CS251760B2 - Method of benzazepines and benzodiazepines production - Google Patents

Abstract

Compounds of general formula I <IMAGE> (wherein A represents a <IMAGE> group, wherein R7 represents a C1-3 alkyl group, and B represents a methylene or carbonyl group or A represents a -CO-CO- group and B represents a methylene group; E represents an optionally substituted ethylene, n-propylene or n-butylene group; G represents an optionally substituted methylene or ethylene group; R1 and R2 represent a hydroxy, alkyl, alkoxy or phenyl-alkoxy group or one of them represents a hydrogen atom or together they represent an alkylenedioxy group; R3 and R4 represent hydrogen atoms, halogen atoms, trifluoromethyl, hydroxy, alkyl, alkoxy or cyano groups or one of them represents a nitro group or together they represent an alkylenedioxy group; R5 represents a hydrogen atom, an alkyl, hydroxy, alkoxy or optionally substituted amino group; and R6 represents a hydrogen atom, an alkyl, alkenyl, phenylalkyl or acyl group) and acid addition salts thereof show heart-rate reducing activity. <IMAGE>

Description

The invention provides a process for the preparation of novel benzazepine and benzodiazepine derivatives and their use as medicaments.

BRI Patent No. 1,548,844 discloses, inter alia, a compound of the formula

CH ₃

OCH ₃ CH ₃ /

CH2-CH2-CH2-N-C1-C4-OCH3 and its physiologically tolerated acid salts, which exhibit valuable pharmacological properties, in particular, in addition to a mild blood-lowering effect, a selective heart-rate-reducing effect.

Surprisingly, it has now been found that new benzazepine and benzodiazepine derivatives of the formula I are disclosed

they also exhibit better pharmacological properties, in particular with longer duration of action and smaller side effects, in particular a stronger heart rate-reducing effect.

The invention thus provides novel benzazepine and benzodiazepine derivatives of the above formula (I), their acid addition salts, in particular their physiologically tolerable addition salts with organic or organic acids, processes for their preparation and medicaments containing said compounds as active ingredients.

In the above general formula (I), the monovalent general symbols have the following meanings: CH ₃

A is -CH ₀ -CIL, -CH = CH-, -NH-CO-, -CH-CO- or -C = N- and

2 5 5 5

H represents a methylene or carbonyl group, or

A is -CO-CO- and H is methylene,

E represents ethylene, n-propylene, n-butylene, 2-methyl-1-propylene or

A 2-hydroxy-n-propylene group,

G 'represents a methylene, ethylene or 1-methylethyeen group,

R 8 represents a methyl group, a hydroxyl group, an Oenzyloxy group or an alkoxy group having 1 to 3 carbon atoms,

R represents a hydrogen atom, a methyl group, a hydroxyl group or a methoxy group, or

Rg and Rj together form methylenedioxyU,

R1 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, a nitro group or an alkyl or alkoxy group containing from 1 to 4 carbon atoms,

represents a hydrogen, chlorine or bromine atom, a methyl group, a methoxy group or a cyano group, or

R3 and R1 together form a methylenedioxy group,

R ^ is hydrogen, methoxy, hydroxyl, amino, acetylamino, ethoxycarbonylamino, bis (ethoxycarbonyl) amino, dimethylamino or beta, beta, beta-trifluoroethylamino and

R 6 represents a hydrogen atom, a C 1 -C 3 alkyl group, an allyl or a benzyl group.

Particularly preferred compounds of formula (I) above are those wherein -CH = CH- or -Č = N · ^{1 L} 5 and V represents a carbonylalkyl group.

nu, · or represents -CH = CH-, -NH-CO- or -СО-СО- а В represents methylene, 5 represents n-propylene, represents ethylene, represents methoxy or hydroxyl, represents methoxy, represents methoxy, trifluoromethyl, chlorine or bromine is methoxy, hydrogen, chlorine or bromine, or

R ₃ and R ₄ together form methylenedioxy,

R ₅ represents a hydrogen atom, an amino group or a methoxy group and

represents a hydrogen atom, a methyl, ethyl, n-propyl or allyl group, and their physiologically tolerable addition salts with inorganic or organic acids.

According to the invention, the above-mentioned novel compounds are prepared by the preparation of compounds of formula II

(II) reacting with a compound of formula (III) wherein:

A, Β, E and G are as defined above,. R 'to R' are each a protected hydroxyl group, for example trimethylsilyloxy, acetoxy, benzyloxy or tetaahydropyranyloxy, or having the meanings given above for Rr to R_, one of U and V being Rg-NH-, where Rg has the aforementioned and the other of U and V is a nucleus leaving group such as a halogen atom or a sulfonyl group, such as chlorine, bromine or iodine, a methanesulfonyl group, a p-tenylphenyl group or a T group in the E position, or represents an oxygen atom and V represents a group R8 -NH-, where R8 is as defined above, and optionally leaving the protecting groups removed from the resulting product.

The above reaction is conveniently carried out in a solvent or mixture of solvents, such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylamide, benzene, chlorobenzene, tetrahydrofuran, benzene and tetrahydrofuran or dioxane, or in an excess of the starting compounds of the general formula. II and / or III and optionally in the presence of an acid-binding agent, for example, as a target of potassium carboxylic oxide, a hydroxide and a lithium metal, such as sodium or potassium hydroxide, an alkali metal carbonate, such as potassium tannate and alkali metal, such as sodium hydride and alkali metal hydride, such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter bases may also serve as a solvent, or VP ^ i ^ i th reaction accelerator such as' jodiciu ^R drastln of ^{EI in} zááislossi ivity on REA ^ nu ^ ^ eo lníhm jícího cleaved to leave a ^ ELN e ^p s t ^ lo ^ mmei 0 and ^150% with výtodou ^p te ^ s MEEI Oto 50 and 120 ° C, for example at the boiling point of the solvent. '*

The reactions can be carried out without solvent. Especially preferably, the reaction is carried out in a tertiary organic base or in an excess of the starting amine III.

The optional subsequent cleavage of the protecting groups used is preferably carried out by hydrolysis in an aqueous solvent, swollen in water, in a mixture of water, tetrahydrofuran and water or dioxane and water, in an acidic acid such as hydrochloric acid or 100% water. Sulfuric or alkali metal-based bases such as hydroxide.

resting place or ^ o ^ ^u droxid raselné ^h l ^{at t} e ^u ll ^I between ⁰ and ¹⁰⁰ with výtotou under reflux ^for rea protrudes Sites.

However, removal of the benzyl residue can be accomplished with dihydroxyols, for example with hydrogen in a catalyst such as palladium on charcoal, in a reaction product such as methanol, ethanol, ethyl acetate or acetic acid, optionally with the addition of acid. ny such acids chllrlVlUíllv ^{E, P} s te ^ OTE between ⁰ and ⁵⁰ ° C, výtotou ^p te ^ s ^ i and the speed at ROOM button ^ ^0, 1 to ^0.7 MPa, preferably 3-5 MPa.

The compounds of the formula I obtained can be converted into acid addition salts, in particular physiologically tolerable addition salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, butyric acid or fumaric acid.

The compounds of formulas II and III used as starting materials are in part known in the literature or can be obtained in a manner known per se.

Thus, for example, the starting material of the formula (II) is obtained by reacting the corresponding benzazepine with the corresponding halogenated derivative and optionally following the reaction with the appropriate amine. The desired benzazepine is obtained by cyclizing the corresponding compound, for example by cyclizing the compound of formula IV

(V) or by cyclization of the appropriate o-amino compound and optionally subsequent catalytic hydrogenation and / or reduction of the carbonyl group, for example with sodium borohydride in glacial acetic acid, and / or by oxidation, for example with selenium dioxide.

As mentioned above, the novel compounds of the formula I and their physiologically tolerable addition salts with inorganic or organic acids exhibit valuable pharmacological properties, in particular with minor side effects, for example with a low antimuscarinic effect, a long-lasting heart rate reducing effect as well as requirements of the heart for oxygen supply.

For example, the biological properties of the following compounds were tested as follows:

A = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- [3]) 4-dimethoxyphenyl / ethyl) amino] propane dihydrochloride,

V = 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 3,4-dimethoxyphenyl) (ethyl) amino] propane hydrochloride,

C = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl] -3- (N-methyl- (2- / 3-methyl-) 4-dimethoxyphenyl / ethyl) amino) propane hydrochloride,

D = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one-3-yl] -3- [N-methyl- (2- / 3-methyl-) - 4-dimethoxyphenyl / ethyl) amino] propane,

E = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- 3,4-dimethoxyphenyl / ethyl) amino] propane hydrochloride,

F 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 4- amino-3,5-dichlorophenyl / ethyl) amino) propane,

G = 1-Q7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N, N-methyl-N- (2- / 4-methoxyphenyl) ethyl] amino] propane hydrochloride

H = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- -methoxyphenyl (ethyl) amino) propane hydrochloride, = 1- [7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-CN- methyl N- (2- (3,4-dimethoxyphenyl / ethyl) amine) propane hydrochloride,

J = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-allyl-N- (2- / 3 (4-dimethoxyphenylethyl) amino] propane hydrochloride a

К = 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3-N-methyl-N- (2- / 3,4-methylenedioxyphenylethyl) amino) propane hydrochloride,

Compared with

L = ^Q-7, 8-dimethooy "l, ^{2, 3,4-tetrahydro-5H-2-benzazepin-l-one-2-yl]} -3- [N-methyl-N- ⁽² - / 3 4 dieet: hox ^y ^ mn / er ^ Daein] ^p ro ^p m- ^y ydrochlor ^d dee.

1. Effect nr heart rate in cats

The effect of test substances at heart rate is investigated for a specific dose of nr. 7 cats both with an average weight of 2.5 to 3.5 kg. In this test, cats are anesthetized with PInOltal (30 µg / kg iodine) at a rate with urethane (40 mg / ml with + 200 mg / ml urethra as needed). The formulated water is injected in the form of an aqueous solution by injection into the sapypore or duodenum. *

The heart rate is determined prior to administration of the test substance by (Grrss) from the tic tic tartar and recorded on the thoracic wall with the polygram (Grass).

The values obtained are summarized in the following table:

Testovmá Dose (mg / kg) Decrease heart rate lPolojas ИГОг (iotaaveotsot) frequency (min) AND 1.0 -55%. > 120 (B) 1.0 -45% > 120 C 1.0 -44% > 90 D 1.0 -41% 80 E 1.0 -45% > 90 F 1.0 -51% > 120 L 1.0 -8.2% 13

2. Effect nr heart rate of atrial atria

The test is performed with spontaneously striking cardiac atria of both patients, with oοοΟ ο ^ ι 300 to 400 g, in an organ bath in Tyrode's solution. The bath was treated with a mixture of 95% strength of 5% oxide and kept at a temperature of 30 ° C. The contamination is isoisolated via hp polygrate grass. The test substances are added to the organ baths at different times for 60 minutes at various times.

Curve effects of copolymers were obtained from the black ore effects and from these the planks were found to reduce the pulse rate by 30% (ΕΟ-βΟ ^ θ).

The values obtained are given in the following table:

Ttstovrná ИЪОг

ΕΟ-60 ₃ θ (^ g / ol)

A0.030

C0.097

D0.058

E0.066

F

G H

AND

J

0.014

0.014

0.0079

0.03

0.050

0.014

3. Acute toxicity

The acute toxicity of the test compound was determined in mice (observation period of 14 days) to which the test substance was administered both intravenously and orally. The results are shown in the following overview:

Test substance

Toxicity (LD _5q ) mg / kg (intravenous use)

350 mg / kg (oral)

Owing to their pharmacological properties, the compounds produced by the process according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prophylaxis and therapy of cardiac heart diseases.

