SI8810229A8 - Process for preparation of tetrahydronaphtalene derivatives - Google Patents

Description

PROCEDURE FOR OBTAINING TETRAHYDRONAFTALINE DERIVATIVES

1. FIELD OF THE INVENTION

The invention falls within the field of chemistry or. Pharmaceuticals, a process for the preparation of a tetrahydronaphthalene derivative of the general formula z:

• · · I II l \ z \ • · 9 ·

nyloxy or lower alkoxy-loweralkylcarbonyloxy, X denotes C 1 -C 4 -g-alkylene, which in this case may be terminated with 1,4-phenylene or terminated or extended with 1,4-cyclohexylene, A denotes di- or tri-substituted , an ethylene group bound by 2-imidazolyl or optionally substituted benzimidazolyl, benzimidazolonyl, imidazo | 4,5-c | pyridinyl, imidazo | 4,5-c | pyridinonyl, benztiazolyl, benzodiazepine-2,5-dione-1-yl

2.

or pyrrolo | 2,1-c || 1,4 | -benzodiazepine-5,11-dione-10-yl in represents the number 0 or 1, in the form of racemates and optical antipodes, as well as N-oxides, and to pharmaceutically acceptable acids addition salts of these derivatives.

These compounds are novel and have valuable pharmacodynamic properties.

2. Technical problem

The technical problem to be solved by the present invention is to provide a process for the preparation of new tetrahydronaphthalene derivatives, which have valuable pharmacodynamic properties.

3. State of the art

In European Patent Publication no. 0.177.960 discloses tetrahydronaphthalene derivatives but having, instead of the heterocyclic residue A, an optionally substituted phenyl residue. The calcium-antagonistic properties of the compounds are also described.

4. Description of a solution to a technical problem with examples of execution

The subject of the present invention are compounds of general formula I,

3.

N-oxides and the pharmaceutically acceptable acid addition salts of these compounds as such and for use as therapeutic active substances, the preparation of these compounds, further the drugs containing them and the preparation of such drugs, and the administration of the compounds of general formula I, N-oxides and their pharmaceutical applicable acid addition salts in the control or prevention of disease or in the recovery of health, especially in the suppression and prevention of angina, ischemia, arrhythmias, high blood pressure and heart failure.

The term lower alkyl used herein, alone or in combination, refers to the branched and branched, saturated carbon-hydrogen residues of 1-6, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, 1 torn alike. The term C 1 -C 4 -alkyl "similarly refers to alkyl groups, in which the alkyl axis has 1-12 carbon atoms. The term lower alkoxy means lower alkyl ether groups in which the term lower alkyl

It has the meaning given above. The term halogen includes four halogen atoms fluorine, chlorine, bromine and iodine. The term C 1 -C 4 -alkylene denotes straight or branched saturated residues of 1-18 carbon atoms, such as methylene, ethylene, propylene, methylethylene, butylene, 1,1-dimethylpropylene, pentamethylene.

1-methylpentylene, 1-methylpentamethylene, hexamethylene, heptamethylene, undecamethylene and friction alike. The term aryl denotes, optionally, by halogen trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino group one or more substituted phenyl. Examples of optionally substituted benzimidazoles, benzylmidazolonyl, imidazo | 4,5-c | pyridinyl, imidazo | 4,5-c | pyridinonyl, benzthiazolyl, benzodiazepin-2,5-dione-1-yl or pyrrolo | 2,1-c | | 1,4 | Benzodiazepine-5,11-dione-104.

or 2-benzimidazolyl, 1-methyl-2-benzimidazolyl, 1-dodecyl2-benzimidazolyl, benzimidazolonyl, 3-methylbenzimidazolonyl,

3-isopropylbenzimidazolonyl, 3-butylbenzimidazolonyl, 3-morphonyloethylbenzimidazolonyl, 3-benzimidazolonyl, 3-benzylbenzimidazolonyl, 2-pyridylmethylbenzimidazolonyl, 2-imidazo | 4,5-c | -pyridinyl, imidazo | 4,5-c | pyridinonyl, 2-benzthiazolyl,

