atom;

provided that when p = 1, X represents a group N(R8); and provided that when R and R' or R" represent an OH group, R1and R2denote hydrogen atoms and (a) when Y represents N(R7), R7denotes hydrogen or alkyl and R3denotes hydrogen, then at least one of R4, R5and R6does not denote hydrogen, halogen, C1-C4-alkyl and C1-C4-alkoxy; b) when Y represents N(R7), R7denotes hydrogen or alkyl, R3represents hydrogen and X represents a simple bond, at least one of R4, R5and R6does not denote hydrogen, halogen, NH2C1-C4-alkyl and C1-C4-alkoxy and nitro; Y represents N(R7), R7denotes hydrogen or alkyl, n = 1, R3represents hydrogen and X represents a simple bond, at least one of R4, R5and R6does not denote hydrogen and OH-group,

and its pharmaceutically acceptable salts and prodrugs.

2. Connection on p. 1, in which R' denotes a hydrogen atom, R and R" represent an OH group, and the carbon atom marked with * has the S-configuration.

3. Connection on p. 1, in which R', R1and R2denote the atoms of the ptx2">

4. Connection on p. 1, in which R4, R5and R6have identical or different meanings and represent hydrogen, OH, methoxy, methyl, nitro, chlorine, methylsulphonyl, NH2, SO2NH2methylsulfonylamino, NHCONH2methoxycarbonyl, acetylamino, CONH2CH2OH, SO3H or methylendioxy or R4and R5when they are in anthopology relative to each other, form a chain of formula-S-CO-NRIVwhere NRIVdenotes a hydrogen atom.

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

6. Pharmaceutical composition having dopaminergic and antihypertensive action, including an active component in a mixture with an acceptable carrier, wherein the active component it contains a compound of formula I under item 1 in a therapeutically effective amount.

 

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