Suitably, a dose of 0.03 to 0.4 mg / kg body weight, preferably 0.07 to 0.25 mg / kg body weight, is desirably administered once or twice daily to achieve the beneficial effect. For the purposes of the present invention, the compounds of formula (I) or their physiologically acceptable inorganic or organic acid addition salts are treated, optionally in combination with other active substances, together with one or more customary inert substances and / or diluents, for example corn. starch, milk sugar, sugar, sugar, magnesia, magnesium sorbate, polyolefins, citric acid, tartaric acid, water, aqueous monolole, aqueous glycerin, aqueous sorbitol, aqueous polyttlyltoglycologlycol, or polylytoglycol glycol, by conventional means, such as tablets, dragees, capsules, powders, suspensions, drops, rmopje, syrups or suppositories.

are

The invention is illustrated by the following examples, which are intended to illustrate the scope of the invention in the eye direction.

none

The following Examples A to I illustrate the preparation of the starting materials.

Example A

7, U-dimetOxxy-l, 3-UilyUro-2H-3-benzazepin ^beta-2-one

(a) Chloride

3,4-dimethoxyphenylacetic acid

To the stirring suspension during 2, the reaction mixture was evaporated and the residue was evaporated

549.4 g of 3,4-dimethoxyphenylacetic acid in 600 ml of oethheenoCl 2 was added dropwise with 600 ml of thionyl chloride. After the evolution of gas (16 hours) subsided, it was refluxed for 1 hour, after which the easily volatile components were distilled under vacuum.

The recovery ^from an ^FSP roducts ot ^ lo ^ bp ¹³⁴ and ^{from 136} ° ^{C (195 p} and amounts. ⁴⁸⁶ g ^(80.8% theor ^.

b) N- (2,2-dimethoxymethyl) -3,4-dimethoxyphenylacetamide

Under ice-cooling, to a solution 246.2 ml Uiolthylrcetalu rminoacetrldeledu nrieleyrlminu and 315 ml of ^2, 2 liters Leth ^le eno ^Cl or ^even at ^p ^ s ^^ about ¹⁵ and ²⁰ ° C was added dropwise extended ^ ^ ^'485.2 g NaCl 3,4-Uioethoxyphthylacetic acid in 1.1 liters of ethyl ether.

Resultant ^A rněs ^with the j ^^ ¹ hour MIC ^{hook p} s ^{16 and 18} ° C, then oё ^t k and ^{O k} r ^s t ^ U is txtr water, dried over hořičnatým and the odpaaí. The delta residue is slowly crystallized.

Yield of product, mp ^66-69 ° C is ⁶ ° 8 ^g (9% of theory ^5).

c) 7,8-dimeehooy-1,3-dihydro-2 H -3-benzazepin-2-one

To a solution of 600.6 g of N- (2,2-dimeehooyeehol) -3,4-dimethoxyphenylacetamide in 3 L of concentrated hydrochloric acid was added 3 liters of glacial acetic acid. After standing for one hour at room temperature, the reaction mixture is poured onto ice, the precipitated crystals are collected, washed with water until a non-European reaction and dried.

^Ez ek howl. product OTE ^th ^^ it ^{from 234} to ²³⁷ ° C ^{or tup 350 g (75.4%} of theory).

Example B '

7.8- dimelhosyyl, 3,4,5-tttaoh drO22I- ^y ^ ~ 3 _{<-btuzrztpin-2-one}

A suspension of 21.9 g (0.1 mol) of 7,8-dimelhosyyl 3-diOydro-2H-3-benzazepin-2-one and 1.5 g of 10% palladium on UHH in ²⁰⁰ ml glacial ^E k ^{y if} u ^{y t} oc .ov ^s at ⁵⁰ ° C for ^0.5 baku voidíb

0.5 MPa Oydrogenates. After removal of the catalyst by distillation, the solvent is evaporated off under vacuum, the residue is taken up in methylene chloride, the organic phase is extracted with sodium bicarbonate solution, washed with water, dried over magnesium sulphate and filtered. .

The residue is purified by filtration to ingestion, first using sodium chloride alone, and then oethoocarbonate with an increasing amount of methanol (up to 10%) as the reagent.

^Ez ek howl. ^P ro ^d uktu a temperature between approximately L T ^and the ⁸⁸ to ¹⁹¹ DEG C. ^No IO ^{Jan 12,} 6 ^g (7% ⁵ Doria). .

He said a d C

7.8-Dinethoxy-2,3-4 5-httrahydro-1H-1-eenzrztpin

To a suspension of 1.3 g (6 mnml) 7, ⁸ -dimethosyyl, ^3,4,5-y httroh DSO-2H-3-2-beuzrzepio ouu and

1.1 g (3 M) of sodium borohydride in 20 ml of dioyann was added dropwise to a solution of 1.8 g of ice-cold acetic acid in 10 ml of dioyr, the mixture was heated at reflux for 3 hours, then evaporated. The residue is quenched with water, shaken twice with ethylene chloride, the extract is evaporated and the residue is taken up in ether and, after fixing, the ether is evaporated off under vacuum.

Yield ^ez e ro ^{d kp} the uktu -tree ^ OTE CLEANING 86 and ⁸⁹ ° C ^No IO ^{as 1.1} g of ^(92, 7% yield).

P Pikl a d D

6.9-dioothosyyl, 3-idydydto-2H-3-butazazepiu-2-su

2.0 g (0.007 mol) of N- (2,2-dioethosyythoУll2,5 ^dioethox-y ^ is ftuylřcetaoidu еЫ ;! 3 ml KYSE polfosfore ^if u ^y ^ s and ⁶⁰ min MIC ^O at 90 ° ^C. К eeak ^ i ^p of the mixture ^can, and water ,. ice and the precipitated product is suctioned off and vyssb axis.

Yield ^EZ ek j ^ oduktu of te ^ t ^ nd the tote ^{ck 188-191 o} C či.ní 0.9. g (6th Ιθογ.θ).

Example E

7,8-dieeOyyl-l 3ldihydt · o-2H-3-btuzrze IU ^{beta-2-sulfonamide}

The title compound was prepared in an analogous manner to that described in Example D from N- (2,2-dimethyloxytho [eta] &lt; 13 &gt; (4-dioctylphenyl) acetamide and polyphosphoric acid).

ProáuJct ^of the temperature ^{T from 220} to 224 ° C in rezuJ exists a howl ^EZK TEOM at ^40.1%.

Example F

7,8-dimethoxy-55-methyl-1,3-dihydro-3,4-benzodiazepin-2-one

19.5 g (0.082 mol) of 2-3-methyl-4,5-methoxy-phenylacetic acid are suspended in 200 ml of ethyl acetate, 8.2 ml of 98% hydaazine hydrate are added and the mixture is heated for 6 hours. to reflux. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography using methanol / 1% ethanol as eluent.

Yield: 9.6 g (50%).

IR (Imtho-eenOoxide): 3

300

830

650

-1 cm cm ¹

-1 cm (NH) ^(OCH3) (CO)

Example G

7.8- dimmthooy-1,3,4,51ttttah ^y dro-2H53- ^b tnztzepPn-2,4-dione

a) 7,8-2-dieethoxy teinx ^{4-Broe-lH-3-yn-p} btnztze Oydrobrxeid

3.7 g (0.017 mol) of 3,4-dieettoxy-OχfeenlθtdidleCenxnrilu was suspended in 10 mL of glacial YSE ^{to Ei} n ^s b ^{s t} oc к and ^the suspension is s a temperature between approximately 20 ° ^C at ^{give 12} ml of 30% ^alkyl S ( ^] _ ⁱ ^ N ^yb Roma ^d IKOV ^Star in glacial acetic acid. the reaction mixture was stirred for 3 hours at míssucosi, the precipitate is suctioned off,. var ^y, first with glacial acetic acid and then with acetone and ether and dried .

^In ýtě ^Z e ro ^{d kp} uktu extended ^to melting point la ^{d p} s at ²¹⁰ to ²¹¹ ° C (at ^{5.3 g} (8 ^2, 8% yield).

(b) 7 8 · 5dimet0oy-LI. , 3,4,5-tettahydro-2H-3-benztzeein-2,4-dione sodium ^h at about filrau

5.3 g (0.014 mol) of 7,8-2-dimetOoxy aminx 4-Bromo-lH-3-btnztztpin Oydrxbrxeidu-l are dissolved in ⁰⁰ ml ^H or ^{Ké dy} in the te ^ OTE 85 ° C ^for extended means of a solution with ^P s ^be 1.3 g tezvotáto acetate and stirred for ^{1 h} ocdinu ^also play V ^{and 90} ° C. The mixture was cooled by sucked ^d, ss ^y te ^to be washed with cold water and dried.

^In YT ^EZ genus e ^kp) <^ the melting point of over 210 rozHadu ^p s and 21 ° C for ¹ Helical ^{5.3 g (82} 8% of theory).

b) 7,8-dimethoxy-1,3,4,5-itetaahydro-2H535benzazeePn-2 _of 4-dione

5.3 g (0.014 mol) of ^7,8-2-yl dimetOox ^{Protein-45broe-lH-3-yn-p} btnzaze Oydrxbrxeidu was dissolved in ¹⁰⁰ ml ^H or ^Ké in the ^soil temperature between approximately 85 ° C, treated with ^{P 1.3 g} of ^PDA-voděto sodium acetate and stirred for ^{1 h} Odin ^of AhR ^s V ^{and 90} ° C. ^R eakční mixture xchlt ^{d s,} sucked from ^the TE ^{to the} filter to rub with cold water and dried.

Prodlet that sets in ^{the P} s rozUadu ^235C rezuJ exists a ^severe above in in ^{2.9 g} (88% ^ttxrit).

Example H

^Q N - ^(7-S dimstfroxy- ^{1, 3,4,5-y} tetta0 drx- ² H ³ N ^N 5benzzle ^EP 52oχn ^5з yl) ^p rop ^y l] ^Protein-yl EEt0 Oy ^d rxchíorid

The title compound was prepared analogously to example B-catalyzed istic ^hyd ro ^g ENaC L · [7-dimethyl ^ OX ^ ⁵ L · ⁵ d ⁱ⁰ y ^d r ^ O ¹ ^ ² H5 ^35b enzl ^ ^(T ^ ^p ^ n ~ ^ - ^ 5 ^ r ^ · ⁵ ^ J ^ ^{J 1y -3-} (N-beenyl.imeehylamino) propane.

The product melting at ¹¹⁰ ° C results in a yield of ⁷ 8% of theory.

Example I

7,8-dimethoxy-2,3-dihydro-1H-3-benzazepine

To a suspension of 0.8 g and encircling lthidwnalml niimh ^ ^ i ^^ Irid 100 dl absolute diooanu was added 2.2 g (0.01 mol) of 7, ⁸ -8 ddPhl ^p) y O ^y, 3-2H-dily8rl The mixture was heated to reflux for 3 hours. A 10% ammonium chloride solution was added thereto under ice-water cooling, and the precipitate was filtered off with suction. The filtrate was evaporated in vacuo to a volume of about 20 dl, the precipitated white precipitate being filtered and washed with a small volume of dioate.

Yield: 0.9 g (43.8% of theory);

The following examples illustrate the preparation of the final products of the invention.

Example 1. ^{1 [8} 7,8 IDD HHO ^{0y P l, 3} - ^d i ^{hyd ro-2H-3-bGenzaepin n} 2 ^{l 2} oon33yl_ -3- [N mmet-N- (2- / 3,4 DIDP hoo ^{p y} phen ^{yl /} et ^hy 1) ami.no] ^p ro ^p an-hour ^yy 8OO ^{c> 1} oz ^I8

a) 1- (7,8-diddPhí) O0l1,3 dihy8rl-2H-3-bennzazpin 220o-3-yl) -3-chloro- ^{p p} An oo

131.5 (0.6 mol) 7,8-8idePhhO0l1,3-8ihydrl-2H-3-benzazepin ^beta-2-one are suspended in 900 ml 8ideehhlsulfooidu susponzi and stirring ^^ ildi 80.8 g (0 , 72 mol) of potassium t-butoid. After 10 minutes the resulting solution under cooling with ice-water is added dropwise to 77 ml (0.72 mol) of L-bood ^3-chloro-p and ^p oo in 300 ml and 1 8idePhhlsulfooi8l ho8ině reaction was ^{characterized} lijp into ice water . After a short time, the oily, precipitate begins to crystallize. The precipitate is filtered off with suction, dissolved in acetone, the product is precipitated again with water, filtered off with suction and dried.

