RU2125983C1 - Ethanolamine derivatives, method of their synthesis, pharmaceutical composition, method of treatment - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention proposes derivatives of ethanolamine of the general formula (I)

where R₁ - phenyl, naphthyl, indalyl, pyridyl, benzofuranyl, benzodioxalyl; R₂ - halogen atom, nitro-group and others; R₃ - hydrogen atom, benzyl and others; n = 0-3. Method of synthesis of compounds of the formula (I) involves an interaction of compound of the formula (II):

with compound of the formula (III)

Description

 The present invention relates to new derivatives of ethanolamine and their pharmacologically acceptable salts, which can be used as drugs.

 Some ethanolamine derivatives are known that exhibit antispasmodic activity and have a relaxing effect when smooth muscle contraction is described, for example, as described in European patents 0211721, 0225415 and 0383686.

 The present invention relates to new derivatives of ethanolamine and their pharmacologically acceptable salts.

 More specifically, it relates to new derivatives of ethanolamine and their pharmacologically acceptable salts, which exhibit selective sympathomimetic and anti-urinary activity against the intestine, a method for their preparation, their pharmacological compositions and a method for their therapeutic use for the treatment and / or prevention of disorders gastrointestinal tract caused by contraction of the smooth muscles of humans or animals, and even more specifically, to a method of treatment and / or prevention spasm of increased peristalsis of the gastrointestinal tract in case of bowel irritation, gastritis, gastric ulcer, duodenal ulcer, inflammation of the small intestine, inflammation of the gallbladder, inflammation of the bile ducts, urolithiasis, etc. and a method for treating and / or preventing urinary disorders, such as rapid urination, urinary incontinence, and the like. in the case of increased nervous urination, neurogenic dysfunction of the bladder, nocturnal polyuria, unstable urination, spasm of the bladder, chronic cystitis, chronic prostatitis, etc. It is also expected that the claimed compounds can be used as therapeutic and / or prophylactic agents against obesity and glaucoma.

 A first object of the present invention is to propose new and useful ethanolamine derivatives and pharmacologically acceptable salts thereof which exhibit selective sympathomimetic and anti-urinary activity in relation to the intestine.

 Another objective of the present invention is to provide a pharmaceutical composition which comprises said ethanolamine derivatives and pharmacologically acceptable salts thereof as active ingredients.

 Finally, another objective of the present invention is to provide a therapeutic method for the treatment and / or prophylaxis of the aforementioned diseases of a human or animal, using said ethanolamine derivatives and pharmacologically acceptable salts thereof.

где R¹ - арильная или гетероциклическая группа, каждая из которых может содержать такие заместители, как галоген, оксигруппа, защищенная оксигруппа, арилоксигруппа, низшая алкоксигруппа, галоид (низшая) алкоксигруппа, нитрогруппа, цианогруппа, аминогруппа или ациламиногруппа;
R² - атом водорода, атом галогена, нитрогруппа, гидроксигруппа, низшая алкильная группа, дополнительно замещенная ацильной группой, низшая алкенильная группа, дополнительно замещенная ацильной группой, низшая алкоксигруппа, дополнительно замещенная ацильной группой, или аминогруппа, дополнительно замещенная ацил (низшей) алкильной группой;
R³ - атом водорода, N-защитная группа или низшая алкильная группа, дополнительно замещенная низшей алкилтио-группой;
n - целое число от 0 до 3;
жирная линия означает простую связь или двойную связь,
при этом, если n = 1, то 1) R¹ - конденсированная ароматическая углеводородная группа или гетероциклическая группа, каждая из которых может содержать такие заместители, как галоген, оксигруппа, защищенная оксигруппа, арилоксигруппа, низшая алкоксигруппа, галоид (низшая) алкоксигруппа, нитрогруппа, цианогруппа, аминогруппа или ациламиногруппа, 2) R² - атом галогена, нитрогруппа, низшая алкильная группа, дополнительно замещенная ацильной группой, низшая алкенильная группа, дополнительно замещенная ацильной группой, низшая алкоксигруппа, дополнительно замещенная ацильной группой, или аминогруппа, дополнительно замещенная ацил (низшей) алкильной группой; 3) R³ - N-защитная группа или низшая алкильная группа, дополнительно замещенная низшей алкилтиогруппой, 4) жирная линия означает двойную связь,
и их фармацевтически приемлемые соли.The inventive ethanolamine derivatives can be represented by the following general formula I

where R ¹ is an aryl or heterocyclic group, each of which may contain substituents such as halogen, oxy group, protected oxy group, aryloxy group, lower alkoxy group, halogen (lower) alkoxy group, nitro group, cyano group, amino group or acylamino group;
R ² is a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a lower alkyl group additionally substituted by an acyl group, a lower alkenyl group additionally substituted by an acyl group, a lower alkoxy group additionally substituted by an acyl group, or an amino group additionally substituted by an acyl (lower) alkyl group ;
R ³ is a hydrogen atom, an N-protecting group or a lower alkyl group additionally substituted with a lower alkylthio group;
n is an integer from 0 to 3;
bold line means a single bond or double bond,
in addition, if n = 1, then 1) R ¹ is a condensed aromatic hydrocarbon group or heterocyclic group, each of which may contain substituents such as halogen, oxy group, protected oxy group, aryloxy group, lower alkoxy group, halogen (lower) alkoxy group, nitro group , cyano, amino or acylamino, 2) R ² - a halogen atom, a nitro group, a lower alkyl group, further substituted by an acyl group, a lower alkenyl group, further substituted by an acyl group, a lower alkoxy group, complementary Tel'nykh substituted acyl group or an amino group, further substituted with acyl (lower) alkyl; 3) R ³ is an N-protecting group or a lower alkyl group additionally substituted with a lower alkylthio group; 4) a bold line means a double bond,
and their pharmaceutically acceptable salts.

Стадия 2

Стадия 3

Стадия 4

Стадия 5

Стадия 6

Стадия 7

Стадия 8

где R¹, R² и R³ и жирная линия имеют указанные значения;
R² _a - низшая алкильная группа, замещенная этерифицированной карбоксигруппой, низшая алкенильная группа, замещенная этерифицированной карбоксигруппой, низшая алкоксигруппа, замещенная этерифицированной карбоксигруппой, или аминогруппа, замещенная этерифицированной карбокси (низшей) алкильной группой;
R² _b - низшая алкильная группа, замещенная карбоксигруппой, низшая алкенильная группа, замещенная карбоксигруппой, низшая алкоксигруппа,замещенная карбоксигруппой, или аминогруппа, замещенная карбокси(низшей)алкильной группой;
R² _a - защитная группа или низшая алкильная группа, дополнительно замещенная низшей акилтиогруппой;
R² _c - низшая алкоксигруппа, дополнительно замещенная ацильной группой;
R⁴ - низшая алкильная группа, дополнительно замещенная ацильной группой;
X - кислотный остаток;
R² _d - низшая алкильная группа, низшая алкенильная группа, низшая алкоксигруппа, каждая из которых включает карбамоильную группу, дополнительно замещенную низшей алкильной группой, низшей алкокси(низшей)алкильной группой, арилсульфонильной группой, низшей алкилсульфонильной группой или гетероциклической группой, или аминогруппа, замещенная карбамоил(низшей)алкильной группой, в которой карбамоил может быть замещен низшей алкильной группой, низшей алкокси(низшей)алкильной группой, арилсульфонильной группой, низшей алкилсульфонильной группой или гетероциклической группой;
R³ _b - N-защитная группа.The inventive compound I or its salts can be obtained by the following processes:
Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Stage 6

Stage 7

Stage 8

where R ¹ , R ² and R ³ and the bold line have the indicated meanings;
R ² _a is a lower alkyl group substituted by an esterified carboxy group, a lower alkenyl group substituted by an esterified carboxy group, a lower alkoxy group substituted by an esterified carboxy group, or an amino group substituted by an esterified carboxy (lower) alkyl group;
R ² _b is a lower alkyl group substituted by a carboxy group, a lower alkenyl group substituted by a carboxy group, a lower alkoxy group substituted by a carboxy group, or an amino group substituted by a carboxy (lower) alkyl group;
R ² _a is a protecting group or a lower alkyl group additionally substituted with a lower acylthio group;
R ² _c is a lower alkoxy group additionally substituted with an acyl group;
R ⁴ is a lower alkyl group further substituted with an acyl group;
X is the acid residue;
R ² _d is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, each of which includes a carbamoyl group optionally substituted with a lower alkyl group, a lower alkoxy (lower) alkyl group, an arylsulfonyl group, a lower alkylsulfonyl group or a heterocyclic group, or an amino group substituted a carbamoyl (lower) alkyl group in which the carbamoyl may be substituted with a lower alkyl group, a lower alkoxy (lower) alkyl group, an arylsulfonyl group, a lower alkylsulfonyl group a group or a heterocyclic group;
R ³ _b is an N-protecting group.

 The above and further description of the present invention, the relevant examples of various definitions that should be included in the scope of the claims of the present invention are explained in detail below.

 The term "lower" is used, unless additional reservations are made, to designate a group containing from 1 to 6 carbon atoms.

 Suitable “halogen” and halogen in the term “halogen (lower) alkoxy group may be fluoro, chloro, bromo or iodo, of which chloro or bromo are preferred.

 A suitable “lower alkyl group” and lower alkyl moiety in the terms “acyl (lower) alkyl group” and “lower alkylthio group” may be a straight or branched chain alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group , butyl group, iso-butyl group, pentyl group, iso-pentyl group, hexyl group, etc., of which methyl group or ethyl group are preferred.

 A suitable "lower alkenyl group" may be a straight or branched chain alkenyl group, for example, an ethenyl group, a propenyl group, a pentinyl group, an isopropenyl group, a butenyl group, a hexenyl group, etc., of which an ethenyl group is preferred.

 A suitable "lower alkoxy group" and lower alkoxy moiety in the term "halogen (lower) alkoxy group" may be a straight or branched chain alkoxy group, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, butoxy group, pentyloxy, etc., pentyloxy, etc. methoxy, ethoxy, propoxy or pentyloxy are preferred.

 A suitable “protected hydroxy group” may be a substituted lower alkoxy group such as a lower alkoxy (lower) alkoxy group (eg, methoxymethoxy group and the like), lower alkoxy (lower) alkoxy (lower) alkoxy group, for example, a methoxyethoxymethoxy group and etc.) a substituted or unsubstituted aryl (lower) alkoxy group (e.g., benzyloxy group, nitrobenzyloxy group, etc.), etc., an acyloxy group such as lower alkanoyloxy group (e.g., acetoxy group, propionyloxy group, pivaloyloxy group, etc. ), aroyloxy group (e.g. zyloxy group, fluorenecarbonyloxy group, etc.), lower alkoxycarboxy group (e.g., methoxycarboxy group, ethoxycarboxy group, propoxycarboxy group, isopropoxycarboxy group, butoxycarboxy group, isobutoxycarboxylic acid group, tert-butoxycarboxyloxy group, penta, t-butoxycarboxyloxy group, penta alkoxycarboxy group (e.g. benzyloxycarboxy group, bromobenzyloxycarboxy group, etc.), etc., three (lower) alkylsilyloxy group (e.g. trimethylsilyloxy group na and the like) and the like.

 A suitable “aryl group” and an aryl moiety in terms of “aryloxy group” and “arylsulfonyl group” may be a non-condensed or fused aromatic hydrocarbon group such as a phenyl group, a naphthyl group, a phenyl group substituted with a lower alkyl group (for example, a tolyl group, a xylyl group , mesityl group, cumenyl group, di (tert-butyl) phenyl group and the like), indenyl group, indanyl group and similar groups, of which phenyl groups are preferred a, a naphthyl group or an indanyl group.

A suitable “heterocyclic group” may be such a heterocyclic group that contains at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen atoms, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic groups, with preferably the heterocyclic group being An N-containing heterocyclic group, such as an unsaturated 3-6 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms, for example, a pyrrolyl group, pyrroline a ln group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a triazolyl group, for example a 4H-1,2,4-triazolyl group, 1H-1,2,3-triazolyl group, 2H-1 , 2,3-triazolyl group, etc.), tetrazolyl group (for example, 1H-tetrazolyl group, 2H-tetrazolyl group, etc.);
saturated 3-6 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms (for example, pyrrolidinyl group, imidazolidinyl group, piperidino group, piperazinyl group, etc.);
unsaturated condensed heterocyclic group containing from 1 to 5 nitrogen atoms, for example, an indolyl group, an isoindolyl group, an indolisinyl group, a benzimidazolyl group, a quinolyl group, an isoquinolyl group, an indazolyl group, a benzotriazolyl group, a tetrazolopyridazinyl group (for example, terazolo [1,5- b] a pyridazinyl group, etc.), etc .;
unsaturated 3-6 membered heteromonocyclic group containing an oxygen atom, for example, a pyranyl group, a furyl group, etc .;
unsaturated 3-6 membered heteromonocyclic group containing from 1 to 2 sulfur atoms, for example, a thienyl group, etc .;
unsaturated 3-6 membered heteromonocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms, for example, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group (for example, a 1,2,4-oxadiazolyl group, 1,3, 4-oxadiazolyl group, 1,2,5-oxadiazolyl group, etc.), etc .;
unsaturated 3-6 membered heteromonocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms (for example, morpholinyl group, etc.);
unsaturated condensed heterocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms (for example, benzofurazanyl group, benzoxazolyl group, benzoxadiazolyl group, etc.);
unsaturated 3-6 membered heteromonocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms, for example, a thiazolyl group, a thiadiazolyl group (for example, a 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, etc.), etc .;
saturated 3-6 membered heteromonocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms (for example, a thiazolidinyl group, etc.);
unsaturated condensed heterocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms (for example, benzothiazolyl group, benzothiadiazolyl group, etc.);
unsaturated condensed heterocyclic group containing from 1 to 2 oxygen atoms (for example, benzofuranyl group, benzodioxolyl group, etc.) and similar groups.

 Preferred of these heterocyclic groups are a pyridyl group, a benzofurazalyl group or a benzodioxolyl group.

 A suitable “acyl group” and an acyl moiety in terms of “acylamino group” and “acyl (lower) alkyl group” may be a carboxyl group, an esterified carboxyl group, a carbamoyl group further substituted with a lower alkyl group, a lower alkoxy (lower) alkyl group, an arylsulfonyl group, a lower alkylsulfonyl group or a heterocyclic group; lower alkanoyl group, aroyl group, heterocyclo-carbonyl group and similar groups.

 The esterified carboxyl group may be unsubstituted or have a lower alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, hexyloxycarbonyl group, 2-iodoethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl as a substituent). ), a substituted or unsubstituted aryloxycarbonyl group (e.g., a phenoxycarbonyl group, a 4-nitrophenoxycarbonyl group, a 2-naphthylphenoxycarbonyl group, etc. .), A substituted or unsubstituted aryl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl group, fenetiloksikarbonilnuyu group, a benzhydryloxycarbonyl group, a 4-nitrobenzyloxycarbonyl group and the like) and the like, of which preferred is a lower alkoxycarbonyl group.

 A carbamoyl group substituted with a lower alkyl group may be a methyl carbamoyl group, an ethyl carbamoyl group, a propyl carbamoyl group, a dimethyl carbamoyl group, a diethyl carbamoyl group, an N-methyl-N-ethyl carbamoyl group, and the like.

 A carbamoyl group substituted with a lower alkoxy (lower) alkyl group may be a methoxymethylcarbamoyl group, a methoxyethylcarbamoyl group, an ethoxymethylcarbamoyl group, an ethoxyethylcarbamoyl group and the like, with a methoxyethylcarbamoyl group being preferred.

 A carbamoyl group substituted with an arylsulfonyl group may be a phenylsulfonylcarbamoyl group, a tolylsulfonylcarbamoyl group, and the like.

 A carbamoyl group substituted with a lower alkylsulfonyl group may be a methylsulfonylcarbamoyl group, an ethylsulfonylcarbamoyl group and the like.

 A carbamoyl group substituted with a heterocyclic group may be a carbamoyl group substituted with one of the heterocyclic groups that are already discussed above.

 The lower alkanoyl group may be unsubstituted or substituted, such as, for example, formyl group, acetyl group, propionyl group, butyryl group, iso-butyryl group, valeryl group, iso-valeryl group, pivaloyl group, hexanoyl group, trifluoroacetyl group or similar groups, preferred are acetyl group, propionyl group, butyryl group and pivaloyl group.

 The aroyl group may be a benzoyl group, a naphthoyl group, a toluene group, a di (tert-butyl) benzoyl group and a similar group.

 The heterocyclic moiety in the term “heterocyclo-carbamoyl group” may be one of the above heterocyclic groups.

 A suitable “N-protecting group” may be a substituted or unsubstituted alkanoyl group (eg, formyl group, acetyl group, propionyl group, trifluoroacetyl group and the like), phthaloyl group, lower alkoxycarbonyl group (eg, tert-butoxycarbonyl group, tert an amyloxycarbonyl group and the like), a substituted or unsubstituted arylalkyloxycarbonyl group (e.g., a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group and the like), a substituted or unsubstituted arenesulfonyl group (on for example, a benzenesulfonyl group, a tosyl group and the like), a nitrophenylsulphenyl group, an arylalkyl group (for example, a trityl group, a benzyl group and the like) or similar groups, of which a benzyl group is preferred.

 A suitable “acid residue” may be a halogen group (eg, fluorine, chlorine, bromine, iodine), and a rensulfonyloxy group (eg, benzenesulfonyloxy group, tosyloxy group and the like), an alkanesulfonyloxy group, for example, a mesyloxy group, ethanesulfonyloxy group and the like. and similar groups, of which one of the halo groups is preferred.

A preferred compound I is one which, as R ¹ contains a phenyl group optionally substituted with halogen, as R ² a lower alkoxy group substituted by a carboxy group or an esterified carboxyl group, as R ³ is hydrogen, n has a value of 0, 2 or 3 , and the thick line means a simple connection.

More preferably, compound I is one which, as R ^1, contains a phenyl group substituted with halogen, as R ² is a methoxy group substituted by an esterified carboxy group (more preferably a lower alkoxycarbonyl group, as R ³ is hydrogen, n is 0, 2 or 3, and the bold line means a simple connection.

Most preferably, compound I is one which, as R ^1, contains a phenyl group substituted with halogen, as R ² is a methoxy group substituted by a lower alkoxycarbonyl group, as R ³ is hydrogen, n is 2, and the bold line means a single bond.

 Suitable pharmacologically acceptable salts of the claimed compound I are conventional non-toxic salts, such as inorganic acid addition salts (e.g. hydrochlorides, hydrobromides, sulfates, phosphates, etc.), organic acid salts (e.g., formates, acetates, trifluoroacetates, oxalates, maleates , fumarates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates and the like), alkali metal salts (e.g. sodium salt, potassium salt, etc.) or similar salts.

 The steps for preparing the claimed compound I are explained in detail below.

 Stage 1

 The target compound I or its salt can be obtained by reacting compound II with compound III or its salt.

 Suitable salts of compound III may be the same salts as those discussed above for compound I.

 The reaction is preferably carried out in the presence of a base, such as an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate and the like), tri (lower) alkylamine (e.g. trimethylamine, triethylamine, etc.), picoline or the like.

 The reaction is usually carried out in a standard solvent such as alcohol (e.g. methanol, ethanol, propanol, iso-propanol, etc.), diethyl ether, tetrahydrofuran, dioxane, or in any other organic solvent that does not adversely affect the course reactions.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 Stage 2

 The target compound Ib or its salt can be obtained by subjecting the compound Ia or its salt to a deesterification reaction.

 Suitable salts of compound Ia may be the same inorganic or organic addition salts as those discussed above for compound I.

 Suitable salts of compound Ib may be the same salts as those discussed above for compound I.

 The reaction is carried out in accordance with standard methods, such as hydrolysis, reduction, and the like.

 The hydrolysis is preferably carried out in the presence of a base or acid, including Lewis acid.

 Suitable bases may include inorganic bases and organic bases such as an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium, etc.), a hydroxide or carbonate or bicarbonate of these metals, trialkylamine (eg, trimethylamine, triethylamine, etc.), picolin, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8- diazabicyclo [5.4.0] undec-7-ene or similar bases.

 Acceptable acids may be organic acid (formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), inorganic acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.) and Lewis acid (for example, boron tribromide, etc.).

 The reaction is usually carried out in solvents such as water, alcohol (e.g. methanol, ethanol, etc.), xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture of these solvents or any other solvent that does not adversely affect the stroke reactions. As the solvent, a liquid base or liquid acid may also be used.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 The reduction is carried out mainly to remove an ether fragment, such as a 4-nitrobenzyl group, a 2-iodoethyl group, a 2,2,2-trichloroethyl group or a similar group. A reduction method suitable for carrying out the elimination reaction may include chemical reduction or catalytic reduction.

 Suitable reducing agents suitable for use in chemical reduction are combinations of a metal (e.g., tin, zinc, iron, etc.) or a metal compound (e.g., chromium chloride, chromium acetate, etc.) with an organic or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

 Suitable catalysts suitable for use in catalytic reduction are standard catalysts such as platinum catalysts (e.g., platinum foil, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. sponge palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g. , reduced copper, Raney copper, Ullmann copper, etc.) or similar catalysts.

 The reaction is usually carried out in a standard solvent which does not adversely affect the course of the reaction, such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), N, N-dimethylformamide or a mixture of these solvents. If the above acids used in chemical reduction are liquids, you can also use them as a solvent. Further, a suitable solvent used in catalytic reduction may be the above-mentioned solvents and other standard solvents such as diethyl ether, dioxane, tetrahydrofuran and the like. or a mixture thereof.

 The temperature of this reaction is not significant; the reaction can be carried out both upon cooling and upon heating.

Under the conditions of this reaction, if compound Ia is used as the starting compound in which the R ³ N-protecting group and / or the bold line is a double bond, it is possible to obtain compound Ib in which R ³ is hydrogen and the bold line is a single bond . This case is included in the scope of the claims of the present invention.

 Stage 3.

 The target compound Id or its salt can be obtained by reacting compound Ic or its salt with compound IV.

 Suitable salts of compounds Ic and Id may be the same salts as those discussed above for compound I.

 When a compound IV containing halogen as a substituent X is used in carrying out this reaction, the reaction is preferably carried out in the presence of a base such as an alkali metal (e.g. lithium, sodium, potassium, etc.), an alkali hydroxide or carbonate or bicarbonate metal (e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.), alkaline earth metal (e.g., calcium, magnesium, etc.), alkali metal hydride (e.g., sodium hydride, etc.), hydride alkaline earth metal (e.g. calcium hydride, alkaline alkoxide metal (e.g., sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), alkaline earth metal alkoxide (e.g., magnesium methoxide, magnesium ethoxide, etc.) and a similar base, or in the presence of alkali metal iodide ( for example, sodium iodide, potassium iodide, etc.) and the specified base.

 This reaction is usually carried out in standard solvents such as tetrahydrofuran, N, N-dimethylformamide, acetone, a mixture of these solvents or any other solvent that does not adversely affect the course of the reaction. If compound IV is a liquid, it can also be used as a solvent.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 Stage 4.

 The target compound Ie or a salt thereof can be obtained by reacting a compound Ib or a reactive derivative thereof at a carboxyl group or a salt of a compound Ib with an amine.

 Suitable salts of compounds Ie and Ib and its reactive derivative at the carboxyl group may be the same as those exemplified for compound I.

 A suitable amine may be ammonia, arenesulfonamide, an amine substituted with a heterocyclic group.

 Arensulfonamide may be benzene sulfonamide, methylbenzenesulfonamide, ethylbenzenesulfonamide, etc., of which methylbenzenesulfonamide is preferred.

 An amine substituted with a heterocyclic group may be an amine substituted with one of the heterocyclic groups that are already described above, such as aminotriazole, aminothiadiazole, aminotriazole, aminotetrazole and similar amines, of which aminotetrazole is preferred.

 Suitable reactive derivatives at the carboxy group of compound Ib may include ester, acid halide, acid anhydride and the like. Suitable examples of reactive derivatives are acid halides (for example, acid chlorides, bromo anhydrides and the like); symmetric acid anhydrides; mixed acid anhydrides with 1,1'-carbonyldiimidazole or an acid such as an aliphatic carboxylic acid, for example acetic acid, pivalic acid and the like, substituted phosphoric acid (for example dialkylphosphoric acid, diphenylphosphoric acid and the like); an ester such as lower alkyl ether (e.g. methyl ether, ethyl ether, propyl ether, hexyl ether, etc.), substituted or unsubstituted aryl (lower) alkyl ether (e.g. benzyl ether, benzhydryl ether, p-chlorobenzyl ether ether, etc.), substituted or unsubstituted aryl ether (e.g., phenyl ether, tolyl ether, 4-nitrophenyl ether, 2,4-dinitrophenyl ether, pentachlorophenyl ether, naphthyl ether, etc.) or ether with N, N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimine or 1-hydroxy-6-chloro-1H-b nzotriazolom etc.

 The reaction is usually carried out in standard solvents such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other solvent that does not have a solid effect on the reaction. The hydrophilic solvents indicated among others can be used in a mixture with water.

 When compound Ib is used as the free acid, the reaction is carried out in the presence of a standard condensing agent such as N, N-dichlorohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide (e.g. chloroformate, isobutylchloroformate, etc.), 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, etc. The reaction is also carried out in the presence of a standard base such as triethylamine, pyridine, edc th soda, etc.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 Stage 5.

 The target compound If or its salt can be obtained by reacting compound V or its salt with compound VI or its salt in the presence of a reducing agent.

 Suitable salts of compound V may be the same inorganic or organic addition salts as those discussed above for compound I.

 Suitable salts of compound VI may be the same as those exemplified for compound I.

 Suitable reducing agents may be diborane, a borane-organic amine complex, for example, a borane-pyridine complex, and the like, an alkali metal cyanoborohydride, for example, sodium cyanoborohydride, lithium cyanoborohydride, and the like. etc.

 The reaction can also be carried out in an acidic environment (for example, in the presence of acetic acid, etc.), and the reaction temperature is not very important, the reaction can be carried out both with cooling and with heating.

 Stage 6.

 The target compound Ih or its salt can be obtained by subjecting the compound Ig or its salt to a reduction reaction.

 Suitable salts of compound Ig may be the same as those described above for compound I.

 The reduction step can be carried out by chemical reduction, catalytic reduction, etc.

 Suitable reducing agents suitable for use in chemical reduction are combinations of a metal (e.g., tin, zinc, iron, etc.) or a metal compound (e.g., chromium chloride, chromium acetate, etc.) with an organic or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

 Suitable catalysts suitable for use in catalytic reduction are standard catalysts such as platinum catalysts (e.g., platinum foil, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. sponge palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g. , reduced copper, Raney copper, Ullmann copper, etc.) or similar catalysts.

 The reduction is usually carried out in a standard solvent which does not adversely affect the course of the reaction, such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), N, N-dimethylformamide or a mixture of these solvents. If the above acids used in chemical reduction are liquids, you can also use them as a solvent. Further, suitable solvents used in the catalytic reduction may be the solvents mentioned above and other standard solvents such as diethyl ether, methylene chloride, dioxane, ethyl acetate, tetrahydrofuran and the like. or a mixture thereof.

 The temperature of this reaction is not significant, the reaction can be carried out both upon cooling and upon heating.

Under the conditions of this reaction, if an Ig compound in which the R ³ is an N-protecting group and / or a bold line is a double bond is used, the compound Ih in which R ² is hydrogen and the bold line is a simple communication. This case is included in the scope of the claims of the present invention.

 Stage 7.

 The target compound I or its salt can be obtained by reacting compound VII or its salt with compound III or its salt in the presence of a reducing agent.

 Suitable salts of compound I and compound III may be the same salts as those discussed above for compound I.

 Suitable reducing agents may be a borohydride compound such as an alkali metal borohydride (e.g., sodium borohydride, sodium cyanoborohydride, lithium cyanoborohydride, lithium triethyl borohydride and the like), tetrabutylammonium cyanoborohydrite, etc., of which alkali metal borohydride is preferred.

 The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate and etc.), tri (lower) alkylamine (e.g. trimethylamine, triethylamine, etc.), picoline or the like.

 The reaction is usually carried out in a standard solvent, such as water, alcohol (for example, methanol, ethanol, propanol, iso-propanol, etc.), dioxane, or in any other organic solvent that does not have a solid effect on the course of the reaction.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 Stage 8.

 The target compound Ij or its salt can be obtained by subjecting the compound Ii or its salt to the elimination reaction of an N-protecting group.

 Suitable salts of compounds Ii and Ij may be the same salts as those discussed above for compound I.

 The reaction is carried out in accordance with standard methods, such as hydrolysis, reduction, and the like.

 The hydrolysis is preferably carried out in the presence of a base or acid, including Lewis acid.

 Suitable bases may include inorganic bases and organic bases such as an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium, etc.), a hydroxide or carbonate or bicarbonate of these metals, trialkylamine (for example, trimethylamine, triethylamine, etc.), picolin, 1,5 - diazabicyclo [4.3.0] non-5-ene, 1,4 - diazabicyclo [2,2,2] octane, 1, 8 - diazabicyclo [5.4.0] unden-7-ene or similar bases.

 Acceptable acids may be organic acid (formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride and the like) and acid addition salts (e.g., pyridine hydrochloride, etc.).

 The elimination reaction using trihaloacetic acid (for example, trichloroacetic acid, trifluoroacetic acid and the like) or a similar acid is preferably carried out in the presence of nucleophilic agents (for example, anisole, phenol and the like).

 The reaction is usually carried out in standard solvents such as water, alcohol (e.g. methanol, ethanol, etc.), methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, a mixture of these solvents or any other solvent which does not adversely affect the reaction . As the solvent, a liquid base or liquid acid may also be used.

 A reduction method suitable for carrying out the elimination reaction may include chemical reduction, catalytic reduction, etc.

 Suitable reducing agents suitable for use in chemical reduction are combinations of a metal (e.g., tin, zinc, iron, etc.) or a metal compound (e.g., chromium chloride, chromium acetate, etc.), with an organic or inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

 Suitable catalysts suitable for use in catalytic reduction are standard catalysts such as platinum catalysts (e.g., platinum foil, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. sponge palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g. , reduced copper, Raney copper, Ullmann copper, etc.) or similar catalysts.

 In the case where the N-protecting group is a benzyl group, the reduction is preferably carried out in the presence of a combination of a palladium catalyst (e.g. palladium black, palladium on carbon, etc.) and formic acid or a salt thereof (e.g. ammonium formate, etc.). P.).

 Recovery is usually carried out in a standard solvent that does not adversely affect the course of the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformide or a mixture of these solvents.

 If the above acids used in chemical reduction are liquids, you can also use them as a solvent. Further, suitable solvents used in the catalytic reduction may be the solvents mentioned above and other standard solvents such as diethyl ether, dioxane, tetrahydrofuran and the like. or a mixture thereof.

 The reaction temperature is not significant; the reaction can be carried out both upon cooling and upon boiling.

 Under the conditions of this reaction, if compound Ii is used as the starting compound, in which R is a lower alkyl group, a lower alkenyl group or a lower alkoxy group, each of which is substituted by an esterified carboxy group, an amino group substituted by an esterified carboxy (lower) alkyl group, or the nitro group and / or the bold line denotes a double bond, it is possible to obtain compound Ij in which R is a lower alkyl group, a lower alkenyl group or a lower alkoxy group, each of which is substituted A carboxyl group, an amino group substituted with a carboxy (lower) alkyl group, or an amino group, and the bold line indicates a single bond. This case is included in the scope of the claims of the present invention.