2,3,4,5-tetrahydro-4-methylbenzodiazepine-2,5-dione-1-yl,

6-chloro-2,3,11,11a-tetrahydro-pyrrolo | 2,1-c | 1,4 | benzodiazepin-5,11-dione-10-yl, 5,6-dimethyl-2-benzimidazolyl and thorne-like . Examples of di- and tri-substituted 2-imidazolyl, which is bonded via the ethylene group, are 1-methyl-4,5-diphenyl-2-imidazolylethyl and 4,5-diphenyl-2-imidazolylethyl and thorne alike. The term outgoing group '* means halogen groups known as leaving groups, preferably chlorine or bromine, arylsulfonyloxy, such as tosyloxy, bromobenzenesulfonyloxy, benzenesulfonyloxy or msitylensulfonyloxy, or alkylsulfonyloxy, such as trifluoromethyloxy

The term pharmaceutically acceptable acid addition salts include salts with inorganic or organic acids, such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, formic, maleic, acetic, amber, tartaric, methanesulfonic, p-toluenesulfonic acid and friction-like. Such salts can be made from the aspect of the prior art and taking into account the nature of the compound which is translated into a single salt, which in any case is not a problem for one of skill in the art.

Of advantage are those compounds of formula I, in which R is isopropyl, R- ^{5 is} preferably isobutyryloxy or methoxyacetyloxy, and is preferably number 1. Further

5.

are suitable compounds of formula I wherein R is fluoro. Such compounds of formula I, in which R is methyl, are also suitable. Also suitable are those compounds of formula I, in which X is C 1 -C 4 -alkylene, especially preferably propylene, butylene, pentamethylene or hexamethylene, and A is preferably 2-benzimidazolyl, 2-benzthiazolyl.

1-methyl-2-benzimidazolyl, 1-dececyl-2-benzimidazolyl, benzimidazolonyl, 2,3,4,5-tetrahydro-4-methylbenzodiazepin-2,5-dione-1-yl, 6-chloro-2,3, 11,11a-tetrahydropyrrolo | 2,1-chili, 4,1-benzodiazepin-5, 11-dione-10-yl, or 1-methyl-4,5-diphenyl-2-imidazolyl, especially suitable 2-benzimidazolyl or 2-benzthiazolyl.

It is apparent from the above that such compounds of formula I, in which R is isopropyl, R ^J is 1 isobutyryloxy or methoxyacetyloxy, R is fluoro, are particularly suitable.

R stands for methyl, X stands for propylene, butylene, pentamethylene or hexamethylene, A stands for 2-benzimidazolyl or 2-benzthiazolyl and n stands for number 1.

Particularly preferred compounds of formula I are:

2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1H-isopropyl-2 / S-naphthylmethoxyacetate, | 1S, 2S | -2- | - || 5- (2-Benzothiazolyl) -pentyl | -methylamino | -ethyl] -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate i | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthylmethoxyacetate.

6.

those salts of these compounds can be obtained thus

The compounds of formula I in the form of racemates and optical antipodes, as well as N-oxides and pharmaceutically acceptable acid additionally

a) the compound of the general formula reacts

OH t \ / \:

T ίί ΐ \ / * v

1 / Λ. / Χ / - * Ϊ2 ^ΙΧ) η- ^Α la

2 in which R, RR, A, X and n. have the meaning given above _r with an acylating agent which attaches to a lower alkylcarbonyl or lower alkoxy-lower alkylcarbonyl group, and if desired,

b) the resulting compound is oxidized to the corresponding N-oxide, and / or

c) separates the resulting racemate into optical antipodes, and / or »j. 'ίί

d) The resulting compound is translated into pharmaceutical applications. J vu acid addition salt.

The acylation of compounds of formula Ia is carried out by methods known per se, suitable acylating agents are particularly activated acid derivatives, such as acid halides and acid anhydrides or mixed acid anhydrides. Reak

7.

which is carried out in an organic solvent which is inert under the given reaction conditions or in a mixture of such solvents at a temperature between about 0 ° C and a reflux temperature. Especially aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxane, and friction-like ones are considered as solvents.

The resulting compound can also be converted in a known manner in a suitable N-oxide by the action of an oxidizing agent, such as hydrogen peroxide or peracid, for example, persicacetic acid or perbenzoic acid, in a solvent such as an alkanol, e.g. , methanol or ethanol, and friction alike, at a temperature between about 0 ° and 50 ° C, preferably at room temperature.