^Of obstructions ⁱⁿ YT ^{d p} ro te uktu of ^p ture ⁰ 1 1 point to ¹⁰³ ° C it ^{cp 155.5 g (87%} t ^ 3 ^ ri.

^b) 1- ^[7, Θ ρ ^ ^^^ ^ ι ι ^{- 3} - ^d i ^hy8 rl- ² H ³ -bennzae n ^{ep -} oll- 2 ^- yl] -3- ^ ^ -ime lN- (~ ^2/3 4 ^{8 pH} regards loy en ^f l ^y / h ^p e ^yl) amino] ^p R ^p · n-hyl8 oo ^Cl or ^P8

A mixture of 5.9 g (0.02 mole) of 1- (7, ⁸ -8 ddPhlooy- ^{p, p} 3'Id ^ly8ro-2H-3-p pp bbPnzap-2-one-N-yl) -3-chloro ^y orpropanu and 11.7 g (0.06 mol) of N-ddPhhУ-2- (3,4-diddtloxofpnn ^s) ptlyZad ^p nu 3 l ho8íny heated to ⁰⁰ ° C, with cooling, if ^p s and ^d rozkutí in sm ^ ip ^ ^^ ation herein and in ^soil.

The organic phase is washed with 3 times with 1% acetic acid and shaken twice with 2N hydrochloric acid. The acidic extract was basified with ammonia and extracted with methylene chloride. The solvent was evaporated from the extract in vacuo, the residue was dissolved in acetone and the desired hyddololoid precipitated from the solution with ethereal hydrochloric acid.

^{The EZ} YT P roducts tljíc ^{kp l} hl detuning s ^{p 190-191} ° C ^No others ^{of 6.9 g (70.3%} of theory). Example 2 ^{1 [} ? δι ^ Ε ^ ι-ΡΙκ ^{-, 3, 4,} 5-tPtza ^hy8 rl-2 H ^-3-b Pnzaaz ^{EP-2-oll-3- yl]} -3- ^[N -im ^Pthya - ^- - ⁽² - ^{/ 3,4 '8} and Me ^p HHO ^{ny oy} FP / eT ^{hydroxypropyl)} amino] ^p R ^p an- ^d8lyd 8OO ^Cl or ^Pd

a) 1 (7, З ^^^ еРЬи ^ у-, 3,4,5- ^p ρ ^p zahy8rl-2H- ^3- bpnnzlzpPn-2Ol-zyl) -3-ch ^y op ^p ю ^p zn

S ^y oučenina title is obtained ana ^y o c ^{k gp} yd procedure as in la) of the reactions

7,8-d pel0oxy ^p-l, 3, ^4, 5 · - ^{p p} e ^d aahy zo22H ^{bpnzazep-3-p-2-one} 0-blod ch0opplPzaned-3 (yield 50% of theory), or catalytic hydrogenation PNACE ^g of 1- (7-8 З dePhl ^p> lOy-, ^{3-dihydro-2H-3-benzazpppn-2-one-3-L)} -3-chloro oo ^{p p} reap (RU ^I above ^{of about} 88% theory). 3 ^{genus p} u] ^k t ^tajp at ^84-85 ° C.

b) 1- [η 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- 4-dimethoxyphenyl / ethyl) amino] propane dihydrochloride

The title compound was prepared in an analogous manner to Example 1b) by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- chloropropane with N-methyl-2- (3,4-dimethoxyphenyl) ethylamine.

The yield of the product melting with decomposition at 135-137 ° C is 75.2% of theory. Example 3

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-methoxyphenyl ⁾ phenyl)] ethyl) amino] propane hydrochloride

The title compound was prepared in an analogous manner to Example 1b) by reaction

1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N-methyl-2- (4-methoxyphenyl) ethylamine.

Yield: 76.2% of theory.

Example 4

1- [7,8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 3,4-dimethoxyphenyl) ethyl] amino] propane hydrochloride

a) 1- (7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yl) -3-chloropropane

The title compound was prepared in a manner analogous to Example 1a) by reaction

7,8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one [m.p. 195 ° C (dec.)] And 1-bromo-3-chloropropane.

The yield of the product melting at 75-79 ° C was 72.1% of theory.

b) 1- [? 8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino] propane -hydrochloride

The title compound was prepared in an analogous manner to Example 1b) by reacting 1- (7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yl) -3-chloropropane with N-methyl- 2- (3,4-dimethoxyphenyl) ethylamine.

M.p. 185 DEG-187 DEG C., yielding 77 _{t of} 2% of theory. Example 5

1- L ⁷ * 8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 3,4) dimethoxyphenyl / ethyl) amino] propane dihydrochloride g (0.075 mol) of NQ- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) propyl] methylamine together with 7.2 g (0.036 mol) of 2- (3,4-dimethoxyphenyl) ethyl chloride were heated at 140 ° C for 20 hours. After dissolution of the reaction product in methylene chloride, the solution was washed once with 2N sodium hydroxide solution and twice with water, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (0.063-0.2 mm particle size; eluent: methylene chloride-methanol 10: 1). The product thus obtained was dissolved in acetone and the dihydrochloride precipitated from the solution with ethereal hydrochloric acid.

M.p. 135 DEG-136 DEG C., yielding 8.0 g (45% of theory).

Example6.

1- [8-methoxy-1,3,4,⁵-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N ']^methyl-N- (2- [2- (2-methyl-N-)] - methoxyphenyl / ethylamino-propane dihydrochloride

a) 1- (8-Methooyl, 3-idihydro-H-3-bennaquinolin-3-yl) -3-chloropropane

The title compound is prepared in an analogous manner to that described in Example (a) by reaction of ^1- . ³ - ^d i ^{d a} s ^-b 3 m- ^2H- NN ^and aaepiy- ^- -nyu (te ^ OTA mp ¹ 89-190 ° C) s / m ° ^-Br-3-CHO rpropanem. Yield: 23%.

Ic ^ ktrum (Mee ^{Hy1 hydroxy} phenyl oxide) ^{1 6} 5 ^{11 5} cm (CO)

b) 1- (8-monooyl-, 3,4,5-heteroaryl-H-3-ben-anaePn ---- n-з-1) -3-chloro-oxopine-

The title compound was prepared in an analogous manner to that in Example B by catalytic oxidation of 1- (8-aminophenyl, 3-diphenoxy-2H-Z-benzenesulfon-3- ^yl ) -3-chloro-petroleum ^. at. Yield: 67%.

IC spectrum (methhenylene oxide): 1,645 cm '(CO)

c) ^{/ y yj-} -πeh χx ^{Y1L, 3, 4, 5-hydroxy} hntna rx ^-2 H ^L3 - ^b en-ene ^np n ^{y y} --x -з зl ^{-1-J [N} -menh ^y 1 -N- (2-l / ^3, 4-dimetУoxy1eny1 / nhУyla prnpan ^{amino-dihydropyrimidine-y} droxhУorid

The title compound was prepared in an analogous manner to Example 2b) by reacting 1- (8-methyl-1,1,3,4,5-httnahydro-H-3-benzoyl-Pn ----> x-з-1) - 3 ^y N ^y chnyppχypnnu metУy1-2- (3,4-dimetУoxyennyl) eУУynam sulfopropyl.

^P xo ^d uct of te ^ t ^ i OTE ^{from 118} to ²¹² ° C in a howl rtzultujt ^{EZK 14%} ttoxi t.

P xíkl Ad 7 ¹ Slightly ^ he ^ ^{-, 3,4,} 3- ^[a-methyl-01 --- ^{(2/4 p} -amino-yo ^y З ciУxxfety1 / ethh1) amino] propane

The title compound is prepared analogously to Example 5 e 3 l of N- (7,8 ^YDP methyχy1-, 3, ^4, 5 hetrahy ^{y d ro-2H-y y} 3 --- benzenenPny χy-з-1) ^y prxp l met.h lnmpyu ^y and - (4-amiУO'-3-ihlnrfn yl8eУhylbxoaidu. Pxodukt rnzultujt in foxmě oil.

IR with ^p ektrum (AAT ^HH1 / e ^hy ox ^{RD): 3380, 3480} cm ^{-1 (N} ₂ H)

645 ^h m ^-1 (CO)

UV spektxum (ttУanyn) _m ^ax: 238 nm (0.16), 280-290 nm (0.05)

Example ⁸

1 -t ^7, 8- methhx ^{dp y} 1 liter, ^3-5-yl-2H- hetnaУydxo ³ - ^b t Eaze ^{EP 2} n -nn- ^{3yy l]} - ³ - ^Q N L tt ^HY --- ^(2y / ^ amino ^^ - ^ DICOM rmfe ^ l / e ^ and ⁰¹ ^ oj ^

The title compound was prepared in an analogous manner to Example 5 e N- 3- (7,8-diaethoxy-11,4,4,5-htxahydro-H-3-ben2JanzePn ----> x-з-1) prxp ^y l · ^y our nth-and 2- (4-N-amino-3,5-dihhlxret- ^yl) tth ^y liУlxridu. The product is consulted in the form of an oil.

IR (aethh1le ^hУoxi-d): 3390, 3480 ^cm-1 (NH ₂₎

650 ^c rn ^-1 (CO)

UV ^p ektrum (8 ^^^): Λ ^ _χ: ²⁴ 0 nm (O ¹³⁾ ^ 0- ^ 0 nm ^{(0.0 5)}

Peak d 9

1- [7,8-dimethoxy-1,3,4,4-tetrahydro- ⁴ H -benzazepin-4-one-B-yl] -3- ^N- methyl-N- (2- / 4-amino-3,5) (dichlorophenyl / ethyl) aminopropane

The title compound was prepared in an analogous manner to that of 5zN-3- (7,8-dimethooyil, 3,4,5-tetrahydro-2H-3-benzerepin-200-yl) propyl methylamine and 2- (4- amino-3,5-dichlorophthyl) ΟΟΙΙΙΙΙΓ ^.

The product had a melting counting ^and from 94 to ¹⁰⁴ ° C.

Example 10 ^lo - [7 'θ-άί ™ ^ ⁰⁰ * ^ ^1/3 4 ⁵ ltttra ^hyd ro- H ^{3 2} - ^{b e} enzerz INZ ^{L2 zl} _n - ^{3 oll-N N-meth} yl ^about N - ( ² ~ '/ ⁴ oamino-3,51dibr · omfennl / thyla amino) propane

The title compound was prepared analogously to přikaadu 5Zn-3i ^^ - dimeehhxyil, 3,4,5 · 1tetaahydro-2H-3-ol-benzzrepinz12onz1) p _r Qpyl amine and 2- (4-amine -3.5 (dibromophenyl) ethyl chloride.

Paodukt ^M pulsation Toni ¹⁰⁸ and ¹¹² ° C.

He said a d 11

l .- ^ ⁷ ^ Mimetltoo ^{l, 3} - ^d i ^hyd ro ^- ^ - ^^ ^ ^ n nzaaz -on-3-yl-N- řHmetoyl ^^ ^{(^} / ^ amino- ^3,5 -dichlxretzyl / ttУyl ) amincj propane

The title compound was prepared analogously VP říkaadu Ab) of 1- (7,8-d: ^ m ^ 1bho ^ y ^ -1 --dihydrx-2H-3-Beno: ereeino0 oχoO ^2-yl) 2-N-amino-5, 5 (4-id-1-acetyl) -N-methylthylamis. The product results in the form of an oil.

IC with ^p ektrum (meth ^hl LTZ ^CY oxide) ^{3-9 0, 3480 cm-1} (NH ^g)

655 ^cm-1 (CO)

UV spectrum (eto a: λ _max ^{: 238} µm (nm, 0.25 ⁾ • 280 nm (0.1)

303 nm (0.12)

Example 12 ^{l '7/8} C ^m ^^ etУ ≤ x ≤ ^1-yl, 3,4 ⁵ -tttra ^hyd RX- ² H ^- - ^b enzzre ^ei n ^{z1 z12} OX - ^o l ^l] - ^ [j et ^--- ^ l ^ - ^ - ^amino-3, 5-dibrxmfety ^l / ETH ^hl) propane amine ^*

The title compound was prepared in a manner analogous to Example 2b) starting from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzylamino ⁾ -2-oxo-ol) -3-chloro-2-prole and 2- (4- aminx-3,5-dibromoethyl) -N- ^2- ethylthyramine. The product is obtained as an oil.