Стадия B

Стадия C

Стадия D

Стадия E

Стадия F

Стадия G

стадия H

Стадия I

Стадия J

где R², R², R³, R³, R⁴, X и жирная линия имеют каждая то же значение, что и ранее;
R⁵ - низшая алкильная группа;
R³ _c - атом водорода или низшая алкильная группа, дополнительно замещенная низшей алкилтиогруппой;
Y¹ - кислотный остаток;
Y² - низшая алкилсульфонилоксигруппа или арилсульфонилоксигруппа;
R³ _d - N-защитная группа или низшая алкильная группа, дополнительно замещенная низшей алкилтиогруппой.The starting compounds II, IIIa, IIIb, IIIc, IIId and VII or their salts can be obtained in the following stages:
Stage A

Stage B

Stage C

Stage D

Stage E

Stage F

Stage G

stage H

Stage I

Stage J

where R ² , R ² , R ³ , R ³ , R ⁴ , X and the bold line each have the same meaning as before;
R ⁵ is a lower alkyl group;
R ³ _c is a hydrogen atom or a lower alkyl group additionally substituted with a lower alkylthio group;
Y ¹ is an acid residue;
Y ² is a lower alkylsulfonyloxy group or an arylsulfonyloxy group;
R ³ _d is an N-protecting group or a lower alkyl group optionally substituted with a lower alkylthio group.

 The above steps for the preparation of the starting compounds are explained in detail below.

 Stage A.

 Compound IX or a salt thereof can be prepared by subjecting a compound VIII or a salt thereof to a dealkylation reaction.

 Suitable salts of compound VIII may include the inorganic and organic acid addition salts already exemplified above for compound I.

 Suitable salts of compound IX may be the same salts as those discussed above for compound I.

 The reaction is carried out in the presence of an acid, including Lewis acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, etc.) or three (lower alkyl) silyl iodide (e.g. trimethylsilyl iodide and the like). )

 The reaction is usually carried out in solvents such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture of these solvents, or in any other solvent that does not adversely affect the course of the reaction.

 Further, if the above acids are liquids, they can be used as a solvent.

 The reaction temperature is not significant; the reaction can be carried out both upon cooling and upon boiling.

 Stage B.

 Compound IIIa or a salt thereof can be prepared by reacting a compound IX or a salt thereof with a compound IV.

 Suitable salts of compound IIIa may be the same salts as those discussed above for compound I.

 When a compound IV containing halogen as a substituent X is used in carrying out this reaction, the reaction is preferably carried out in the presence of a base such as an alkali metal (e.g. lithium, sodium, potassium, etc., an alkali metal hydroxide or carbonate or bicarbonate ( e.g. caustic soda, potassium carbonate, potassium bicarbonate, etc.), alkaline earth metal (e.g. calcium, magnesium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, alkali alkoxide metal, e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), alkaline earth metal alkoxide (e.g. magnesium methoxide, magnesium ethoxide, etc.) or a similar base, or in the presence of an alkali metal iodide (e.g. , sodium iodide, potassium iodide, etc.) and the specified base.

 Further, the reaction is preferably carried out under phase transfer catalysis (for example in the presence of tetra-n-butylammonium bromide and the like).

 The reaction is usually carried out in standard solvents such as tetrahydrofuran, dioxane, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), N, N-dimethylfomamide, acetone, a mixture of these solvents or any other solvent which does not cause harmful impact on the course of the reaction. If compound VI is a liquid, it can be used as a solvent.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 Stage C.

 Compound IIIc or a salt thereof can be prepared by subjecting a compound IIIb or a salt thereof to the elimination reaction of an N-protecting group.

 Suitable salts of compound [IIIb] and [IIIc] may be the same salts as those discussed above for compound [I].

 This reaction can be carried out in the same way as stage 8, therefore, information on the conditions of its carrying out (for example, the solvent used, process temperature, etc.) can be taken from the description of stage 8.

 Stage D.

 Compound VII can be prepared by subjecting compound X to an oxidation reaction.

 A suitable oxidizing agent used in this reaction may be selenium dioxide and the like.

 The reaction is usually carried out in standard solvents such as water, dioxane, acetic anhydride or any other solvent that does not adversely affect the course of the reaction, or a mixture of these solvents.

 The reaction temperature is not significant, the reaction is usually carried out by boiling.

 Stage E.

 Compound II can be prepared by subjecting compound XI to a base.

 A suitable base may be an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkali metal hydroxide or carbonate or bicarbonate (e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.), an alkaline earth metal (e.g. , calcium, magnesium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, tert- potassium butoxide, etc.), alkaline earth metal alkoxide (e.g. magnesium methoxide, e magnesium oxide, etc.) or a similar base.

 The reaction is usually carried out in a standard solvent, such as water, alcohol (e.g. methanol, ethanol, etc.), diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or in any other organic solvent that does not adversely affect the course of the reaction, or mixtures of these solvents.

 The reaction temperature is not significant; the reaction can be carried out both upon cooling and upon boiling.

 Stage F.

 Compound XIII or a salt thereof can be prepared by reacting a compound XII or a salt thereof with a lower alkanesulfonyl halide or arenesulfonyl halide.

 Suitable salts of compounds XII and XIII may be the addition salts of inorganic and organic acids already exemplified above for compound I.

 Suitable lower alkanesulfonyl halides may be mesityl chloride, ethanesulfonyl bromide and the like.

 Suitable arenesulfonyl halides may be benzenesulfonyl chloride, tosyl chloride and the like.

 The reaction is preferably carried out in the presence of a base, as explained in the description of stage I.

 The reaction is usually carried out in a standard solvent, such as water, alcohol (e.g. methanol, ethanol, etc.), diethyl ether, tetrahydrofuran, dioxane, pyridine, or in any other organic solvent that does not adversely affect the course of the reaction, or mixtures of these solvents.

 The reaction temperature is not significant, the reaction can be carried out both upon cooling and upon heating.

 Stage G.

 Compound IIIc or its salt can be prepared by the following method, namely: 1) the compound XIII or its salt is first acted upon by the azide compound, and then 2) the resulting product is subjected to catalytic reduction.

 Suitable salts of compounds IIIc and XIII may be the same salts as those discussed above for compound I.

 The azide compound used in the first step may be an alkali metal azide (e.g., sodium azide, potassium azide, etc.), an alkaline earth metal azide (e.g., calcium azide, etc.), hydrogen azide, etc. The reaction is usually carried out in a standard solvent, such as tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N-dimethylformamide, or in any other organic solvent that does not adversely affect the course of the reaction. The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

 The second stage of this reaction can be carried out in the same way as the catalytic reduction described in stage 8, therefore, information about the catalyst, the type of reaction and the conditions of its conduct (for example, the solvent used, process temperature, etc.) can be taken from the description the catalytic reduction process described for step 8. Reduction can also be carried out in the presence of a combination of a palladium catalyst (for example, palladium black, palladium on carbon, etc.) and formic acid or its salt (for example, formate mmoniya etc.).

 Stage F.

 Compound IIId or a salt thereof can be prepared by reacting compound IIIc or a salt thereof with an N-protecting agent or lower alkylthio (lower) alkyl halide.

 Suitable salts of compounds IIIc and IIId may be the same salts as those discussed above for compound I.

 A suitable N-protecting agent may be a halogen derivative of the already mentioned N-protecting groups, such as acetyl chloride, tert-butoxycarbonyl chloride, benzyl chloride, benzyl bromide and the like.

 Suitable lower alkylthio (lower) alkyl halide may be methylthiomethyl chloride, methylthioethyl chloride and the like.

 The reaction is usually carried out in the presence of a base, as described for stage I.

 The reaction is usually carried out in standard solvents such as water, alcohol (e.g. methanol, ethanol, etc.), dioxane, tetrahydrofuran, pyridine or any other solvent that does not adversely affect the course of the reaction, or mixtures of these solvents.

 The reaction temperature is not very important, the reaction can be carried out both upon cooling and upon boiling.

Stage I
Compound XIV or a salt thereof can be prepared by reacting compound XII or a salt thereof with phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate.

 Suitable salts of compounds XII and XIV may be the same salts as those discussed above for compound I.

 The reaction is usually carried out in a standard solvent, such as diethyl ether, tetrahydrofuran, dioxane, or in any other organic solvent that does not adversely affect the course of the reaction.

 The reaction temperature is not significant, the reaction is preferably carried out at room temperature and both when heated and when boiled.

 Stage J.

 Compound IIIc or a salt thereof can be prepared by reacting a compound XIV or a salt thereof with hydrazine.

 Suitable salts of compounds IIIc and XIV may be the addition salts of inorganic and organic acids already exemplified above for compound I.

 The reaction is usually carried out in standard solvents such as water, alcohol (for example, methanol, ethanol, etc.), or any other solvent that does not adversely affect the course of the reaction, or mixtures of these solvents.

 The reaction temperature is not significant; the reaction can be carried out at room temperature and both by heating and by boiling.

 Compounds obtained by the processes described above can be isolated and purified by conventional methods, such as spraying, recrystallization, column chromatography, reprecipitation, etc., and converted by conventional methods, if necessary, to the desired salts.

 It should be noted that compound I and other compounds may include, due to asymmetric carbon atoms, one or two stereoisomers, and all such isomers or mixtures thereof are included in the scope of the claims of the present invention.

 The inventive compound I and its pharmacologically acceptable salts exhibit selective sympathomimetic and anti-urinary activity with respect to the intestine, and can be used to treat and / or prevent gastrointestinal upset caused by contraction of the smooth muscles of humans or animals, and even more specifically , for the treatment and / or prevention of spasm of increased peristatics of the gastrointestinal tract in case of bowel irritation, gastritis, stomach ulcers, twelve ulcers ersnoy ulcer, inflammation of the small intestine, gall bladder inflammation, inflammation of the bile ducts, urolithiasis, etc. and for the treatment and / or prevention of urination disorders, such as rapid urination, urinary incontinence, etc. in the case of rapid urination, neurogenic dysfunction of the bladder, nocturnal polyurin, unstable urination, spasm of the bladder, chronic cystitis, chronic prostatitis, etc. It is also expected that the claimed compounds can be used as therapeutic and / or prophylactic agents against obesity and glaucoma.

 In order to illustrate the usefulness of the claimed compound I, the pharmacological data for compound I are given below.

Test 1. The impact on the isolated peripheral colon of rats
(a) Test method:
Male rats of different ages are used (weight 180 - 230 g). Before the experiment, animals are not fed for 24 hours. The peripheral colon is removed immediately after killing the animals and placed in a bath containing 25 ml of Tyrode solution, through which a gas mixture containing 95% oxygen and 5% carbon dioxide is purged at 37 ^° C. The sample is fixed under a load of 0.5 g and spontaneous contractions are recorded isometrically. After the mobility becomes uniform, the test compound is introduced into the bath and contractions are observed for 30 minutes. The effect of the test compound is evaluated by comparing the reduction before and after adding the test compound.

 (b) Test results (see table 1).

Test 2. Impact on the isolated uterus of non-pregnant rats
(a) Test method:
Female rats of different ages are used (weight 150 - 180 g). 48 and 24 hours before use, rats are injected subcutaneously with estradiol (trade name ovagormone benzoate, Teikoku Hormone Mfg.Co., Ltd) at a dose of 40 micrograms per rat to rats to induce estrus. Animals are killed and uterine horns are removed. Each sample under a load of 1 g is placed in a bath containing 25 ml of Locke solution, through which a gas mixture containing 95% oxygen and 5% carbon dioxide is blown at 37 ^° C. Spontaneous contractions are recorded isometrically. After the spontaneous contractions become uniform, the test compound is introduced into the bath. Observe mobility for 20 minutes. The effect of the test compound is evaluated by comparing the reductions before and after adding the test compound.

 (b) Test results (see table. 2).

 For therapeutic purposes, compound I and its pharmacologically acceptable salt of the present invention can be used in the form of a pharmacological preparation containing, as an active ingredient, one of these compounds in admixture with a pharmacologically acceptable carrier, such as an organic or inorganic solid, semi-solid or liquid excipient, suitable for oral, parenteral or external (local) use. Pharmaceutical preparations may be in the form of capsules, tablets, dragees, granules, suppositories, solutions, lotions, inhalants, ophthalmic preparations, suspensions, emulsions, ointments, gels, and the like. If desired, excipients, stabilizing agents, wetting or emulsifying agents, buffering mixtures or other commonly used additives may be included in these preparations.

 Since the dosage of compound I varies depending on the age and condition of the patient, average doses of 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of compound I can be effective in the treatment of these diseases. In general, the average daily dose for one person is from 0.1 mg to 1000 mg.

 The following preparations and examples are provided to illustrate the present invention.

 The drug 1.

 To a mixture of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (3.6 g), benzylamine (2.5 ml) and acetic acid (27 ml) under cooling in water sodium cyanoborohydride (0.49 g) was added in portions and the mixture was stirred at room temperature for 5 hours. Additional benzylamine (2.5 ml) and sodium cyanoborohydride (0.10 g) were added to the mixture, and stirring was continued for another 2 hours. The reaction mixture was made basic (pH> 8) with 10% sodium hydroxide solution (150 ml) and extracted once with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, n-hexane-ethyl acetate, 3: 1 to 2: 1 to 1: 1) to obtain N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H -benzocycloheptene-6-amine (4.8 g) as an oil.

IR (film): 3320 cm ^-1
NMR spectrum (chloroform-d, δ): 1.3 - 2.2 (5H, mult.), 2.6 - 3.0 (5H, mult.), 3.78 (3H, single), 3 79 (1H, double, J = 13 Hz), 3.89 (1H, double, 13 Hz), 6.63 (1H, doublet of doublets, J = 8 Hz), 6.73 (1H, double. , J = 2 Hz), 6.99 (1H, double, J = 8 Hz), 7.2 - 7.4 (5H, mult.).

Mass spectrum (m / z): 281
The drug 2.

The following compounds were obtained by a method similar to that described for preparation 1:
1) N-benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine
IR (film): 3320 cm ^-1
NMR spectrum (chloroform - d, δ): 1.2 - 2.2 (5H, mult.), 2.6 - 3.0 (5H, mult.), 3.77 (3H, single), 3 77 (1H, double, J = 13 Hz), 3.87 (1H, double, 13 Hz), 6.6 - 6.7 (2H, mult), 7.0 - 7.1 (1H , mult.) 7.1 - 7.4 (5H, mult.)
Mass spectrum (m / z): 281
2) N-benzyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine
T. pl. 64 - 68 ^o C
IR (Nujol): 1520; 1335 cm ^-1
NMR spectrum (chloroform-d, δ): 1.4-1.65 (1H, multip.),
1.75 - 2.15 (3H, mult.) 2.65 - 3.05 (5H, mult.),
3.80 (1H, double, J = 13 Hz), 3.89 (1H, double, 13 Hz),
7.2 - 6.5 (6H, mult.), 7.93 - 8.03 (2H, mult.)
Mass spectrum (m / z): 296
3) N-methylthioethyl- (7-nitro-1,2,3,4-tetrahydro-2-naphthyl) amine
IR (film): 3300, 1510, 1340 cm ^-1
NMR spectrum (chloroform-d, δ): 1.56 - 1.82 (1H, mult.),
2.00 - 2.19 (1H, multip.), 2.11 (3H, single),
2.60 - 3.20 (9H, multip.), 7.22 (1H, double, J = 9.1 Hz),
7.89 - 8.02 (2H, mult.)
Drug 3
A mixture of N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (3.0 g) and 47% hydrobromic acid (106 ml) was stirred at a temperature of 130 ^o C in within 1.5 hours. After cooling, the reaction mass is evaporated in vacuo. A 28% aqueous ammonia solution was added to the residue, and the mixture was extracted once with ethyl acetate. The extract was washed twice with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, chloroform-methanol, 25: 1 to 15: 1) to obtain 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene - 2-ol (1.9 g) in the form of oil, which freezes when standing.

Mp 87 - 89 ^o C
IR (Nujol): 3470 cm ^-1
NMR spectrum (chloroform - d, δ): 1.4 - 2.2 (4H, mult.), 2.5 - 3.7 (7H, mult.), 3.80 (2H, single), 6 4 - 6.6 (2H, mult) 6.8 - 7.0 (1H, mult) 7.1 - 7.4 (5H, mult)
Mass spectrum (m / z): 267
Drug 4.

The following compounds were obtained by a method similar to that described for preparation 3
1) 6-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol.

T. pl. 124 - 125 ^o C
IR (Nujol): 3280 cm ^-1
NMR spectrum (chlorofor-d, δ): 1.4 - 2.2 (4H, mult.),
2.2 - 3.6 (7H, mult.), 3.78 (1H, double, J = 13 Hz),
3.88 (1H, oak., J = 13 Hz), 6.4 - 6.6 (2H, mult.),
6.9 - 7.0 (1H, mult.), 7.2 - 7.4 (5H, mult.)
Mass spectrum (m / z): 267
2) 9-benzylamino-5,6,7,8,9,10-hexahydrobenzocycloocten-2-ol
IR (liquid): 3280, 2680, 2580, 1605 cm ^-1
NMR spectrum (chloroform-d, δ): 1.1-1.8 (6H, mult.), 2.5-3.0 (5H, mult.), 3.87 (2H, single), 6 54 (1H, double, J = 2.7 Hz), 6.61 (1H, doublet of doublets, J = 2.7 Hz, 8.1 Hz), 6.96 (1H, double, J = 8 , 1 Hz), 7.15-7.5 (5H, mult.)
Mass spectrum (m / z): 281
Drug 5.

To an ice-cooled solution of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (1.7 g) in toluene (56 ml) was added portionwise sodium hydride (60% dispersion in mineral oil , 0.31 g). After the addition is complete, the mixture is stirred at 70 ^° C. for 1 hour. After cooling, a mixture of ethyl bromoacetate (0.81 ml) and tetra-n-butylammonium bromide (0.10 g) in toluene (14 ml) was added, and the resulting mass was stirred at 70 ^° C. for 4 hours. After cooling, the mixture was poured into a saturated aqueous solution of ammonium chloride and extracted once with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, chloroform-ethanol, 25: 1 to 5: 1) to obtain benzyl-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine ( 2.0 g) as an oil).

IR (film): 3600, 3300, 1750 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (3H, triple., J = 7 Hz), 1.3-2.2 (5H, mult.), 2.6-3.0 (5H, mult.), 3.78 (1H, double, J = 13 Hz), 3.88 (1H, double, J = 13 Hz), 4.26 (2H, quarter, J = 7 Hz), 4 58 (2H, single), 6.61 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.76 (1H, double, J = 2 Hz), 6.98 (1H, double. , J = 8 Hz), 7.0-7.4 (5H, mult.)
Mass spectrum (m / z): 353
Drug 6.

 The following compounds were obtained by a method similar to that described in preparation 5.

1) benzyl-2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine
IR (film): 3300, 1740 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (3H, triple., J = 7 Hz), 1.3-2.2 (5H, mult.), 2.5-3.0 (5H, mult.), 3.77 (1H, double, J = 13 Hz), 3.87 (1H, double, J = 13 Hz), 4.26 (2H, quarter, J = 7 Hz), 4 58 (2H, single), 6.62 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.69 (1H, double, J = 2 Hz), 7.06 (1H, double. , J = 8 Hz), 7.1 - 7.4 (5H, mult.)
Mass spectrum (m / z): 353
2) N-benzyl-2-bis- (ethoxycarbonyl) methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine
IR (film): 3320, 1740 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (6H, triple, J = 7 Hz), 1.38 (1H, broad single), 1.4-1.6 (1H, mult. ), 1.6-2.1 (3H, mult), 2.5-2.9 (5H, mult), 3.7-3.9 (2H, mult), 4.30 (4H, quart., J = 7 Hz), 5.15 (1H, single.), 6.66 (1H, doublet of doublets, J = 2 Hz), 7.05 (1H, double., J = 8 Hz), 7 1-7.4 (5H, mult.)
Mass spectrum (m / z): 426 (M + H) ⁺
3) N-benzyl-3-ethoxycarbonylmethoxy-5,6,7,8,9,10-hexahydro-5H-benzocyclooctene-6-amine
IR (film): 1750, 1600 cm ^-1
NMR spectrum (chloroform-d, δ): 1.1-2.0 (6H, multip.), 1.29 (3H, triple, J = 7.1 Hz), 2.6-3.0 ( 5H, mult), 3.85 (1H, double, J = 13.4 Hz), 3.93 (1H, double, J = 13.4 Hz), 4.25 (2H, quarter, J = 7.1 Hz), 4.57 (2H, single), 6.6-6.8 (2H, mult.), 6.95-7.1 (1H, mult.), 7.2-7 , 55 (5H, mult.)
Mass spectrum (m / z): 367
4) Ethyl 2- [8- (benzylamino) -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy] propionate
IR (film): 3320, 1720, 1600 cm ^-1
NMR spectrum (chloroform-d, δ): 1.28 (3H, triple., J = 7.0 Hz), 1.35-2.10 (4H, multip.), 1.60 (3H, double. , J = 6.8 Hz), 2.6-2.95 (5H, mult), 3.77 (1H, double, J = 13 Hz), 3.87 (1H, double, J = 13 Hz), 4.20 (2H, quart., J = 7.0 Hz), 4.70 (1H, quart., J = 6.8 Hz), 6.56 (1H, doublet of doublets, J = 2, 7 Hz, 8.2 Hz), 6.74 (1H, double, J = 2.7 Hz), 6.96 (1H, double, J = 7.2 Hz), 7.2-7.4 (5H, mult.)
Drug 7.

 A mixture of N-benzyl-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (1.8 g), ammonium formate (3.2 g) 10% palladium on carbon (50 % vl. 0.72 g) and ethanol (50 ml) are refluxed for 0.5 hour. After cooling, the catalyst was filtered off and the residue was purified by silica gel column chromatography (gradient elution, chloroform-ethanol, 10: 1 to 5: 1) to obtain 3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6- amine (1.2 g) as an oil).

IR (film): 3360, 1750 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (3H, triple., J = 7 Hz), 1.4-2.5 (6H, mult.), 2.5-3.2 (5H, mult.), 4.26 (2H, quart., J = 7 Hz), 4.58 (2H, single), 6.62 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.75 (1H, double, J = 2 Hz), 6.98 (1H, double, J = 8 Hz)
Mass spectrum (m / z): 263
Drug 8.

 The following compound was obtained by reacting a compound obtained by a method similar to that described for preparation 7 with hydrogen chloride.

2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 151-156 ^o C
IR (Nujol): 3100-2000, 1740 cm ^-1
NMR spectrum (MDMCO-d ₆ , δ): 1.0-1.5 (1H, multip.), 1.21 (3H, triple, J = 7 Hz), 1.6-2.3 (3H , mult.), 2.5-3.2 (5H, mult.), 4.16 (2H, quart., J = 7 Hz), 4.72 (2H, single), 6.66 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.74 (1H, double, J = 2 Hz), 7.04 (1H, double, J = 8 Hz), 8.0-8.5 ( 3H, wide single)
Mass spectrum (m / z): 263 (M ⁺ - HCl)
Drug 9.

 The following compound was obtained by reacting a compound obtained by a method similar to that described for preparation 1 with hydrogen chloride.

N-benzyl-3-methoxy-5,6,7,8,9,10-hexahydrobenzocyclooctene-6-amine hydrochloride
T. pl. 178-180 ^o C
IR (Nujol): 2640, 2575, 1600, 1580 cm ^-1
NMR spectrum (DMCO-d ₆ , δ) 0.8-1.1 (1H, mult), 1.3-1.55 (1H, mult), 1.88-1.9 (4H, mult .), 2.55-2.8 (2H, mult), 2.95-3.3 (3H, mult), 3.72 (3H, single), 4.27 (2H, mult) 6.7-6.85 (2H, mult), 7.0-7.1 (1H, mult), 7.35-7.65 (5H, mult), 9.2-9.5 (1H, mult.), 9.6-8.9 (1H, mult.)
Drug 10.

 The following compounds were prepared by reacting compounds obtained by a procedure similar to that described for preparation 5 with hydrogen chloride.

1) N-benzyl-2-pentyloxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 188-193 ^o C
IR (Nujol): 1605, 1580 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.9 (3H, triple., J = 7.0 Hz), 1.1-1.5 (5H, mult.), 1.6-2.1 (4H, mult.), 2.25-2.45 (1H, mult.), 2.6-3.3 (5H, mult.), 3.91 (2H, triple, J = 6.4 Hz ), 4.1-5.3 (2H, mult), 6.68 (1H, doublet of doublets, J = 8.2 Hz), 6.84 (1H, double, J = 2.5 Hz), 7.01 (1H, double, J = 8.2 Hz), 7.35-7.5 (3H, mult.), 7.6-7.7 (2H, mult.), 8.3-7 , 5 (2H, mult.)
2) N-benzyl-3- (2-oxopentyloxy) -6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 166 - 169 ^o C
IR (Nujol): 2425, 2375, 1715, 1610 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.87 (3H, triple., J = 7.4 Hz), 1.05-1.4 (1H, multip.), 1.54 (2H, sext ., J = 7.4 Hz), 1.8-2.1 (1H, mult.), 2.3-2.45 (1H, mult.), 2.45-2.6 (2H, mult. ), 2.6-3.3 (5H, multip.), 4.26 (2H, single), 4.75 (2H, single), 6.64 (1H, doublet of doublets, J = 2.6 Hz, 8.3 Hz), 6.84 (1H, double, J = 2.6 Hz), 7.02 (1H, double, J = 8.3 Hz), 7.35-7.5 ( 3H, mult.), 7.6-7.7 (2H, mult.), 9.35-9.75 (2H, mult.).

3) N-benzyl-3 - [(RS) -2-oxopentan-3-yloxy) -6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 162-166 ^o C
IR (Nujol): 2420, 2350, 1715, 1605 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.8-1.1 (3H, multip.), 1.05-1.4 (1H, multip.), 1.7-2.1 (4H, mult.), 2.14 (3H, single), 2.2-2.4 (1H, mult.), 2.6-3.3 (5H, mult.), 4.25 (2H, single. ), 4.65 (1H, mult.), 6.5-6.7 (1H, mult.), 5.8-6.9 (1H, mult.), 7.0-7.05 (1H, mult.), 7.4-7.65 (5H, mult.), 8.8-9.2 (2H, mult.).

Mass spectrum (m / z): 351 (M-HCl) ⁺
4) N-benzyl-2-ethoxycarbonylmethoxy-6,7-dihydro-5H-benzocycloheptene-7-amine hydrochloride
T. pl. 121.5-131 ^o C
IR (Nujol): 2750-2300, 1755, 1600-1570, 1200 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.21 (3H, triple., J = 7.1 Hz), 2.16 (1H, mult.), 2.39 (1H, mult.), 2 7-2.95 (2H, mult), 4.02 (1H, mult), 4.1-4.25 (4H, mult), 4.76 (2H, single), 6.11 (1H, doublet of doublets, J = 11.8 Hz, 3.4 Hz), 6.67 (1H, double., J = 11.8 Hz), 6.78 (1H, doublet of doublets, J = 8.3 Hz, 2.6 Hz), 6.89 (1H, double, J = 2.6 Hz), 7.14 (1H, double, J = 8.3 Hz), 7.4-7.45 ( 3H, mult.), 7.55-7.65 (2H, mult.), 9.7 (2H, broad).

Mass spectrum (m / z): 351 (M ⁺ ), 244 (Main), 91
5) (S) -benzyl-2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 129-130 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ = + 28.9 ^o (c = 0.34, EtOH)
IR (Nujol): 3500, 3420, 1730 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.1-1.4 (1H, multip.), 1.21 (3H, triple, J = 7 Hz), 1.7-2.1 (2H, mult.), 2.2-2.4 (1H, mult.), 2.6-2.8 (2H, mult.), 2.8-3.3 (3H, mult.), 4.17 ( 2H, quart., J = 2 Hz), 4.2-4.4 (2H, mult.), 4.72 (2H, single), 6.67 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.86 (1H, double, J = 2 Hz), 7.04 (1H, double, J = 8 Hz), 7.3-7.5 (3H, multi), 7.5 -7.7 (2H, mult.), 9.2-9.6 (2H, broad. Mult.)
Mass spectrum (m / z): 353
6) (R) -benzyl-2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 129-131 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = -28.4 ^o (c = 0.38 EtOH)
IR (Nujol): 3550 - 3100, 1730 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.1 - 1.4 (1H, multip.), 1.21 (3H, triple, J = 7 Hz), 1.8 - 2.2 (2H , mult.), 2.3 - 2.5 (1H, mult.), 2.6 -2.8 (2H, mult.), 2.8 - 3.3 (3H, mult.), 4.17 (2H, quart., J = 2 Hz), 4.2 - 4.4 (2H, mult.), 4.72 (2H, single), 6.67 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.86 (1H, double, J = 2 Hz), 7.03 (1H, double, J = 8 Hz), 7.4 - 7.5 (3H, mult), 7, 6 - 7.8 (2H, mult.), 9.2 - 9.8 (2H, broad. Mult.)
Mass spectrum (m / z): 353
Drug 11.

To a mixture of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (970 mg) and 1,1,1-trichloro-2-methyl-2-propanol hydrate (1.28 g) 30 ml of acetone are added portionwise with KOH powder (1.71 g) and the resulting mixture is stirred at room temperature for 20 hours. After removing the solvent in vacuo, the residue was poured into a 1N sodium hydroxide solution (30 ml) and washed with diethyl ether. The pH of the aqueous layer was adjusted to 6.0 with a 3N hydrochloric acid solution. The precipitate formed is filtered off. The filtrate was evaporated in vacuo and water was added to the residue. The resulting precipitate was isolated by filtration and dried, yielding 2- [8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy] -2-methylpropionic acid (0.51 g)
T. pl. 187 - 189 ^o C
IR (Nujol): 3450, 1600 cm ^-1
NMR spectrum (NaOD, δ): 1.20 - 1.45 (1H, multip.), 1.48 (6H, single), 1.5 - 2.0 (3H, multip.), 2.45 - 2.95 (5H, mult.), 3.65 - 3.9 (2H, mult.), 6.6 - 6.8 (2H, mult.), 6.95 - 7.05 (1H, mult.) .), 7.2 - 7.4 (5H, mult.).

Mass spectrum (m / z): 354 (M + 1) ⁺
Drug 12.

Thionyl chloride (0.2 ml) was added at -10 ^° C and with stirring to ethanol (5 ml). After 10 minutes, 2- [8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy] -2-methylpropionic acid (0.49 g) was added in portions to the mixture. The reaction mass is stirred at room temperature for 1 hour, then boiled under reflux for 3 hours. After cooling, the mixture was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform-methanol (100: 1) as an eluent, and ethyl 2- [8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy] - 2-methylpropionate (0.43 g)
IR (liquid): 1725, 1600 cm ^-1
NMR spectrum (chloroform-d ₆ , δ): 1.25 (3H, triple., J = 7 Hz), 1.35 - 1.55 (1H, mult.), 1.57 (6H, single.) 1.65 - 2.1 (3H, mult), 2.6 - 2.9 (5H, mult), 3.76 (1H, double, J = 13 Hz), 3.87 (1H, double, J = 13 Hz), 4.22 (2H, quart., J = 7.1 Hz), 6.55 (1H, doublet of doublets, J = 2.6 Hz, 8.2 Hz), 6, 71 (1H, double, J = 2.6 Hz), 6.92 (1H, double, J = 8.2 Hz), 7.2 - 7.35 (5H, dm.)
Mass spectrum (m / z): 381
Drug 13.