The starting materials of the formula la are new and mcgu is debuted by having a compound of the general formula? OH / * \ / * \:

and II ¹¹

R ^{X /} V in which Z denotes a leaving group and R and R ¹ have the meaning given above, reacts with an amine of the general formula

HN- (X) -A n

III

8.

v in which R, A, X and n have the meaning given above.

The compound of formula II is reacted by methods known per se with the amine of formula III. The reaction is carried out in the presence or absence of an organic solvent which is inert under the given reaction conditions, at a temperature between about 20 ° and 150 ° C, preferably between about 80 ° and 120 ° C. In this reaction, solvents include dimethylformamide, dimethylsulfoxide, alcohols, such as isopropanol or tert-butanol, ethers, such as tetrahydrofuran or dioxa, aromatic hydrocarbons, such as benzene, toluene or xylene, chlorinated hydrocarbons, such as methylene chloride, hydrochloride, carbon towers similarly. The reaction is conveniently carried out in the presence of an acid-binding agent, such as a tertiary amine, such as trimethylamine, triethylamine, ethyldiisopropylamine or 1,5-diazabicyclo | 4.3 · 0 | non-5-ene, wherein the acid-binding agent may also serve an excess of an amine of formula III. It is expedient to operate at atmospheric pressure, although higher pressures may also apply.

The preforms of formulas II and III are. known or may be obtained in analogy with the preparation of known compounds. The following Schemes I-III show one process for the preparation of one compound of formula III, in which A denotes a heterocycle attached via a nitrogen or carbon atom, or di- or tri-substituted 2-imidazolyl which is linked via an ethylene group, e.g. to which Boc stands for tert-butoxycarbonyl, Bz stands for benzyl and Ph stands for phenyl ring. The reaction conditions for the reactions shown in the above schemes are described in the embodiment examples section.

9.

Scheme I h ₂ n- (CH ₂ ) ₆ -oh

IV

Boc-NH- (CH _O ), 0H Z oi

Boc-NH- (CH ₂ ) _g -OSO ₂ CH ₃

VI · '\.

BOC-NH- (CH „).-Nf \ j- · (

With b \ / x \ /

VII / '\ z Boc-N- (CH,) ^ ^CH 3

VIII

HN- (CH_) _c -N _x ; NH

Au 2 6 \ /

CH ₃ z ** \? \ • · \ / lila _B ° cn- (ch ₂ ) ₆ -n ( ^X > h ^ČH 3 / 'T * · \ /

IX / \

Boc-N (CH _{0) C-N.} N-CH-,

ČH ^{25 X} .-. ^{Z 3 Un} 3 '/ \ / \

HN- (CH „) - N; N-CH _q 6h, ^{2 6} > - < ^{3 3} / \ \ / • - ·

IHb

10.

Scheme II

BzOC-NH-CH ₂ - «\ / * - COOH XI

BzOC-N-CH „- * f ^ '- COOH XII

OC-tiJ-CH ₂ ' ^H 3

HN-CH ₂ - ·

: h.

XIV

Illd _t ^{7 x} i - · · - ♦ \ /

.

, / \ /

Scheme III

HOOC-CH - / i 2

^Ph / ^ph

XV

Ph

HNOC-CH-- ·; |

A _h ² \ z * \ ^CH 3 ^X N ^ZX Ph

XVI * A with ^h

HNCH _n CH _n - »C ί: h.

S / ^X Ph

Ule

Ph ./ \ /

BzO-CN-CH-CH--; 1 ^: «3 ^{2 2} V \ _h

XVII

CH z \ / ^Ph r ^H a

XVIII

CH

IX / ^Ph

HN-CH-CH ,, - * / '

CH-. ^{2 2} \ / '\ ^X N Ph

Illf

12.

The compounds of general formula I contain at least one asymmetric center (position 2) and can therefore be in the form of optical antipodes or racemates. Compounds of formula I containing more than one asymmetric center are in the relative configuration given by formula I. The racemates of formula I mcgu are separated by applying known methods, for example, by reaction with an optically active acid and by fractional crystallization of the resulting salt, at resulting in separation into optical antipodes.

The compounds of formula I have a pronounced calcium-antagonistic effect and can therefore be used as medicaments, especially for the suppression or prevention of angina, ischemia, arrhythmias, high blood pressure and heart failure.