IR (methhlltcCУoxid): 3380, 3480 cm ^-1 (NHG) * 1645 ^c m ^-1 (CO)

UV spectrum (ethanool: 4 _max : 240 nm (arm, 0.13)

280-290 nm (0.04)

Example 13

1- [7- ⁸ - ^d imethhx ^{yl 1,3, 4, 5} "tttaah ^{l 'd} RX- ^{2H o3ob} toeaze ^Ti n-2-PN-3-yl ^χ P / ^4-

1aminx - / 5 dichlxrftol1 / ttУ ^yl) amino] prxpan

The title compound was prepared in an analogous manner to that in Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzzizin-22-one-3-yl) -3-chloropropane and 2- (4-amino-3,5-dichlorophenyl) -N-methylethylamine.

The product is the ^ ^th pilot ⁹⁴ to ¹⁰⁴ ° C. *

Example 14 ^l ^ -_ 7, ⁸ - imethooy ^{d-1, 3, 4, 5} - ^t Etla RR- ^{2- hyd} - ^- -benzalz in- ^{e 2} 2 N ² - ^- --- f LJ ^- - is rojDyl · ^ --- (2- / 4 ^- lmino- ^{- 5} - ^d ic ^{h y} l lnrfen / ehhyl) amine ⁿ J ^p ro ^p n

The title compound was prepared in an analogous manner to Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-2-benzazin-2-one-3-yl) 23-chloropropane and 2- (42a (ii) 2, 2,5 (5) di-chlorophenyl) -spropropylethylamine.

thyro-fluoride melts to ^d 90 ° C (sinters ⁷⁰ ° C).

IR (meehhlennClorid): 3390, 3480 cm ₍₉ NH) _- 1 ²

650 cm @ ^-1 (CO) uv spectrum (ethane D: λ: 238 nm (0.13) may

180-190 nm (0.05)

EXAMPLE 15 ¹ [_7, ⁸ - ^di methyl] юny ^{yl, 3, 4, 5} - ^t Etla RR- ^{2н hydroxy-3-} benzalepin-2-on-3-yl] - 3- ^[1 ^^ к ·! --- ^(1-h meeh-2- / 4 - ^^ 0-3.5-dichlorophenyl · / еНоу атапю ^] ^p PRN an-H ^y ldOl! C1orid

The title compound was prepared in an analogous manner to Example 2b) from 1- (7,82-dimethoxy-1,3,4,5-tetraethyldrr-2H-3-benzalepine-2-m 2 -2-l) -3-C1 -norpnopane and 2- (4- amino-3,5-dichloreenyl - ^L-2-yl me1h N met1ylethylaminu.

Herein ^p aodukt for stretched at ^{118 from} L and ²⁸ ° C.

Example 16 ¹ С ⁷ в- те ^ ^ ^ ш ^-, 3 ^4, 5 ^-t Etla ^hyd RN ^{- H} 2 - ^{3 2} -bennzlepinn -2rn ^{2-2 l]} -з - [N- (^ 2/42 4- ⁽ 5-Dichloro-phenyl / trifluoromethyl) -amino] pyrimidine-hydr (dichloride)

The title compound was prepared in an analogous manner to that in Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-2-benzalzpin-2-2n-3-yl) -32-cycloapnopane and 2- (4-amino-3,5-dichloro-phenyl) -ethylamine. The product melts at 236-241 ° C.

Example 17 ^{3-4 5 HLD} tetra RR-2 ^H - ^3- benzalz ^{e-2-one n-3-yl] -3-} [N-mm ^ y! ^- - ⁽ 2- [ ^4- (3-Chloro-5-methyl-phenyl) -ethyl) amino] propane *

The title compound was prepared in an analogous manner to Example 2b) from 1- (7,8-dimethylmethoxy-1,34,5-tetraethyldrr-2H-2-benzalzein-2-om2-yl) -3-chloropropane and 2- (4-amino-2-cyclo-5-methylphenyl) -N-methylethylamine.

The product melts at 60 ° C and is at ⁷³ ° C.

IC spectrum (meutheniumCl 3): 3 390, 3 480 cm ¹ (NH 2)

650 ^c m ^-1 (CO)

UV spectrum (ethanol): λ max ^: 237 nm (0.14)

280-290 nm (0.05)

Example 18 1Q, 8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 3,5- dichloro-3-hydroxyphenyl / ethyl) amino] propane hydrochloride

The title compound was prepared in an analogous manner to Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- chlorpropane and 2- (3,5-dichloro-4-hydroxyphenyl) -N-methylethylamine.

The product melts at 225 ° C.

Example 19

1- [η 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 3-chloro)] -5-fluoro-4-beta, beta, beta-trifluoroethylaminophenyl / ethyl) amino] propane

The title compound was prepared in analogy to Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) -3-chloropropane and 2- (3-chloro-5-fluoro-4-beta, beta, beta-trifluoromethylaminophenyl) -N-methylethylamine.

Mass spectrum: m / e = 545/547; for ^C 26 ^H 32 ^ClF 4 ^N 3 ° 3 calculated 546.03

Example 20

1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 4-amino) 3-chloro-5-fluorophenyl / ethyl) amino] propane

The title compound was prepared in an analogous manner as in Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- chlorpropane and 2- (4-amino-3-chloro-5-fluorophenyl) -N-methylethylamine.

Mass spectrum: m / e = 463/465; calcd for ^C 24 ^{H 31 ClFN} 3 ^O 3 463.99

Example 21 LQ ^7, 8-d'imethoxy-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 4 amino-3-chloro-5-trifluoromethylphenyl / ethyl) amine-propane

The title compound was prepared in an analogous manner to Example 2b) from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- chlorpropane and 2- (4-amino-3-chloro-5-trifluoromethylphenyl) -N-methylethylamine. The product results in the form of an oil.

iC spectrum (methylene chloride) : 3 410 , 3,510 cm ¹ (nh ₂ ) 1 650 -1 cm (WHAT) 1 610 , 1,520 cm ¹ (C = C) 2 800 cm 1 (N-alkyl) 2 830 -1 cm (och ₃ ) UV spectrum (ethanol): 241 nm (0.33) 285 nm (0,10) 310 nm (0,08)

Example 22

1- [? <8-Dimethoxy-13,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- / 4-amino-3-cyano)] -5-fluorophenyl / ethyl) amino] propane

The title compound was prepared in a manner analogous to that of Example 2b) 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazin-2-one-2-en-3-yl) 2-en- chnoipniparlu and N-methyl-2- (4-amino-3-cyano-5H-fluorophen-1 / ethyl) amine.

IC spectrum (CDCl3): 3400, 3490 cm (NH2) ²

830 cm (OCH.J

-1 ^J

220 cm ¹

650 cm- ¹ (CO)

Example 23 ¹ - [_ ^{7, 8-l3,3} diiiehhny -di ^hyd rn ^з2н -3-BBE-erepin ^- 2 ^{2 on-3-yl з} y ^3з | N Enz ^b l ^{e -} U N /! ^ dimettox ^1f t ^y l / eth ^yl) am ^- amino] ^p for r ^зhyd rnchlorid.

The title compound is prepared analogously to Example 1b) from 1- (7,8-dimethox).^y-1.3^зdnhy^drnз2H^з3-ben-ereein-32зn-3ззl) -3зchloropnopa and 2- (3,4-dimethylamino-1-N-benzylated) ethylamine.

The product of t ^{and r a} c ^{s p} s dec ¹⁰² ° C was obtained in the above ^severe in ^51% yield.

He said a 24.

¹ - ^£ 7.8 ^зd iieehhn ^χl3, dihydrofuran ^З з ^y dro- ^{2H з3зb} enzzr ^zei n ^-3з зn ^-3зy l] ^{- З} з £ ^Nз meěh ^hlз N- ^{4- methylthiophenyl} only ^- dioxo-ene; ^ ^^^^^ π ^ ργο ^ - ^ ydrocli ^h or ^nd

Naeve compound was prepared analogously přikaadu lb) of 1- (7,8-dimethoxy -1 ^{y, d} ro- ^3з dihydro ^{2H з} 3-benzyl-3-erepin зn-3ззУ) -3зchlorpnopr-u and 2- (3,4-ieethУen-iooχlen-У) зN ^з methhrethylami-u.

The product t i ^{and i} ^ ^s c s ^p a temperature between approximately ¹⁶⁰ to ¹⁶² ° C results in a howl ^{EZK 48%} of theor ^.

Example 25.

1- [7^,8-^dand^andeehhn^χl³ ^ -d ^^ ro - ^ - 1 - ^ - zaze ^ n- ^ one³³³¹!] -³- (N-^benz^ylmith^ylrminn)^prn -hydrochloride

Naeve compound was prepared analogously to example lb) of 1- (7,8-dimethoxy, 1,3 ^з dihydrn- ^{2H-3-benzyl-3-elepin} зn-3зyУ) - ³ зchlor noianu and ^P N-Methylbenzylamine.

^{M.p. 208} DEG- ²⁰⁹ DEG C. ^{yields 92} % of theory.

Example 26

1- ^[7, 8-di ethho ^{χ e y3, dihydrofuran-3-yl} divot 2H-3-benzyl-N- ERE ^{tp 3з} зn ^-3зχ · l] ^-4- [Nзeet ^t h ^l -N- ⁽² - / ^3,4 - ^{di meth} ylettyl-hydroxyphenyl) amino] ^b utan- ^h y ^{d c} ROC lori ^d

Naeve compound was prepared analogously to the case Ib) of 1- (7,8зdieethox ^s -1 _l 3- ^{dihydro-2H з З зb} et-eretin-3-зn 3зyl <-4-chloro-but-U N-i- imUthy U ^ t -dimethoxyPr ^the duct ^and it s ^{C p} s ^p te ture 162-164 ° C was obtained in the chop ^85%.

Scheming II D 27 l-8 ^"r ° P propoxy-l, 3-dihydro-2H-3-benzazepin-2-one-3-yl-2- [N 'mthyl-N- (2- / 3,4 dimethoxyphenyl / ethyl) amino] -thanohydride

Compound náavu sn Prepared analogously to Example lb) and 1- (8ipropoxy-l, 3-3ldihydrOl2H benзalapinз22 nзЗзyl _O) ^ ichlorethanu menhy1-2- and N (3,4-dimnthoxyi fnnyllnthylaainu.

The product, te ^ ^t U ^s OTE ^155-157 ° C rezultuje vt chop ^-1% of theory.

Example 28 '

A mixture of isomeric ^ L · ⁸ - ^^ ^^ 60 ^{11 3 LD} i ^hyd rn ^H -3-bbnзalep P ^{i-2-on-3-yl yl]} - ³ L ^j N ant ^hy l ^l -Nl

- (- / - ia 4-зitroieзyliet1 ^y l) aa3nn] propanes

A mixture of the isomered nasal isomers was prepared in an analogous manner to Example 1b) and 1-1 (7,8-diaanone-11,3-dihydro-12H-3-benza-alanine-12-naphthyl) -3-quinopropyl-N-amino-S- (4a-nitroeenyl) eth ^y laaiзu.

The product resulted in a yield of 70% of theory.

IC Spectrum (manh1enзCtonid): 1655 cm (CO)

510 ^and 1-45 ^cm-1 (NO ^g )

NMR Spectrum (CD / CD):

.delta. = 8.10 ppm, doublet. (J = 9Hh), 2H (aromatic) (4-nitrosonate), delta = 7.83 ppm, doublet (J = 7Hh), 2H (iromtLka).

Example 29 ·

1- E ^7, 8-diaenhon ^χ 15 aa ^N H ^H 1-L-ri ^ · ^ m - ^3, 4- ^b enзa ⁿ u ^0d Alan ^{з 2-one з1-yl]} ^ -Εν- ι ^ Η ^ Ι-Ν- ⁽² 1 / 3,4 · 1diaaehonχ1enз1lethyl) aaiз (nprnpaaзddh ^y ddanCtanid)

The title compound is prepared in a manner analogous to Example 1b) by reaction

1- (7 .8 diaaehooχ11 ^{з з з} meth ^{yl-1,3-dihydro} ^ · ³ - 4 ^з benзa0dalannuз1! - nз1зy1) -з ctlon ^{p-well of p-aзu} mehhl N-1 ^ · (3.4 ^з dimettox ^y fnз ^yl) ethylam3nea.