 To a suspension of methyltriphenylphosphonium bromide (4.2 g) in tetrahydrofuran (10 ml), potassium tert-butoxide (1.34 g) was added portionwise while cooling in an ice bath. Upon completion of the addition, the ice bath was removed and the mixture was stirred at room temperature for 2.5 hours. Then, 7-methoxy-1-tetralone (1.78 g) was added to the mixture, and the mixture was further stirred for another 30 minutes. It is poured into ice water, then n-hexane is then added. Precipitated precipitates are filtered off and washed with n-hexane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was triturated with hexane and filtered. The filtrate was evaporated in vacuo to give 1-methylene-7-methoxy-1,2,3,4-tetrahydronaphthalene (1.69 g) as an oil.

IR (film): 3080, 1620 (wide band), 1600 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.6 - 1.9 (2H, mult.), 2.4 - 2.6 (2H, mult.), 2.71 (2H, triplet-like, J = approx. 6 Hz), 3.74 (3H, single), 4.96 (1H, double, J = 1 Hz), 6.78 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 7.03 (1H, double, J = 8 Hz); 7.16 (1H, double, J = 2 Hz).

Mass spectrum (m / z): 175
Drug 14.

 To a solution of thallium nitrate (2.4 g) in methanol (24 ml), a solution of 1-methylene-7-methoxy-1,2,3,4-tetrahydronaphthalene (1.0 g) in methanol (7 ml) is added in one portion. .

 The mixture was stirred for 1 minute and diluted with chloroform (24 ml). The precipitate formed is filtered off and the filtrate is washed with saturated sodium bicarbonate and then with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate, 8: 1) to obtain 3-methoxy-1,2,3,4-tetrahydro-5H-benzocyclohepten-6-one (0.78 g).

Mp 50 - 52 ^o C
IR (film): 1700 cm ^-1
NMR spectrum (chloroform -d ₆ , δ) 1.8 - 2.1 (2H, multip.), 2.56 (2H, triplet-like, J = approx. 7 Hz), 2.8 - 3.0 ( 2H, mult), 3.68 (2H, single), 3.78 (3H, single), 6.7 - 6.8 (2H, mult), 7.0 - 7.1 (1H, cartoon.)
Mass spectrum (m / z): 190
Drug 15.

 (S) -3-Methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (35.5 g) was neutralized with cold 2N sodium hydroxide solution (155 ml) and the mixture was extracted once with ethyl acetate ( 310 ml). The extract was washed once with brine (155 ml), dried over anhydrous sodium sulfate, evaporated in vacuo to give (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (30 , 1 g). A mixture of (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (30.1 g) 10% palladium on carbon (50% vl., 5.96 g) acetic acid (0.89 ml), benzaldehyde (31.6 ml) and ethanol (300 ml) were stirred at room temperature for 3 hours. After that, hydrogen is supplied to the mixture and stirred for another 1.5 hours. The catalyst is filtered off and washed with ethanol. Removal of the solvent in vacuo affords a residue which is dissolved in ethyl acetate (423 ml). To the resulting solution, with mechanical stirring and cooling in a water bath, a 4N solution of hydrogen chloride in ethyl acetate (77 ml) was added. After stirring at room temperature for 1.5 hours, the mixture was filtered and the crystals on the filter were washed with ethyl acetate (50 ml). The resulting product was dried in vacuo to give (S) -N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (47.3 g) as white crystals.

T. pl. 223 - 224 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ = +39.2 ^o (c = 0.49, EtOH)
IR (Nujol): 3050 - 2100, 1600, 1570 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.1 - 1.4 (1H, mult.), 1.8 - 2.1 (2H, mult.), 2.3 - 2.5 (1H, mult.), 2.6 - 2.8 (2H, mult.), 2.8 - 3.0 (1H, mult.), 3.0 - 3.3 (2H, mult.), 3.72 ( 3H, single), 4.26 (2H, broad. Single), 6.69 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.84 (1H, double, J = 2 Hz) 7.03 (1H, double, J = 8 Hz), 7.3 - 7.5 (3H, mult), 7.6 - 7.8 (2H, mult), 9.3 - 9, 8 (2H, broad cartoon).

Mass spectrum (m / z): 281
Drug 16.

 The following compound was obtained by a method similar to that described for preparation 15.

(R) -N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 223 - 224 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -42.7 ^o (C = 0.36, EtOH)
IR (Nujol): 3100 - 2100, 1610, 1580 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.4 (1H, mult.), 1.8 - 2.1 (2H, mult.), 2.3 - 2.5 (1H, mult.), 2.6 - 2.8 (2H, mult.), 2.8 - 3.0 (1H, mult.), 3.0 - 3.3 (2H, mult.), 3.72 ( 3H, single), 4.2 - 4.4 (2H, mult), 6.69 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.84 (1H, double, J = 2 Hz), 7.03 (1H, double, J = 8 Hz), 7.3 - 7.5 (3H, mult.), 7.6 - 7.8 (2H, mult.), 9.3 - 9.8 (2H, broad cartoon).

Mass spectrum (m / z): 281
Drug 17.

1) To a suspension of (S) -N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (46.8 g) in dichloromethane (147 ml) at -10 ^o C, a 1M solution of boron tribromide in dichloromethane (294 ml) was added dropwise over 50 minutes, allowing the mixture to warm to a temperature of 10 ^° C during the indicated time. Upon completion, the mixture was allowed to warm to room temperature and stirred so that the total stirring time was 3 hours The solvent was almost completely evaporated in vacuo and the remaining mixture was rapidly cooled in an ice bath with a mixture of water (600 ml) and ethyl acetate (450 ml). The pH of the mixture was adjusted to 8.0 by first adding solid sodium bicarbonate (74 g) and then a 1N sodium hydroxide solution (60 ml).

 The layers are separated from each other and the aqueous layer is extracted once more with ethyl acetate. The organic extracts are combined, washed with brine (300 ml), dried over anhydrous sodium sulfate and evaporated in vacuo.

 2) The resulting residue was dissolved in ethyl acetate (377 ml) and treated with cooling in a water bath with a 4N solution of hydrogen chloride in ethyl acetate (73 ml). After stirring at room temperature for 1 hour, the mixture was filtered and the filter cake washed with ethyl acetate (45 ml). The product was dried in vacuo to give (S) -8-benzylamino-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol hydrochloride (43.3 g) as white crystals.

T. pl. 232 - 233 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = +36.6 ^o (c = 0.42, EtOH)
IR (Nujol): 32200, 2380 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.4 (1H, mult.), 1.7 - 2.1 (2H, mult.), 2.2 - 2.4 (1H, mult.), 2.5 - 2.7 (2H, mult.), 2.8 - 3.2 (3H, mult.), 4.24 (2H, broad single), 6.52 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.67 (1H, double, J = 2 Hz), 6.89 (1H, double, J = 8 Hz), 7.3 - 7.5 ( 3H, mult.), 7.5 - 7.7 (2H, mult.), 9.2 - 9.5 (2H, br. Mult.), 9.24 (1H, single).

Mass spectrum (m / z): 267
Drug 18.

 The following compound was obtained by a method similar to that described for the preparation 17-1).

(R) -8-benzylamino-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol
Mass spectrum (m / z): 267
Drug 19.

To the mixture of (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (enantiomeric excess of 54% according to chiral HPLC chromatography 13.8 g) of N-benzyloxycarbonyl-D-leucine (20.9 g), N-hydroxybenzotriazole (10.6 g) and N, N-dimethylformamide (276 ml) were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (12.2 g). After stirring for 3 hours at room temperature, the mixture was evaporated in vacuo. The residue was diluted with methylene chloride and washed successively with water, 3N hydrochloric acid, saturated aqueous sodium bicarbonate and salt, dried over anhydrous sodium sulfate and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gave a crude product, which was further purified by recrystallization from ethanol to obtain mixtures of (6R) and (6S) -NN-benzyloxycarbonyl-D-leucyl) -3-methoxy-6,7,8,9-tetrahydro-5H diastereomers - benzocycloheptene-6-amine (15.0 g)
T. pl. 158-159 ^o C
IR (Nujol): 3300, 1680, 1640 cm ^-1
NMR spectrum (chloroform-d, δ): 0.87 (12H, double, J = 6 Hz), 1.3 - 1.8 (12H, mult), 1.8 - 2.0 (4H, mult.), 2.6 - 3.1 (8H, mult.), 3.74 (3H, single), 3.75 (3H, single), 3.9 - 4.3 (4H, mult. ), 4.9 - 5.2 (4H, mult.), 5.5 - 5.7 (1H, mult.), 5.7 - 5.9 (1H, mult.), 6.6 - 6, 75 (4H, mult.), 6.9 - 7.1 (2H, mult.), 7.2 - 7.5 (10H, mult.).

Mass spectrum (m / z); 438
Drug 20.

 The following compound was obtained by a method similar to that described for preparation 19.

(6R) - and (6S) -N- (N-benzyloxycarbonyl-L-leucyl) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine
T. pl. 168-173 ^o C
IR (Nujol): 3280, 1685, 1635 cm ^-1
NMR spectrum (chloroform-d, δ): 0.87 (12H, double, J = 6 Hz), 1.3 - 1.8 (12H, mult), 1.8 - 2.0 (4H, mult.), 2.6 - 3.1 (8H, mult.), 3.74 (3H, sing.), 3.75 (3H, sing.), 3.9 - 4.3 (4H, mult. ), 4.9 - 5.25 (5H, mult.), 5.6 - 5.9 (1H, mult.), 6.55 - 6.75 (4H, mult.), 6.9 - 7, 1 (2H, mult.), 7.2 - 7.4 (10H, mult.).

 Drug 21.

 A mixture of (6R) - and (6S) -N- (N-benzyloxycarbonyl-D-leucyl) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (6R: 6S = 77: 23, 20 g) of ammonium formate (11.5 g) of 10% palladium on charcoal (50% vl, 4.0 g) and ethanol (450 ml) are refluxed for 0.5 hour. After cooling, the catalyst was filtered off and washed with ethanol. The filtrate and washings were combined and evaporated in vacuo. The residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate and salt solutions, dried over anhydrous sodium sulfate and evaporated in vacuo to give a mixture of (6R) - and (6S) -ND-leucyl-3-methoxy-6,7,8,9- diastereomers tetrahydro-5H-benzocycloheptene-6-amine (13.5 g).

 Optical cleavage of the diastereomers is carried out by recrystallization from di-iso-propyl ether to give the (6R) -isomer (7.0 M 92.8 diastereomeric excess according to HPLC). An additional amount of product (1.8 g of a 91.6% diastereomeric excess) is obtained from the mother liquor after removal of the solvent, followed by recrystallization from di-iso-propyl ether. The next portion of the product (0.61 g, 92.3% diastereomeric excess) is obtained from the second mother liquor after silica gel column chromatography (20-400 mesh, gradient elution, first chloroform isopropanol, from 50: 1 to 25: 1, then iso-propanol) followed by recrystallization from di-isopropyl ether. All of the obtained gray samples of the (6R) -isomer (9.4 g) were combined and again purified by recrystallization from diisopropyl ether to give (6R) -ND-leucyl-3-methoxy-6,7,8,9-tetrahydro-5H -benzocycloheptene-6-amine (7.9 g, 95.2% diastereomeric excess).

Mp 117 - 118 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ = + 5.6 ^o (c = 0.60, EtOH)
IR (Nujol): 3380, 3320, 1610 cm ^-1
NMR spectrum (chloroform-d, δ): 0.8 - 1.0 (6H, mult.), 1.2 - 1.4 (1H, mult.), 1.47 (2H, broad single) , 1.5 - 1.8 (4H, mult.), 1.8 - 2.1 (2H, mult.), 2.7 - 2.8 (2H, mult.), 2.8 - 3.1 (2H, mult.), 3.2 - 3.4 (1H, mult.), 3.76 (3H, single), 4.0 - 4.2 (1H, mult.), 6.6 - 6 7 (2H, mult.), 6.9 - 7.1 (2H, mult.).

Mass spectrum (m / z): 304
Drug 22.

 The following compound was obtained by a method similar to that described for preparation 21.

(6S) -NL-leucyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine
T. pl. 117 - 118 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ = - 5.4 ^o (c = 0.66, EtOH)
IR (Nujol): 3380, 3320, 1610 cm ^-1
NMR spectrum (chloroform-d, δ): 0.8 - 1.0 (6H, mult.), 1.2 - 1.4 (1H, mult.), 1.33 (2H, broad single) , 1.5 - 1.8 (4H, mult.), 1.8 - 2.1 (2H, mult.), 2.7 - 2.8 (2H, mult.), 2.8 - 3.1 (2H, mult.), 3.2 - 3.4 (1H, mult.), 3.76 (3H, single), 4.0 - 4.2 (1H, cult.), 6.6-6 7 (2H, multip.), 6.9 - 7.1 (2H, multip.).

Mass spectrum (m / z): 304
Drug 23.

A mixture of (6R) -ND-leucyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (8.0 g) and 47% hydrobromic acid (262 ml) was stirred at 150 ^o C for 15.5 hours. After cooling to room temperature, the reaction mixture was left in the refrigerator overnight. The precipitate formed is separated, washed with di-isopropyl ether and dried, yielding the hydrobromide of the desired product (2.9 g). This salt was neutralized with a 28% aqueous ammonia solution and the resulting mixture was evaporated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted three times with n-butanol. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give (R) -8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol. The resulting product, according to NMR and IR spectroscopy, is contaminated with ammonium bromide, but can be used in the next step without further purification. Additionally, the amount of product (3.46 g), which is also contaminated with ammonium bromide, is obtained from the mother liquor by a similar treatment, as described above. Physical data are given for the hydrobromide of the target product.

T. pl. 298 - 299 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ = - 24.6 ^o (c = 0.55, EtOH)
IR (Nujol): 3400, 1610, 1580 cm ^-1
NMR spectrum (DMSO-d ₆ , δ): 1.1 - 2.2 (4H, mult.), 2.5 - 3.2 (5H, mult.), 6.4 - 6.6 (2H, mult.), 6.85 - 6.95 (1H, mult.), 7.85 (3H, broad single), 9.20 (1H, single).

Mass spectrum (m / z): 177
The drug is 24.

 The following compound was obtained by a method similar to that described for preparation 23.

(S) -8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol hydrobromide
T. pl. 297 - 299 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ = + 24.6 ^o (c = 0.65, EtOH)
IR (Nujol): 3400, 1610, 1580 cm ^-1
NMR spectrum (DMSO-d ₆ , δ): 1.1 - 2.2 (4H, mult.), 2.5 - 3.2 (5H, mult.), 6.4 - 6.6 (2H, mult.), 6.85 - 6.95 (1H, mult.), 7.85 (3H, broad single), 9.20 (1H, single).

Mass spectrum (m / z): 177
Drug 25.

 A mixture of (R) -8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-3-ol (5.8 g is contaminated with ammonium bromide), benzaldehyde (5.3 ml), acetic acid (0.15 ml) of 10% palladium on charcoal (50% vl. 1.1 g) and ethanol was stirred under hydrogen pressure for 1 hour, and then an additional amount of benzaldehyde (5.3 ml) was added. After stirring for 0.5 hours. a stream of hydrogen is allowed through the mixture and stirring is continued for another 3 hours. An additional portion of acetic acid (0.15 ml) was added to the reaction mass, and the mixture was stirred under a hydrogen pressure of 1 atm for another 1 hour. The catalyst is filtered off and washed with ethanol. Removing the solvent in vacuo, a residue is obtained which is diluted with ethyl acetate, washed with saturated solutions of sodium bicarbonate and salt, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, first chloroform, then chloroform-methanol, from 100: 1, to 50: 1 to 10: 1) to obtain (R) -8-benzylamino-6,7,8,9- tetrahydro-5H-benzocyclohepten-2-ol (6.6 g). Physical data are given for the hydrochloride of the target product, which is recrystallized from a mixture of di-iso-propyl ether-ethanol (3: 1).

T. pl. 234: 235 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ = - 34.5 ^o (c = 0.51, EtOH)
IR (Nujol): 3250, 2400 cm ^-1
NMR spectrum (DMSO-d ₆ , δ): 1.0 - 1.4 (1H, mult.), 1.7 - 2.1 (2H, mult.), 2.2 - 2.4 (1H, mult.), 2.5 - 2.7 (2H, mult.), 2.8 - 3.2 (3H, mult.), 4.24 (2H, broad single), 6.52 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.67 (1H, double, J = 2 Hz), 6.89 (1H, double, J = 8 Hz), 7.3 - 7.4 ( 3H, mult.), 7.5 - 7.7 (2H, mult.), 9.2 - 9.5 (2H, br. Mult.), 9.24 (1H, single).

Mass spectrum (m / z): 267
Drug 26.

 The following compound was obtained by a method similar to that described for preparation 25.

(S) -8-Benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol hydrochloride
T. pl. 233 - 235 ^o C
Drug 27.

A mixture of N-benzyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (2.8 g), formic acid (8 ml) and acetic anhydride (16 ml) was stirred at room temperature within 15 hours. The reaction portion was poured into an aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and evaporated to give N-benzyl-N-formyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (2.71 g)
T. pl. 126 - 128 ^o C
IR (Nujol): 1650, 1510 cm ^-1
NMR spectrum (chloroform-d, δ): 1.20 - 1.50 (1H, mult), 1.85 - 2.40 (3H, mult), 2.60 - 2.95 (3H, mult .), 3.15 - 3.70 (2H, mult.), 4.36 (0.5H, double, J = 15.5 Hz), 4.49 (0.5H, double, J = 15 Hz), 4.52 (0.5H, double, J = 15.5 Hz), 4.76 (0.5H, double, J = 15 Hz), 7.10 - 7.47 (6H, mult .), 7.65 - 7.78 (1H, mult.), 7.90 - 8.15 (1H, mult.), 8.31 (0.5H, single), 8.42 (0.5H single.).

Mass spectrum (m / z): 324
Drug 28.

N-Benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (6.0 g) was neutralized with a 7% ammonia solution and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give an oil (54.29 g). The oil was dissolved in 1-propanol (10 ml) and the resulting solution was added to a hot solution of D - (-) - tartaric acid (3.1 g) in 1-propanol (50 ml). After cooling, the precipitated crystals are filtered off and recrystallized twice with additional D - (-) tartaric acid (first 0.7 g, then 68 mg) from 1-propanol, obtaining (S) -N-benzyl-3-methoxy-6,7 , 8,9-tetrahydro-5H-benzocycloheptene-6-amine (D) tartrate (1: 1) (1.7 g). Enantiomeric excess (100%) was determined on two chiral columns (CHIRALCEL, OD). HPLC chromatography conditions — eluent: hexane-2-propanol (9: 1), liquid flow rate 0.6 ml / min, column temperature 25 ^° C., controlled wavelength 220 nm. Retention time is 24.6 minutes.

T. pl. 152 - 153 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +18.6 ^o (c = 0.78, DMSO)
IR (Nujol): 3520, 3300, 1730, 1620 cm ^-1
NMR spectrum (DMSO-d ₆ , δ): 1.1 - 1.4 (1H, mult.), 1.65 - 2.05 (2H, mult.), 2.1 - 2.3 (1H, mult.), 2.55 - 3.15 (5H, mult.), 3.71 (3H, single), 3.99 (2H, single), 4.07 (1H, double, J = 14 5 Hz), 4.17 (1H, double, J = 13.5 Hz), 6.66 (1H, doublet of doublets, J = 2.7 Hz, 8.2 Hz), 6.80 (1H, double, J = 2.7 Hz), 7.00 (1H, double, J = 8.2 Hz), 7.3 - 7.6 (5H, mult).

 Drug 29.

 A mixture of N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (68.7 g) ammonium formate (68.15 g) and 10% palladium on carbon (50 % vl. 6.8 g) in ethanol (1.2 L) was refluxed for 1 hour. After cooling, the catalyst was filtered off and the solvent was removed in vacuo. Water and a 28% aqueous ammonia solution were added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (35.8 g) as an oil.

 NMR spectrum (chloroform-d, δ): 1.38 - 2.10 (4H, multip.), 1.45 (2H, broad single), 2.6 - 3.06 (5H, multip.) , 3.77 (3H, single), 6.64 (1H, doublet of doublets, J = 2.7 Hz, 8.1 Hz), 6.71 (1H, double, J = 2.7 Hz) 6.98 (1H, double, J = 8.1 Hz).

Mass spectrum (m / z): 191
The drug 30.

 The following compound was obtained by reacting a compound obtained by a method similar to that described for preparation 29 with hydrogen chloride.

3-ethoxycarbonylmethoxy-5,6,7,8,9-10-hexahydrobenzocyclooctene-6-amine hydrochloride
IR (chloroform-d): 1760, 1600 cm ^-1
NMR spectrum (DMSO-d, δ): 0.9 - 1.9 (6H, mult), 1.21 (3H, triple, J = 7.1 Hz), 2.5 - 3.6 ( 5H, mult.), 4.17 (2H, quart., J = 7.1 Hz), 4.73 (2H, single), 6.7 - 6.9 (2H, mult.), 7.01 (1H, mult.), 8.20 (3H, broad single).

Mass spectrum (m / z): 277 (M - HCl) ⁺
Drug 31.

 The following compound was obtained by a method similar to that described for preparation 29.

2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-becycloheptene-7-amine
IR (film): 3610, 3360, 3300, 3180, 1755, 1610, 1580, 1205, 1180 cm ^-1
NMR spectrum (chloroform-d, δ): 1.15 - 1.3 (2H, multip.), 1.30 (3H, triple, J = 7.1 Hz), 1.41 (2H, broad. single), 2.0 - 2.15 (2H, mult.), 2.65 - 2.75 (4H, mult.), 2.9 - 3.05 (1H, mult.), 4.27 ( 2H, quart., J = 7.1 Hz), 4.59 (2H, single), 6.62 (1H, doublet of doublets., J = 8.2 Hz, 2.6 Hz), 6.72 ( 1H, doublet, J = 2.6 Hz), 7.01 (1H, doublet, J = 8.2 Hz).

Mass spectrum (m / z): 263 (M ⁺ ), 248, 246, 161 (basic)
Drug 32.

To a hot solution of D-mandelic acid (25.65 g) in ethyl acetate (300 ml) was added a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (35.8 g) in ethyl acetate (150 ml). After cooling, the precipitated crystals are filtered off and recrystallized from ethyl acetate-ethanol (2: 1) to obtain (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (D) -indamines ( 23.4 g). Enantiomeric excess (54%) was determined on a chiral column (ULTRON ES-OVM). Conditions HPLC chromatography - eluent: buffer 0.02 M phosphoric acid solution - acetonitrile (9: 1), fluid flow rate 1.0 ml / min, column temperature 25 ^o C, controlled wavelength 220 nm. Retention time is 11.8 minutes. Both filtrates are combined and evaporated in vacuo. The residue is converted to its (L) amygdala in the usual way. The crystals were recrystallized from ethyl acetate-ethanol (2: 1), to give (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (L) -indamines (17.98 g) . Enantiomeric excess (70%) was determined on the same column and under the same conditions. Retention time is 7.9 minutes.

 Drug 33.

 A solution of benzylamine (8.18 g) in benzene (100 ml) was added dropwise over a period of 20 minutes to a suspension of 8.9-dihydro-3-nitro-5H-benzocyclohepten-5-one (15.51 g) in ethanol ( 155 ml) at room temperature. The resulting mixture was stirred at the indicated temperature for 3.5 hours, left at the same temperature overnight and filtered. The filtrate was evaporated to give 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (25.41 g) as a dark brown oil.

IR (film): 3330, 1680, 1515, 1350 cm ^-1
NMR spectrum (chloroform-d, δ): 1.75 - 1.95 (2H, mult.), 2.1 - 2.3 (1H, mult.), 2.9 - 3.15 (3H, mult .), 3.2 - 3.4 (2H, mult.), 3.81 (1H, double, J = 13.2 Hz), 3.91 (1H, double, J = 13.2 Hz) 7.25 - 7.45 (6H, multip.), 8.23 (1H, doublet of doublets, J = 8.2 Hz, 2.4 Hz), 8.60 (1H, double, J = 2, 4 Hz).

 Drug 34.

 An aqueous solution (92 ml) of sodium borohydride (18.29 g) was added dropwise at room temperature to a stirred solution of 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (25 , 01 g) for more than 20 minutes. The resulting mixture was stirred for 4 hours, left overnight at the same temperature and evaporated in vacuo. The residue was diluted with water and extracted twice with dichloromethane. The extracts are combined, washed with brine, dried over sodium sulfate, treated with 4N solution of hydrogen chloride in ethyl acetate and evaporated in vacuo. The residue was suspended in methanol and filtered. The filtrate was evaporated in vacuo, diluted with aqueous ammonia and extracted twice with dichloromethane. The extracts are combined, washed with brine, dried over anhydrous sodium sulfate and chromatographed on silica gel using dichloromethane methanol as eluent. The eluent was evaporated in vacuo and the residue was washed with diethyl ether to obtain 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (7.33 g) as a dark yellow powder (mixture diastereomers).

T. pl. 109 - 120 ^o C
IR (Nujol): 3310, 3150, 1515, 1350 cm ^-1
NMR spectrum (chloroform-d, δ): 1.75 - 2.05 (8H, mult.), 2.3 (2H, mult.), 2.6 - 2.85 (2H, mult.), 3 15 - 3.65 (4H, mult), 3.85 (2H, double, J = 12.8 Hz), 4.02 (2H, double, J = 12.8 Hz), 4.98 (1H, double, J = 8.2 Hz), 5.32 (1H, mult.), 7.2 - 7.4 (14H, mult.), 8.01 (2H, doublet of doublets, J = 8 , 2 Hz, 2.2 Hz), 8.14 (1H, double, J = 2.2 Hz), 8.29 (1H, double, J = 2.2 Hz).

Mass spectrum (m / z): 312 (M ⁺ ), 221, 91 (basic).

 Drug 35.

A mixture of 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (6.51 g) potassium bisulfate (13.0 g) is heated at a temperature of 210 ^o C for 20 minutes and suspended with a mixture of dichloromethane (150 ml), water (100 ml) and 28% ammonia solution. The suspension is filtered. The dichloromethane layer was separated, dried over anhydrous sodium sulfate and chromatographed on silica gel using dichloromethane methanol as eluent. The first eluent gave N-benzyl-6,7-dihydro-2-nitro-5H-benzocycloheptene-7-amine (3.11 g) as a dark brown solid.

T. pl. 62.5 - 69 ^o C
IR (Nujol): 3310, 1660, 1580, 1520, 1340 cm ^-1
NMR spectrum (chloroform-d): 2.0 (1H, broad), 2.00 - 2.15 (8H, mult), 2.8 - 2.95 (2H, mult), 3.45 - 3.55 (1H, multip.), 3.89 (2H, single), 6.11 (1H, doublet of doublets, J = 12.2 Hz, 4.2 Hz), 6.50 (1H, doublet doublets, J = 12.2 Hz, 1.6 Hz), 7.2 - 7.4 (6H, mult.), 7.97 (1H, doublet of doublets, J = 8.2 Hz, 2.4 Hz) 8.04 (1H, doublet, J = 2.4 Hz),
Mass spectrum (m / z): 294 (M ⁺ ), 203, 91 (main).

 The second eluent gave 6,7-dihydro-2-nitro-5H-benzocycloheptene-7-amine (95 mg) as an oil.

IR (film): 3350, 3280, 3170, 1610, 1580, 1510, 1340 cm ^-1
NMR spectrum (chloroform-d, δ): 1.58 (1H, broad sing.), 1.85 - 2.1 (2H, mult.), 2.85 - 2.95 (2H, mult.) , 3.71 (1H, mult.), 6.01 (1H, doublet of doublets, J = 12.2 Hz, 4.0 Hz), 6.42 (1H, doublet of doublets, J = 12.2 Hz, 1 , 6 Hz), 7.2 - 7.4 (6H, mult.), 7.28 (1H, double, J = 8.2 Hz), 7.97 (1H, doublet of doublets, J = 8.2 Hz, 2.4 Hz), 8.04 (1H, double, J = 2.4 Hz).

Mass spectrum (m / z): 204 (M ⁺ , basic)
Drug 36.

A solution of N-benzyl-6,7-dihydro-2-nitro-5H-benzocycloheptene-7-amine (3.03 g) in ethanol (19 ml) and dioxane (19 ml) was added dropwise to a stirred mixture of iron powder ( 3.03 g) and ammonium chloride (0.36 g) in ethanol (15 ml), dioxane (15 ml) and water (15 ml) while boiling for 20 minutes. The resulting mixture was refluxed for 20 minutes and the still hot reaction mixture was filtered. The filtrate was evaporated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent, and N ^7- benzyl-6,7-dihydro-5H-benzocycloheptene-2,7-diamine (2.52 g) was obtained as a brown oil.

IR (film): 3440, 3350, 3220, 1620 cm ^-1
NMR spectrum (chloroform-d, δ): 1.57 (1H, broad), 1.95 - 2.1 (2H, mult), 2.6 - 2.8 (2H, mult), 3 4 - 3.6 (3H, mult), 3.8 (2H, single), 5.92 (1H, doublet of doublets, J = 12.0 Hz, 4.0 Hz), 6.32 (1H doublet of doublets, J = 12.0 Hz, 1.8 Hz), 6.4-6.55 (2H, mult), 6.92 (1H, double, J = 7.8 Hz), 7, 2 - 7.4 (5H, mult.).

Mass spectrum (m / z): 264 (M ⁺ ), 157 (basic) 91
Drug 37.

An aqueous solution (6 ml) of sodium nitrite (609 mg) was added dropwise to a stirred suspension of N ^7- benzyl-6,7-dihydro-5H-benzocycloheptene-2,7-diamine (2.22 g) in a 6N solution of sulfuric acid ( 22 ml) for 15 minutes under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. The resulting solution was added dropwise with stirring to a solution of sulfuric acid (3 ml.) In water (15 ml) at 75 ^o C for 15 minutes. The resulting mixture was stirred at this temperature for another 30 minutes, cooled in an ice bath, made basic with 28% aqueous ammonia (15 ml) and extracted with dichloromethane six times. The extracts were combined, evaporated in vacuo and chromatographed over silica gel using dichloromethane and methanol as the eluent to give N-benzylamino-6,7-dihydro-5H-benzocyclohepten-2-ol (1.72 g) as a pale brown oils.

IR (film): 3270, 2650, 1600, 1570 cm ^-1
NMR spectrum (chloroform-d, δ): 1.95 - 2.15 (2H, multip.), 2.6 - 2.8 (2H, multip.), 3.30 (1H, broad), 3 45 - 3.55 (1H, multip.), 3.83 (1H, double, J = 13.2 Hz), 3.90 (1H, double, J = 13.2 Hz), 5.92 (1H, doublet of doublets, J = 12.2 Hz, 4.0 Hz), 6.31 (1H, doublet of doublets, J = 12.2 Hz, 11.8 Hz), 6.5 - 6.65 (2H , mult.), 6.96 (1H, double, J = 7.8 Hz), 7.2 - 7.35 (6H, mult.).

Mass spectrum (m / z): 265 (M ⁺ ), 158 (basic), 91
Drug 38.

Under a nitrogen atmosphere, a solution of methylmagnesium bromide in diethyl ether (3M, 5.65 ml) was added at 0 ^° C to a solution of 6-chloro-2-pyridylaldehyde (2.0 g) in diethyl ether (20 M) and stirred for 1.5 hour, then a saturated aqueous solution of ammonium chloride (30 ml) was added and the organic layer was separated. The aqueous layer was further extracted with diethyl ether. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by distillation under reduced pressure to obtain 1- (6-chloro-2-pyridyl) ethanol (2.13 g).

T. bale. 140 - 145 ^o C / 5 mm. Hg

IR (film): 3375, 1585, 1560, 1435, 1410 cm ^-1
NMR spectrum (CDCl ₃ -D ₂ O, δ): 1.52 (3H, double, J = 6.6 Hz), 4.87 (1H, quart., J = 6.6 Hz), 7, 2 - 7.34 (2H, multip.), 7.66 (1H, triple., J = 7.8 Hz).