The test described below has shown calcium-antagonistic activity as blood pressure lowering properties by the compounds of the present invention:

A. H-Desmetoxiverapamil-binding determinations:

Determination was performed on partially cleared membranes of the heart of a black pig. The reaction mixture was combined (0.3 ml)

About 0.2-0.8 mg of membrane protein, 2.5 nM of H-desmethoxyrapamil and various concentrations of test substances. The incubation lasts for 120 minutes at 37 ° C and is stopped by dilution with incubation buffer; followed by filtering. The radioactivity associated with the filtrate is measured by a scintillation counter. Specific binding (ie receptor bound) is defined as the difference between total and non specific binding

13.

radioactivity. Non-specific binding was determined in the presence of excess verapamil (10 / UM) that was not radioactive.

The activity (potency) of a compound in this test is defined by the value of Ιΰ ^ θ. ΙΟ ^ θ is that concentration of a substance (in Mol / 1) that causes half the maximum inhibition of specific binding of H-desmethoxyrapamil. This value is extrapolated from the curve representing the concentration and binding function.

B. Isolated, perfused guinea pig according to Langendorff:

The sleeping piglet weighs approximately 400 g with urethane (1 g / kg i.p.) and quickly removes its heart. The aorta is cannulated and the heart is retrograde perfused with a modified Krebs-Henseleit solution of the following composition in mM:

NaCl 114.7, KC1 4.7, MgSO ^ 1.2, KH ₂ PC ₄ 1.5, NaHCO ₃ 25,

CaCl ₂ 2.5 and glucose 11.1. This solution was quenched with oxycarbon (a mixture of 95% oxygen and 5% carbon dioxide) at pH 7.3 at 37 ° C. The perfusion pressure was kept constant at 90 cm H ₂ 0 (8.83 kPa).

A Miller microtype catheter was inserted into the left heart chamber as a pressure transducer (PC-350) to measure left ventricular pressure. The entire course of the cardiac artery was collected in a funnel and measured using an electromagnetic flowmeter. All measured parameters are displayed on the parameter recording apparatus (Gould, model 2800). After the adaptation, the experiment begins within 45 minutes. The substances were infused at a rate of 1% relative to the total heart rate (coronary-ncg flow). It is made for each test substance

14.

-1 Ο complete effect-concentration curve (10 to 10 M). The two most important measurement parameters are: (1) CBF:

coronary blood flow (in ml / min) - rate of blood flow through the coronary arteries and (2) dp / dt: rate of growth of left ventricular pressure (in mmHg / sec) - representing the rate of increase of left ventricular pressure, as a measure of spike (mcc ) contractility of the heart; this value is given as% of maximal change from baseline (A%) by given dose.

C. Hemodynamic parameters in a narcotic dog:

The four most important measurement parameters (with appropriate measurement units) of hemodynamic examinations are: (1) CBF: Coronary Blood Flow (in ml / min) - rate of blood flow through coronary arteries; (2) HR: Heart Rate (in beats / min) - heart rate; (3) BP: Blood Pressure (in mmHg) - blood pressure; and (4) dp / dt: Rate of increase in left ventricular pressure (in mmHg / sec) - rate of increase of left ventricular pressure as a measure of cardiac contractility (strength of contraction). Values are given as% of maximal change in baseline (Δ%) by given dose.

In this way, not only the overall picture of the action of the substance is obtained, but also the assessment of the potential selectivity for a particular part of the bloodstream system in the whole organism. After administration of the anesthetic agent, the dog is intubated and allowed to breathe artificially. Blood Ph, pCC ^, p0 ₂ and hemoglobin were measured every hour using a blood and gas analyzer. Blood pressure (systolic and diastolic) was measured by the probe tube abdominally in the abdominal aorta. Heart frequency

15.

was monitored by a tachometer separated from the blood pressure pulse. For other measurements, the heart must first be released in order to insert a single probe for pressure measurements (dp / dt) into the left veritrix (left heart chamber). Coronary blood flow was measured on the left coronary artery (descedens) using a single probe to measure flow.