The recovery ^from the EC ^P ro ^d uktu of te ^ OTE mp ¹⁰⁶ DEG act :! ^24.2 % of theory.

Example 30

1- [7^,8^зdiaenhoo^χ1¹,^3зddhydro-^2Hз3зbeззalaⁿⁿat^з12OO^з1-yl]^-2-hy^dro^xy33-N-methyl-N^{- (2- / 3}, 4 -diaethox^χhairdryer^{n1 /}nt^hy(l) aaiή^n] propane

a) 1- (7,8- (13 ^ 1 ^ 1- , 3-dihydro-2H ^{з з3зb} enзalzpinз22ooз3-1) -, - ^з NPN · ^χ yprn NTN

The title compound was prepared in a manner analogous to Example 1) by reaction

7-d aimetOχy ^y -3 Зtdihnd2н-2H-3-naazenen 21nзonu with npichlnrhydrзnea. The product resulted in a yield of 94.5% of theory.

With IC ^ ktrum ^(t1 Maehata enзh onid ^{t): 2830 cm -1 (OH)}

660 cm- ¹ (CO)

b) 1- Q 8 diaeehoo ^χ 1 l, 3 ^{2 2} H dthydro2 ^- -bnзztгen ⁿ n ^- -one ^{"f 3-yl]} ox y ^ ^^ ^ y - ^ - methyl ^ l ^ h ^ ¹ - / 3,4 ^з diaethoo ^{χ1 з1} en / et ^azetidinyl) amine is present ^{n] p} roptn

251 * 760 '

8.25 g (0.03 mol) of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-22on-3-yl) -2,3-epoxypropane are dissolved in 100 ml of methanol, 5.85 g (0.03 mol) of N-methanol-2- (3,4-dimethoxyphenyl) ethylamine are added and the mixture is refluxed for 3 hours. The methanol is distilled off in vacuo and the residue is purified by chromatography on a silica gel column using methylene chloride with 1% ethanol as binder.

Yield: 7.8 g (55.2% of theory).

IR spectrum (ImPhoiethCiocide): 3600 cm * (OH)

650 c ^ ² (CO)

Analysis: for ^C 26H34 ^N 2 ^O 6 '(470.6) calculated 66.36% C, 7.28% H, 5.95% N,' found 66.16% C, 7.26% H, 5 80% N.

Example 31

1- ^[7, S ^ ime ^ h ^ ¹¹ 34 5- ^lt TTAA ^hyd ro- ^2Ho3ob tnzaze ^{ei-2-oo-3- o} L] З ^{of 2} [N-RNE ^^ - N- ^(2- I-phenylene / thyD amine] iroian-hydocC-orid

The title compound was prepared analogously příkaadu 3b) reacting 1- 7,81dieethony12,3,4,5 1tttaah · ^{y dro22H-3-on-2} btnzaztpin22 3 ^2y l y3ychlorpoopanu mePhh1-2y with N-1 ^(s 41nitnfPen (l) e01 ^and lemitee.

Yield ^ei e ^kp ro ^d uktu melting ^p s 1 ⁸ 2 ° ^C in ^I 5 ^6, 5% ^ theor.

He said a 32

1 "L ⁷ ^ (Jim ^ he ^ ² 3.45 ^{0 yards-tttaa} an ^o2н -3-i- ⁿ bbtnzze ^pp -one ^n2y 1 -3 ^{y 20} N-Mett ^TI1 N- (Ы / '^ О ту 24oact tyl am.rn3 ft nn 1 / tt hyl) a mi n ^ pr opan n - d ih ^y ddoo li ho r id

0.3 g (1.18 mol) of N- 3- (7,8-dimethhoy11,3,4,5 tttaa0ydro ^2-2H-3-2 btnnzlzpin ynn1-2-y1) propyl yl methyl-amine and 0.34 g (1.3 mm> l) 2- (3-nitro-4-acttylaeincftny ²⁾ tthybbcoeidu in 5 ml chlorbtnzenu and 0.1 ml of pyridine was heated for an hour under reflux. The reaction mixture is cooled, the precipitated pyridine hydrobromide is filtered off with suction, the filtrate is evaporated in vacuo and the residue is purified by chromatography on neutral H2O (activity II) by sewing with methylene chloride and 0.5% of ethanol as the leaching agent. The resulting organic material was dissolved in acetone, and dihydrocyclicide was precipitated from the solution with thttric hydrochloric acid.

^In Yt Zt ^{of kp} io ^d u ^ ^to the Pajić EHO ^p s ¹⁷⁰ ° ^{C No} others ⁽²³⁰ mg, ⁵ 7, ^7% yield).

Example 33 IL ⁷ ^ (^ ^ mePhho ^1, 3,4, B-tPtaahyciro- Hy ^ ^ ^ · pnzazep 2oxazolidinone 2 ^{2 y 3} y] J-ι'ρΝ-ιηεΡ -Ν--UM-fluoro yftnyiPeh] yyiamiňn Iropaa-ddydyddocC-orid

The title compound is prepared analogously to Example 2b), by reacting 12 (7 S dimethony11,3,4 tttrahydrO 5 ^{2 2} 2 H 3ybtnzalzpinn22onnЗ-yl) -3-N-chCoiinipanu mePhh1 ² 2y 2 (4-fSuoreen ⁽ l) eOУ ^y lamnpem.

^P roducts melting ^p s 203 ° ^C in a howl iezuiPujt ^eik in 6.8, ^7% Teoc ⁱ t.

Example 34

1 L ^7, 8- ^d imethoo ^y 1 ¹ 3.4 ^5-1 tpPdz ^hyd ro ^{b Y2H} -3- eazzlz ^pi A- ² -YC ⁿ² - ^yy] yЗ- ^{L H12} N-methyl N- ^(2- P ^2, ^ 2 2dic01nrPen1lPe0У ^y l ·) amnnc] iropan-diO ^y drochoride

The title compound was prepared in a manner analogous to Example 2b) by reacting 1- (7,8-dimethoxy, 1,3,4,5-tetrafluoro-2H-3-benzafelin). 1- (2-Chloro-polypropylene) with N (4-ethoxy) -4- (N-dichlorophenyl) ethyl-amine. ..

^P roducts ^{ta r a} c ^s at ¹⁴⁷ ° C in a howl rezuJLtuje ^EZK at ^70.5% teoxi ^e.

Example 35 l- ^{[7-dimethyl-e} ^ i oo 3 ^4,5 -tltrah ^{yd 2} RX- ³ H - ^L ini eniZfz ^{L-2-χiЗзy yl]} -3- (2- / 3,4 di chl o χΙθ n -Vel-i a faaín o] po op fn-di h-dro c li ho rid

The title compound was prepared in a manner analogous to Example 2b) by reacting 1- (7,7-dime-ethoxy-1,3,4,5-tetrahydro-2H-2-methylphenyl-2-carboxylic acid) - 2- (3,4-dichlorophenyl) ethoxyphaine.

^m.p. = ¹⁶¹ ° C, ^{yields 57.6} % of the theoretical yield.

Example 36

1 ^{| j,} S-Dame ^ h ^ ^{-, 3} -di ^hydroxy DRX ^- 2 ^H -3-azepine beliaf -OO ^ -yl ^ ^- 2 ^- ^ -meUiy! --- (2- ^ ⁴ -dimethoyy ^f liyf / eth ^yl) Zain ^o] ethane

a) 1- (7,8-dihydro-2,3-dihydrol-2H-benzylphosphin-2-ol-3-yl) -2-chlorophenyl

The title compound was prepared by a process analogous to Example 1a) by reaction

7.8-Diaoxy-3-dihydrx-2H-3-biphenyl-2-xiu with 1-hex-2-olefin.

^P ro ^d uct a temperature T ^ rezuftuje ¹¹⁴ ° C in the above ^severe in ^20% yield.

b) 1- [7,8-diaelhoxyll - ^{diOldxx-2H-3-2} beeiZfepini -oχiЗ- ^y l-2- [- θ ^ ^ ο ---- (2- / 3,4-dimethyl hoy- f ^ - / ^ У-!) and mi noje than

The title compound was prepared in an analogous manner to Example Ib) by reacting 1- (7,8-diaelhoxyl-1-dioxydrx-2H-1-naphsolin-2-ox- ³ - ^yl ) -4-chloroethane with -alcohol. 2- (3,4-diaeehoxyfenyl) eth ^y aaminea.

Yield: 72%.

IR (melh ^h- elch ^h oo ^r d): 2

883

790

655

- 1 cm ml cm ml cm (OCHI ₃ ) (N-alk ^-1 ) (CO)

NMR Spectrum (CDCl3): (singlet, 12H, 1H, 6.15 (doublet, J1H, olefin) .delta. = 8 Hz, .delta. In ppm): 2.3 (singlet, 3H, NCH3), 3.85

1H, olefinic proton), 6.35 (doublet, J = 8 Hz,

PPiklfd 3 7

1 L ⁷ »3 'ibmΙΗο ^^ ^{-', 3, 4, 5} - ^t · ^2H ltaahydro- ^{'- - l} liZf zepin- ² ^ ^ion-3 (2- / 3,4-diaéltюxylfeil / ltO- (l) aaiixJprxpan-OyddCxhhcxid

a) 1- (7'-Dimethyl-1,3,4,5-trifluoromethyl-2H-3-bisphenylene-2,4-piperazin-3-yl)] 3jc ^ 1Lrpro ^ 1 ^ 5Ln

The title compound is prepared by a phphogenetic procedure as in Example 1f) by reaction

7.8- diaalhox ^{y l, -, 4,} 5 ^{tltfahydro-2H-l} liZfze ^lp --- i- ^2,4 - ^d ixiu temperature T ^ ^i-235 DEG C. (dec Ia ^{to d)} with L-bxoa --- chXoxpxofinea . The product resumes in 26% yield.

IC spectrum (KBr-technique): 1 · 660 cm (CO).

^b) l- [7 ^ Q- ^ ime Ooy-l, 3,4- ^{2 H 5} -tetzahyčlro- -3- eiuazep ^{of p n-2, 4} ^ <^ ^ion-3-yl, i ^ -3 ~ NN-methyl-N- (2- / ^3,4-beta mettouy U-enn- / ethyl amino] prupan-hydroxy-uouChorid

The title compound was prepared in an analogous manner to that of Example 2b) by reaction of 1- (7,8-Uimide-1,3,4,5-tetrahydro-Uro-2H-3-Oenzazupin-2,4-Uun-3-1). 13-Chlorppoppan with N-methyl-2- (3,4-dimethoxyphenyl) methyl. .

Prochikt a melting temperature ^{of from 164} and ¹⁶³ ° C results in a howl ^{EZK 35%} of theory.

Example 38.

1- [2-Oeniuloxy-8-hydroxy-uouy-l, 3,4,5-Tetz ^{Upo-2H-3-ini-P} ienizzz 2OUi-з - 1] -3-Qί mettyl-N- ( 2 '(3,4-dimethoxy-eni- (ethyl) amino] propane

a) 1- (7,8-Dihyduoxy-1,3,4,5-tetzate-Uru-2H-3-OenzuzzePni-2OUn-z-1) -z-ctorporpopzi

8.9 g (0.03 mol) of 1- (7,8-Uimethhuy-l, 3,4,5-tttzahydro2 ² H -3-btnzaztpii - 22-Unl ---) - 3-chlorpoopanu ^e rozkutí in ¹⁰⁰ mL of methylene ^ к riennlúorriu and ^{tetrabutylammonium} s temperature ^of - ⁶⁰ ° C for ^{2 PrPc,} 1ml ^ rtriboomidu. The temperature was allowed reatóní uráíěi pommlu ^{characterized} hundredth t ^up to ²⁰ ° C and the mixture was stirred at this temperature for 10 hours. The resinous precipitate was converted in crystalline form by adding 100 ml of water followed by stirring for 1 hour. The precipitate is filtered off with suction and washed with water and methyl chloride. For purification, crystalline crystals were wasted. Stir with acetone and aspirate.