Mass spectrum (m / z): 156 (M ⁺ ), 142, 114, 78
Drug 39.

 A mixture of 1- (6-chloro-2-pyridyl) ethanol (2.13 g) and manganese dioxide (8.4 g) in chloroform (21 ml) was refluxed for 8 hours. After cooling, the mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo. The residue was purified by distillation under reduced pressure to obtain 2-acetyl-6-chloropyridine (1.84 g).

T. bale. 105 - 110 ^o C / 5 mm. Hg

IR (film): 1700, 1570, 1560 cm ^-1
NMR spectrum (chloroform-d, δ): 2.71 (3H, single), 7.52 (1H, doublet of doublets, J = 1.0 Hz, 7.9 Hz), 7.81 (1H, pseudo triple., J = 7.8 Hz), 7.97 (1H, doublet of doublets, J = 1.0 Hz, 7.6 Hz).

Mass spectrum (m / z): 156 (M ⁺ )
Drug 40.

To a solution of 2-acetyl-6-chloropyridine (7.48 g) in 1,4-dioxane (112 ml) was added a 4N solution of hydrogen chloride in 1,4-dioxane (12.6 ml). Sulfuryl chloride (13.51 ml) was added dropwise to the resulting solution at 30 ^° C. After stirring for 0.5 hour, ice water (150 ml) was added to the mixture, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of p-hexane and toluene (1: 1) as eluent, and chloromethyl 6-chloro-2-pyridylketone (7.05 g) was obtained as a solid.

T. pl. 61 - 62 ^o C
IR (Nujol): 1720 cm ^-1
NMR spectrum (chloroform - d, δ): 5.07 (2H, single), 7.57 (1H, doublet of doublets, J = 1 Hz, 7.9 Hz), 7.86 (1H, pseudo triple. , J = 7.7 Hz), 8.03 (1H, doublet of doublets, J = 1.0 Hz, 7.6 Hz).

 Drug 41.

A solution of chloromethyl 6-chloro-2-pyridylketone (8.126 g) in tetrahydrofuran (32 ml) and a solution of borane in tetrahydrofuran (1.0 M, 25.7 ml) are simultaneously added to a mixture of a solution of (R) -tetrahydro-3.3 -phenyl-1H-3H-pyrrolo [1,2-c] [1,3,2] oxazaborol in tetrahydrofuran (approx. 0.335 M, 8.9 ml) and a solution of borane in tetrahydrofuran (1.0 M, 4.3 ml) at -5 ^o C in a nitrogen atmosphere for at least 0.5 hours and the resulting mixture was stirred for another 3.5 hours. At 0 ^° C., methanol was added dropwise to the reaction mixture, and it was left under stirring overnight at room temperature. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform as the eluent to obtain (-) - 2-chloro-1- (6-chloro-2-pyridyl) ethanol (7.98 g) as an oil.

[α] $\genfrac{}{}{0ex}{}{\text{32}}{\text{D}}$ = -16.3 ^o (c = 0.81, methylene chloride)
Drug 42.

 The following compound was obtained by a method similar to that described for preparation 41.

(-) - 2-chloro-1- (2-naphthyl) ethanol
T. pl. 93 - 94 ^o C
[α] _D = -40.09 ^° (c = 1.07, methylene chloride)
IR (Nujol): 3210 cm ^-1
NMR spectrum (chloroform-d, δ): 2.80 (1H, broad), 3.5 - 3.9 (2H, mult), 5.05 (1H, doublet of doublets, J = 3.6 Hz , 8.5 Hz), 7.4 - 7.5 (3H, mult.), 7.8 (4H, mult.).

 Drug 43.

 A mixture of (-) - 2-chloro-1- (6-chloro-2-pyridyl) ethanol (1.028 g) of isopropenyl acetate (1.8 ml) and PS Amano lipase (2.06 g) in absolute di-iso propyl ether (31 ml) was stirred at room temperature for 2.5 days. Insoluble material was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform as the eluent to obtain (-) - 2-chloro-1- (6-chloro-2-pyridyl) ethanol (0.40 g).

[α] $\genfrac{}{}{0ex}{}{\text{28.8}}{\text{D}}$ = -30.0 ^o (c = 0.935, methylene chloride)
IR (liquid): 3375, 1580, 1560 cm ^-1
NMR spectrum (chloroform-d, δ): 3.54 (1H, double, J = 6.3 Hz), 3.80 (1H, doublet of doublets, J = 6.1 Hz, 11.1 Hz), 3.91 (1H, doublet of doublets, J = 4.8 Hz, 11.1 Hz), 4.90 - 5.04 (1H, multip.), 7.29 (1H, double, J = 7.9 Hz), 7.40 (1H, double, J = 7.6 Hz), 7.71 (1H, pseudo triple, J = 7.7 Hz).

 Drug 44.

 A mixture of (-) - 2-chloro-1- (6-chloro-2-pyridyl) ethanol (390 mg), 2M sodium hydroxide solution (3.9 ml) and diethyl ether (0.2 ml) was stirred at room temperature in within 3 hours. Next, brine and ethyl acetate were added to the mixture. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform as the eluent to obtain (-) - 1- (6-chloro-2-pyridyl) -1,2-epoxyethane (250 mg) as an oil.

[α] $\genfrac{}{}{0ex}{}{\text{30.8}}{\text{D}}$ = -34.4 ^o (c = 0.57, methylene chloride)
IR (liquid): 1590, 1560, 1540, 1420 cm ^-1
NMR spectrum (chloroform-d, δ): 2.88 (1H, doublet of doublets, J = 2.5 Hz, 5.8 Hz), 3.18 (1H, doublet of doublets, J = 4.1 Hz, 5 8 Hz), 3.99 (1H, doublet of doublets, J = 2.5 Hz, 4.1 Hz), 7.16 (1H, doublet of doublets, J = 9.7 Hz, 7.6 Hz), 7 , 27 (1H, doublet of doublets, J = 0.7 Hz, 7.9 Hz), 7.65 (1H, pseudo triple., J = 7.7 Hz).

Mass spectrum (m / z): 156 (M ⁺ ).

 The drug is 45.

 The following compound was obtained by a method similar to that described for preparation 44.

(+) - 2-naphthyloxyran
Mp: 75 - 76 ^o C
[α] _D = +34.17 ^o (c = 1.03, toluene)
IR (Nujol): 1265, 1240, 820, 740 cm ^-1
NMR spectrum (chloroform-d, δ): 2.89 (1H, doublet of doublets, J = 2.6 Hz, 5.5 Hz), 3.20 (1H, doublet of doublets, J = 4.1 Hz, 5 5 Hz), 4.01 (1H, doublet of doublets, J = 2.6 Hz, 4 Hz), 7.31 (1H, doublet of doublets, J = 1.7 Hz, 8.5 Hz), 7.4 - 7.5 (2H, mult.), 7.8 (4H, mult.).

Mass spectrum (m / z): 170 (M ⁺ ), 141
Drug 46.

To a suspension of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (7.0 g) in methanol (70 ml) at 21 ^° C - 30 ^° C, sodium borohydride (1 , 29 g.) And the resulting mixture was stirred for 1 hour. The mixture was poured into ice water (210 ml) and the precipitate formed was filtered off, washed with water and dried to obtain 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (6.81 g).

T. pl. 116 - 118 ^o C
IR (Nujol): 3260, 3160, 1520, 1340 cm ^-1
NMR spectrum (chloroform-d, δ): 1.25 - 2.18 (7H, mult), 2.66 - 3.10 (2H, mult), 4.89 - 5.06 (1H, mult .), 7.23 (1H, double, J = 8.2 Hz), 7.98 (1H, doublet of doublets, J = 2.5 Hz, 8.2 Hz), 8.38 (1H, double. , J = 2.5 Hz).

 Drug 47.

A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (70.67) and sodium bisulfate (53.00 g) was heated at 160 ^° C. for 1 hour. After cooling, a mixture of water (400 ml) and ethyl acetate (400 ml) is added to the reaction mass. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (200 ml). The organic extracts are combined, washed with brine (150 ml), dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of n-hexane and chloroform (1: 1) as an eluent, and 2-nitro-6,7-dihydro-5H-benzocycloheptene (48.1 g) was obtained.

T. pl. 43 ^o C.

IR (Nujol): 1520, 1340, 1280, 1085, 930, 900, 835, 760, 740 cm ^-1
NMR spectrum (chloroform-d, δ): 1.88 - 2.10 (2H, mult.), 2.40 - 2.59 (2H, mult.), 2.83 - 3.03 (2H, mult .), 6.06 (1H, doublet of triplets, J = 12.2 Hz, 4.5 Hz, 4.5 Hz), 6.45 (1H, doublet of triplets, J = 12.2 Hz, 2.0 Hz , 2.0 Hz), 7.2 (1H, double, J = 8.2 Hz), 7.93 (1H, doublet of doublets, J = 2.4 Hz, 8.2 Hz), 8.00 ( 1H, doublet, J = 2.4 Hz).

Drug 48
A mixture of 2-nitro-6,7-dihydro-5H-benzocycloheptene (48.10 g) and m-chlorobenzoic acid (80%, 65.75 g) in chloroform (962 ml) was refluxed for 4 hours. After cooling, a 1N sodium hydroxide solution (350 ml) was added to the mixture. The organic layer was separated, and the aqueous layer was further extracted with chloroform. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and silica gel (100 g) is added to the mixture. The insoluble material was filtered off and the filtrate was evaporated in vacuo to give 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclo-5,6-epoxyheptane (53.90 g).

T. pl. 62 - 64 ^o C
IR (Nujol): 1610, 1580, 1520, 1340 cm ^-1
NMR spectrum (chloroform-d, δ): 1.43 - 2.32 (4H, mult.), 2.82 - 3.08 (2H, mult.), 3.35 - 3.54 (1H, mult .), 4.06 (1H, double, J = 4.2 Hz), 7.26 (1H, double, J = 8.3 Hz), 8.08 (1H, doublet of doublets, J = 2, 4 Hz, 8.3 Hz), 8.37 (1H, double, J = 2.4 Hz).

 Drug 49.

 In a nitrogen atmosphere, a solution of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclo-5,6-epoxyheptane (53.9 g) in benzene (540 ml) is added to zinc chloride (41.9 g) and the resulting mixture was stirred for 1 day. Silica gel is added to the mixture and insoluble material is filtered off. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform as the eluent to obtain 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (33.83 g).

T. pl. 84 - 86 ^o C
IR (Nujol): 1700, 1550, 1505, 1340 cm ^-1
NMR spectrum (chloroform-d, δ): 1.95 - 2.172 (2H, mult.), 2.55 - 2.71 (2H, mult.), 3.00 - 3.16 (2H, mult.) 3.83 (2H, single); 7.34 (1H, double., J = 8.0 Hz); 8.01 - 8.17 (2H, mult.).

 The drug is 50.

 A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (0.20 g) of iron powder (218 mg), ammonium chloride (52 mg), water (1.2 ml) and ethanol (4 ml) is refluxed for 2 hours. After cooling, insoluble material was filtered off and the filtrate was evaporated in vacuo. Ethyl acetate and water are added to the residue. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform as the eluent to obtain 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (153 mg).

IR (chloroform): 375, 1690, 1610 cm ^-1
NMR spectrum (chloroform-d, δ): 1.90 - 2.0 (2H, mult), 2.48 - 2.66 (2H, mult), 2.77 - 2.94 (2H, mult .), 3.62 (2H, single), 6.45-6.60 (2H, mult.), 6.93 (1H, double, J = 8.6 Hz).

 Drug 51.

 The following compound was obtained by a method similar to that described for preparation 50.

N-benzyl-N-formyl- (3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amine
IR (liquid): 3680, 3450, 3390, 1660 cm ^-1
Conformer A: NMR spectrum (CDCl ₃ - D ₂ O, δ): 1.14 - 1.46 (1H, mult.), 1.78 - 2.20 (3H, mult.), 2.39 - 2 , 73 (3H, mult), 3.04 - 3.88 (2H, mult), 4.36 - 4.78 (2H, mult), 6.26 - 6.90 (3H, mult) 7.20 - 7.44 (5H, multip.); 8.27 (1H, single).

Conformer B: NMR spectrum (CDCl ₃ -D ₂ O, δ): 1.14 - 1.46 (1H, mult.), 1.78 - 2.20 (3H, mult.), 2.39 - 2 , 73 (3H, mult), 3.04 - 3.88 (2H, mult), 4.36 - 4.78 (2H, mult), 6.26 - 6.90 (3H, mult) 7.20 - 7.44 (5H, multip.); 8.39 (1H, singlet).

Conformer A: Conformer B = 1: 2,3
Mass spectrum (m / z): 294 (M ⁺ ), 159, 144, 131, 91
Drug 52.

To a solution of 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (9.42 g) in a mixture of acetic acid (1.85 ml), concentrated sulfuric acid (9.24 ml) and water (24.56 ml) while cooling in a bath with ice and salt, a solution of sodium nitrate (4.08 g) in water (6.00 ml) is added in portions and the resulting mass is stirred for 1 hour. The resulting solution was added to a solution of copper bromide (10.02 g) and sodium bromide (9.40 g) in a mixture of 47% hydrobromic acid (27.72 ml) and water (61.52 ml) at 75 ^° C and the resulting the mass is stirred for another 0.5 hour. After cooling, ice water (100 ml) and chloroform (200 ml) are added to the reaction mass. Insoluble material is filtered off. The organic layer was separated, and the aqueous phase was further extracted with ethyl acetate. The extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and treated with activated carbon (0.65 g). The resulting solution was evaporated in vacuo, and the residue was purified by silica gel column chromatography using toluene as eluent, and 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (6.34 g) was obtained.

T. pl. 51 - 59 ^o C
IR (Nujol): 1700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.89 - 2.08 (2H, mult), 2.47 - 2.65 (2H, mult), 2.83 - 3.00 (2H, mult .), 3.68 (2H, single), 7.03 (1H, double, J = 7.7 Hz), 7.31 (1H, double, J = 2.0 Hz), 7.33 (1H, doublet of doublets, J = 7.7 Hz, 2.0 Hz).

 Drug 53.

A mixture of 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (2.00 g) ethyl acrylate (91.26 g) palladium acetate (94 mg), tris (2-methylphenyl) phosphine ( 764 mg), triethylamine (1.69 g) in N, N-dimethylformamide (20 ml) was stirred in a hydrogen atmosphere at a temperature of 100 ^o C for 20 hours. After cooling, ice water (20 ml) was added to the mixture. The precipitate formed is filtered off and dissolved in ethyl acetate (20 ml). The resulting solution was washed three times with water (20 ml), dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform as eluent to obtain (E) -3- (8-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl) acrylate (1.34 g )

T. pl. 87 - 88 ^o C
IR (Nujol): 1705, 1690 cm ^-1
NMR spectrum (chloroform-d, δ): 1.34 (3H, triple., J = 7.1 Hz), 1.91 - 2.12 (2H, multip.), 2.52 - 2.67 ( 2H, mult.), 2.89 - 3.07 (2H, mult.), 3.74 (2H, single), 4.26 (2H, quart., J = 7.1 Hz), 6.40 (1H, double, J = 16.0 Hz), 7.18 (1H, J = 7.7 Hz), 7.32 (1H, double, J = 1.0 Hz), 7.36 (1H doublet of doublets, J = 7.7 Hz), 7.64 (1H, doublet of doublets, J = 16.0 Hz).

 Drug 54.

 A solution of (E) -3- (8-oxo-6,6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl) acrylate (400 mg) in ethanol (8 ml) is hydrogenated with 10% palladium on charcoal (24 mg). After removal of the catalyst, the solution was evaporated in vacuo and the residue was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (10: 1) as an eluent, and (E) -3- (8-oxo-6,7,8, 9-tetrahydro-5H-benzocyclohepten-2-yl) propionate (311 mg).

T. pl. 66-68 ^o C
IR (Nujol): 1720, 1695 cm ^-1
NMR spectrum (chloroform-d, δ): 1.23 (3H, triple., J = 7.1 Hz), 1.91 - 2.08 (2H, multip.), 2.48 - 2.70 ( 4H, mult.), 2.80 - 3.02 (4H, mult.), 3.70 (2H, single), 4.13 (2H, quart., J = 7.1 Hz), 6.96 - 7.06 (3H, mult.).

 Drug 55.

 A solution of N-benzyl-N-formyl- (3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amine (0.80 g) in formic acid (16 ml) is refluxed within 2 hours. After cooling, the solution was evaporated in vacuo. The residue was dissolved in ethyl acetate, and the resulting solution was washed successively with 1N sodium hydroxide solution, 1N hydrochloric acid solution, saturated brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform-methanol (20: 1) as an eluent to obtain N-benzyl-N-formyl- (3-formylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene- 6-yl) amine (0.84 g).

IR (chloroform): 3660, 3425, 3400, 1690, 1660 cm ^-1
NMR spectrum (chloroform-d, δ): 1.16 - 1.49 (1H, mult.), 1.80 - 2.30 (3H, mult.), 2.42 - 2.82 (3H, mult .), 3.07 - 3.90 (3H, mult.), 4.28 - 4.86 (2H, mult.), 6.50 - 7.20 (3H, mult.), 7.20 - 7 46 (5H, mult.), 7.66 - 7.93 (1H, mult.), 8.25 - 8.66 (2H, mult.).

Mass spectrum (m / z): 322 (M ⁺ ), 187, 172, 159
Drug 56.

 Sodium hydride (in the form of a 60% dispersion in oil, 100 mg) is washed with petroleum ether and a solution of N-benzyl-N-formyl- (3-formylamino-6,7,8,9) is added to it while cooling in an ice bath -tetrahydro-5H-benzocyclohepten-6-yl) amine (675 mg) in tetrahydrofuran (10 ml). The mixture was stirred for 20 minutes, and then a solution of ethyl bromoacetate (0.28 ml) in tetrahydrofuran (1 ml) was added and stirred for another 1 hour. A saturated solution of ammonium chloride was added to the mixture. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using chloroform-methanol (50: 1) as an eluent to give ethyl N - [(8-N-benzylformylamino) -6,7,8,9-tetrahydro-5H-benzocycloheptene-2 -yl] formylamino acetate (752 mg).

IR (chloroform): 2940, 1745, 1665 cm ^-1
NMR spectrum (chloroform-d, δ): 1.28 (3H, triple., J = 7.1 Hz), 1.22 - 1.50 (1H, mult.), 1.83 - 2.84 ( 6H, mult.), 3.09 - 3.76 (2H, mult.), 4.20 (2H, quart., J = 7.1 Hz), 4.28 - 4.86 (4H, mult.) 8.24 - 8.46 (2H, mult.).

Mass spectrum (m / z): 408 (M ⁺ ), 307, 273, 245, 172
Drug 57.

 A mixture of ethyl N - [(8-N-benzylformylamino) -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl] formylaminoacetate (501 mg), 6N hydrochloric acid solution (6.1 ml) and ethanol ( 10 ml) is refluxed for 1 day. After cooling, the solution was poured into ice water (20 ml) and its pH was adjusted to 12 with a solution of caustic soda. The aqueous phase was extracted with ethyl acetate and the extract was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo.

 The residue was purified by silica gel column chromatography using chloroform-ethanol (20: 1) as an eluent, and ethyl N - [(8-N-benzylamino) -6,7,8,9-tetrahydro-5H-benzocycloheptene-2 was obtained -yl] amino acetate (217 mg).

IR (liquid): 3400, 1735, 1610, 1585, 1510 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (3H, triple., J = 7.1 Hz), 1.34 - 2.09 (5H, mult.), 2.52 - 2.95 ( 6H, mult), 3.82 (1H, single), 3.85 (1H, single), 3.88 (2H, double, J = 7.1 Hz), 4.15 (1H, triple ., J = 3.5 Hz), 4.24 (2H, quart., J = 7.1 Hz), 6.35 (1H, doublet of doublets, J = 2.5 Hz, 8.0 Hz), 6 47 (1H, double, J = 2.5 Hz), 6.90 (1H, double, J = 8.0 Hz), 7.17 - 7.36 (5H, cartoon)
Mass spectrum (m / z): 352 (M ⁺ ), 219, 207, 146
Drug 58.

While maintaining the temperature at 30 ^o C for 0.5 hour, a solution of (Z) is added to a vigorously stirred suspension of sodium borohydride (15.77 g) in a mixture of 1,4-dioxane (315 ml) and ethanol (98 ml) - 2- (3-methoxyphenyl) -2-nitroethane (33.85 g) in 1,4-dioxane (315 ml). After stirring for another 2 hours, the resulting mass was diluted with ice water (393 ml) and the excess borohydride was decomposed with a 50% aqueous solution of acetic acid (47.4 ml). Sodium chloride (68 g) and ethyl acetate were added to the resulting solution. The organic layer was separated, and the aqueous phase was further extracted with ethyl acetate. The extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by distillation under reduced pressure to obtain 1-methoxy-3- (2-nitroethyl) benzyl (23.62 g)
T. bale. 104 - 107 ^o C / 1 mm. Hg. Art.

IR (liquid): 1540, 1375 cm ^-1
NMR spectrum (chloroform-d, δ): 3.29 (2H, triple., J = 7.4 Hz), 3.80 (3H, single.), 4.60 (2H, triple., J = 7 4 Hz), 6.70 - 6.87 (3H, mult.), 7.19 - 7.33 (1H, mult.)
The drug 59.

To a solution of 1-methoxy-3- (2-nitroethyl) benzene (22.59 g) and tert-butyl acrylate (15.98 g) in dichloromethane (180 ml), a 1.8- solution is added while cooling in an ice bath diazabicyclo [5.4.0] undec-7-ene (1.90 g) in dichloromethane (45 ml.). After stirring at room temperature for 18.5 hours, ice water (70 ml) was added to the solution. The organic layer was separated and washed sequentially with 1N hydrochloric acid and brine. The resulting solution was treated with silica gel (70 g) and evaporated in vacuo to give tert-butyl-5- (3-methoxyphenyl) -4-nitroverate (29.39 g)
IR (liquid): 1720, 1600, 1545 cm ^-1
NMR spectrum (chloroform-d, δ): 1.37 (9H, single), 1.98 - 2.34 (4H, multip.), 2.94 (1H, doublet, doublets, J = 5.9 Hz, 14.1 Hz), 3.18 (1H, doublet of doublets, J = 8.5 Hz, 14.1 Hz), 3.71 (3H, single), 4.64 - 4.83 (1H, mult.), 6.61 - 6.75 (3H, mult.), 7.09 - 7.21 (1H, mult.)
Mass spectrum (m / z): 308 (M ⁺ -1)
The drug is 60.

To a solution of tert-butyl-5- (3-methoxyphenyl) -4-nitroverate (10.00 g) in 1,4-dioxane 10 ml), while cooling in an ice bath, a 4N solution of hydrogen chloride in 1,4-dioxane was added (17.8 ml). After stirring for 3 days at room temperature, ice water (60 ml) was added to the resulting solution, and sodium chloride (6 g) was adjusted to pH 9.5 with saturated aqueous sodium bicarbonate and the solution was washed with ethyl acetate. Further, after the pH of the solution was adjusted to 1 with a 6N hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous brine, dried over anhydrous sodium sulfate, treated with silica gel (20 g) and evaporated in vacuo to give 5- (3-methoxyphenyl) -4-nitrovaleric acid (8.00 g)
IR (liquid): 2950 - 2300, 1700, 1540 cm ^-1
NMR spectrum (chloroform-d, δ): 2.03-2.57 (4H, multip.), 3.03 (1H, doublet of doublets, J = 6.1 Hz, 14.1 Hz), 3.28 (1H, doublet of doublets, J = 8.2 Hz, 14.1 Hz), 3.79 (3H, single), 4.72-4.91 (1H, mult.), 6.68-6.90 (3H, mult.), 7.17-7.31 (1H, mult.)
Mass spectrum (m / z): 252 (M ⁺ -1)
Drug 61.

A mixture of 5- (3-methoxyphenyl) -4-nitrovaleric acid (1.00 g) and thionyl chloride (0.34 ml) in 1,2-dichloroethane (2 ml) was refluxed for 1 hour. After cooling, aluminum chloride (0.53 g) was added to the solution at -12 ^° C and the resulting mass was stirred for 0.5 hour. The solution was poured into ice water (15 ml.). The organic layer was separated, and the aqueous phase was further extracted with dichloromethane. The extracts are combined, washed with saturated sodium bicarbonate and salt, dried over anhydrous sodium sulfate and evaporated in vacuo to give 2-methoxy-8-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (772 mg .).

T. pl. 120 - 122 ^o C
IR (Nujol): 1665, 1590, 1545 cm ^-1
NMR spectrum (chloroform-d, δ): 2.21-2.55 (2H, multip.), 2.65 - 2.84 (1H, multip.), 2.93 - 3.14 (1H, multip. .), 3.37 (1H, doublet of doublets, J = 5.6 Hz, 14.6 Hz), 3.62 (1H, doublet of doublets, J = 7.8 Hz, 14.6 Hz), 3.87 (3H, single), 4.85 - 5.03 (1H, mult.), 6.76 (1H, double, J = 2.5 Hz), 6.91 (1H, doublet of doublets, J = 2 5 Hz, 8.7 Hz), 7.82 (1H, double, J = 8.7 Hz).

 Drug 62.

To a solution of (S) - (-) - 4-acetylamino-5- (3-methoxyphenyl) valerianic acid (706 mg) in 1,2-dichloroethane (2.1 ml), thionyl chloride (0.25) is added at 0 ^° C. ml) and the mixture is stirred for 3 hours. Dichloromethane (2.1 ml) was added to the mixture, and then aluminum chloride (0.72 g) was added portionwise at -10 ^° C.

 After stirring for 2 hours, the solution was poured into ice water and acidified with dilute hydrochloric acid. It is extracted with dichloromethane, the extract is washed with a saturated solution of sodium bicarbonate and salt, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of n-hexane and ethyl acetate to obtain (S) - (-) - 8-acetoamino-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (329 mg) as powder.

Mp 132 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{21.1}}{\text{D}}$ = -97.2 ^o (c = 0.51, MeOH)
IR (Nujol): 3310, 1650, 1595 cm ^-1
NMR spectrum (chloroform-d, δ): 1.38 - 1.60 (1H, multip.), 1.98 (3H, single), 2.10 - 2.32 (1H, multip.), 2 50 - 2.84 (2H, mult), 2.90 (1H, doublet of doublets, J = 14.4 Hz, 5.0 Hz), 3.19 (1H, doublet of doublets, J = 14.4 Hz , 5.2 Hz), 3.86 (3H, single), 4.37 - 4.58 (1H, mult.), 5.53 (1H, double, J = 7.5 Hz), 6, 67 (1H, double, J = 2.5 Hz), 6.87 (1H, doublet of doublets, J = 2.5 Hz, 8.6 Hz), 7.79 (1H, double, J = 8, 6 Hz).

 Drug 63.

 A solution of 2-methoxy-8-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.20 g) in acetic acid (2 ml) is hydrogenated under a pressure of 4 atm hydrogen in the presence of palladium on coal (0.20 g). After removal of the catalyst, the pH of the solution was adjusted to 12 with sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (153 mg).

 NMR spectrum (chloroform-d, δ): 1.38 - 2.10 (4H, multip.), 1.41 (2H, broad single), 2.60 - 3.06 (5H, multip.) , 3.77 (3H, single), 6.64 (1H, doublet of doublets, J = 8.1 Hz, 2.7 Hz), 6.71 (1H, doublet, J = 2.7 Hz), 6.98 (1H, double, J = 8.1 Hz).

 Drug 64.

 A mixture of tert-butyl 5- (3-methoxyphenyl) -4-nitroverate (0.31 g) 10% palladium on carbon (0.31 g) and ammonium formate (0.63 g) in methanol (3 , 1 ml) was stirred at room temperature for 0.5 hour. After removal of insoluble material, the filtrate was evaporated in vacuo. Ethyl acetate and water were added to the residue, and the organic layer was separated. The aqueous phase is further extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give tert-butyl-4-amino-5- (3-methoxyphenyl) valerate (245 mg).

IR (liquid): 3455, 1620, 1600, 1580 cm ^-1
NMR spectrum (chloroform-d, δ): 1.44 (9H, single), 1.51 - 1.95 (2H, multip.), 2.05 (2H, broad single), 2.21 - 2.47 (2H, mult.), 2.50 (1H, doublet of doublets, J = 8.6 Hz, 13.3 Hz), 2.80 (1H, doublet of doublets, J = 4.8 Hz, 13 , 3 Hz), 3.80 (3H, single), 6.65 - 6.86 (3H, mult.), 7.15 - 7.30 (1H, mult.).

Mass spectrum (m / z): 280 (M ⁺ ), 224
A solution of tert-butyl-4-amino-5- (3-methoxyphenyl) valerate (0.22 g) in 1,4-dioxane (0.2 ml) was added acetic anhydride (0.08 ml) and the solution was stirred in for 80 minutes. Next, ethanol was added to the solution, and the mixture was stirred for 15 minutes. The pH of the reaction mixture was adjusted to 12 with sodium hydroxide solution and the aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give tert-butyl 4-acetylamino-5- (3-methoxyphenyl) valerate (246 mg.).

IR (liquid): 3275, 3060, 1720, 1640, 1540, 1365 cm ^-1
NMR spectrum (chloroform-d, δ): 1.43 (9H, single), 1.52 - 1.90 (2H, multip.), 1.83 (2H, broad single), 2.15 - 2.42 (2H, mult.), 2.70 (1H, doublet of doublets, J = 7.2 Hz, 13.5 Hz), 2.85 (1H, doublet of doublets, J = 5.6 Hz, 13 5 Hz), 3.79 (3H, single), 4.01 - 4.24 (1H, mult.), 6.56 (1H, broad double, J = 8.5 Hz), 6, 67 - 6.84 (3H, mult.), 7.15 - 7.28 (1H, mult.)
Mass spectrum (m / z): 322 (M ⁺ ), 266, 206
The drug is 65.

 To a solution of tert-butyl 4-acetylamino-5- (3-methoxyphenyl) valerate (508 mg) in 1,4-dioxane (2 ml) was added a 4N solution of hydrogen chloride in 1,4-dioxane (4 ml) and the resulting solution was stirred within 1 hour. The mixture is poured into ice water (6 ml) and the resulting solution is adjusted to pH 12 with sodium hydroxide solution, the mixture is washed successively with di-isopropyl ether and ethyl acetate, and then the solution is adjusted to pH 1 with a 6N hydrochloric acid solution. It is extracted with ethyl acetate, the extract is washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 4-acetylamino-5- (3-methoxyphenyl) valeric acid (362 mg).

IR (liquid): 3300, 2950 - 2300, 1700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.55-1.98 (2H, multip.), 1.93 (3H, single), 2.30 - 2.47 (2H, multip.), 2 65 - 2.92 (2H, multip.), 3.78 (3H, single), 4.09 - 4.3 (1H, multip.), 5.88 (1H, broad double, J = 8.9 Hz), 6.67 - 6.87 (3H, mult.), 7.13 - 7.26 (1H, mult.), 9.42 (1H, wide single)
Mass spectrum (m / z): 266 (M ⁺ +1)
Drug 66.

 A mixture of 4-acetylamino-5- (3-methoxyphenyl) valerianic acid (151 mg) and (+) - zinconine (110 mg) in 1,4-dioxane 92.6 ml) is refluxed and then allowed to cool. The precipitated crystals are separated by filtration and dried, obtaining a salt of (S) -4-acetylamino-5- (3-methoxyphenyl) valerianic acid and (+) - zinconine (117 mg). The resulting compound was recrystallized from 1,4-dioxane to give a pure salt (61 mg.).