^P ro ^d uct a temperature ^of the ^{177 th} and ^{from 178} ° C PTU .tuj ^ ¹ ^ t in the howl ^EZK with ^{7.3 g (90.2%} of theory).

b) 1- (7-hydrooy-δ-bi! Tiu-Ooy-l, 3,4,5-tetaah ^{dzo--2H-3-benizzue p-ni-2OUi} зy -) - 3-ctUozpuopan and 1- (7-ien-ooy-8-hy-uruy-1,3,4,5-tetzate-Upu-2H-3-ienzuzuPni-2OUi-зχ -) - 3-chloapoopane

To 19 g (0.07 mol) of 1- (7,8-ditydrooy -, 3, ^4, 5-tetzztyUpu -bonizzepen ^{3-2H-i-one-i-yl)} ---- C ^ lozpropanu and 10.6 g of potassium chloride in 250 ml of Uimethosulfoxide was added 19.5 g (0.154 mol) of iodine-chlorine. The mixture was stirred at room temperature for 2 days, then poured into ice-water and extracted twice with ethyl acetate. The organic extracts were washed three times with water, dried over magnesium sulphate and evaporated in vacuo. The isomers are separated by chromatography on silica gel using methylene chloride with 3% acetone as eluent.

Yield ^EZ ek ⁷ -h ^y druyylluu ^No tnii ^y tajiící at I6 I6 ^{3, and 5} ° C ^No others 6 ^{g (2} 4 ^8% of theory @

Yield ^EZ-8 e ^k H ^{y y} Druy lluu tnii ^{No Ici y} taj ^p s 1.8 ⁵ and ^from 186 ° C wheee ^{4.5 g (1 7.9%} teorieH

c) 1- [7-Ethyl-ouy-8-hh-uouy-1,3,4-tetzat-Uru-2H-3-Oenzazzin- ^2- one-yl] -3- [N-methyl-N- (2- / 3,4-Uimethouy-eni) -th-llamino] propane

The title compound was prepared in an analogous manner to Example 2b) by reaction

1- (7-ien-ooy-8-hy-UPoy -, 3,45-tetzahydro- 2H-3-OenzazuePn-2-non- ^2- naphthyl) -z-chopropoxy with N-methyl-- ^2- (3,4 (Dimethuxyphthyl) ethylamine.

Product tajíd ^p s and ^Z 12 128 ⁹ ° C results in a howl ^EZK at ^75.4% of theory.

Píkl a d 39

^{1-hydroxy-Q7 in} Roy ^- - ⁸ - ENI ^{i z} oo ^y l, ^3, 4, 5- ^t Etra ^td Ru- ^2H - ^3-i Enzo ^{UE P i n-2-Un-з} -l] - ^{3- [N} -methh ^- N- ⁽² - / 3, ^{4--Uimethouχ} eni- / ETT-yl) amino] propane

The title compound was prepared in a manner analogous to Example 2b). reaction of 1- (7-Oydroxy- ⁸ -betzzloxyll, 3,4,5-httla0ldro-2H-3-L-btnzzlztin! -on-l-yl) L3-c01op ^p ro ^p flax N-eethy1i2- (3, ^4-y Fe ^y dieet0ox 1) et01naminem.

Product H ^{s and} j ^s at ¹⁵ C and 7 ° C ^{from 158} rtzulhujt výhěžto ⁴ in 7.2% of theory.

Example 40

1- ^ 7 ^ (Hzetl-Iyo ^ ^{-, 3,4,5-1} httrah drχl2H 3-bet-zlepin-2-oх --- y1] -3- [N-EET ^HO1 -N- ⁽² - / ^3, 4- ^d IEE th ^y l ^y 1 ^f tn / propan-ditydr och ^y i or ^d

The title compound was prepared in an analogous manner to Example 2b) by reacting 1- (7,8-dimethooy-1,3,4,5-tetrahydro-2H-3-benzalene-22-o-3-yl) -3-chloropropane with N-methyl-2- (3,4-dimethylphenil) ollylemite.

The product, ^p Lohe HE Hani ^{170-1 72} ° C in rezulhuje výhěžto ^54.3% H ^ ⁱ ^ t tωr.

Example 41

1- ^ ^Q ^^ ее ох ^ ^{-, 3,} 4, ^5-d httrahy ^ro-l 2Hl3 btnzalz ^{e-2-one-3-yl] -} 3 ^- [^ -ее у1- ^ ^ ^(2/4 tert -butylphenyl (tocyl) elino] propane dihydrochloride

The title compound was prepared in an analogous manner to Example 2b) by reacting 1- (7,8-diethyl-3,4,4,5-hydroxy-2H-3-benzylpiperazin-1-yl) -3- (3-carboxylic acid). ^ O ^ C ^ ^ i? o ^ e ^ i ^ -US --те «1у1-2- (4-HTRC. fni11 -but ^y f) ^) ^ 0 ^ 1 ^ ^] ^ ^ ζτ - ) ^ ζ.

The product, ^p Lohe HE Hani 146 to 149 ° C in rezulhuje výhěžto ^49.4% e-Toor.

P

and

1- [7,8-dieethoх ^y 1- ^, 3 ^, 4 ^, 5-httrah ¹ drh ¹² H-3-ben-znzpin --- oх ^- З ^зy 1] -3- ( ^- "-the-NU- / ^{4 l} Butyl ^yf t- ^yy / eth ^yy ) min ^χ ] propane

The title compound was prepared in an analogous manner to that in 2b) by reacting 1- (7,8-diethoxy-3,4,4,5-methyl-2H-3-benzyl-oxo-1-yl) -13-chloro-3-ol ^. u s Ν - πζ ο1-2l (4 - lbutoУ1ft-11) th01naeinee.

HA product .mu.Ci at ^67-69 ° C in rtzulhujt výtožto ^55.3% toorle.

Example 43

1- £ ^7, 8-dieethoх ^y 1, ^{3, 4,5-1} tttnahd ^{RX-2H-3-zazzpin LBT-2-xx-yy} 3] - ^^ - Mete ¹ -] - ⁽² - / ^2,4, 6-hr hhoy1fen11 IME / th011) amino] propane,

The title compound was prepared by an analogous procedure as described in 2b) reacting 2- (7,8-dieethoхy1l, 3,4 ', 5'-hetra01drх ^{2Hl3lbtnzanzpin-2-yy-3-} oх) -3-cО xrpхxpn ^y-u s --те) 1101-2- (2,4,6-triethylphen1f t ^ D ζ ^ 11ζζ! χζζ).

The product rtzulhujt in a yield of 57/8% htorite.

IC spetorum (meth ^o1 ln - ^Ch o ^{r r} : ^1,650 cm ^-1 (CO)

520 cm ^-1 (C = C ss ^y arommaickéto TKU)

Analysis: C27H3gN2O6.HC1 (523.2) V ^y reckoned 62.00 »C 7.51% H 5.35% N Found 61.75% C 7.52% H 5.18% N ,

6.77% Cl,

7.34% Cl.

Example 44.

1- [7,8-dimethyl-l, S-dihydro-benzazepine-HS - ^ - one-l-yl 3- [.N-methyl-N- ^(- - / ^3, 4-dimethoxyphenyl / ethyl) amino] iroian-hyldochhoride

a) 1- (7, 4-dihydric-4H-4-bennezepi 11 - 00--3-1 1 - 4-hlopropane

The compound of the invention is prepared by a reaction analogous to that of Example 1a)

7.8- dimeehyl · ol lddi ^yd RCO-hh ^l - ^t enzaet ^II N ^- 'one (t ½ lota point ²²⁰ to 22 · ⁴ ° C) with l-bromo--chlorpropanem.

^The product ^s esophagus PI ^62-64 C ^ reznl is mined in 99% yield.

b) l · ^- dimeUtý- ^ ^-., n ^{oH 3ldihyd} -l·lb (^ i ^ ^ei -eae i- ^L- a- ^l ^ -) ^l1l - ³ o ^ ^t ^ Noe ^^ i ^]. ONL ^{(2/3, 4-di-} eethycy1et 1/1 etУ ^yl) amino] ircian-hyclrochУorid.

Naeve compound was prepared analogously příkaadu b) by reaction of 1- (7,8-d eetУh1 ^{p-l, 3-yl} dУУ DCO-NH-3- t ^b --- zazetin-on-3- ^yl, and N - (3,4-dimethooyphenyl) ethylenediamine. .

Product taj ^{p I} C ^s s I ⁰⁵ 7 ^{and 10} ° C in the above reeultuje ^heavy at 70.9% of theory.

Example 45

Г ÍJ7,, Ι ^ ^ ^^ ΡΗο 3-d ⁱ У ^y dro - H ^b 3o enzaae ^{tp-2-en-3-yl]} --omtt ^ ^y ^ 1-3o [N-1 mmehir -N- ^(2/3, f ⁴ odieethoc eyVet ^ ^y1) -amino-propan

a) 1- (7H-Dimethylcyclohexyl-3-dihydropyrrole-H-3-berlazine-oc-o1) o-ethyl-3-chloropcoia-

The title compound is prepared in a manner analogous to Example 1a) by reaction

7.8- dimethoxyphenyl ^y -l, 3-doo dУУ ^{y-HH-3-benzaztii} --ou · l with l-bromo - eetУ ^{yi-3-chCoipoipaleem.}

Product tai ^s c ^{s p} s 45th ^{and 4} ° C for 7 reeultuje mined in 97.5% yield.

b) 1 - (11 ^ 8 ^ 1 ^^^ ^- -d ^yyd DCO ^-H H-3 ^- - ^b t-background ^{I n-2-one 3} - ^y i ^{i oo} eetУ ^{yl o3o [-} oeetУ ^yl] .- N- ⁽² - ^{/ 3 4} odieethocy1ft ^1leth-yl) amino] propane

Naeve compound was prepared analogously to Example lb) by reacting 1- (7,8-dieethocy1l, 3-dihydro - Ho3obtnzaaetin --- --- oc ^yl) --- eeth ^{yl-3-chCopporpa-} with N-methy1 --- (3,4-dieethox ^y FTN ^yl) eУh ^y AEM-eee.

The product, te ^ OTE mp ^30-32 ° C rtzul UJT ^t in ^36% yield

Peak d 46. 1- [б ,, 3-diУ^ydr11-H-30^btnzaae^tpn-2-on-3^ylJ l3^O[-oeeth^y1-^N- (2- /^3.4-d^pmtt^yoyy fen-1 / ethyl) armino propane

a) 1 ~ (6.9-d ^{p y} EET hcy1l, 3-d У1drc ^P - H --- 3obtnzaaeein alpha-l-ol) -3-hУCoppcopan

The title compound is prepared analogously to Example 1a) by reaction

6.9- d ^im ethox ^y -l, ³ -d ^y1d dco- ^H H 3- ^b eneazt ^ip no ^- -ou (t ^ d lota Ы ^188-19 1 ° ^C) with ^{3-bromo -> p} hУaoipci ante.

M.p. ⁹⁷ DEG-99 DEG C. (yield: ²⁷ % of theory).

t

b) 1- [1,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3-N-methyl-N- (2- / 3,4-dimethoxyphenyl) ethyl amino] propane

The title compound was prepared in an analogous manner to Example 1b) by reacting 1- (6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N- methyl 2- (3,4-dimethoxyphenyl) ethylamine.

The product resulted in a yield of 90% of theory.

IR (methylene chloride): 1658 cm (CO)

Nuclear Magnetic Resonance Spectrum (Deuterochloroform / Deuterium Oxide, .delta. Ppm): 2.2 (singlet, 3H, NCH3), 3.7-3.8 (4 singlets, 12H, OCH3),

6.25 (doublet, J = 9 Hz, 1H, olefinic proton).

Example 47

1- [8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N, N-methyl-N- (2- / 3,4-dimethoxyphenyl) ethyl] amino] propane hydrochloride

a) 1- (8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane

The title compound was prepared in a manner analogous to Example 1a) by reaction

8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p. 165-168 ° C) with 1-bromo-3-chloropropane.