T. pl. 122 - 126 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{23,2}}{\text{D}}$ = +123.3 ^o (c = 1, EtOH)
IR (Nujol): 3250, 3180, 2725, 1660, 1590 cm ^-1
NMR spectrum (DMSO-d, δ): 1.29 - 2.00 (7H, multip.), 1.75 (3H, single), 2.02-2.39 (3H, multip.), 2 41 - 2.84 (5H, mult), 2.90 - 3.15 (2H, mult), 3.20 - 4.90 (1H, broad mult), 3.72 (3H, single .), 3.78 - 4.04 (1H, mult.), 4.99 - 5.20 (2H, mult.), 5.28 - 5.45 (1H, mult.), 5.98 - 6 , 21 (1H, mult.), 6.68 - 6.85 (3H, mult.), 7.10 - 7.26 (1H, mult.), 7.49 - 7.82 (2H, mult.) 7.45 (1H, double, J = 4.4 Hz), 8.00 (1H, double, J = 8.4 Hz), 8.25 (1H, double, J = 8.4 Hz ) 8.83 (1H, doublet, J = 4.4 Hz).

 Drug 67.

The salt of (S) -4-acetylamino-5- (3-methoxyphenyl) valerianic acid and (+) - zinconin (55.7 g) was suspended in ethyl acetate and the solution was adjusted to pH 1 with dilute hydrochloric acid. The organic layer was separated, and the aqueous phase was further extracted with ethyl acetate. The extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (S) - (-) - 4-acetylamino-5- (3-methoxyphenyl) valerianic acid (26.40 g)
Mp 66-70 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{23,2}}{\text{D}}$ = -4.3 ^o (c = 1.06, MeOH)
IR (Nujol): 3270, 1730, 1610 cm ^-1
NMR spectrum (chloroform-d, δ): 1.55 - 1.98 (2H, multip.), 1.92 (3H, single), 2.30 - 2.46 (2H, multip.), 2 64 - 2.92 (2H, multip.), 3.76 (3H, single), 4.08 - 4.30 (1H, multip.), 6.19 (1H, broad double, J = 8.8 Hz), 6.67 - 6.85 (3H, mult.), 7.13 - 7.26 (1H, mult.), 9.82 (1H, wide single)
Drug 68.

To a solution of (S) - (-) - 8-acetoamino-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (1.2 g) in the boron trifluoride complex (approx .47%, 23.9 ml), triethylsilane (3.42 ml) was added at room temperature and the resulting mixture was stirred for 3 days, poured into ice water and the pH of the solution was adjusted to 9 with sodium hydroxide solution. The mixture is extracted with chloroform, the extract is washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by recrystallization from g-hexane to give (S) - (-) - N-acetyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (1.09 g)
T. pl. 185 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{21,2}}{\text{D}}$ = -45.0 ^o (c = 0.51, MeOH)
IR (Nujol): 3290, 1635 cm ^-1
NMR spectrum (chloroform-d, δ): 1.43 - 1.80 (2H, multip.), 1.85 - 2.00 (2H, multip.), 1.89 (3H, single) 2, 64 - 2.82 (2H, mult.), 2.84 (1H, doublet of doublets, J = 13.8 Hz, 7.8 Hz), 3.02 (1H, doublet of doublets, J = 13.8 Hz, 1.7 Hz), 3.78 (3H, single), 4.13 - 4.31 (1H, multip.) 5.26 (1H, double, J = 7.7 Hz), 6.64 - 6.75 (2H, multip.) 7.02 (1H, double, J = 8.9 Hz).

 The drug is 69.

 A mixture of (S) - (-) - N-acetyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (0.75 g) and potassium hydroxide (15.84 g. ) in a mixture of water (11.2 ml) and methanol (45 ml) is refluxed for 3 days. After cooling, the mixture was evaporated in vacuo. Water and ethyl acetate were added to the residue. The organic layer was separated, the aqueous phase was further extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over potash and evaporated in vacuo. The residue was dissolved in ethyl acetate and a 4N solution of hydrogen chloride in ethyl acetate (0.71 ml) was added. The precipitate formed was filtered off and dried, yielding (S) - (+) - 3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (606 mg) as colorless crystals.

[α] $\genfrac{}{}{0ex}{}{\text{18.0}}{\text{D}}$ = +30.3 ^o (c = 1.49, MeOH)
The drug is 70.

To a solution of 7-methoxy-1-tetralone (50 g) and trimethylsulfonium iodide (69.48) in dimethyl sulfoxide (330 ml), a solution of potassium tert-butoxide (38.21 g) was added dropwise at 24 ^° C - 28 ^° C. in dimethyl sulfoxide (165 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture is poured into cold water (500 ml) and extracted with ethyl acetate. The organic layer was separated, washed with water (500 ml, three times), dried over magnesium sulfate and evaporated in vacuo to give crude spiro (3,4-dihydro-7-methoxynaphthalene-1- (2H), 2'-oxiran) (48 , 15 g.) In the form of a pale yellow oil.

IR (film): 1610, 800, 720 cm ^-1
NMR spectrum (chloroform-d, δ): 1.75 - 1.95 (1H, mult), 1.95 - 2.20 (3H, mult), 2.80 - 2.95 (2H, mult .), 2.96 (2H, single), 3.76 (3H, single), 6.61 (1H, double, J = 2.7 Hz), 6.76 (1H, doublet of doublets, J = 8.4 Hz, 2.7 Hz), 7.02 (1H, double, J = 8.4 Hz)
Mass spectrum (m / z): 189 (M-1)
The drug 71.

 To a solution of benzylamine (22.53 g) in 1-propanol (120 ml), a solution of spiro (3,4-dihydro-7-methoxynaphthalene-1 (2H), 2'-oxirane (40.0 g) in 1-propanol (40 ml) with gentle boiling. The mixture is heated under the same conditions for 4 hours. The solvent is removed and ethyl acetate (200 ml) is added to the residue. The extract is washed with water (200 ml, four times), dried over sodium sulfate and The residue is taken up in a 4N solution of hydrogen chloride in ethyl acetate to give 1-benzylaminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol hydrochloride as a white powder.

T. pl. 188 - 189 ^o C
IR (Nujol): 3340, 1610, 100, 740, 700 cm ^-1
NMR spectrum (DMSO-d, δ): 1.4 - 1.90 (3H, multip.), 2.97 (2H, broad single), 3.69 (3H, single), 4.19 (2H, broad single), 5.93 (1H, wide single), 6.75 - 6.80 (1H, mult.), 6.95 - 7.05 (2H, mult.), 7 , 35 - 7.55 (3H, mult.), 7.60 - 7.70 (2H, mult.), 8.94 (1H, broad single), 9.57 (1H, wide single) .

Mass spectrum (m / z): 298 (M + 1) ⁺
The drug 72.

 A mixture of 1-benzylaminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-nephthalenol hydrochloride (45.00 g) ammonium formate (25.50 g) and 10% palladium on carbon (50% vl. 4.5 g) in methanol is refluxed for 40 minutes. After cooling, the catalyst was filtered off and the filtrate was evaporated in vacuo. Water (45 ml) was added to the residue), 1N hydrochloric acid solution (90 sludge) and diethyl ether (120 ml), and the organic layer was separated. The aqueous layer was alkalinized with 5N aqueous sodium hydroxide solution (45 ml) and extracted with ethyl acetate (6 times in 600 ml). The organic extracts were combined, dried over sodium sulfate and evaporated in vacuo to give 1-aminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (27.89 g) as a pale yellow powder.

Mp 79 - 81 ^o C
IR (Nuhol): 3360, 3300, 1610, 810, 730, 700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.60 - 2.20 (7H, mult), 2.60 - 2.80 (2H, mult), 2.80 - 3.00 (2H, mult .), 3.79 (3H, single), 6.75 (1H, doublet of doublets, J = 8.4 Hz, 2.7 Hz), 6.99 (1H, doublet of doublets, J = 8.4 Hz), 7.06 (1H, double, J = 2.7 Hz).

Mass spectrum (m / z): 207 (M ⁺ ), 178, 121
Drug 73.

To a solution of 1-aminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (27.50 g) in a 10% aqueous solution of acetic acid (250 ml) was added dropwise at 8 ^° C - 9 ^o C a solution of sodium nitrate (10.07 g) in water (61 ml.). The resulting mixture was stirred at the indicated temperature for 2 hours. The precipitate formed is filtered off and dissolved in ethyl acetate. Dry the resulting solution over magnesium sulfate and evaporate in vacuo. The residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate: chloroform = 5: 1: 3) to obtain 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (19.39 g. ) in the form of a white powder.

 The spectral data of the obtained compound coincide with similar data for the authentic sample.

 Drug 74.

To a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (220 g) in methanol (1300 ml), sodium borohydride (2.0) was added portionwise at 6 ^° C - 30 ^° C. g), and then the mixture is stirred for 40 minutes and evaporated in vacuo. The residue was partitioned between ethyl acetate (1 l.) And water (1 l.). The organic layer was washed with 1N hydrochloric acid (500 ml), aqueous sodium bicarbonate (500 ml) and salt (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol as a white powder.

Mp 57 - 59 ^o C
IR (film): 3350, 1610, 760, 740, 700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.40 - 1.65 (2H, mult.), 1.70 - 1.95 (2H, mult.), 1.95 - 2.20 (1H, mult .), 2.5 - 2.75 (2H, mult.), 2.90 - 3.10 (2H, mult.), 3.78 (3H, single), 3.65 - 3.90 (1H , mult.) 6.66 (1H, doublet of doublets, J = 8.1 Hz, 2.7 Hz), 6.73 (1H, double, J = 2.7 Hz), 6.98 (1H, double ., J = 8.1 Hz).

Mass spectrum (m / z): 192 (M ⁺ ), 135
Drug 75.

 A mixture of (RS) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (221 g), iso-propenyl acetate (380 ml) and PS lipase (Amano) (221 g) in di-iso-propyl ether (4.8 L) was stirred at room temperature for 4 days. The reaction mixture was filtered through celite and evaporated under reduced pressure. The residue was purified by thin layer chromatography (silica gel, dichloromethane and dichloromethane-methanol (20: 1) were used successively as eluent). (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl acetate (138.2 g) is isolated from the first eluate as a pale yellow oil, and (S) is isolated from the second eluate ) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (104.4 g) as a colorless powder.

 (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl acetate.

[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ = +16.01 ^o (c = 1.18, methylene chloride)
IR (film): 1715, 1610, 810 cm ^-1
NMR spectrum (chloroform-d, δ): 1.35 - 1.65 (1H, multip.), 1.65 - 2.00 (2H, multip.), 2.01 (3H, single), 2 , 00 - 2.20 (1H, mult), 2.65 - 2.80 (2H, mult), 2.87 (1H, broad double, J = 13.6 Hz), 3.10 ( 1H, doublet of doublets, J = 13.6 Hz, 0.8 Hz) 3.77 (3H, single), 4.70 - 4.90 (1H, mult.), 6.60 - 6.75 (2H , mult.), 6.99 (1H, double, J = 7.9 Hz).

Mass spectrum (m / z): 234 (M ⁺ ), 174
(S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol.

T. pl. 75 - 78 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{D}}$ = +16.11 ^o (c = 0.72, methylene chloride)
IR (Nujol): 3350, 3270, 1610, 810, 700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.30 - 1.65 (2H, mult.), 1.65 - 1.95 (2H, mult.), 1.95 - 2.15 (1H, mult .), 2.60 - 2.75 (2H, mult.), 2.90 - 3.10 (2H, mult.), 3.70 - 3.90 (1H, mult.), 3.78 (3H single), 6.66 (1H, doublet of doublets, J = 8.1 Hz, 2.7 Hz), 6.74 (1H, doublet, J = 2.7 Hz), 7.00 (1H, double., J = 8.1 Hz).

Mass spectrum (m / z): 192 (M ⁺ ), 135
Drug 76.

 To a solution of (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl acetate (136 g) in methanol (1.36 L) was added dropwise a solution of sodium hydroxide (46, 4 g) in water (232 ml) at room temperature. The mixture was stirred for another 1 hour. and evaporated in vacuo. The residue was partitioned between ethyl acetate (1.1 L) and brine (550 ml). The organic layer was washed with 1N hydrochloric acid solution (550 ml), dried over magnesium sulfate and evaporated to give (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (108.96 g .) in the form of a white powder.

T. pl. 76 - 78 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{19}}{\text{D}}$ = -15.16 ^o (c = 1.2, methylene chloride)
IR (Nujol): 3300, 1610, 810, 700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.40 - 1.65 (2H, mult.), 1.70 - 1.95 (2H, mult.), 1.95 - 2.20 (1H, mult .), 2.65 - 2.75 (2H, mult.), 2.90 - 3.10 (2H, mult.), 3.78 (3H, single), 3.65 - 3.90 (1H , mult.), 6.66 (1H, doublet of doublets, J = 8.1 Hz, 2.7 Hz), 6.73 (1H, double, J = 2.7 Hz), 6.98 (1H, double, J = 8.1 Hz)
Mass spectrum (m / z): 192 (M ⁺ ), 135
Drug 77.

To a solution of (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (108.96 g) in pyridine (550 ml) at 10 ^o C - 13 ^o C added in portions p-toluenesulfonyl chloride (129.66 g). The resulting mixture was stirred at room temperature for 1 day. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (1600 ml) and water (1080 ml). The organic layer was washed successively with 1N hydrochloric acid (1080 ml), aqueous sodium bicarbonate (1080 ml) and brine (500 ml), dried over magnesium sulfate and evaporated to give a colorless powder. It is washed with n-hexane (twice) to give (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl-4-methylbenzenesulfonate (182.23 g)
T. pl. 88 - 89 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +26.40 ^o (c = 2.5, methylene chloride)
IR (Nujol): 1610, 1590, 1350, 1180, 760 cm ^-1
NMR spectrum (chloroform-d, δ): 1.20 - 1.50 (1H, multip.), 1.75 - 2.25 (3H, multip.) 2.46 (3H, single), 2, 55 - 2.70 (2H, mult.) 2.84 (1H, triplet doublet, J = 13.8 Hz, 1.7 Hz), 3.08 (1H, doublet of doublets, J = 13.8 Hz, 10 , 1 Hz), 3.75 (3H, single), 4.54 - 4.55 (1H, mult.), 6.44 (1H, double, J = 2.7 Hz), 6.65 ( 1H, doublet of doublets, J = 8.2 Hz, 2.7 Hz), 6.95 (1H, double, J = 8.2 Hz), 7.30 - 7.40 (2H, mult.) 7, 75 - 7.85 (2H, mult.)
Mass spectrum (m / z): 346 (M ⁺ ), 174
Drug 78.

 The following compounds were obtained by a method similar to that described for preparation 77.

1) (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl-4-methylbenzenesulfonate
T. pl. 92 - 95 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = -30.99 ^o (c = 1.01, methylene chloride)
IR (Nujol): 1610, 1600, 1580, 1350, 1180, 760, 720 cm ^-1
NMR spectrum (chloroform-d, δ): 1.10 - 1.50 (1H, multip.), 1.75 - 2.20 (3H, multip.), 2.46 (3H, single), 2 55 - 2.75 (2H, mult), 2.75 - 2.95 (1H, mult), 2.95 - 3.15 (1H, mult), 3.75 (3H, single) , 4.35 - 4.55 (1H, multip.), 6.45 (1H, double, J = 2.6 Hz), 6.65 (1H, doublet of doublets, J = 8.2 Hz, 2, 6 Hz), 6.95 (1H, double, J = 8.2 Hz), 7.34 (2H, double, J = 8.1 Hz), 7.79 (2H, double, J = 8 , 1 Hz).

Mass spectrum (m / z): 346 (M ⁺ ), 174
2) 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl-4-methylbenzenesulfonate
T. pl. 76 - 78 ^o C
IR (Nujol): 1600, 1350, 1170, 820, 750 cm ^-1
NMR spectrum (chloroform-d, δ): 1.15 - 1.50 (1H, multip.), 1.75 - 2.20 (3H, multip.), 2.46 (3H, single), 2 60 - 2.70 (2H, mult), 2.80 - 2.90 (1H, mult), 3.00 - 3.15 (1H, mult), 3.76 (3H, single) , 4.35 - 4.55 (1H, multip.), 6.45 (1H, double, J = 2.7 Hz), 6.65 (1H, doublet of doublets, J = 8.2 Hz, 2, 7 Hz), 6.95 (1H, double, J = 8.2 Hz), 7.34 (2H, double, J = 8.1 Hz), 7.79 (2H, double, J = 8 , 1 Hz).

Mass spectrum (m / z): 346 (M ⁺ ), 174
3) 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylmethanesulfonate
T. pl. 96 - 97 ^o C
IR (Nujol): 1610, 1340, 1200, 770, 740, 720 cm ^-1
NMR spectrum (chloroform-d, δ): 1.35 - 1.70 (1H, mult), 1.75 - 2.15 (2H, mult), 2.15 - 2.40 (1H, mult .), 2.70 - 2.75 (2H, mult), 3.00 (3H, single), 3.10 - 3.30 (2H, mult), 3.78 (3H, single) 4.65 - 4.85 (1H, multip.), 6.65 - 6.80 (2H, multip.), 7.00 (1H, double, J = 8.1 Hz).

Mass spectrum (m / z): 270 (M ⁺ ), 159
The drug 79.

To a solution of (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl-4-methylbenzenesulfonate (181.0 g) in dimethyl sulfoxide (2170 ml), azide was added in portions at room temperature sodium (67.93 g) and the resulting mixture was stirred at 40 ^o C for 2 days. The reaction mixture was poured into a mixture of ethyl acetate (2.2 L) and ice water (2.2 L). The organic layer was separated, washed successively with aqueous sodium bicarbonate (1.1 L), water (1.1 L three times) and brine (550 ml), dried over magnesium sulfate, treated with activated carbon and evaporated in vacuo. The residue was purified by column chromatography (silica gel 350 g, n-hexane: ethyl acetate = 10: 1) to obtain the azido derivative [IR spectrum (film), 2100 cm ^-1 (-N ₃ )]. The resulting compound (111.2 g) was mixed with ammonium formate (96.82 g) and 10% palladium on charcoal (50% vl. 7.78 g) in methanol and refluxed for 1 hour . After cooling the mixture, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate (1 L) and 2N aqueous sodium hydroxide solution (1.5 L). The organic layer was separated, washed with water (1 liter) and brine (500 ml), dried over potash and the solvent was removed in vacuo. The residue was treated with a 4N solution of hydrogen chloride in ethyl acetate while cooling in an ice bath to obtain (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride (86.8 g) in colorless crystals.

T. pl. 258 - 261 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +30.59 ^o (c = 1.50, MeOH)
IR (Nujol): 2610, 2500, 1610, 830, 760, 720 cm.

 NMR spectrum (DMSO-d, δ): 1.15 - 1.25 (1H, mult.), 1.65 - 2.05 (2H, mult.), 2.05 - 2.25 (1H, mult .), 2.60 - 2.75 (2H, mult.), 2.85 - 3.10 (3H, mult.), 3.72 (3H, single), 6.60 - 6.75 (2H , mult.), 7.00 - 7.10 (1H, mult.), 8.15 (3H, broad single).

Mass spectrum (m / z): 191 (M ⁺ ), 148
The drug is 80.

 The following compounds were obtained by a method similar to that described for the preparation 79.

1) (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
T. pl. 264 - 265 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = -29.59 ^o (c = 1.22, MeOH)
IR (Nujol): 2610, 2500, 1610, 830, 760, 720 cm ^-1
NMR spectrum (DMSO-d, δ): 1.15 - 1.25 (1H, mult.), 1.65 - 2.05 (2H, mult.), 2.05 - 2.25 (1H, mult .), 2.60 - 2.75 (2H, mult.), 2.75 - 3.10 (3H, mult.), 3.72 (3H, single) 6.60 - 6.75 (2H, mult.), 7.00 - 7.10 (1H, mult.) 8.20 (3H, wide single)
Mass spectrum (m / z): 191 (M ⁺ ), 148
2) 3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride
Mp 230 - 233 ^o C (decomp.)
IR (Nujol): 2600, 2520, 1610, 760 cm ^-1
NMR spectrum (DMSO-d, δ): 1.15 - 1.45 (1H, mult.), 1.60 - 2.05 (2H, mult.), 2.05 - 2.30 (1H, mult .) 2.55 - 2.80 (2H, mult) 2.80 - 3.15 (3H, mult), 3.72 (3H, single), 6.60 - 6.85 (2H, mult) .), 6.95 - 7.10 (1H, multip.) 8.19 (3H, broad single).

Mass spectrum (m / z): 191 (M ⁺ ), 148
Drug 81.

To a mixture of (S) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (1.00 g) phthalimide (0.77 g) and triphenylphosphine (1.36 g. ) in absolute tetrahydrofuran at 26 ^° C - 33 ^° C, a solution of diethyl azodicarboxylate (0.91 g) in absolute tetrahydrofuran (3 ml) is added dropwise. The mixture was stirred at room temperature for 2 days. The solvent was evaporated in vacuo. Diethyl ether (30 ml) was added to the residue and the mixture was stirred, the precipitated triphenylphosphine oxide crystals were separated by filtration. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate (5: 1) to obtain (R) -N- (3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6 -yl) phthalimide in the form of a white powder (0.43 g)
T. pl. 132 - 133 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -40.76 ^o (c = 0.91, methylene chloride)
IR (Nujol): 1770, 1610, 800, 720 cm ^-1
NMR spectrum (chloroform): 1.15 - 1.70 (1H, multip.), 1.90 - 2.20 (2H, multip.) 2.40 - 3.00 (4H, multip.), 3, 77 (3H, single), 3.90 - 4.10 (1H, mult.), 4.10 - 4.30 (1H, mult.), 6.60 - 6.70 (2H, mult.), 7.00 - 7.10 (1H, mult) 7.60 - 7.75 (2H, mult), 7.80 - 7.90 (2H, mult)
Mass spectrum (m / z): 321 (M ⁺ ), 227, 174
Drug 82.

 A mixture of (R) -N- (3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) phthalimide (0.50 g) and hydrazine hydrate (0.2 ml) in ethanol (78.0 ml) was refluxed for 1 hour. The precipitates which are separated out are filtered off and the filtrate is evaporated in vacuo. The residue was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was treated with a 4N solution of hydrogen chloride in ethyl acetate to give (R) -3-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine hydrochloride.

Mp 264 - 265 ^o C
A solution of 2-bromoacetylnaphthalene (7.00 g) and tetra-n-butylammonium bromide (0.906 g) in 1,2-dichloroethane (226 ml) was refluxed for 3.5 hours, then the mixture was evaporated in vacuo and extracted dichloromethane. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with n-hexane to give 2-chloroacetylnaphthalene (4.43 g) as a yellow powder.

IR (Nujol): 1680 cm ^-1
NMR spectrum (chloroform-d, δ): 4.81 (2H, sing.) 7.5 - 7.6 (2H, multip.) 7.8 - 8.0 (4H, multip.) 7.43 ( 1H single.)
Mass spectrum (m / z): 206 and 204 (M ⁺ ), 155, 127
The drug 84.

A mixture of 2-acetoneftone (3.40 g) and selenium dioxide (4.88 g) in a mixture of dioxane (200 ml) and water (1 ml) is boiled with stirring for 6 hours and filtered, the filter is concentrated in vacuo and extracted with diethyl ether. The extract was washed three times with brine, dried over magnesium sulfate and evaporated in vacuo to give a pale brown powder of 2.2 '' - oxybis (2-hydroxy-2'-acetoneftone) (3.21 g)
Mp: 112 - 122 ^o C
IR (Nujol): 3320, 1690 cm ^-1
NMR spectrum (chloroform-d, δ): 5.06 (2H, broad single), 6.58 (2H, single), 7.2 - 8.3 (12H, mult), 8.75 (2H, single.).

Mass spectrum (m / z): 184, 155, 127
The drug is 85.

 The following compounds were obtained by a method similar to that described for preparation 84.

1) 2.2 '' - oxybis (2-hydroxy-1'-acetonaphton)
Mp: 89 - 91 ^o C
IR (Nujol): 3410, 3270, 1665 cm ^-1
NMR spectrum (chloroform-d, δ): 5.16 (2H, broad single), 6.50 (2H, single) 7.4 - 7.7 (6H, mult) 7.85 (2H doublet, J = 8.6 Hz), 8.06 (2H, doublet, J = 8.2 Hz), 8.40 (2H, doublet of doublets, J = 1.1 Hz, 7.4 Hz) 8.99 (2H, doublet of doublets, J = 0.8 Hz, 8.4 Hz)
Mass spectrum (m / z): 184, 155
2) 2.2 "- oxybis [2-hydroxy-1- (5'-indanyl) ethanone]
T. pl. 111 - 122 ^o C
IR (Nujol): 3380, 1670, 1600 cm ^-1
NMR spectrum (chloroform-d, δ): 2.06 (2H, triple., J = 7.4 Hz), 2.14 (2H, triple., J = 7.4 Hz), 2.94 (8H triple, J = 7.4 Hz), 5.06 (2H, double, J = 10.0 Hz), 6.33 (2H, double, J = 10.0 Hz), 7.29 ( 2H, double, J = 11.9 Hz), 7.92 (2H, double, J = 11.9 Hz), 7.95 (2H, single)
3) 2.2 "- oxybis [1- (5'-benzofurazanil) -2-hydroxyethanone]
NMR spectrum (chloroform-d, δ): 4.46 (2H, double, J = 10 Hz), 5.72 (2H, double, J = 19 Hz), 7.9 - 8.2 (4H , mult.), 8.6 - 8.7 (2H, mult.)
Drug 86.

To a suspension of potassium tert-butoxide (0.82 g) in tetrahydrofuran (6.6 ml), cooled in an ice bath, a solution of trimethylsulfonium iodide (98% pure, 1.5 g) in dimethyl sulfoxide (6.6 ml) was added . Upon completion of the addition of the indicated solution to the mixture, the temperature of which is kept below 5 ^° C., a solution of piperonal (1.0 g) in tetrahydrofuran (3.3 ml) is added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into water and extracted once with ethyl acetate. The extract was washed twice with water and once with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 3,4-methylenedioxyphenyloxyran (1.0 g), which was used in the next reaction without further purification.

NMR spectrum (chloroform-d, δ): 2.74 (1H, doublet of doublets, J = 2 Hz, 5 Hz), 3.09 (1H, doublet of doublets, J = 4 Hz, 5 Hz), 3.78 (1H, doublet of doublets, J = 2 Hz, 4 Hz), 5.94 (2H, single), 6.6 - 6.9 (3H, mult.)
Mass spectrum (m / z): 164
Drug 87.

Methyl formate (7.8 ml) was added to a mixture of p-toluenesulfonate of benzyl ester of L-tyrosine (41.0 g), pyridine (16.4 ml) and dichloromethane (92 ml) cooled in an ice bath. The mixture was stirred in an ice bath for 1 hour, diluted with water and extracted once with dichloromethane. The extract was evaporated in vacuo, the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. Purifying the product by silica gel column chromatography (gradient elution, chloroform-ethyl acetate: 10: 1 to 5: 1) gives N-methoxycarbonyl L-tyrosine benzyl ester (22.0 g)
T. pl. 100 - 101 ^o C
IR (Nujol): 3360, 1720, 1700 cm ^-1
NMR spectrum (chloroform-d, δ): 3.01 (2H, double, J = 6 Hz), 3.65 (3H, single) 4.5 - 4.8 (1H, mult) 4, 8 - 5.6 (4H, mult.) 6.6 - 6.8 (2H, mult.) 6.8 - 7.0 (2H, mult.), 7.2 - 7.6 (5H, mult. )
Mass spectrum (m / z): 329
Drug 88.

A mixture of N-methoxycarbonyl L-tyrosine benzyl ester (22.0 g) methyl iodide (10.8 ml) potassium carbonate (24.0 g) and N, N-dimethylformamide (87 ml) was stirred at room temperature for 5 hours. The mixture was diluted with dichloromethane (87 ml) and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The crude product is purified by spraying in petroleum ether to give N-methoxycarbonyl-O-methyl-L-tyrosine benzyl ester (16.0 g)
T. pl. 83 - 84 ^o C
IR (Nujol): 3430, 1730 cm ^-1
NMR spectrum (chloroform-d, δ): 3.03 (2H, double, J = 6 Hz), 3.66 (3H, single) 3.76 (3H, single) 4.5 - 4, 8 (1H, mult) 5.0 - 5.3 (3H, mult) 6.7 - 6.8 (2H, mult) 6.8 - 7.0 (2H, mult) 7.2 - 7.5 (5H, mult.)
Mass spectrum (m / z): 268 (MH ₂ CO ₂ Me) ⁺
The drug 89.

A mixture of N-methoxycarbonyl-O-methyl-L-tyrosine benzyl ester (15.5 g) of 10% palladium-carbon (0.73 g) and tetrahydrofuran (14.5 ml) was shaken at room temperature in a hydrogen atmosphere within 2 hours. An additional amount of 10% palladium on carbon (0.73 g) was added and shaking was continued for another 2 hours. The catalyst is filtered off and washed with hydrofuran. The filtrate and wash solution were combined and evaporated in vacuo to give N-methoxycarbonyl-O-methyl-L-tyrosine (10.5 g)
T. pl. 85 - 86 ^o C
IR (Nujol): 3260, 3140, 1730, 1660 cm ^-1
NMR spectrum (chloroform-d, δ): 2.9 - 3.2 (2H, multip.) 3.67 (3H, single) 3.79 (3H, single) 4.5 - 4.8 ( 1H, mult.) 5.0 - 5.2 (1H, mult.) 6.7 - 6.9 (2H, mult.) 7.0 - 7.2 (2H, mult.)
Mass spectrum (m / z): 221 (M-CH ₃ OH) ⁺
The drug is 90.

Thionyl chloride (0.29 ml) was added to a solution of N-methoxycarbonyl-O-methyl-L-tyrosine (0.5 g) in dichloromethane (2 ml). After stirring for 1 hour at room temperature, the reaction mixture was evaporated in vacuo. The residue was dissolved in dichloromethane (5 ml) and treated with cooling in an ice bath with a 0.9 M solution of ethyl aluminum dichloride in dichloromethane (4.4 ml). Allow the resulting mixture to warm to room temperature and leave to mix overnight. It is poured into concentrated hydrochloric acid over ice chips and extracted once with dichloromethane. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using dichloromethane-ethyl acetate (10: 1) as an eluent to give 6-methoxy-2- (methoxycarbonylamino) indan-1-one (0.12 g)
T. pl. 174 - 177 ^o C
IR (Nujol): 3330, 1720, 1680 cm ^-1
NMR spectrum (chloroform-d, δ): 2.86 (1H, doublet of doublets, J = 5 Hz, 16 Hz), 3.38 (1H, doublet of doublets, J = 8 Hz, 16 Hz), 3.54 (3H, single.) 3.80 (3H, single.), 4.26 (1H, doublet of doublets of doublets, J = 5 Hz, 8 Hz), 7.11 (1H, doublet, J = 2 Hz), 7.28 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 7.45 (1H, double, J = 8 Hz), 7.69 (1H, double, J = 8 Hz).

Mass spectrum (m / z): 235
Drug 91.

 A mixture of 6-methoxy-2- (methoxycarbonylamino) indal-1-one (0.30 g) boron trifluoride etherate (0.90 ml) and ethanedithiol (0.90 ml) was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The extracts are combined, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, n-hexane-ethyl acetate, 5: 1 to 2: 1) to obtain 6-methoxy-2- (methoxycarbonylamino) indan-1-one ethylenedithioacetal (0.48 g) as oils.