M.p. 67 DEG-71 DEG C. yields 45% of theory.

b) 1- [8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3-N-methyl-N- (2- / 3,4-dimethoxyphenyl) ethyl amino] propane hydrochloride

The title compound was prepared in an analogous manner to Example 1b) of 1- (8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N- methyl 2- (3,4-dimethoxyphenyl) ethylamine.

The product melting at 64-68 ° C resulted in a yield of 64% of theory.

Example 48

1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl-1-N- (2- / 3,4) 5-trimethoxyphenyl / ethyl) amino] propane dihydrochloride

The title compound was prepared in an analogous manner to Example 2b) by reacting 1- (7,8-dimethoxy-3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3 -chlorpropanu with N-methyl-2-) 3,4, s-trimethyl ^7: ή '.cv г-Uyl) .thylaminem.

The product, decomposed at 131 DEG C., yields 44% of theory.

Example 1 · 49

Isomeric 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-N-methyl-N- (2- / 2- 4-nitrophenyl / ethyl) amino] propanes

The title isomer mixture was prepared in an analogous manner to Example 1b) from 1-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl-3-chloropropane and N-methyl-2- (2- and 4-nitrophenyl) ethylamine.

Yield 72%.

IR (meehyleechlooid): 1650 cm @ ¹ (CO)

Example 50

1- Г ^7, S- imet-hyoy ¹ ! , 3,4,5-tetrahydro-2H ^{yid-bencazepincl 3,} 2- ^d ion-3-yl] -3- [N-methyl-N- (2- / 4-amico-3, ⁵ -dic ^y lorfecil / etoyDamino] -propan ^p

Naeve compound was prepared analogously příkZadu 2b) and 7,8-1- ^yl -dimethy yoy1l 3,4 _/ 5-tPtzaУ1dro 2н-3-bpnzazepinc - OOCL-yl-3- Ν-Ν-ιηθΡΙτιΙ - (2- [4-Amino-3,5-dicollortecyl] ^yl ) amico propane and selenium trioxide.

^P s Procdukt melts ^118-130 ° C.

Hmoonnotmí spectrum: m / p - 493/495 (for C24H2 _{2 9} C1 N3 O4 Calculated 494, 43)

Example 51

1- [7,8-dioe^phyx^yi1,34, 4'-tetaaíi ^ ro-^2H-3-bPnzaae^ppand^c2-r-3-yl]^-3-^^N- ^ mP^t^ h^1-N^ - (²- /^3-aoi cy-4-Cleofpecyleetl) aminyopropane

Compound Naeve prepared analogously by reacting 5 příkaadu N ³ - (7,8-dioethyoyil, 3,4,5-tetzaУ1dro-2H-3-bpncezepincl2- clз _n-1) iroiyl oopyylaminu and 2- (3 -Ziolinol4-cloofePc1) ePУy1cùIotí) The product reacts in the form of an oil.

UV spectrum (ptlarxl): λ 238 nm (0.26) ^r max

285 nm (0.13).

304 nm (0.06)

IC spectrum (dicymeromethane): ³ 390 and ³ 480 cm ¹ (NH ₂ )

650 ^cm-1 (CO)

830 cm- ¹ (OCH ₃ )

520 and 1620 ^{cm -1} (C = C)

Example 52

1- [8-5-Г1ооРУуху11,34 Tetz ydrx ^{yl-2H-3-bpnaazepίn-2-xn-3-l]} - 3- [ν - dimethyl-N- (2- / 2- ^ ζο.ny 1-Propanediol

The compound of formula (st) is prepared in an analogous manner to Example 1b) by reacting 1- (7,8-) 1-oxo-11,3,4,5-tetrahydro-2H-3-benzazapirn-2-o-ox-3-yro-3-chroipxipane with N - 2- (2-Zino-3,5-dichloro-hexyl) -ethyl- ^3- ol. The product reacts in the form of lithium.

UV sp J ^ - ^ et et et et et et et et et et et et et et et et et et 240 240 240 240 240 _at 240 nm (0.34) ^r max

285 nm (0.15)

306 nm (0.10)

IC spectrum (Π ^ ^χγορΙΙζπ): ^2,810 cm ^-1 ( ^N -aa ^k ya) '2,840 cm ^-1 (O-CH ³⁾

655cm ¹ (C = 0)

520 and 1620 cm ” ¹ (C = C) '

Example 53

1- (7,8-diyydrxx^yand^l, 3,4,5-tetza^yldrx-^2н-3-^bPnzaaa^Friin2-ox^cl-yl^l]^{- 31} N -metoyl^--^{(2- / 3}, 4 -di (m-t: 1 - [(1 - [(1 - [(1 - [(et.

0.52 g (0.001 mol) of 1- 7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl-3-N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino-propane was hydrogenated at 20 DEG C. under 0.5 MPa for 5 hours in 100 ml of methanol in the presence of 0.2 g of 10% palladium on carbon. The catalyst was filtered off with suction, the filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel using methylene chloride with 1% ethanol as eluent.

Yield 0.2 g (43.9%).

IR (methylene chloride): 3520 cm @ ¹ (OH)

640 cm ¹ (CO)

Analysis: for ^C 24 ^J 32 ^N 2 ^H 2 ° 5 ° (455.5) calculated 63.28% C, 7.74% H 6.15% N Found 63.44% C, 7.77% H , 6.13% N.

Example 54 1- [7-Hydroxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl-3- [N-methyl-N- (2- 3,4-dimethoxyphenyl / ethyl) amino] propane hydrochloride

The title compound was prepared in an analogous manner to Example 53 by catalytic debenzylation of 1- 7-benzyloxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl -3 N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino propane hydrochloride.

Yield: 45.2%.

IR spectrum (methylene chloride): 3530 cm ^-1 (OH)

830 cm ^-1 (OCH ₃ )

650 cm ^-1 (CO)

Analysis: for ^C 25 ^H 34 ^N 2 ° ^xHC1 5 (479.0) calculated 62.69% C 7.36% H 5.85% N Found 63.15% C, 7.57% H, 5 , 64% N.

Example 55

1- [i-methoxy-8-hydroxy-1,3,4,5-thihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N (2- (3,4-dimethoxyphenyl) ethyl) aminopropane

The title compound was prepared in an analogous manner to Example 53 by catalytic debenzylation of 1- [7-non-thoxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl] -3- (N-methyl-3,4,4-dimethoxyphenyl / ethyl) amino] propane.

Yield. -4 <· .... 29.4% of theory.

IR spel; : methylene chloride): 1 640 cm ¹ (CO)

Analysis: ^С 25 ^ 34 ^М 2 ° 5 (442.56) calculated 67.85% C, 7.74% H 6.33% N Found 67.50% C, 7.97% H, 6 18% N.

6

P fikl a d 56

1- [7, β-direthoxy] 1^{, 3,}4⁵ttt: a ^ 1^y^^atl ^ l ^^²^^H-3^-btnz ^ í ^ í ^^t^ ln-²-ln-³-^y 1^{] -3-}[—-Re ^ il-^-- (2- / 4-^andri nophenyl / triethyl) propane

4.85 g (0.0107 mole) of 1- 7.8 "Uireehcuoχ-, ^{3,4,5-tetaahχUrl-2H-3-le-zalztUn-2-on-3-yl-3-} N medíl- N- (2-M-acetylarinofennl / ethyl) propane Arino 34 hours stirred at 40 ° C with 80 ml of ¹ meehaainoidé Selin C ^ lr ^clay: ovl ^thanks b ^s. After evaporation of the reaction solution, the mixture is stirred in Ineethlene Chloride _/ extracted with sodium bicarbonate solution and treated. The organic phase is dried, odpaaí in vacuo and the oily residue was extrusions ^under vacuum ai te ^ o ^ ⁵⁰ ° C.

Yield: 88%.

IR (re ^t h ^íχ et hloo ^{r-d): first 645} cm ¹ ( ^CO )

NMR ^(χ Ueuteroch lrlflrr / dtuteriuroxiU delta in ppie): 2.25 (single,

3H, NCR3, 3.8 (singlet, 12H, OCR ', 6.9 (duet, J = 7 Hz, 2H, aromatic residue).

The following compounds are also prepared in an analogous manner to that described in the following:

1- ^[4 8- Iret ^{d h oxy-2, 34-tetra} ro ^ ^^ H ^ ^ n ^-3-1 -tenzaaz] - ³ - [^ --- Meet -N- (2- / 3 ^{4-dimethoxχfen-1} / TTI ^χχ) amine 'with ^{r an} lP "diíydrocCloriU m.P. 270-271 ° C.

1- [7,8-Uirethílχχ-, 3,4,5-tttlahχUrl) - ^{2 x} H-3 ltnzalztUn-2-one- ³ χl] -3-Q --- diluted N- (2- / 4- reehíloXftnXletíχl) amino] urlU ⁿ · ^з hχXuooCloriU mp 175-177 ° C.

^{1 '7,} S-re ^ i ^ nchoxx ^{1 1 3.4 5 -} tt.tra ^íyU RL · ^-2н - ^3-1-et ZLZ ^Here, N ⁿ зoln - χl] - 3 ^{χ [Νχ 'βηιχ} χ -Ν- (2- / ^3, 4-UireehcuχXftnXletíχl) ami.no] urluaa-híXuolClooiU mp 210-212 ° C.

8- rD ^the IR ^et hhlχ ^{X-, 3,} 4, ⁵ - ^t χ ttra ^{s u} rl ^{-2H-3- ene-1} Zlzpin ^{n 2-ol-3-yl} -χ -3 - [- · (2- / ³ 4 ^{- e} ee hi ^χ ETX ol ^{in 1 liter χχ} ftχ et χl ^d) to an amine-prluan hχ UOL ^{y c} Lori ot ^ ture mp 191-193 ° C.

1- [7,8-Uirethíl0y-, 3,4,5-tttraíyUrl-2H-3-bet-zleptu-2-one --- χlJ-3- [N- (2- / 3,4udiretíloχ tm ^ ^{f: L} / tt ^ ⁱ ^ ^{1 ^))} m ⁱ ^ - ^ o] ^p l ^p l-r ^-I; ^ (^ r ^ (c ^ ^c ^ ll ^ l: ^IU of te ^ o ^ ^T the ^{1 2} 5 and ¹⁵⁴ ° C.

L ^{7 1, 8-u} im ^ ^I ^ C ^ ^{Ox- l, 3,} 4, ^{5 t} t ⁱ ^ rj ^ ^íyU rl ^- L · ^H 2 - ¹ ^ j ^ ^t -zlz in- ^- 2Ol- -зyXj -3 - [- ^аИ у ---- 1 ^(2/3, 4-UiretholoXfrn1 / ttíχ ^χ) amino] urlU ^an -hyXuooCloriU mp 153-155 ° C.

Q ^{1, 8-U} Lm ^ ^t ^ l ^ ^l c χ ^{X-, 3,} 4, ⁵ -t tra ^{i t} y ^u rl ^-2н - ³ -blt zleρ ^{t-U- -} -one ^- - l1 ^з ] -3 - [- prop --- ^u 1 ^(2/3, 4-Uiretíox fenn1 ^y / ttíyl) arinЦ urlpan h ^y XuooCloriU melting at 80 ° C.

· l - ^, ^ в-чИтеию хЪ ^{3, 4, 5} - ^t TTAA ^I y ^{u ro-2H-en-l} З ZLZ ^tU n ^-, 2-Xion - ^3-yl-3- [- -πθ ^^ - Ν- (2- / ^{3-4-diretíoxχ1en} У / ttíχ ^χ) Arino] prluan-hχXuolCloriU mp 196-197 ° C.

1- ^[7-1 tnzχllxχ- ⁷ -re ^t hílχ ^x- , 3,4, ⁵ - ^{t t} í U ^{ro 2 2 2} H-3- ¹ en-zlz ^t in- ² 2O1-Ззχ11] -3 ^{x [} - ^xr EET ^h X --- (2 / 3,4 ^x UiretholoXen-X / ttíχl) Arino] urlpamdύh ^χ duooClooiU mp 117-120 ° C.