IR (film): 3330, 1700 cm ^-1
NMR spectrum (chloroform-d, δ): 2.63 (1H, doublet of doublets, J = 7.8 Hz, 15 Hz) 3.0 - 3.6 (5H, mult) 3.72 (3H, single. ) 3.81 (3H, single) 4.5 - 4.8 (1H, mult), 5.3 - 5.6 (1H, mult), 6.78 (1H, doublet of doublets, J = 2 Hz) 8 Hz) 6.9 - 7.1 (2H, mult.)
Mass spectrum (m / z): 311
Drug 92.

 A mixture of 6-methoxy-2- (methoxycarbonylamino) indan-1-one ethylenedithioacetal (0.12 g), Raney nickel (suspension in water, 5 ml) and ethanol (12 ml) was refluxed for 0.5 hour. filter and rinse the catalyst with hot ethanol. The filtrate and wash solution are combined and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent — chloroform) to obtain 5-methoxy-N-methoxycarbonylindan-2-amine (0.08 g).

T. pl. 120-121 ^o C
IR (Nujol): 3290, 1670 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 2.5 - 2.9 (2H, multip.) 2.9 - 3.2 (2H, multip.), 3.52 (3H, single) 3.69 (3H, single), 4.1 - 4.3 (1H, mult) 6.68 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.77 (1H, double. J = 2 Hz), 7.07 (1H, doubled, J = 8 Hz) 7.3 - 7.5 (1H, mult.)
Mass spectrum (m / z): 221
Drug 93.

A mixture of 5-methoxy-N-methoxycarbonylindan-2-amine (0.25 g) and 47% hydrobromic acid (20 ml) was refluxed for 4 hours. After cooling, the mixture was evaporated in vacuo. Toluene was added to the residue, and the resulting solution was evaporated to dryness in vacuo to give 5-hydroxyindan-2-amine hydrobromide (0.26 g)
T. pl. > 235 ^o C (decomp.)
IR (Nujol): 3370 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 2.7 - 3.0 (2H, mult) 3.0 - 3.3 (2H, mult) 3.8 - 4.1 (1H, mult) 6, 5 - 6.8 (2H, mult) 7.04 (1H, double. J = 7 Hz), 8.03 (3H, broad single). 9.24 (1H, broad single).

Mass spectrum (m / z): 149
The drug 94.

A mixture of 5-hydroxyindan-2-amine hydrobromide (0.66 g) triethylamine (0.95 ml) di-tert-butyl dicarbonate (0.75 g) and N, N-dimethylformamide (6.6 ml) was stirred at room temperature in for 4 hours, diluted with ethyl acetate and the precipitated precipitate is filtered off. The filtrate was evaporated in vacuo to give a crude product, which was further purified by silica gel column chromatography (eluent 5: 1 - n-hexane-ethyl acetate) to obtain N-tert-butoxycarbonyl-5-hydroxyindan-2-amine (0.44 g)
IR (film): 3330, 1670 cm ^-1
NMR spectrum (chloroform-d, δ): 1.45 (9H, single) 2.6 - 2.8 (2H, mult) 3.1 - 3.4 (2H, mult), 4.3 - 4.6 (1H, broad multip.), 4.6 - 4.9 (1H, broad, multip) 5.32 (1H, broad single), 6.64 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.70 (1H, broad, single) 7.04 (1H, double, J = 8 Hz)
Mass spectrum (m / z): 249
Drug 95.

 A mixture of N-tert-butoxycarbonyl-5-hydroxyindan-2-amine (0.42 g), potassium carbonate (0.34 g) ethyl bromoacetate (0.24 ml) and N, N-dimethylformamide (4.2 ml) was stirred at room temperature for 20 hours. An additional amount of ethyl bromoacetate (0.12 ml) and potassium carbonate (0.17 g) were added and stirring was continued for another 12 hours. The mixture is diluted with ethyl acetate and the precipitated precipitate is filtered off. The filtrate was evaporated in vacuo, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, 5: 1 n-hexane-ethyl acetate) to obtain N-tert-butoxycarbonyl-5-ethoxycarbonylmethoxyindal-2-amine (0.44 g).

T. pl. 73 - 75 ^o C
IR (Nujol): 3400, 1750, 1700 cm ^-1
NMR spectrum (chloroform-d, δ): 1.30 (3H, trip. J = 7 Hz), 1.44 (9H, single) 2.6 - 2.9 (2H, multip.) 3.1 - 3.4 (2H, mult) 4.27 (2H, quart J = 7 Hz), 4.3 - 4.5 (1H, broad mult) 4.58 (2H, single) 4.6 - 4.9 (1H, broad cartoon) 6.72 (1H, doublet of doublets, J = 2 Hz), 6.76 (1H, broad single), 7.10 (1H, double. J = 8 Hz).

Mass spectrum (m / z): 335
Drug 96.

A mixture of N-tert-butoxycarbonyl-5-ethoxycarbonylmethoxyindan-2-amine (0.39 g) and a 4 N solution of hydrogen chloride in 1,4-dioxane (11.6 ml) were allowed to stand at room temperature for 2 hours. The mixture was evaporated in vacuo to give a solid product, which was washed with di-isopropyl ether and dried in vacuo to give 5 - (ethoxycarbonylmethoxy) indan-2-amine hydrochloride (0.247 g)
T. pl. 155 - 160 ^o C
IR (Nujol): 2600, 1750 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.21 (3H, triple, J = 7 Hz),
2.8 - 3.0 (2H, mult.) 3.0 - 3.4 (2H, mult.) 3.9 - 4.1 (1H, mult.) 4.15 (2H, quart., J = 7 Hz), 4.73 (2H, single),
6.75 (1H, doublet of doublets, J - 2 Hz, 8 Hz),
6.85 (1H, double, J = 2 Hz), 7.16 (1H, double, J = 8 Hz),
8.23 (3H, broad single).

Mass spectrum (m / z): 235
Example 1

1) A mixture of 6-amino-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.0 g) oxide (R) -3-chlorostyrene (0.58 g) and n-propanol ( 7.6 ml) was refluxed for 3 hours. After cooling, the reaction mixture was evaporated in vacuo. Primary chromatography on silica gel (gradient elution, first g-hexane-ethyl acetate 3: 1, then ethyl acetate, finally ethyl acetate-ethanol, from 25: 1 to 10: 1) yields about 0.8 g of crude product. Thin film chromatography on silica gel was carried out (gradient elution, 1: 3 n-hexane-ethyl acetate to 25: 1 ethyl acetate-ethanol) and a mixture of (1R, 6'R) and (1R, 6'S) - 2 - [(3-ethoxycarbonylmethoxy) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol (0.60 g)
2) The resulting mixture (0.60 g) was dissolved in ethyl acetate (2.5 ml) and, while cooling, it was treated with a 4N solution of hydrogen chloride in ethyl acetate (3.5 ml). Stirred for 5 minutes, evaporated the mixture in vacuo. Dissolve the residue in ethanol (5 ml) and precipitate by adding n-hexane (40 ml). The solvent was removed in vacuo, the resulting solid was collected, washed with n-hexane and dried, yielding a mixture of (1R, 6'R) - and (1R, 6'S) - 2 - [(3-ethoxycarbonylmethoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol hydrochloride (0.54 g)
T. pl. 114-119 ^o C
IR (Nujol): 3400, 3170, 1740 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.19 (3H, triple. J = 7 Hz), 1.20 (3H, triple. J = 7 Hz), 1.1 - 1.5 (2H, mult.), 1.7 - 2.1 (4H, mult) 2.2 - 2.5 (2H, mult.) 2.5 - 2.9 (4H, mult.) 2.9 - 3.4 ( 12H, mult.) 4.14 (2H, quarter J = 7 Hz), 4.16 (2H, quarter J = 7 Hz), 4.70 (2H, single) 4.71 (2H, single) 4.9 - 5.1 (2H, mult.), 6.3 - 6.4 (2H, mult.) 6.6 - 6.8 (2H, mult.) 6.8 - 6.9 (2H, mult.) 7.0 - 7.1 (2H, mult.) 7.3 - 7.6 (8H, mult.) 8.8 - 9.6 (2H, mult.).

FAB mass spectrum (m / z): 420 (M ⁺ + 3 - HCl), 418 (M ⁺ + 1-HCl)
Example 2

 The following compounds were obtained by a method similar to that described in example 1.

1) (1R, 6'R) - and (1R, 6'S) - 2 - [(2-ethoxycarbonylmethoxy-6,6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol hydrochloride
IR (Nujol): 3300, 1740 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.29 (6H, triple. J = 7 Hz), 1.3 - 2.3 (8H, mult.) 2.3 - 2.6 (2H, mult .) 2.6 - 2.9 (4H, mult.) 2.9 - 3.5 (10H, mult.), 4.26 (2H, quart. J = 7 Hz), 4.56 (4H, single .), 5.2 - 5.8 (2H, mult.) 6.4 - 6.8 (4H, mult.) 6.9 - 7.6 (10H, mult.) 8.2 - 8.8 ( 2H, mult.) 9.6 - 10.4 (2H, mult.)
FAV mass spectrum (m / z): 420 (M ⁺ + 3-HCl), 418 (M ⁺ + 1-HCl)
2) (1R, 6'R) and (1R, 6'S) -2 - [(3-ethoxycarbonylmethoxy-5,6,7,8,9,10-hexahydrobenzocycloocten-6-yl) amino] -1- (3- chlorophenyl) ethanol hydrochloride
T. pl. 62-66 ^o C
IR (Nujol): 3275, 1750, 1605, 1575, 1500, 1200 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.80-1.0 (2H, multip.), 1.20 (6H, triple, J = 7.1 Hz), 1.30 - 1.90 (10H, mult.), 2.57 - 2.89 (4H, mult.) 3.0 - 3.45 (10H, mult.), 4.16 (4H, quart. J = 7.1 Hz), 4.72 (4H, mult), 4.95 - 5.13 (2H, mult) 6.3 - 6.4 (2H, mult).)
6.7 - 6.8 (2H, mult) 6.8 - 6.9 (2H, mult)
7.0 - 7.1 (2H, mult) 7.35 - 7.6 (8H, mult) 8.5 - 9.4 (4H, mult)
FAB mass spectrum (m / z): 434 (M ⁺ + 3-HCl), 432 (M ⁺ + 1-HCl)
3) (1R, 6'S) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] 1- (3-chlorophenyl) ethanol hydrochloride
T. pl. 91 - 98 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = +12.45 ^o (c = 0.53, EtOH)
IR (Nujol): 3360, 1750, 1595 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.19 (3H, triple. J = 7 Hz), 1.2 - 1.4 (1H, mult) 1.7 - 2.1 (2H, mult .) 2.2 - 2.4 (1H, mult.) 2.6 - 2.8 (2H, mult.) 2.9 - 3.3 (5H, mult.) 4.15 (2H, quarter J = 7 Hz), 4.70 (2H, single) 4.9 - 5.1 (1H, mult) 6.33 (1H, double J = 4 Hz) 6.6 (1H, doublet of doublets, J = 2 Hz, 8 Hz) 6.87 (1H, double J = 2 Hz), 7.03 (1H, double J = 8 Hz), 7.3 - 7.6 (4H, mult) 8.6 - 9.3 (2H, mult.)
FAB mass spectrum (m / z): 420 (M ⁺ + 3-HCl), 418 (M ⁺ + 1-HCl)
Chemical analysis for: C ₂₃ H ₂₈ ClNO ₄ HCl • H ₂ O
Calculated,%: C 58.47; H 6.61; N, 2.96;
Found,%: C 58.63; H 6.79; N, 2.98.

4) (1R, 6'R) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol hydrochloride
IR (Nujol): 3500-2000, 1740 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.20 (3H, triple, J = 7 Hz), 1.1-1.4 (1H, mult), 1.6-2.1 (2H , mult.), 2.2-2.4 (1H, mult.), 2.6-2.8 (2H, mult.), 2.9-3.4 (5H, mult.), 4.16 (2H, quart., J = 7 Hz), 4.71 (2H, single.), 4.9-5.1 (1H, mult.), 6.34 (1H, double., J = 3 Hz) 6.67 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.81 (1H, double, J = 2 Hz), 7.04 (1H, double, J = 8 Hz), 7 3-7.6 (4H, mult), 8.6-8.9 (1H, mult), 9.1-9.4 (1H, mult)
FAB mass spectrum (m / z): 420 (M ⁺ + 3-HCl), 418 (M ⁺ -HCl)
5) (1R, 2'R) - and (1S, 2'S) -2 - [(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) amino] -1- (3,4-methylenedioxyphenyl ) ethanol hydrochloride
T. pl. 175-180 ^o C
IR (Nujol): 3320, 2500, 2400, 1750 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.20 (CH, triple. J = 7 Hz), 1.6-2.0 (2H, multip.), 2.2-2.5 (2H, mult.), 2.6-3.6 (14H, mult.), 4.15 (4H, quart., J = 7 Hz), 4.71 (4H, single), 4.9-5.1 (2H, mult.), 6.02 (4H, single.), 6.1-6.2 (2H, mult.), 6.6-6.8 (4H, mult.), 6.8-7 , 1 (8H, mult.), 8.7-9.1 (2H, broad. Mult.), 9.2-9.6 (2H, broad. Mult.)
Mass spectrum (m / z): 414 (M + 1) ⁺
6) (1R, 2'R) - and (1S, 2'S) -2 - [(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) amino] -1- (5-benzofurazanyl) ethanol hydrochloride
T. pl. 205-220 ^o C
IR (Nujol): 3300, 1750 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.20 (CH, triple, J = 7 Hz), 1.6-2.0 (2H, mult), 2.2-2.5 (2H , mult.), 2.6-3.7 (14H, mult.), 4.15 (4H, quart., J = 7 Hz), 4.72 (2H, single), 5.25 (2H, mult.), 6.5-6.9 (4H, mult.), 7.02 (2H, double, J = 8 Hz), 7.71 (2H, double, J = 9 Hz), 8, 05 (2H, single), 8.12 (2H, double, J = 9 Hz), 8.9-9.3 (2H, broad cartoon), 9.4-9.8 (2H, broad .mult.)
Mass spectrum (m / z): 412 (M + 1) ⁺
7) (1R, 6'R) - and (1R, 6'S) -2- [N-benzyl [3- (2-ethoxycarbonylpropan-2-yloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6 -yl] amino] -2- (3-chlorophenyl) ethanol hydrochloride
T. pl. 95-106 ^o C
IR (Nujol): 3170, 1720, 1600 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.0-1.3 (8H, multip.), 1.4-1.6 (12H, multip.), 1.8-2.2 (4H, mult.), 2.4-2.8 (6H, mult.), 2.9-3.7 (10H, mult.), 4.05-4.3 (4H, mult), 4.6-5 6 (6H, mult), 6.3-8.0 (26H, mult), 10.2-11.2 (2H, mult)
Mass spectrum (m / z): 536 (M ⁺ + 1-HCl)
8) (-) - (2'S) -1- (6-chloro-2-pyridyl) 2 - [(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) amino] ethanol
T. pl. 107-109 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{28,4}}{\text{D}}$ = -93.4 ^o C (c = 0.20, EtOH)
IR (Nujol): 3260, 1730 cm ^-1
NMR spectrum (chloroform-d, δ): 1.30 (3H, triple., J = 7.1 Hz), 1.46-1.73 (1H, multip.), 1.96-2.15 ( 1H, multip.), 2.44-3.30 (7H, multip.), 1.70-3.10 (2H, broad multip.), 4.27 (2H, quart., J = 7.1 Hz), 4.66-4.81 (1H, mult.), 6.59 (1H, double, J = 2.5 Hz), 6.69 (1H, doublet of doublets, J = 2.7 Hz, 8.4 Hz), 6.98 (1H, double, J = 8.4 Hz), 7.23 (1H, double, J = 7.8 Hz), 7.44 (1H, double, J = 7.6 Hz), 7.67 (1H, pseudo triple., J = 7.7 Hz).

9) (1R, 2'R) - and (1R, 2'S) -1 - [(3-chlorophenyl) -2- (N-methylthioethyl-7-nitro-1,2,3,4-tetrahydro-2-naphthyl ) aminoethanol
IR (liquid): 3400, 1510, 1340 cm ^-1
NMR spectrum (chloroform-d, δ): 1.46-1.95 (2H, multip.), 1.99-2.24 (2H, multip.), 2.16 (3H, single), 2 , 17 (3H, single), 2.40-3.24 (22H, mult), 4.26 (2H, broad single), 4.57-4.75 (2H, mult), 7 26 (10H, single), 7.40 (2H, single), 7.90-8.09 (4H, mult.)
10) (1R, 6'R) - and (1R, 6'S) 2- [N-benzyl- [3-ethoxycarbonylmethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl] amino] -1 - (3-chlorophenyl) ethanol dihydrochloride
T. pl. 132-134 ^o C.

IR (Nujol): 3225, 1740 cm ^-1
Example 3

 The following compounds were obtained by a method similar to that described in example 1-1).

1) (1R, 2'R) - (1R, 2'S) 2 - [(5-ethoxycarbonylmethoxy-2-indanyl) amino] -1- (3-chlorophenyl) ethanol
T. pl. 104-105 ^o C
IR (Nujol): 1760 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (6H, triple., J = 7 Hz), 1.6-3.3 (12H, mult.), 3.6-3.8 (2H, mult.), 4.26 (4H, quart., J = 7 Hz), 4.58 (4H, single), 4.65 (2H, doublet of doublets, J = 3 Hz, 8 Hz), 6.6 -6.8 (4H, mult.), 7.09 (2H, double, J = 7 Hz), 7.1-7.5 (8H, mult.).

FAB mass spectrum (m / z): 392 (M ⁺ +3), 390 (M ⁺ +1)
2) (1R, 6'R) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino-1- (3-chlorophenyl) ethanol
T. pl. 98-100 ^o
[α] $\genfrac{}{}{0ex}{}{\text{29th}}{\text{D}}$ = -38.3 ^° C (c = 0.62, EtOH)
IR spectrum (solution in methylene chloride): 3450 -3400, 1740 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.18 (3H, triple., J = 7 Hz), 1.2-2.1 (4H, mult.), 2.5-2.9 (7H , mult.), 4.14 (2H, quart., J = 7 Hz), 4.5-4.7 (1H, mult.), 4.68 (2H, single), 5.3-5, 6 (1H, mult.), 6.58 (1H, doublet of doublets, J = 2 Hz, 8 Hz), 6.73 (1H, double, J = 2 Hz), 6.96 (1H, double, J = 8 Hz), 7.2-7.5 (4H, mult.)
FAB mass spectrum (m / z): 420 (M + 3), 418 (M + 1)
Chem. analysis for C ₂₃ H ₂₈ ClNO ₄
Calculated,%: C 66.19; H 6.75; N, 3.35;
Found,%: C 66.21; H 6.94; N, 3.36.

3) (1R, 6'R) - or (1R, 6'S) or (1S, 6'R) - or (1S, 6'S) -1- (2-naphthyl) 2- [N-benzyl- (3-hydroxy -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] ethanol (isomer A)
NMR spectrum (chloroform-d, δ): 1.2-1.3 (1H, br), 2.0 (3H, br), 2.6-2.8 (7H, mult), 3 67 (1H, double, J = 13.6 Hz), 3.97 (1H, double, J = 13.6 Hz), 4.70 (1H, doublet of doublets, J = 3.9 Hz, 9 , 9 Hz), 6.51 (1H, doublet of doublets, J = 2.6 Hz, 8.0 Hz), 6.62 (1H, double, J = 2.6 Hz), 6.88 (1H, double, J = 8.0 Hz), 7.1-7.5 (8H, mult.), 7.8 (4H, mult.)
Mass spectrum (m / z): 438 ((M ⁺ + 1)
4) (1R, 6'R) - or (1R, 6'S) or (1S, 6'R) - or (1S, 6'S) -1- (2-naphthyl) -2- [N-benzyl (3-hydroxy -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] ethanol (isomer B)
NMR spectrum (chloroform-d, δ): 1.2-1.3 (1H, broad), 1.4-1.7 (1H, mult), 1.9-2.0 (1H, mult .), 2.2-2.3 (1H, mult.), 2.6-3.1 (7H, mult.), 3.60 (1H, double, J = 13.6 Hz), 3, 84 (1H, doublet, J = 13.6 Hz), 4.59 (1H, doublet of doublets, J = 3.6 Hz, 10.1 Hz), 6.51 (1H, doublet of doublets, J = 2, 6 Hz, 9.0 Hz), 6.59 (1H, double, J = 2.6 Hz), 6.87 (1H, double, J = 9.0 Hz), 7.1-7.5 (8H, mult.), 7.7-7.8 (4H, mult.)
5) (1R, 2'S) - or (1S, 2'S) -1- (2-naphthyl) -2 - [(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) amino] ethanol
T. pl. 113-114 ^o C
[α] _D = -74.16 ^o (s = 0.48 MeOH)
IR (Nujol): 3430, 1725 cm ^-1
NMR spectrum (chloroform-d, δ): 1.29 (3H, triple., J = 7.2 Hz), 1.5-1.7 (1H, multip.), 2.0 (1H, multip. ), 2.2-3.2 (9H, multip.), 4.22 (2H, quart., J = 7.2 Hz), 4.56 (2H, single), 4.89 (1H, doublet doublets, J = 3.6 Hz, 8.8 Hz), 6.59 (1H, double, J = 2.5 Hz), 6.68 (1H, doublet of doublets, J = 2.5 Hz, 8, 3 Hz), 6.99 (1H, oak., J = 8.3 Hz), 7.4-7.5 (3H, mult.), 7.8-7.9 (4H, mult.)
Mass spectrum (m / z): 420 (M ⁺ + 1), 401 and 388
Example 4

1) A mixture of 2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (0.69 g) of (R) -3-chloro-styrene oxide (0.44 g) and n-propanol (5.2 ml) is refluxed for 1.5 hours. After cooling, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-ethanol, 100: 1) to obtain a mixture of (1R, 6'R) - and (1R, 6'S) -2 - [(2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro -5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol (0.46 g)
The resulting mixture (0.33 g) was dissolved in ethanol (3.3 ml) and treated with a solution of oxalic acid (71 mg) in ethanol (3.3 ml). After 5 minutes, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (3.3 ml) and precipitated by the addition of di-iso-propyl ether (3.3 ml). The solvent was removed in vacuo and the precipitate was dried, yielding a mixture of (1R, 6'R) - and (1R, 6'S) -2 - [(2-ethoxycarbonylmethoxy 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl ) amino-1- (3-chlorophenyl) ethanol oxalate (0.40 g).

T. pl. 65-87 ^o C
IR (Nujol): 3500-2200, 1750-1730 cm ^-1 .

NMR spectrum (DMCO-d ₆ , δ): 1.1-1.5 (2H, multip.), 1.20 (6H, triple, J = 7 Hz), 1.6-2.4 (6H , mult.), 2.5-2.8 (4H, mult.), 2.9-3.4 (10H, mult.), 4.15 (4H, quart., J = 7 Hz), 4, 7 (4H, single), 4.8-5.1 (2H, mult.), 5.1-6.5 (4H, mult.), 6.5-6.8 (4H, mult.), 7.0-7.2 (2H, mult.), 7.3-7.6 (8H, mult.)
FAB mass spectrum (m / z): 420 (M ⁺ + 3 - C ₂ H ₂ O ₄ ), 418 (M ⁺ + 1 - C ₂ H ₂ O ₄ )
Example 5

To a suspension of (1R, 6'R) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol (0, 30 g) in a 50% aqueous solution of ethanol (7.0 ml) sodium hydroxide (0.09 g) is added. After stirring at room temperature for 0.5 hour, the reaction mixture was treated with 3M hydrochloric acid (0.8 ml) and the precipitate formed was collected and washed with cold water. The precipitate was suspended in ethanol (20 ml) and the resulting mixture was allowed to stir overnight at room temperature. After filtration, followed by drying in vacuo, (R) - [8- [R -2- (3-chlorophenyl) -2-hydroxyethylamino] -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy] acetic acid is obtained acid (0.22 g)
T. pl. 265 - 266 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{thirty}}{\text{D}}$ = -22.4 ^o (c = 0.56, 1NNaOH)
IR (Nujol): 3500 - 2200, 1600 cm ^-1
NMR spectrum (DMCO-d ₆ + NaOD, δ): 1.0 - 2.1 (4H, mult.), 2.3 - 3.0 (7H, mult.) 3.9 - 4.2 (2H , mult.) 4.5 - 4.8 (1H, mult.), 6.4 - 7.0 (3H, mult.) 7.1 - 7.5 (4H, mult.)
Mass spectrum (m / z): 392 (M + 3), 390 (M + 1)
Example 6

 The following compounds were obtained by a method similar to that described in example 5.

 1) (S) - [8 - [(R) -2 - (3-chlorophenyl) -2-hydroxyethylamino] -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy] acetic acid.

Mp 247 - 249 ^o C (decomp.)
[α] $\genfrac{}{}{0ex}{}{\text{22.8}}{\text{D}}$ = + 26.2 ^o (s = 0.205, 1NNaOH)
IR (Nujol): 2700, 2350, 1600, 1580, 1540 cm ^-1
NMR spectrum (DMCO-d ₆ + NaOD, δ): 1.19 - 2.04 (5H, multip.) 2.42 - 2.86 (6H, multip.) 4.02 (2H, single) 4 47 - 4.66 (1H, multip.) 6.47 (1H, doublet of doublets, J = 8.1 Hz, 2.5 Hz), 6.61 (1H, doublet, J = 2.5 Hz), 6.88 (1H, oak. J = 8.1 Hz) 7.17 - 7.55 (4H, mult.)
Chemical analysis for C ₂₁ H ₂₄ ClNO ₄
Calculated,%: C 64.69; H 6.20; N, 3.59;
Found,%: C 64.47; H 6.29; N, 3.59.

2) 2- {(RS) - 8 - [(R) - 2 - (3-chlorophenyl) - 2 - hydroxyethylamino] 6,7,8,9-tetrahydro-5H-benzocyclohepten-2 - yloxy} 2 - 2 - methylpropionic acid
Mp 134 - 141 ^o C (decomp.)
IR (Nujol): 1565, 1145 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.3 (2H, multip.) 1.47 (6H, signal) 1.50 (6H, single) 1.43 - 3.1 (20H, mult.), 4.9 - 4.95 (2H, mult.) 6.55 (2H, double, J = 8.0 Hz), 6.68 (2H, single) 6.89 ( 2H, double J = 8.0 Hz) 7.3 - 7.5 (8H, mult.)
3) - {(RS) - [8 - [(R) -2 - (3-chlorophenyl) - 2 - hydroxyethylamino] - 6,7,8,9 - tetrahydro-5H-benzocyclohepten-2-yl} propionic acid
Mp 221 - 224 ^o C
IR (Nujol): 3210, 2650, 2325 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.18 - 2.10 (8H, multip.) 2.39 - 3.00 (22H, multip.) 4.58 - 4.75 (2H, multip. ), 5.51 (2H, broad sing.) 6.86 - 7.08 (6H, mult.) 7.23 - 7.48 (8H, mult.)
(E) - 3 - {(RS) - 8 - [(R) -2 - (3-chlorophenyl) 2 - hydroxyethylamino] 6,7,8,9 - tetrahydro-5H-benzocyclohepten-2 - yl} acrylic acid
Mp 222 - 228 ^o C
IR (Nujol-d ₆ , δ): 3500, 2670, 2340 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.20 - 2.23 (8H, multip.) 2.58 - 3.25 (14H, multip.) 4.74 - 5.00 (2H, multip. ), 5.55 (2H, broad sing.) 6.48 (2H, double. J = 15.9 Hz), 7.13 (2H, double. J = 7.8 Hz) 7.25 - 7, 64 (14H, mult.)
Example 7

 The following compounds were obtained by a method similar to that described in example 4.

1) (1R, 7'R) - and (1R, 7'S) - 1 - (3-chlorophenyl) - 2 - [(2-ethoxycarbonylmethoxy - 6,7,8,9 - tetrahydro-5H-benzocyclohepten-7-yl ) amino] ethanol oxalate
Mp 90 - 93 ^o C (decomp.)
IR spectrum (Nujol) 3300, 2750 - 2300, 1745, 1600, 1195 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.21 (6H, triple. J = 7.1 Hz), 1.15 - 1.45 (4H, mult.) 2.2 - 2.35 (4H , mult.) 2.65 - 2.85 (8H, mult.) 2.95 - 3.35 (6H, mult.), 4.16 (4H, quart J = 7.1 Hz) 4.71 ( 4H single), 4.90 (2H, broad double J = 7.4 Hz), 5.55 (8H, wide), 6.63 (2H, doublet of doublets, J = 8.2 Hz) 7.39 (6H, mult), 7.48 (2H, mult).

FAB mass spectrum (m / z): 420 and 418 (M ⁺ (free +1)
2) (1R, 2'R) - and (1R, 2 ') - 1 - [(3-chlorophenyl) - 2 - (N-methylthioethyl - 7 - nitro-1,2,3,4 - tetrahydro - 2 - naphthyl) aminoethanol oxalate
T. pl. 90 - 109 ^o C
IR (Nujol): 3250 cm ^-1
NMR spectrum (DMCO-d ₆ + D ₂ O, δ): 1.66 - 2.05 (2H, mult.) 2.10 - 2.35 (2H, mult) 2.13 (6H, single) 2.72 - 3.50 (22H, mult.), 4.88 - 5.07 (2H, mult.), 7.27 - 7.61 (10H, mult.) 7.90 - 8.13 ( 4H, mult.)
3) (1R, 2'S) and (1S, 2'S) 1 - (6 - chloro-2-pyridyl) 2 - [(7-ethoxycarbonylmethoxy-1,2,3,4 - tetrahydro-2 - naphthyl) amino] ethanol oxalate
T. pl. 111 - 125 ^o C (s. Decomp.)
IR (Nujol): 3250 (wide), 2800 - 2300 (wide), 1750, 1640, 790, 700 cm ^-1
NMR spectrum (DMCO-d ₆ + D ₂ O, δ): 1.20 (3H, triple. J = 7.1 Hz) 1.21 (3H, triple. J = 7.1 Hz), 2.05 - 2.40 (4H, mult.) 2.95 - 3.35 (12H, mult.) 4.15 (2H, quart., J = 7.1 Hz) 4.16 (2H, quart. J = 7 , 1 Hz), 4.30 - 4.45 (2H, mult) 4.70 (2H, single) 4.71 (2H, single), 4.95 - 5.05 (2H, mult) 6 65 - 6.95 (6H, mult), 7.35 - 7.55 (8H, mult)
Mass spectrum (m / z): 418 (M-1), 388, 278, 249
4) [(1R, 6'R) (1R, 6'S) - or [(1S, 6'R) and (1S, 6'S)] - 1 - (6-chloro-2-pyridyl-2 - [(3- ethoxycarbonylmethoxy- 6,7,8,9 - tetrahydro-5H-benzocyclohepten-6-yl) amino] ethanol oxalate
Mp 60 - 66 ^o C
IR (Nujol): 3150, 2660, 2350, 1730, 1580 cm ^-1
NMR spectrum (chloroform-d, δ): 1.1 - 1.2 (6H, multip.) 1.95 (4H, multip.) 2.24 (2H, multip.) 2.5 (4H, multip. ) 2.63 (4H, mult) 3.0 - 3.5 (10H, mult) 4.0 - 4.2 (4H, mult) 4.70 (2H, single) 4.71 (2H single) 4.9 (2H, multip.) 6.67 (2H, doublet of doublets, J = 8.1 Hz, 2.6 Hz) 6.79 (1H, double. J = 2.6 Hz), 6.85 (1H, doublet, J = 2.6 Hz), 7.04 (2H, doublet of J = 8.1 Hz), 7.48 (2H, doublet, J = 7.9 Hz), 7 5 - 7.6 (2H, mult.), 7.9 - 8.0 (2H, mult.)
Mass spectrum (m / z): 421 and 419 (M ⁺ (free d + 1)
Example 8

A mixture of (1R, 6'R) - and (1R, 6'S) - 2 - [N-benzyl - (3-hydroxy - 6,7,8,9-tetrahydro-5H - benzocycloheptene - 6 - yl) amino] -1 - (3-Chlorophenyl) ethanol (0.20 g) potassium carbonate (98 mg) and N, N-dimethylformamide (2 ml) were stirred at 60 ^° C. for 1 hour. The mixture was allowed to cool to room temperature and then cooled in an ice bath, n-tetrabutylammonium bromide (7 ml) and diethyl bromalonate (95% pure, 0.12 ml) were added and stirring was continued under cooling in an ice bath for 1, 5 h. Dilute the mixture with ethyl acetate, filter off the precipitate and wash with ethyl acetate. The filtrate and the wash solution are combined, washed twice with water, then with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (230-400 mesh. 7.1-n-hexane-ethyl acetate) to obtain a mixture of diastereomers (1R, 6'R) and (1R, 6'S) - [N-benzyl - [(3-bis - ethoxycarbonyl) methoxy - 6,7,8,9 - tetrahydro-5H - benzocycloheptene-6-yl] amino] - 1 - (3-chlorophenyl) ethanol (0.12 g)
IR (film): 3400, 1710 cm ^-1
NMR spectrum (chloroform-d, δ): 1.1 - 1.4 (14H, multip.) 1.4 - 2.4 (10H, multip.) 2.4 - 3.2 (10H, multip.) 3.6 - 4.1 (4H, mult) 4.2 - 4.5 (9H, mult) 5.5 - 4.7 (1H, mult) 6.8 - 7.1 (6H, mult.) 7.1 - 7.5 (18H, mult.)
Mass spectrum (m / z): 582 (M + 2 + H) ⁺ , 580 (M + H) ⁺
Example 9

 To a solution of (1R, 6'R) and (1R, 6'S) - 2 [(N-benzyl (3-hydroxy-6,7,8,9 - tetrahydro-5H-benzocyclohepten-6-yl) amino] - 1 - (3-Chlorophenyl) ethanol (0.42 g) in N, N-dimethylformamide (5 ml), potassium carbonate (0.15 g) was added, the mixture was stirred for 0.5 hour, bromoacetone (0.1 ml) was added to it. ) and stirred at room temperature for 18 hours. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography using as an eluent, a mixture of chloroform-methanol (100: 1). The isolated free amine is converted into its hydrochloride in the usual manner. The resulting solid is triturated with di-isopropyl ether and a mixture of (1R, 6'R) - and (1R, 6'S) - 2 - [N- (benzyl - [3 - (2-oxopropoxy) - 6,7,8,9 - tetrahydro-5H - benzocyclohepten-6-yl] amino] - 1 - (3 - chlorophenyl) ethanol hydrochloride.