^lx77x h ^χU rl> o ^y 8 ^- re holχ ^{y t,} 3.4, ⁵ - ^t ttra ^íyU rl- ² H ^3-1-er ZLZ ^t-yn-22Ol Зз χJ ^{yl-3- (-} eth ^{r í} X-- (2 ^- / 3, ^4-d: Lm ^ ^t ^ l ^ l ¢ ¢ ^oy ^ t ^ ^nχ / TT ^{diyl) l} ^ ⁱ r - ^{Ц] in} an ^{RL-h y} xluooCloriU.

^iC spelktrum (meth ^I1 eth- loo ^c d ^{r): 3530} cm ^-1 (OH)

830 cm ^-1 (OCH ³ )

650 cm ^-1 (CO)

Axalysis: calculated for C ₂₅ H ₃₄ N ₂ O ₅ xHCl (479.0) 62.69% C, 7.36% H, 5.85% N, found 63.15% C, 7.57% H, 5 , 64% N.

Ь- ^{(6, 9-dimethoxy-yl, 3-dihydro-2} H- ³ -benzzze ^e-2-on-3-yl] ^ - [N-meehyl N - ^ - / ^3, 4-dim ^{e o} x ^y th phenyl / ethyl) amino] propane.

^iC spel (rum): 1,658 cm ^-1 (CO)

NMR spectrum (CDCl3 / CDCl3): 2.2 (single,

3H, NCC-), 3.7-3.8 (singlets, 12H, OCC-). 6.25 (doublet, J = 9 Hz, 1H, x ^y protic proton).

1-f^6,Mimettoxjy,¹,³,⁴, 5-^tetn^aУyχrx-²3^зbenceaepiχc²-ox^з3-^yУ] -3- [N-m + 1] -N- (2- / 3^,4 -^χieethxnylfecl1eth^yy) amine] irnian-h^yM.p. 73-76 ° C.

^ ^1, ^ Μ Ημχ ^{1-, 3} - ^d l y ^{0 d} rx ^{-23 '3} - ^{b t} Swinburne incl2 _O χclзyyl 3- | N-yn imth ^of (2- / 7 4-di- ^{hydroxyphenyl m} eth tc ^yy / e h ^{y yy)} am ^{c χ x]} n- ^{and i} rn · h ^yy rrx chloride rt ^hy ^ ture mp 64-68 ° C.

1-Qj, 9-^diett^yxxy^{yl, 3}, 4^,5-^tttrah^ydrx-²3-3-beczaze^tIII-2-yl-3-yl-3- (4-carbonyl) -4- (2 - / 3 -) -dieethxxyУeecУ (ethyl) aeicχ] irxian^yh^ym.p. 131-133 ° C.

1- ^C 8 dieeehox ^y l ^{y l, 3,} 4 ⁵ - ^t e ^t RC ^Lloyd RX- ^2H ^ ^B ^ lll ncze иic ^t-L 2 ^{-Y 1} χcЗз ^з l l ^[N ^ _i ^ ^ _e ^{et ol} _ ^- _ (~ ^{2 / 3,4,5} -trietthχy ^yl ec ^y l / TT ^Oy l) and m ^ o] ^as an RX ^{and Y} drxx ^{hy hy} di xxid melting roekíaclu e ^p s ¹³¹ ° C.

1- [7,8 ^- dieethon ^y ll ^, 3 4 5 ^y ttrra ^hy drx ^{y2 Hyl ,} З ^зb exce ^χ i ^and ae ^ti χc2 ~ xχc ^- - ^y l] ^-3 · ^[N · ee ^tt ^ ^ol- l ^- - ⁽² - / 4-aeicn ^{y 3,} 5-dihydrofuran ^h1 xr ^t e ^yy en ^YYT yl) EILI ^c xx ⁱ poxpan rt ^and the ^163-166 ° C.

1 l ^[7, 8 ^y dieet ox ^{y yll1} 3.4 5-theta ^yy drx- ^23-3-b enzaae ^Ti n ^y2 - ^y3 · on · - ^yy] -dimethylamino, N, 5 ^2d ihУ xrftcy ^{y y} / ^y eУhy) aeicx] propane.

IC spectrum (eet ^y hl1tchУxxid): 1650 cm ^-1 (CO)

UV spectrum (ethane-) max 227 nm (arms, 0.16)

280 nm (0.12)

1- [7 ^, 8 ^y die ^y hx ^y l ^1, 3 ^, 4 - - ^^ хп ⁰¹ ^^ ² - ^{-, 3} -bence ⁿ iaaepii-2 ² on- ^с ~ ^уУ ] - ³ - ^[-з те ^ ^у у2- ⁽² l / ^{3, 4} females -dieethxx ^{χ nl} / ^HY et У) aeinx] ^ o ^ her notes ^{and 116} and ^{from 117} ° C.

1- ^[8-one Inee ^{y y yl,} 3 4 5 ^{hyd y} tttra RX- ²³ - ^3yb enceae ^e in ^{c 2 c} 3 lx ^з y ^{y1 -3-} [methyl ^{E -2} h. ^Oy - ^{-2 (2} - / 3 4 <ϋeet hxylfenl ^y / ETH ^yy) amino] propainaihydroxhУoxid mp 118-121 ⁰ C.

1- ^[7, 8-di-m ^ 3 fLhc ^ ^ ^x ^ - ^: ^1, 34, Б tttxa ^{Lloyd-xx з2} II- ^{-., 3yb} ence iaae ^χ n ^I Xn ^{C3 -C22} - ^yl] ^ - —I-methyl. ^3- ^ ²³ l / ^s 3.4 dieet xx ^{yy y cl} en ^/ et ^hy l) aeinx] Pxx ^p CLEANING An about 116, and ^from 117 ° C.

1) 7,8-d 11 ^ 1 ^ 1-- ^3, R 4 R 5 ² tttraO drx- ^{y 2 y 3} 3 - ^{b 2} eeceae ^beta II- -XN- ^c - ^yl] - ³ - ^[N -Other ^tb H ^L -N- ⁽² ~ / 3 ~ ⁴ di ^ er ^ ^^ fe / e ^ yl) amino] rx ^{i c i} n di DXXX ^{hy hy d} XXI of te ^ OTE T ^and the ^154-157 ° C .

1- ^[7, 8 dieeehox ^{y y} y ^{l, 3,} 4.5 ^y tetna ^Oy drx- ^23-3-b enгeae ^{Ti n-2} lx ^{c c} l ^{з-yl] -2- eyyУl3l} ee ^[-l ee ^{ebyУl з} -N- (2 ² / 3,4-dieet xxyletc'l ^y / ^y ethyl) amino] iroian ^зy ollxxxhУxxid mp 99-101 ° C.

1- ^[6, 9 ^з dieee ox ^{y y} y ^l 34 5 ^зt etnah clxx ^з23lb exzaae ^y ^ n - ^ - ^ xn ^{3уУ] -3з [-з те} ^ ^{у уз-3- (2} - / 3 ⁴ "di ^{2 e} eehon Lee ^{χ n} l / ETH ^yy) nminoOpropanch ^oy divot XXI ^{hy d} ^ o ^ plo compounding ⁷³ and ⁷⁶ ° C.

1- [8,9 ^з dieeehhx ^y l ^-1 3 ⁴ 5 ^з tttxa rx ^{hyd -23з3зb} eeceaepii ^{з2з 2C2yy} xx] ^{23з [e ah} about ^{-2 E yз з} N ⁽² - / 3 ⁴ Ldi ethxx ^{χ e cl} FEX (eh ^hy l) ae ⁱ c ^{n i i} x ^{i n n 2hyd} xxx ^hy x x ^{i i h h} ei ^{m t 131-133} ° C.

1 - [* ⁷ 81dieethoo ^y - ^{5,3, 4,} 5-tetL ^Lloyd RX- ^2H - ³ - ^{b l} e tnza ^EP 2 n ^{n n} З- ^{ox-yl] 531 [5 m} e N ^e h ^y l ^- N- (З · / ² -a ^{l! c t} butyl menoXeey - / - EtO ^yl) aeinx] prxptn- ydroc ^{cO O} or ^ID relating to the temperature T ^and the ^102-105 ° C (гдек1М) ·

1- [7,8-di ^e ethoxy ^{χy -l, 3,} 4, 5 ^{tettahydrx--2H-3-btnaaze tp} n ² · -xn ^{13th-yl] -3-} [N-methyl-hl ^ N- ^{(2- / 4} - ^t c ^e t ^y l ^y l ^artery oftn / tth ^yl) aeino] for an ^{n p} h ^{y d} xr ddxxh ^PD TE lot ^of TALI ^{p 88-93} C (xozkl ^).

Claims (6)

SUBJECT OF THE INVENTION What is claimed is: 1. A process for the production of novel beenaaefins and beenoodazefins of the general formula I in which ÍH3 A represents a -CH-CIH-, -CH = CH-, -NH-CO-, - ^ CH? -CO- or -C = N- and 5 ^{2 2} 5th B represents a methylene or carbonyl group, or A is -CO-CO- and B is methylene, E represents an ethylene, n-propylene, n-butytenχvxu ^2-yl ln eeth ^prop-yl or 2-heptenoic Oydrχy ^y -n-heptenoic prxp ^yl group, G is methylene, ethylene or 1-eethylttOylenxvxu group, ^R 1 represents eethylovou group Oydroyylxvou group or benzyloyyskupinu alkoyyskupinu having 1-3 carbon atoms, ^R 2 represents a hydrogen atom, methyl group, or a group Oydroyylovχu ϋ ^ οχγskupinu or R and ^R 2 together form eethyltndiχyyskupinu, ^R 2 represents hydrogen, fluorine, chlorine or bromine, triUluormeOhyXovxu group, or an alkyl or nitooskupinu alkoyylxvou xbsatojící group has 1 to 4 carbon atoms. R is hydrogen, chlorine or bromine, methyl, methoxy or cyano, or and R is taken together to form an ethanedinedioxy, ^R5 is hydrogen, methoxy, hydroxyl, amino, tertiarylamino, etOoycyclobonylthio, beta (e) diethylamino, beta (e) ethoxy), , bett-1-trifluoromethylamine group and R 8 represents a hydrogen atom, a C 1 -C 3 alkyl group, a C 1-6 alkyl group or a benzyl group. and acid addition salts thereof, in particular physiologically tolerable inorganic or organic acid addition salts, characterized in that the compound of formula II (II) is allowed to be regulated with a compound of formula III (III) in which: A, V, E and G have the meanings given above to R ₅ are in each case a hydroxyl group protected by a protecting group, or have the meanings given above for up to R 6, one of the symbols U and V being Rg-ΝΗ-, and the other of U and V is a nucleophilic leaving group, or U together with a hydrogen atom at the beta position of the residue E is an oxygen atom and V is a group Rg-NH-, where Rg is as defined above, optionally with protecting groups present and the resulting compound of formula (I) is optionally converted into its acid addition salt, in particular its physiologically compatible salt with an inorganic or organic acid. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula Ia (Ia) in which: Aa represents a group -CH ₂ ^y CH ₂ -, -CH = CH- or -NH-CO-, V represents a methylene or carbonyl group, Ea represents an ethylene, n-propylene or n-butylene group, Ga represents an ethylene group, R _1a represents a C 1 -C 3 alkoxy group, each of R _2a to R _4a , which may be the same or different, each represents a hydrogen atom or a methoxy group, or Ia together with R 2 _and / or R 1 _and together with R 2 _and they are always methylenedioxy and _And Rg is hydrogen, z0kylovlu group having 1-3 carbon atoms, or a group bpnzylovou Zii ^ verifies group · SOU and their addition with acids, especially physiologically acceptable acid addition salts with inorganic or organic acids. 3. The process of claim 1 wherein the reaction is carried out in a solvent. 4. The process of claim 3, wherein the reaction is carried out in a present base. 5. Method according to claims 3 and 4, vyznaZčlící in that the reaction is carried out at 0 to ¹⁵ 0 C above the boiling point for Oda ^{H U} sing the extended ^eh ^ ^ mouth la. 6. The process of claim 3, wherein the protecting group used is removed by hydrolysis in the presence of an acid or base or a benzylic residue used as a protecting group by hydrogenolysis.