Mp 66 - 75 ^o C
IR (Nujol): 3200, 2600, 1725 cm ^-1
NMR spectrum (DMCO-d ₆ δ): 0.9 - 1.3 (2H, mult) 1.8 - 2.25 (10H, mult) 2.5 - 2.9 (6H, mult) 2 9 - 3.65 (10H, mult) 4.4 - 5.55 (10H, mult) 6.3 - 7.95 (26H, mult) 9.9 - 10.3 (2H, mult. )
Mass spectrum (m / z): 478 (M ⁺ + 1-HCl)
Example 10

 The following compounds were obtained by a method similar to that described in example 9.

1) (1R, 6'R) and (1R, 6'S)) 2 - [N-benzyl - 3 - 2-oxobutoxy - 6,7,8,9 - tetrahydro-5H-benzocyclohepten-6-yl] amino] - 1 - (3-chlorophenyl) ethanol hydrochloride
T. pl. 81 - 88 ^o C
IR (Nujol): 3200, 2570, 1715, 1600 cm ^-1
NMR spectrum ((DMCO-d ₆ δ): 0.8 - 1.4 (8H, mult.), 1.65 - 2.25 (4H, mult.) 2.25 - 2.8 (10H, mult. .) 2.9 - 3.7 (10H, mult.) 4.4 - 5.6 (10H, mult.), 6.2 - 8.0 (26H, mult.), 10.0 - 10.9 (2H, mult.)
Mass spectrum (m / z): 492 (M ⁺ - HCl)
2) (1R, 6'R) - and (1R, 6'S) - 2 - (N-benzyl- [3 - (3,3-dimethyl-2-oxobutoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-6-yl] amino] 1 - (3-chlorophenyl) ethanol hydrochloride
T. pl. 93 - 101 ^o C
IR (Nujol): 3180, 2580, 1710, 1600 cm ^-1
NMR spectrum (DMCO-d ₆ , δ) 1.0 - 1.3 (20H, mult.) 1.9 - 2.2 (4H, mult.) 2.4 - 2.8 (10H, mult.) 2.8 - 3.7 (10H, mult) 4.4 - 5.5 (10H, mult) 6.3 - 8.0 (26H, mult) 9.9 - 10.8 (2H, mult) .)
Example 11

To a solution cooled in an ice bath (1R, 6'S) - and (1R, 6'S) 2 - [[(2-bis (ethoxycarbonyl) methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl] amino] -1- (3-chlorophenyl) ethanol (0.63 g) in ethanol (6.3 ml) was added 1N sodium hydroxide solution (2.6 ml) After stirring at room temperature for 5 hours, the mixture was evaporated in vacuum and a greenish solid is recovered, washed with ethanol and dried, yielding a crude product, which is then purified by reverse phase high-resolution chromatography (C silica gel, 15% acetonitrile in water) and the disodium salt of (2R, 6'R) - and (2R, 6S) -6 - [(2- (3-chlorophenyl) 2-hydroxyethylamino] 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yloxy ] malonic acid (0.38 g) as white crystals
IR (Nujol): 3380, 1620 cm ^-1
NMR spectrum (D ₂ O, δ): 1.4 - 2.3 (8H, mult) 2.6 - 3.3 (14H, mult) 6.6 - 6.9 (4H, mult) 7.09 (2H, double, J = 8 Hz), 7.2 - 7.6 (8H, mult)
Example 12

Mixture of (1R, 6'R) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol (0.30 g) and 2-methoxyethylamine (6 ml) was stirred at room temperature for 72 hours. After removing the solvent, the residue was purified by silica gel column chromatography (gradient elution, first ethyl acetate, then ethyl acetate-ethanol from 50: 1 to 25: 1 to 5: 1) to obtain the desired product, which was precipitated by the addition of chloroform. The resulting solid was suspended in a mixture of di-isopropyl ether-chloroform (10: 1, 11 ml) and stirred at room temperature for 3 hours. The precipitate was filtered off and dried in vacuo to give (1R, 6'R) -1- (3-chlorophenyl) -2 - [[3- (2-methoxyethyl) aminocarbonylmethoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-6-yl] amino] ethanol (0.21 g)
T. pl. 55 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{31}}{\text{D}}$ = -33.6 ^o (c = 0.25, EtOH)
NMR spectrum (chloroform-d ₆ , δ): 1.2 - 2.2 (5H, mult), 2.5 - 2.9 (7H, mult) 3.1 - 3.4 (4H, mult. ) 3.22 (3H, single) 4.39 (2H, single) 4.5 - 4.7 (1H, mult) 5.39 (1H, double J = 4 Hz) 6.64 (1H doublet of doublets, J = 2 Hz, 8 Hz) 6.67 (1H, double. J = 2 Hz) 6.98 (1H, double. J = 8 Hz) 7.2 - 7.4 (4H, mult. ) 7.9 - 8.1 (1H, mult.)
Mass spectrum (m / z): 449 (M + 2 H) ⁺ , 447 (M + H) ⁺
Example 13

 Solution of (1R, 2'S) -2 - [(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) amino] -1- (3-chlorophenyl) ethanol (30 mg.) And 2-methoxyethylamine ( 300 mg) in ethanol (0.5 ml) was stirred at room temperature for 72 hours. and evaporated in vacuo. The residue was redistributed between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was converted to oxalate in the usual manner, washed with diethyl ether to give (1R, 2′S) -1- (3-chlorophenyl) -2 - [[(7- (2-methoxyethyl) aminocarbonylmethoxy-1,2,3, 4-tetrahydro-2-naphthyl] amino] ethanol (20 mg) as a colorless powder.

Mp 120 - 124 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{30,4}}{\text{D}}$ = -69.75 ^o (c = 0.205, MeOH)
IR (chloroform): 3430, 3400, 3250, 2950 - 2400, 1735, 1650, 1605, 1240 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.75 (1H, mult), 2.2 (1H, mult) 2.65 - 2.95 (3H, mult) 3.05 - 3.45 (11H, mult) 4.42 (2H, single) 4.98 (1H, double J = 9.4 Hz), 5.1 (4H, br.) 6.65 - 6.8 ( 2H, mult) 7.03 (1H, double J = 8.4 Hz), 7.35 - 7.55 (4H, mult) 8.05 (1H, mult)
Example 14

 To a mixture of (R) -2-amino-1- (3-chlorophenyl) ethanol (172 mg) 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (205 mg) and acetic acid (0.27 ml) in methanol (4 ml) sodium cyanoborohydride (94 mg) was added portionwise and the mixture was stirred at room temperature for 1.5 hours. Dilute the reaction mass with water, make alkaline with a 28% ammonia solution and extract with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of chloroform-methanol (50: 1) as an eluent. The resulting free amine is converted in the usual way into its hydrochloride salt. The resulting solid was triturated with diethyl ether to give a mixture of (1R, 6'S) and (1R, 6'S) -2- (3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] - 1- (3-chlorophenyl) ethanol hydrochloride (220 mg).

Mp 178 - 182 ^o C
IR (Nujol): 3270, 1518, 1340 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.17 - 1.47 (2H, mult), 1.80 - 2.20 (4H, mult) 2.25 - 2.45 (2H, mult. ) 2.80 - 3.5 (14H, mult.) 5.0 - 5.18 (2H, mult.), 6.32 - 6.45 (2H, mult.), 7.33 - 7.6 ( 10H, mult.), 8.0 - 8.1 (2H, mult.) 8.1 - 8.3 (2H, mult.) 8.75 - 9.05 (2H, mult.) 9.3 - 9 , 7 (2H, mult.)
Mass spectrum (m / z): 361 (M ⁺ + 1 - HCl)
Example 15

To a solution of (R) -2-amino-1- (3-chlorophenyl) ethanol (343 mg) and 7-nitro-2-tetralone (354 mg) in methanol (9 ml) at 26 ^° C - 29 ^° C are added cyanoborohydride (189 mg) and acetic acid (0.6 ml) and allowed to stir overnight at room temperature. Concentrated hydrochloric acid (1 ml) was added to the resulting solution at 0 ^° C. Stirred for 3.5 hours. water (10 ml) and a 28% solution of ammonium hydroxide are added and extracted with ethyl acetate. The extract was washed with brine, dried over potash and evaporated in vacuo. The residue was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.6 ml) was added to the resulting solution. The precipitates formed are collected and dried, yielding (1R, 2'R) - and (1R, 2'S) -1- (3-chlorophenyl) -2 - [(7-nitro-1,2,3,4-tetrahydro-2- naphthyl] amino] ethanol hydrochloride (0.60 g). The resulting powder was recrystallized from a mixture of ethanol (12 ml) and methanol (5 ml) and (1R, 2'R-) or (1R, 2'S) -1- (3 -chlorophenyl) -2 - [(7-nitro-1,2,3,4-tetrahydro-2-naphthyl] amino] ethanol hydrochloride (0.17 g)
Mp 216 - 219 ^o C (decomp.)
[α] $\genfrac{}{}{0ex}{}{\text{21,2}}{\text{D}}$ = +18.5 ^o (c = 0.35, DMCO)
IR (Nujol): 3325, 2750, 2660 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.71 - 2.03 (1H, mult), 2.28 - 2.52 (1H, mult) 2.76 - 3.69 (7H, mult. ) 5.03 - 5.21 (1H, mult) 6.39 (1H, double J = 3.8 Hz), 7.30 - 7.60 (5H, mult), 7.92 - 8, 13 (2H, mult) 9.13 (1H, broad single) 9.74 (1H, wide single)
The filtrate was evaporated in vacuo and the residue was triturated with iso-propanol and diethyl ether to give (1R, 2'R) - and (1R, 2'S) -1- (3-chlorophenyl) -2 - [(7-nitro-1,2 , 3,4-tetrahydro-2-naphthyl] amino] ethanol hydrochloride (0.32 g)
Diastereomer A: NMR spectrum (DMCO-d ₆ , δ): 1.72 - 2.05 (1H, mult), 2.30 - 2.50 (1H, mult) 2.78 - 3.69 (7H , mult.) 4.80 - 4.95 (1H, mult.), 6.24 (1H, double. J = 4.3 Hz), 7.30 - 7.58 (5H, mult.), 7, 94 - 8.10 (2H, multip.) 9.11 (1H, broad single) 9.74 (1H, wide single)
Diastereomer B: NMR spectrum (DMCO-d ₆ , δ): 1.72 - 2.05 (1H, mult), 2.30 - 2.50 (1H, mult) 2.78 - 3.69 (7H , mult) 5.02 - 5.21 (1H, mult), 6.40 (1H, double, J = 3.8 Hz), 7.30 - 7.58 (5H, mult), 7 94 - 8.10 (2H, multip.) 9.11 (1H, broad single) 9.74 (1H, wide single)
Diastereomer A: Diastereomer B = 1: 7
Example 16

 A solution of (1R, 2'R) - and (1R, 2'S) -1- (3-chlorophenyl) -2 - [(7-nitro-1,2,3,4-tetrahydro-2-naphthyl] amino] ethanol hydrochloride (200 mg) in methanol (5 ml) was made alkaline with 28% ammonium hydroxide solution, extracted with ethyl acetate and the extract washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and methanol and the resulting solution was hydrogenated over 10% palladium-carbon (8.5 mg). The catalyst was removed by filtration and a 4N solution of hydrogen chloride in ethyl acetate was added to the filtrate. The solution was evaporated in vac. ume and the residue are triturated with iso-propanol and diethyl ether to give (1R, 2'R) and (1R, 2'S) -1- (3-chlorophenyl) -2 - [(7-amino-1,2,3,4 -tetrahydro-2-naphthyl] amino] ethanol dihydrochloride (191 mg.).

T. pl. 182 - 185 ^o C
IR (Nujol): 2750 - 2500 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.66 - 2.02 (2H, mult.) 2.24 - 2.46 (2H, mult.) 2.60 - 3.81 (16H, mult) , 5.12 (2H, broad double J = 7 Hz), 6.40 (2H, wide cartoon) 7.06 - 7.60 (14H, cartoon) 9.04 (2H, wide single .) 9.70 (2H, broad single). 10.31 (4H, wide single)
Example 17

 The following compounds were obtained by a method similar to that described in example 14.

1) (1R, 6'R) - and (1R, 6'S) -2 - [(3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3 -chlorophenyl) ethanol
T. pl. 107 - 120 ^o C
IR (Nujol): 3140, 3060, 1590, 1570 cm ^-1
NMR spectrum (CDCl ₃ -D ₂ O, δ): 1.40 - 2.15 (8H, multip.) 2.48 - 3.10 (14H, multip.) 4.50 - 4.67 (2H, mult), 6.95 (2H, double J = 7.8 Hz), 7.14 - 7.42 (12H, mult)
2) Ethyl-3- {(RS) -8 - [(2- (3-chlorophenyl) -2-hydroxyethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)} propionate
T. pl. 81 - 85 ^o C
IR (Nujol): 3300, 3100, 1720 cm ^-1
NMR spectrum (chloroform-d, δ): 1.23 (6H, triple. J = 7.1 Hz) 1.44 - 2.14 (6H, multip.) 1.60 - 2.90 (4H, broad mult.), 4.50 - 4.66 (2H, mult.), 6.90 - 7.44 (14H, mult.),
Example 18

 The following compound was obtained by a method similar to that described in example 15.

Ethyl (E) -3 - {(RS) -8 - [(R) -2- (3-chlorophenyl) -2-hydroxyethylamino] - 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl) } Acrylate Oxalate (2: 1)
Mp 123 - 140 ^o C
IR (Nujol): 3250, 1700 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.25 (6H, triple. 0 7.0 Hz), 1.13 - 1.44 (2H, multip.) 1.71 - 2.20 (6H, mult.) 2.65 - 3.36 (14H, mult.) 4.18 (quart J = 7.0 Hz), 4.88 - 5.07 (2H, mult.) 5.66 - 7.40 (10H, broad cartoon), 6.56 (2H, double J = 16.0 Hz), 7.12 - 7.70 (16H, cartoon)
Example 19

 A mixture of (1R, 6'R) - or (1R, 6'S) - or (1S, 6'R) - or (1S, 6'S) -1- (2-naphthyl) -2- [N-benzyl- (3- hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] ethanol] (Isomer A) (110 mg), 60% sodium hydride in oil (11 mg) and ethyl bromoacetate (46 mg ) in N, N-dimethylformamide (2 ml) was stirred at room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried, evaporated in vacuo to give (1R, 6'R) - or (1R, 6'S) - or (1S, 6'R) - or (1S, 6'S) 1- (2-naphthyl) -2- [N-benzyl- (3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptin-6-yl) amino] ethanol as an oil (mono-isomer A).

NMR spectrum (chloroform-d, δ): 1.29 (3H, triple., J = 7.1 Hz) 2.0 - 2.8 (11H, multip.) 3.74 (1H, doublet. J = 13.7 Hz), 4.00 (1H, double, J = 13.7 Hz), 4.27 (2H, quarter, J = 7.1 Hz), 4.59 (2H, single) 4 72 (1H, doublet of doublets, J = 3.6 Hz, 9.9 Hz), 6.58 (1H, doublet of doublets, J = 2.7 Hz), 8.2 Hz), 6.78 (1H, doublet) ., J = 2.7 Hz), 6.96 (1H, double. J = 8.2 Hz), 7.2 - 7.5 (7H, mult.) 7.8 (4H, mult.) 8, 01 (1H, single.)
Mass spectrum (m / z): 524 (M ⁺ +1), 506 and 366
Example 20
The following compound was obtained by a method similar to that described in example 19.

 (1R, 6'R) - or (1R, 6'S) - or (1S, 6'R) - or (1S, 6'S) -1- (2-naphthyl) -2- [N-benzyl- (3-ethoxycarbonylmethoxy -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] ethanol] (mono-isomer B).

NMR spectrum (chloroform-d, δ): 1.2 (3H, triple., J = 7.1 Hz) 1.3 - 3.1 (12H, multip.) 3.70 (1H, doublet J = 13.7 Hz), 3.77 (1H, double. J = 13.7 Hz) Oe, 4.20 (2H, quart., J = 7.1 Hz), 4.5 (2H, single.) 4 5 - 4.7 (1H, multip.), 6.59 (1H, doublet of doublets, J = 2.6 Hz, 8.1 Hz), 6.73 (1H, doublet, J = 2.6 Hz) 6.94 (1H, double. J = 8.1 Hz), 7.2 - 7.5 (7H, mult.) 7.6 - 7.8 (4H, mult.) 8.01 (1H, single .)
Mass spectrum (m / z): 524, (M ⁺ +1), 506 and 366
Example 21

 A mixture of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol hydrochloride (5.0 g) N, N-di-iso-propylene triamine (5.7 ml) oxide (R) - 3-chlorostyrene (3.8 g) and ethanol (16.4 ml) are refluxed for 40 hours. After cooling, the reaction mass is evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. Purifying the crude product using silica gel column chromatography (eluent n-hexane-ethyl acetate 4: 1) gives a diastereomeric mixture of (1R, 6'R) - and (1R, 6'S) -2- [N-benzyl- (3-hydroxy -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol (6.3 g) as an oil.

IR (film): 3250 cm ^-1
NMR spectrum (chloroform-d, δ): 0.8 - 1.0 (1H, multip.), 1.1 - 1.5 (3H, multip.) 1.5 - 1.8 (1H, multip. ) 1.8 - 2.1 (4H, mult) 2.1 - 2.4 (1H, mult) 2.4 - 2.9 (11H, mult) 3.07 (1H, doublet of doublet J = 19 Hz, 13 Hz), 3.75 (2H, quart. J = 13 Hz), 3.80 (2H, quart., J = 13 Hz), 4.0 - 5.2 (2H, wide mult. ) 4.35 (1H, doublet of doublets, J = 4 Hz, 10 Hz) 4.46 (1H, doublet of doublets, J = 4 Hz, 10 Hz), 6.52 (2H, doublet of doublets, J = 2 Hz, 8 Hz), 6.61 (1H, double J = 2 Hz) 6.64 (1H, double J = 2 Hz), 6.98 (2H, double J = 8 Hz), 7.0 - 7 , 4 (18H, mult.)
Mass spectrum (m / z): 424 (M + 2 + H) ⁺ , 422 (M + H) ⁺
Example 22

 A solution of (R) -3-chlorostyrene oxide (48 mg) and 6,7-dihydro-2-nitro-5H-benzocycloheptene-7-amine (84 mg.) In ethanol (3 ml) and dioxane (1 ml) is boiled with reflux for 1 hour. and evaporated in vacuo. The residue was chromatographed over silica gel using dichloromethane and methanol as the eluent, and the resulting oil was converted to oxalate in the usual manner. The oxalate is recrystallized from diethyl ether to give (1R, 7'R) - and (1R, 7'S) -1- (3-chlorophenyl) -2 - [[6,7-dihydro-2-nitro-5H-benzocycloheptene -7- il) amino] ethanol] oxalate (48 mg) as a light brown oil.

T. pl. 100 - 108 ^o C (decomp.)
IR (Nujol): 3300, 2750 - 2300, 1710, 1600, 1515, 1350 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 2.1 (2H, mult) 2.35 (2H, mult) 2.95 - 3.3 (8H, mult) 4.15 (2H, mult .), 4.95 (2H, mult) 6.14 (1H, broad double J = 12.8 Hz) 6.20 (1H, wide double J = 12.8 Hz) 6.86 ( 2H, double J = 12.8 Hz) 7.25 - 7.55 (10H, multip.) 8.06 (2H, doublet of doublets, J = 8.4 Hz, 2.4 Hz) 8.19 (2H double J = 2.4 Hz) 6.0 - 9.0 (8H, br. half)
FAB mass spectrum (m / z): 361 and 359 (M ⁺ -C ₂ H ₂ O ₄ +1)
Example 23

A solution of 2,2'-oxybis of 2-hydroxy-2'-acetonaphthone (77.3 mg) (S) -2-amino-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (114.3 mg) and triethylamine (0.07 ml) in ethanol (3 ml) was stirred at room temperature for 30 minutes and cooled with ice water. Sodium borohydride (45.4 mg) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The isolated oil is converted in the usual way into hydrochloride to give a colorless powder (1R, 2'R) - and (1R, 2'S) 2 - [(7-ethoxycarbonylmethoxy) 1,2,3,4-tetrahydro-2-naphthyl) amino] - 1- (2-naphthyl) ethanol hydrochloride (90.7 mg)
T. pl. 154 - 256 ^o C
IR (Nujol): 3350, 2800 - 2300, 1730 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.20 (6H, triple. J = 7.1 Hz), 1.7 - 2.0 (2H, mult) 2.2 - 3.6 (16H , mult) 4.15 (4H, quart J = 7.1 Hz), 4.72 (4H, single) 5.2 - 5.4 (2H, mult) 6.3 - 6.4 ( 2H, mult) 6.6 - 6.8 (4H, mult) 7.02 (2H, double J = 8.3 Hz), 7.5 - 7.7 (6H, mult) 7.8 - 8.1 (8H, mult.) 9.03 (2H, br. Single) 9.63 (2H, br. Single)
Mass spectrum (m / z): 262, 233
Example 24

 The following compounds were obtained by a method similar to that shown in example 23.

1) (1R, 2'S) - and (1S, 2'S) -2 - [(7-ethoxycarbonylmethoxy- 1,2,3,4-tetrahydro-2-naphthyl) amino] -1- (1-naphthyl) ethanol hydrochloride
T. pl. 70 - 84 ^o C
IR (Nujol): 3300, 2750 - 2250, 1750 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.20 (6H, triple. J = 7.1 Hz), 1.6 - 2.0 (2H, mult.), 2.2 - 3.6 ( 16H, mult.), 4.15 (4H, quart. J = 7.1 Hz), 4.70 (2H, single) 4.71 (2H, single) 5.8 - 6.0 (2H, mult .) 6.33 (2H, double. J = 3.7 Hz), 6.6 - 6.8 (4H, mult.) 7.01 (2H, double. J = 8.3 Hz), 7.5 - 7.7 (6H, mult) 7.80 (2H, double J = 6.9 Hz), 7.9 - 8.1 (4H, mult) 8.3 - 8.4 (2H, mult .) 8.91 (2H, broad sing.) 9.96 (2H, broad, single)
Mass spectrum (m / z): 420 (M ⁺ +1), 262, 233
2) (1R, 2'S) - and (1S, 2'S) -2 - [(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) amino] -1- (5-indanyl) ethanol hydrochloride
T. pl. 141 - 146 ^o C
IR (Nujol): 3325, 2750, 2510, 2490, 1740 cm ^-1
NMR spectrum (CDCl ₃ , δ) 1.29 (6H, triple. J = 7.1 Hz), 2.01 (2H, triple. J = 7.4 Hz), 2.08 (2H, triple., J = 7.4 Hz), 2.00 - 2.28 (2H, mult.) 2.42 - 2.62 - (2H, mult.) 2.65 - 3.02 (14H, mult.) 3, 10 - 3.61 (10H, mult.) 4.25 (4H, quart J = 7.1 Hz), 4.51 (4H, single) 5.44 (2H, broad cartoon) 6.55 (2H, doublet, J = 2.5 Hz), 6.71 (2H, doublet of doublets, J = 2.5 Hz, 8.4 Hz) 6.97 (2H, doublet, J = 8.4 Hz) 7.14 - 7.26 (4H, multip.) 7.31 (2H, single) 8.91 (2H, broad single), 10.17 (2H, wide single)
Example 25

 A mixture of (1R, 6'S) - and (1R, 6'S) -2 [(N-benzyl- (3-ethoxycarbonyl-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl amino] -1- (3-chlorophenyl) ethanol (0.34 g) 10% palladium on charcoal (50% hyd., 68 mg), ammonium formate (0.25 g) and ethanol (17 ml) are refluxed 20 minutes, the catalyst is filtered off and washed with ethanol. Removing the solvent in vacuo gives a residue which is washed with saturated aqueous sodium bicarbonate and salt and evaporated in vacuo. Purification of the crude product by silica gel column chromatography (eluent-ethyl acetate-et nol, 25: 1) allows to isolate the diastereomeric mixture of (1R, 6'S) - and (1R, 6'S) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino ] -1-phenylethanol (0.21 g) as an oil. It is dissolved in ethyl acetate (2.1 ml) and treated with a 4N solution of hydrogen chloride in ethyl acetate (1.4 ml). After removing the solvent, the mixture is sprayed with di of iso-propyl ether-ethyl acetate (3: 1, 2.0 ml), the precipitate was filtered off, washed with di-iso-propyl ether and dried in vacuo to give (1R, 6'R) - and (1R, 6'S) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl ) amino-1-phenolethanol hydrochloride in the form of a white powder. Chiral HPLC analysis indicates that partial epimerization of the hydroxy group in the benzyl position is observed during the reaction.

T. pl. 152-154 ^o C
IR (Nujol): 3550, 3270, 3160, 2770, 1730 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.4 (2H, multip.) 1.19 (3H, triple. J = 7 Hz), 1.20 (3H, triple. J = 7 Hz), 1.7 - 2.1 (4H, mult.) 2.2 - 2.4 (2H, mult.) 2.5 - 2.8 (4H, mult.) 2.9 - 3.4 ( 10H, multip.) 4.15 (2H, quart. J = 7 Hz), 4.18 (2H, quart. J = 7 Hz), 4.70 (2H, single) 4.71 (2H, single. ) 4.9 - 5.1 (2H, mult) 6.20 (2H, double J = 4 Hz) 6.67 (2H, doublet of doublets J = 2 Hz, 8 Hz), 6.81 (1H, double J = 2 Hz), 6.87 (1H, double J = 2 Hz) 7.03 (2H, double J = 8 Hz), 7.2 - 7.5 (10H, mult) 8, 6 - 9.0 (2H, br. Mult.), 9.1 - 9.6 (2H, br. Mult.).

Mass spectrum (m / z): 384 (M + H) ⁺
Example 26
Mixture of (S) -N-benzyl-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-amine (35.5 g) (P) -3-chlorostyrene oxide (enantiomeric excess> 97 % 20.0 g) and ethanol (99 ml) are refluxed for 45 hours. After cooling, the mixture was evaporated in vacuo and the obtained residue was purified by silica gel column chromatography (230-400 mesh, eluent dichloromethane) to give (1R, 6'S) -2- [N- (benzyl- (3-ethoxycarbonylmethoxy-6,7,8, 9- tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol (37.7 g), as a pale yellow oil, It was dissolved in ethyl acetate (340 ml) and treated under cooling in ice bath with a 4N solution of hydrogen chloride in ethyl acetate (37 ml). The ice bath was removed, the solution was heated to 40 ^° C. and slowly diluted with di-iso-propyl ether (300 ml), pre but heated to 40 ^° C. The resulting suspension was allowed to cool to room temperature and stirred for another 3.5 hours, the precipitate was isolated by filtration and washed on the filter with a mixture of di-isopropyl ether and ethyl acetate (4: 5, 90 ml). dried in vacuo to give (1R, 6'S) -2 - [(N-benzyl- (3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3- chlorophenyl) ethanol hydrochloride (35.7 g) as a white powder. Chiral HPLC analysis shows that the diastereomeric purity of the resulting product is> 99%.

T. pl. 152 - 153 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = + 29.2 ^o (c = 0.140, EtOH)
IR (Nujol): 3270, 2670, 2600, 1750 cm ^-1 )
NMR analysis shows that the product in dimethyl sulfoxide exists in the form of two rotamers.

Chemical shifts are indicated for the main rotamer
NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.4 (1H, mult.) 1.22 (3H, triple. J = 7 Hz), 1.9 - 2.3 (2H, mult .) 2.3 - 2.5 (1H, mult.) 2.5 - 2.9 (mult.) 2.9 - 3.7 (5H, mult.) 4.18 (2H, quart. J = 7 Hz), 4.4 - 4.8 (3H, mult.) 4.73 (2H, single) 6.3 - 6.4 (1H, mult.), 6.6 - 6.8 (1H, mult. .) 6.9 - 7.0 (1H, mult.) 7.03 (1H, oak. J = 8 Hz), 7.2 - 7.6 (7H, mult.) 7.8 - 8.0 ( 2H, mult.) 9.8 - 10.0 (1H, mult.)
Mass spectrum (m / z): 540 (M + 2 + H) ⁺ , 508 (M + H) ⁺ .

 Example 27

 The following compounds were obtained by a method similar to that described in example 26.

1) (1R, 6'R) -2 - [(N-benzyl- (3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl ) ethanol hydrochloride
T. pl. > 128 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = 53.2 ^o (s = 0.53, EtOH)
IR (Nujol): 3250, 2600, 1760 cm ^-1
NMR analysis shows that the product in dimethyl sulfoxide exists in the form of two rotamers.

 Chemical shifts are indicated for the main rotamer.

NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.4 (1H, multip.) 1.21 (3H, triple, J = 7 Hz), 1.9 - 2.3 (3H, mult.) 2.4 - 2.9 (3H, mult) 2.4 - 2.9 (3H, mult) 2.9 - 4.0 (4H, mult) 4.16 (2H, quart. J = 7 Hz), 4.4 - 5.0 (3H, mult) 4.70 (2H, single) 6.49 (1H, broad, mult) 6.64 (1H, doublet of doublets, J = 2 Hz 8 Hz) 6.83 (1H, broad single) 6.9 - 7.1 (1H, mult) 7.2 - 7.6 (7H, mult) 7.84 (2H, broad single) 10.2 - 10.6 (1H, broad cartoon)
Mass spectrum (m / z): 510 (M + 2 + H) ⁺ , 508 (M + H) ⁺
2) (1R, 6'R) and (1R, 6'S) -2 - [(N-benzyl- (3-pentyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] - 1- (3-chlorophenyl) ethanol hydrochloride
T. pl. 154 - 165 ^o C
IR (Nujol): 3280, 2600, 1600 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.9 - 1.0 (6H, mult.) 1.0 - 1.5 (10H, mult.) 1.6 - 1.8 (4H, mult. ) 1.85 - 2.2 (4H, mult.) 2.35 - 2.8 (6H, mult.) 2.95 - 3.7 (10H, mult.) 3.8 - 4.0 (4H, mult), 4.4 - 5.5 (6H, mult.) 6.25 - 7.95 (26H, mult.) 9.9 - 10.2 (2H, mult.)
3) (1R, 6'R) and (1R, 6'S) -2- [N-benzyl-3- (2-oxopentyloxy) - 6,7,8,9, -tetrahydro-5H-benzocyclohepten-6-yl) -amino] -1- (3-chlorophenyl) ethanol hydrochloride
T. pl. 79 - 85 ^o C
IR (Nujol): 3200, 2600, 1720, 1610 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.87 (6H, triple. J = 7.3 Hz), 1.0 - 1.4 (2H, multip.) 1.4 - 1.7 (4H , mult.) 1.8 - 2.3 (4H, mult.) 2.3 - 2.9 (10H, mult.) 2.9 - 3.7 (10H, mult.) 4.4 - 5.6 (10H, mult.) 6.2 - 8.0 (26H, mult.) 10.1 - 11.1 (2H, mult.)
Mass spectrum (m / z): 506 (M ⁺ + 1 + HCl)
4) (1R, 6'R) - and (1R, 6'S) -2- [N-benzyl- [3- (RS) -2-oxopentan-3-yloxy) -6,7,8,9-tetrahydro 5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol hydrochloride
T. pl. 104 - 109 ^o C
IR (Nujol): 3200, 2580, 1710, 1600 cm ^-1
NMR spectrum (DMCO-d ₆ , δ) 6 0.9 - 1.35 (8H, mult) 1.6 - 2.25 (14H, mult) 2.35 - 2.9 (6H, mult. ) 2.9 - 3.7 (10H, mult.) 4.35 - 5.5 (8H, mult.), 6.3 - 8.0 (26H, mult.) 9.8 - 10.8 (2H , mult.)
Mass spectrum (m / z): 506 (M ⁺ + 1 + HCl
5) (1R, 6'R) - and (1R, 6'S) -2- [N-benzyl- [2-bis- (ethoxycarbonyl) methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6- yl] amino] -1- (3-chlorophenyl) ethanol hydrochloride
T. pl. > 95 ^o C
IR (Nujol): 3400, 1740 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.1 - 1.4 (2H, multip.) 1.19 (12H, triple. J = 7 Hz), 1.8 - 2.3 (4H, mult .) 2.3 - 2.9 (8H, mult) 2.9 - 3.8 (mult) 4.22 (8H, quart J = 7 Hz), 4.3 - 4.8 (6H, mult.) 5.62 (1H, single) 5.64 (1H, single) 6.3 - 6.6 (2H, mult.) 6.7 - 6.9 (4H, mult.) 7.1 - 8.0 (20H, mult.) 9.7 - 10.1 (1H, mult.)
Mass spectrum (m / z): 582 (V + 2H), 580 (M + H) ⁺
Example 28

The following compounds were obtained by a method similar to that shown in example 21
1) (1R, 6'R) - and (1R, 6'S) -2- [N-benzyl-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1 - (3-chlorophenyl) ethanol
IR (film): 3400, 3000, 2900, 2830, 1740 cm ^-1
NMR spectrum (chloroform-d, δ): 1.28 (3H, approx. J = 7 Hz), 1.2 - 1.4 (2H, mult) 1.5 - 3.0 (2H, br. mult.) 1.6 - 1.8 (1H, mult.) 1.8 - 2.9 (18H, mult.) 3.09 (1H, doublet of doublets, J = 10 Hz, 13 Hz), 3.77 (2H, quart., J = 13 Hz), 3.82 (2H, quart. J = 13 Hz), 4.26 (2H, quart. J = 7 Hz), 4.28 (2H, quart. J = 7 Hz), 4.30 (1H, doublet of doublets, J = 3 Hz, 10 Hz), 4.48 (1H, doublet of doublets, J = 3 Hz, 10 Hz) 4.57 (2H, single.) 4, 59 (2H, single) 6.5 - 6.7 (2H, multip.), 6.73 (1H, double. J = 2 Hz), 6.78 (1H, double. J = 2 Hz), 6 95 (2H, doubled, J = 8 Hz) 7.1 - 7.4 (18H, mult.)
Mass spectrum (m / z): 510 (M + 2 + H) ⁺ , 508 (M + H) ⁺
2) (1R, 6'R) -and (1R, 6'S) -2- [N- (benzyl-3 - [(RS) -1-ethoxycarbonyl) ethoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-6-yl) amino] -1-1 (3-chlorophenyl) ethanol
T. pl. 90 - 99 ^o C
IR (film): 3300, 2580, 1730 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.0 - 1.4 (8H, mult.) 1.4 - 1.6 (6H, mult.) 1.8 - 2.2 (4h, mult. ) 2.4 - 2.9 (6H, mult) 2.9 - 3.7 (10H, mult) 4.0 - 4.3 (4H, mult) 4.4 - 5.6 (8H, mult.) 6.3 - 8.0 (26H, mult.) 10 - 11.2 (2H, mult.)
Example 29

 1) A mixture of (1R, 6'R) - and (1R, 6'S) -2 - [(N-benzyl- [3- (2-oxopropoxy) -6,7,8,9-tetrahydro-5H-benzocycloheptane-6 -yl] amino-1- (3-chlorophenyl) ethanol hydrochloride (290 mg) is catalytically hydrogenated at room temperature in a mixture of ethanol (3 ml) and chlorobenzene (3 ml) using 10% palladium on carbon (50% hyd. , 20 ml) After removal of the catalyst, the solvent was evaporated in vacuo. Ethyl acetate and water were added to the residue, the organic layer was separated, it was saturated with sodium bicarbonate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a as eluent, a mixture of chloroform-methanol (50: 1). The fractions containing the target product are collected and evaporated in vacuo to give (1R, 6'R) - and (1R, 6'S) -2 - [[(3- (2- oxopropoxy) 6,7,9,9 (tetrahydro-5H-benzocyclohepten-6-yl] amino] -1- (3-chlorophenyl) ethanol.

 2) The isolated free amine is converted in the usual way into its hydrochloride. The resulting solid was triturated with diethyl ether to give a mixture of (1R, 6'R) - and (1R, 6'S) -2 - [[(3- (2-oxo-propoxyl) -6,7,8,9-tetrahydro-5H- benzocyclohepten-2-yl] amino] -1- (3-chlorophenyl) ethanol hydrochloride.

T. pl. 155-161 ^o C
IR (Nujol): 1720, 1575 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.1 - 1.35 (2H, multip.) 1.75 - 2.1 (4H, multip.) 2.14 (6H, single) 2.2 (2H, mult.) 2.6 - 2.8 (4H, mult.), 2.3 -3.3 (10H, mult.) 4.73 (2H, single) 4.75 (2H, single. ) 4.95 - 5.1 (2H, mult.), 6.3 - 6.4 (2H, mult.), 6.6 - 6.7 (2H, mult.), 6.75 - 6.9 (2H, mult.), 6.95 - 7.1 (2H, mult.) 7.3 - 7.55 (8H, mult.), 8.7 - 8.9 (2H, mult.) 9.05 - 9.35 (2H, mult.)
Mass spectrum (m / z): 388 (M + 1 + HCl) ⁺
Example 30

 The following compounds were obtained by a method similar to that described in example 29-1).

1) (1R, 6'R) and (1R, 6'R) - 2 - [(3 - (3,3-dimethyl-2-oxobutoxy) -6,7,8,9-tetrahydro-5H-benzocycloheptene- 6-yl] amino] -1- (3-chlorophenyl) ethanol
T. pl. 100 - 103 ^o C
IR (Nujol): 1715, 1600 cm ^-1
NMR spectrum (chloroform-d, δ): 1.24 (18H, single)
1.4 - 3.1 (22H, mult) 4.5 - 5.65 (2H, mult) 4.84 (4H, single) 6.55 - 6.75 (4H, mult) 6, 95 - 7.05 (2H, mult.) 7.15 - 7.4 (8H, mult.)
Mass spectrum (m / z): 430 (M + 1) ⁺
2) (1R, 6'R) -and (1R, 6'S) - 2 - [[3-pentyloxy) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl] amino] -1- ( 3-chlorophenyl) ethanol
T. pl. 102 - 106 ^o C
IR (Nujol): 1605, 1570, 1285 cm ^-1
NMR spectrum (chloroform-d, δ): 0.92 (6H, triple. J = 7.0 Hz) 1.3 - 2.1 (22H, mult) 2.5 - 3.1 (14H, mult .) 3.92 (4H, triple. J = 6.5 Hz), 4.5 - 4.6 (2H, mult.) 6.6 - 6.75 (4H, mult.), 6.95 - 7 05 (2H, mult.), 7.15 - 7.40 (8H, mult.)
3) (1R, 6'R) - and (1R, 6'S) -2 - [[3 [(2-oxopentyloxy) -6,7,8,9 - tetrahydro-5H-benzocyclohepten-6-yl} amino] - 1- (3- [chlorophenyl) ethanol
T. pl. 94 - 95 ^o C
IR (Nujol): 3320, 3260, 1720 cm ^-1
NMR spectrum (chloroform-d, δ): 0.94 (6H, triple. J = 7.4 Hz) 1.4 -2.1 (12H, mult) 2.5 - 3.1 (18H, mult .), 4.51 (4H, single) 4.45 - 4.65 (2H, mult) 6.55 - 6.75 (4H, mult) 6.9 - 7.05 (2H, mult) 7.15 - 7.4 (8H, mult.) 4) (1R, 6'R) - and (1R, 6'S) - 2 - [[3 - ((RS) -1-ethoxycarbonyl) ethoxy - 6.7 , 8,9-tetrahydro-5H-benzocyclohepten-6-yl] amino] - (3-chlorophenyl) ethanol
T. pl. 97 - 101 ^o C
IR (Nujol): 1742, 1605 cm ^-1
NMR spectrum (chloroform-d, δ): 1.24 (6H, triple. J = 7.1 Hz), 1.60 (6H, doublet. J = 6.8 Hz), 1.50 -2.10 (10H, mult.) 2.45 - 3.1 (14H, mult.) 4.10 - 4.30 (4H, mult.) 4.50 - 4.65 (2H, mult.), 4.70 (2H, quart. , J = 6.8 Hz), 6.50 - 6.65 (2H, mult) 6.65 - 6.75 (2H, mult) 6.90 - 7.00 (2H, mult) 7, 15 - 7.40 (8H, mult.)
5) (1R, 6'R) - and (1R, 6'S) -2 - [(3-ethoxycarbonylmethylamino - 6,7,8,9 - tetrahydro-5H-benzocycloheptene -6-yl) amino] -1- (3 -chlorophenyl) ethanol
IR (chloroform): 3420, 1735, 1615, 1580 cm ^-1
NMR spectrum (chloroform-d, δ): 1.28 (6H, triple. J = 7.1 Hz), 1.34 - 2.20 (8H, mult) 2.54 - 3.16 (16H, mult ) 3.86 (4H, single); 4.22 (4H, quart. J = 7.1 Hz), 4.31 (4H, broad. Single), 4.72 - 4.89 (2H, mult. ) 6.28 - 6.54 (4H, mult) 6.89 (2H, double J = 8.0 Hz) 7.26 - 7.46 (8H, mult)
Mass spectrum (m / z): 417 (M ⁺ ), 275, 246
6) (1R, 6'R) or (1R, 6'S) or (1S, 6'R) - or (1S, 6'S) -1- (2-naphthyl) -2- [(3-ethoxycarbonylmethoxy-6,7 , 8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] ethanol (mono-isomer B).

T. pl. 97 -99 ^o C
[α] _D = - 26.42 ^o (s = 0.28 methylene chloride)
IR (Nujol): 3200, 1778 cm ^-1
NMR spectrum (chloroform-d, δ): 1.25 (3H, triple. J = 7.1) Hz) 1.48 (1H, br.) 1.84 (2H, mult.) 2.11 (1H, mult.) 2.6 - 3.0 (7H, mult.) 3.17 (1H, doublet of doublets, J = 8.8 Hz, 3.2 Hz), 4.55 (2H, single) 5.05 (1H, multip.) 6.62 (1H, doublet of doublets, J = 2.5 Hz, 8.1 Hz), 6.76 (1H, doublet, J = 2.5 Hz), 6.96 (1H, double. J = 8.1 Hz), 7.4 - 7.5 (3H, mult.) 7.8 - 7.9 (4H, mult.)
Mass spectrum (m / z): 434 (M ⁺ +1) and 416
7) (1R, 6'R) - (1R, 6'S) -2 - [(3-hydroxy-6,7,8,9 - tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3- chorphenyl) ethanol
T. pl. 180 - 181 ^o C
IR (Nujol): 3150, 2620 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.2 - 2.0 (10H, multip.) 2.4 - 2.9 (14H, multip.) 4.5 - 4.7 (2H, multip. ) 5.39 (2H, broad single) 6.43 (2H, doublet of doublets, J = 2 Hz, 8 Hz), 6.5 - 6.6 (2H, mult.) 6.83 (2H, double .J = 8 Hz), 7.2 - 7.5 (8H, mult.) 8.99 (2H, wide single)
Mass spectrum (m / z): 334 (M + 2 + H) ⁺ , 332 (M + H) ⁺
8) (1R, 6'R) - and (1R, 6'S) - 2 - [[2-bis (ethoxycarbonyl) methoxy-6,7,8,9 - tetrahydro-5H-benzocycloheptene - 6-yl] amino] - 1- (3-chlorophenyl) ethanol
T. pl. 95 ^o C
IR (Nujol), 1700, 1740 cm ^-1
NMR spectrum (chloroform-d, δ): 1.30 (12H, triple. J = 7 Hz), 1.4 - 1.7 (2H, multip.) 1.7 - 2.0 (4H, multip. ) 2.0 -2.3 (2H, mult.) 2.6 - 3.8 (18H, mult.) 4.31 (8H, quart., J = 7 Hz), 4.7 - 4.9 (2H , mult.) 5.15 (2H, single) 6.65 (2H, doublet of doublets, J = 2 Hz, 8 Hz), 6.75 (2H, doublet, J = 2 Hz), 7.06 (2H , double J = 8 Hz), 7.2 - 7.3 (6H, multip.) 7.37 (2H, broad single)
Mass spectrum (m / z): 492 (M + 2 + H) ⁺ , 490 (M + H) ⁺
9) (1R, 6'R) - 2 [(3 - ethoxycarbonylmethoxy - 6,7,8,9, - tetrahydro-5H-benzocycloheptene-6 - yl) amino] -1- (3-chlorophenyl) ethanol
T. pl. 98 - 100 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{29th}}{\text{D}}$ = -38.3 ^o (c = 0.62 EtOH)
IR (Nujol): 3500 - 2500, 1760, 1720 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.18 (3H, triple. J = 7 Hz), 1.2 - 2.1 (6H, mult) 2.4 - 2.9 (6H, mult .) 4.14 (2H, quart. J = 7 Hz), 4.5 - 4.6 (1H, mult.) 4.68 (2H, single.) 5.40 (1H, double. J = 4 Hz ), 6.58 (1H, doublet of doublets, J = 2 Hz, 8 Hz) 6.72 (1H, double. J = 2 Hz), 6.96 (1H, double. J = 8 Hz), 7.2 - 7.5 (4H, mult.)
Mass spectrum (m / z): 420 (M + 2 + H) ⁺ , 418 (M + H) ⁺
10) (1R, 6'R) - and (1R, 6'S) - 2 - [[(3 - (2-ethoxycarbonylpropan-2-yloxy) - 6,7,8,9 - tetrahydro-5H-benzocycloheptene -6 - yl] amino - 1 - (3-chlorophenyl) ethanol
T. pl. 101 - 115 ^o C
IR (Nujol): 1735, 1600 cm ^-1
NMR spectrum (chloroform-d, δ): 1.24 (6H, triple. J = 7.1 Hz), 1.57 (12H, single) 1.40-2.05 (8H, mult.), 2.45 - 3.10 (14H, multip.) 4.21 (4H, quart. J = 7.1 Hz), 4.12 (2H, quart. J = 7.1 Hz), 4.50 - 4 , 60 (2H, mult) 6.50 - 6.65 (2H, mult) 6.65 - 6.70 (2H, mult) 6.85 - 7.00 (2H, mult) 7.15 - 7.40 (8H, mult.)
Example 31

 The following compounds were obtained by a method similar to that shown in the example in example 29.

1) (1R, 6'R) - 2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3-chlorophenyl) ethanol hydrochloride
T. pl. : 103 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = + 11.5 ^o (c = 0.32, EtOH)
IR (Nujol): 3380, 2400, 1760 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 1.1 - 1.4 (1H, multip.) 1.19 (3H, triple. J = 7 Hz) 1.7 - 2.1 (2H, multip. ) 2.2 - 2.4 (1H, mult) 2.6 - 2.8 (2H, mult) 2.9 - 3.3 (5H, mult) 4.15 (2H, quarter J = 7 Hz), 4.70 (2H, single) 5.0 - 5.2 (1H, broad cartoon) 6.34 (1H, broad double J = 4 Hz), 6.67 (1H, doublet of doublets. J = 2 Hz, 8 Hz) 6.88 (1H, double. J = 2 Hz, 7.03 (1H, double. J = 8 Hz), 7.3 - 7.6 (4H, mult. ), 8.6 - 9.4 (2H, broad cartoon)
Mass spectrum (m / z): 420 (M + 2 + H), 418 (M + H) ⁺
2) (1R, 6'R) and (1R, 6'S) -2 - [[3- (2-oxobutoxy) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl] amino] -1 - (3-chlorophenyl) ethanol hydrochloride
T. pl. = 119 - 121 ^o C
IR (Nujol): 3400, 3190, 1715 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.95 (3H, triple. J = 7.3 Hz) 0.96 (3H, triple. J = 7.3 Hz), 1.1 - 1.35 (2H, mult.) 1.75 - 2.1 (4H, mult.), 2.2 - 2.4 (2H, mult.) 2.5-2.8 (8H, mult.) 2.95 - 3.3 (10H, mult) 4.74 (2H, single) 4.75 (2H, single) 4.95 - 5.1 (2H, mult) 6.3 - 6.4 (2H, mult.) 6.6 - 6.7 (2H, mult) 6.75 - 6.9 (2H, mult) 6.95 - 7.1 (2H, mult) 7.3 - 7.55 (8H , mult.) 8.7 - 8.95 (2H, mult.) 9.1 - 9.4 (2H, mult).

Mass spectrum (m / z): 402 (M + 1-HCl) ⁺
Example 32

 The following compounds were prepared by reacting compounds obtained by a procedure similar to that described in example 29-1) with oxalic acid.

1) (1R, 6'R) - (1R, 6'S) - 2 - [[3- bis - (ethoxycarbonyl) methoxy - 6,7,8,9 - tetrahydro-5H-benzocyclohepten-6-yl] amino] - 1 - (3 - chlorophenyl) ethanol oxalate
NMR spectrum (DMCO-d ₆ + D ₂ O, δ): 1.1 - 1.4 (14H, multip.) 1.7 - 2.1 (4H, multip.) 2.1 - 2.4 (2H , mult.) 2.6 - 2.8 (4H, mult.) 2.9 - 3.4 (10H, mult.) 4.0 - 4.4 (8H, mult.) 4.8 - 5.0 (2H, mult) 5.57 (2H, single), 6.6 - 7.2 (6H, mult) 7.3 - 7.6 (8H, mult)
Mass spectrum (m / z): 492 (M + 2 + H) ⁺ , 490 (M + H) ⁺
2) (1R, 6'R) - and (1R, 6'S) - 2 - [[3 - ((RS) - 2 - oxopentan-3-yloxy) - 6,7,8,9 - tetrahydro-5H-benzocycloheptene -6-yl) amino] - 1 - (3-chlorophenyl) ethanol oxalate
T. pl. 70-79 ^o C
IR (Nujol): 1710 cm ^-1
NMR spectrum (DMCO-d ₆ , δ): 0.75 - 1.0 (8H, mult.), 1.15 - 1.4 (2H, mult.) 1.7 - 2.05 (6H, mult .) 2.13 (6H, single) 2.15 - 2.35 (2H, mult) 2.4 - 3.35 (14H, mult) 4.5 - 4.65 (2H, mult) 4.85 - 5.0 (2H, mult) 6.5 - 7.1 (6H, mult) 7.3 - 7.6 (8H, mult)
Mass spectrum (m / z): 416 (M + 1 - C ₂ H ₂ O ₄ )
3) (1R, 6'R) - or (1R, 6'S) - or (1S, 6'R) - or (1S, 6'S) - 1- (2-naphthyl) -2 - [(3-ethoxycarbonylmethoxy-6 , 7,8,9-tetrahydro-5H-benzocycloheptene-6-yl) amino] ethano oxalate (mono-isomer A).

T. pl. : 90 - 99 ^o C
IR (KBr): 3183, 2856, 1751, 1207 cm ^-1
NMR spectrum (chloroform-d, δ): 1.25 (3H, triple, J = 7.1 Hz) 1.5 - 3.4 (12H, mult) 4.2 (2H, quart. J = 7 , 1 Hz) 4.46 (2H, single) 4.86 (1H, br. Half), 6.5 - 6.9 (3H, mult.) 7.2 - 7.4 (3H, mult. ) 7.6 - 7.8 (4H, mult.)
Mass spectrum (m / z): 434 (M ⁺ +1) and 416
The compound with neutral components is ground into powder, mixed and placed in dry gelatin capsules (see table. 3).

 The compound is finely ground and mixed with also ground inert ingredients according to the recipe, and then pressed into tablets using standard equipment (see table 4).

Additional biological activity data
Test 1.

 Effect on the remote peripheral colon of the rat.

/ i / Test method:
Male rats SD (180≈230 g) were used. Animals were not given food for 24 hours before the experiment. Immediately after killing the animals, the peripheral colon was removed and placed in an organ bath containing 25 ml of Tyrod solution with a mixture of 95% O ₂ , 5% CO ₂ at 37 ^° C. A strip of sample was fixed with a tension of 0.5 g and isometrically recorded spontaneous contractions. After the mobility of the sample became uniform, a test compound was added to the bath, and contractions were observed for 30 minutes. The effect of the test compound was calculated by comparing the abbreviations before and after administration of the test compound.

 / ii / Test results (see table. 5).

 Test 2.

Effect on the isolated uterus of a non-pregnant rat:
/ i / Test method:
Female rats SD (150-180 g) were used. 48 and 24 hours before use, rats were injected subcutaneously with estradiol (egg hormone (Orahormon) benzoate: brand name, Feikoku Hovmone Mfg Co. Ztd at a dose of 40 μg) per rat to induce estrus. Animals were sacrificed and uterine horny processes were removed. Each strip of the sample was placed in an organ bath containing 25 ml of Lacke solution with a purge of 95% O ₂ , 5% CO ₂ at a temperature of 37 ^° C and a tension of 1 g. The contraction of the sample was isothermally recorded. After the spontaneous contractions became uniform, a test compound was added to the bath. The mobility of the sample was observed for 20 minutes. The effect of the test compound was calculated by comparing the abbreviations before and after administration of the test compound.

 (ii) Test results (see table 6).

Other activity data
Test
Test for action against frequent urination by cystometry.

/ i / Test method:
(a) Preparation of rat test sample
Male W: Star rats (7-8 weeks old) anesthetized with sodium pentobarbital (nitroperitoneal administration at 45 mg / kg) were operated according to the method of Dubois et al. (1995) and Hava et al. (1992). Rats were placed in a stereotactic apparatus (Kopf Insiruments, Fujunga, California) and the brain was affected on both sides by injection of ibotenie acid. The coordinates used for the cannula premises were as follows: front 7.7 mm; lateral 2.4 mm; 2.9 mm horizontal according to Paxinos and Watson (1982). Ibeotenic acid was injected through a 0.4 mm stainless steel cannula connected by a Teflon tube to a Hamilton microsyringe. Ibotenoic acid (reslavch Biochemieals, Inc., Natick, ms) was dissolved in Dulbecco phosphate buffered saline (D-PBS, pH 7.4) at a concentration of 10 mg / ml and injected in a volume of 0.75 μl for 3 minutes using syringe. Rats that simulated surgery were administered only D-PBS.

Literature
Dubois, B., Mayo, W., Agid, Y., Le Moal, M. and Simon, H., Profound disturbances of spontareous and Learned behaviors following Lesions of the nucleus bosalis magnocellu Laris in the rat. Brain Res., 338: 249, 1985.

 Hara, C., Kasahara, N. and Ogawa. N .: Characteristics of behavioral and physical disturbances of rats With biloteral Lesions of basal forebrain by ibotlnic acid. Jpn. J. Pharmacol., Suppl. 1.58: 58P, 1992.

 Paxinos, G. and Watson, C.: The rat braik in stereotaxil Coordinates. Sydnley, Australia: Academic Press, 1982.

(c) Cystometography
1-3 weeks after surgery, the rats were subjected to cystometry. The rats were anesthetized with ether, the abdominal cavity was opened with an incision in the middle and a thin cannula (outer diameter 1 mm) made of stainless steel was implanted into the bladder. The cannula was connected to a dual lumen tube (outer tube: outer diameter 1.7 mm, inner tube: outer diameter 0.61 mm) to inject saline (37 ^° C) and to measure intravesicular pressure at the same time. A polyethylene tube (outer diameter 0.97 mm) was placed into the stomach through the esophagus for oral administration of drugs. Rats were placed in Ballman cells and allowed to move away from anesthesia for about 3 hours. The free ends of the tubes from the bladder were connected to a pressure transducer (TP-4OOT, Nihon kohden: external tube) and to an injection syringe (internal tube). Saline solution (37 ^° C.) was injected into the bladder using an injection syringe at a rate of 61.5 μl per minute, and intravesicular pressure was continuously recorded using a printing system (PM-6000. Nihon kohen). The pause between urinations was measured to calculate the volume of the injected saline solution at each cystometrogram. The following cystometric parameters were studied: bladder filling, urinary pressure and threshold pressure (intravesicular pressure immediately before urination). Test drugs were administered orally through a previously inserted polyethylene tube after the cystometrogram became stable. The number of rats in each group was 5 with only minor exceptions (4 or 7). Cystometography was performed 30 minutes (or 2 or 3 hours) after drug administration, and the effect on cystometric parameters (average values of 2 or 3 cystometrograms) was evaluated by comparing the average values of 3 cystometrograms immediately before drug administration.

Bladder fullness was calculated as follows: [Bladder fullness] (μl) - [pause between urinations] (min) x [61.5: injection rate] (μl / min)
/ ii / Test results (see table. 7).

Claims (9)

1. Ethanolamine derivatives of the general formula I

where R ¹ is phenyl, naphthyl, indalyl, pyridyl, benzofurazanil or benzodioxalyl, each of which may contain substituents such as a halogen atom or hydroxy;
R ² is a halogen atom, a nitro group, an oxy group, a lower alkyl group optionally substituted by an acyl group, a lower alkenyl group optionally substituted by an acyl group, a lower alkoxy group optionally substituted by an acyl group, or an amino group optionally substituted by an acyl (lower) alkyl group;
R ³ is a hydrogen atom, benzyl or a lower alkyl group optionally substituted with a lower alkylthio group;
n = 0 - 3, an integer;
bold line means a single bond or double bond,
in addition, if n = 1, then 1) R ¹ is naphthyl, pyridyl, benzofurazanil or benzodioxalyl, each of which may contain substituents such as halogen or hydroxy, 2) R ² is a halogen atom, a nitro group, a lower alkyl group, optionally substituted by an acyl group, a lower alkenyl group optionally substituted by an acyl group, a lower alkoxy group optionally substituted by an acyl group or an amino group optionally substituted by an acyl (lower) alkyl group, 3) R ³ is benzyl or a lower alkyl group optionally substituted by a lower alkylthio group, 4) a bold line means a double bond,
and its pharmaceutically acceptable salts. 2. The compound of formula I according to claim 1, in which R ¹ is a phenyl group optionally substituted by a halogen atom, R ² is a lower alkoxy group substituted by a carboxyl group or an esterified carboxyl group, R ³ is a hydrogen atom, n = 0, 2 or 3 , and the thick line means a simple connection. 3. The compound according to claim 2, in which R ¹ is a phenyl group substituted by a halogen atom, R ² is a methoxy group substituted by a lower alkoxycarbonyl group. 4. The compound according to claim 3, in which R ¹ is a phenyl group substituted by a chlorine atom, R ² is a methoxy group substituted by a lower ethoxycarbonyl group, n = 2.  5. The compound according to claim 4, which is (1R, 6'S) -2 - [(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino] -1- (3- chlorophenyl) ethanol or its hydrochloride. 6. A method of obtaining derivatives of ethanolamine of General formula I

where R ¹ is phenyl, naphthyl, indalyl, pyridyl, benzofurazanil or benzodioxalyl, each of which may contain substituents such as a halogen atom or hydroxy;
R ² is a halogen atom, a nitro group, an oxy group, a lower alkyl group optionally substituted by an acyl group, a lower alkenyl group optionally substituted by an acyl group, a lower alkoxy group optionally substituted by an acyl group, or an amino group optionally substituted by an acyl (lower) alkyl group;
R ³ is a hydrogen atom, benzyl or a lower alkyl group optionally substituted with a lower alkylthio group;
n = 0 - 3, an integer;
bold line means a single bond or double bond,
in addition, if n = 1, then 1) R ¹ is naphthyl, pyridyl, benzofurazanil or benzodioxalyl, each of which may contain substituents such as halogen or hydroxy, 2) R ² is a halogen atom, a nitro group, a lower alkyl group, optionally substituted acyl group, a lower alkenyl group, an optionally substituted acyl group, a lower alkoxy group, an optionally substituted acyl group, or amino optionally substituted with acyl (lower) alkyl group, 3) R ³ - benzyl, or a lower alkyl group, further substituted with lower alkylthio group, 4) a thick line represents a double bond, and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula II

with a compound of formula III

or its salt in order to obtain a compound of formula I

or its salt,
where R ¹ , R ² , R ³ and the bold line have the indicated meanings.  7. A pharmaceutical composition for the treatment and / or prophylaxis of urinary disorders, spasms or increased motility of the gastrointestinal tract, comprising an effective amount of a compound of general formula I according to claim 1 together with a pharmaceutically acceptable non-toxic carrier or excipient.  8. Derivatives of ethanolamine of the formula I according to claim 1, having antispasmodic, antihyperanakinesiatic and antidysuriotic activity.  9. A method of treating and / or preventing urinary disorders, spasms or increased motility of the gastrointestinal tract, which consists in administering to humans or animals an effective amount of a compound of formula I according to claim 1.

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