The results obtained in these tests are summarized and shown in the following table:

Table

Foods- her A ic _cn 50 CH] B C BP Δ t dp / dt Δ l Dose mg / kg i.v. CBF ^IC 50 [Μ] dp / dt Δ t CBF Δ l HR Δ 1 A 1,3-10 ^-7 -8 4,7 * 10 250 86 - 7 -22 25 0.3 B -8 3.2 · 10 -9 1,1 * 10 162 22. -25 -21 6 0.03 C -6 1,0 * 10 i, o * io ^-5 164 57 0 - 8 10 1 . .D. -8 3.4 * 10 -8, 2.8 * 10 j 130 46 - 2 - 3 4 0.3 E l, 5 * 10 “ ⁷ -9 i 1.8 * 10 237 96 -15 -20 11 0.3 F -8 2.8 * 10 -9 2,4 * 10 222 146 -41 -28 25 0.3 Mr i, o * io ⁷ -8 2,2 * 10 124 82 - 9 -14 18 0.3

16.

A = | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamines | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl2- naphthylmethoxyacetate

B = | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 | methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -amino | ethyl | -2-naphthylmethoxyacetate

C = | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methyl-knoxidoamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1isopropyl- 2-naphthylmethoxyacetate

D = | 1S, 2S | -2- | 2- | 7- (1-dodecyl-2-benzimidazolyl) -heptyl | methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate

E = | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 || 3- (1-methyl-4,5-diphenylimidazol-2-yl) - propyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate

F = | 1S, 2S | -2- | 2- || 5- (2-Benzthiazolyl) -pentyl | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthylmethoxyacetate

G = | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 || 4- | (2-benzimidazolyl) -methyl | -benzyl | -methylamino | ethyl -2-naphthylmethoxyacetate

Formula I supplements may be administered as medicaments, for example, in the form of pharmaceutical preparations. These pharmaceutical preparations may be administered orally, for example, in the form of tablets, light tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration may also be rectal, for example,

17.

in the form of suppositories, or parenterally, e.g., in the form of injectable solutions.

For the preparation of tablets, light tablets, dragees and hard gelatin capsules, compounds of formula I may be processed with a pharmaceutically inert, inorganic or organic excipient. As such excipients can be used, for example, for tablets, dragees and capsules with hard gelatin, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.

For soft gelatin capsules as excipients are suitable e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

Suitable excipients are suitable for the preparation of solutions and syrups. water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for excipients include, for example, water, alcohols, polyols, glycerin, vegetable oils, etc.

For suppositories, excipients are suitable e.g. natural and hardened oils, waxes, fats, semi-liquid or liquid pclioles, etc.

In addition, pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting, emulsifying, sweetening, coloring, flavoring, osmotic pressure salts, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.

According to the present invention compounds of the general formula I can be

18.

to be used to combat or prevent angina, ischemia, arrhythmias, high blood pressure and heart failure. The dosage may vary within wide limits and of course in each individual case it must be adapted to the individual characteristics, in general, when administered orally, the daily dose should be from about 25 to 150 mg of the compounds of general formula I, which may be exceeded if the upper limit is given. it proves to be useful.

The following examples should further explain the present invention, however, they do not in any way limit the scope of the invention. All temperatures are given in degrees Celsius.

Example 1

A mixture of 5.4 g (28.7 mmol) 2 - 3- (phenylamino) -propyl | -benzimidazole, 11.4 g (28.7 mmol) of 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-10Z-isopropyl-2 73-naphthyl) -ethyl-p-toluenesulfonate and 3.74 (28.7 mmol) of Hunig's base was heated at 120 ° C for 30 minutes. The mixture was then poured onto ice water and extracted with methylene chloride. After drying the organic phase over magnesium sulfate, the solvents are evaporated off, the residue is chromatographed on silica gel with a 6: 1 mixture of methylene chloride and methanol as the eluting agent. 6.2 g (49%) of 1S, 2S | -2- | 2 - | 3- (2-benzimidazolyl) -propyl | -methylamino | ethyl | -6-fluoro-1,2,3 are obtained , 4-tetrahydro-1-isopropyl-2-naphthalinol, ladfg = + 41.2 ° (c = 0.8%; methanol).

2- | 3- (Methylamino) -propyl | -benzimidazole, which is used herein as a starting material, is debuted as follows:

19.

22.8 g (91 mmol) of 4- | 1- (Benzyloxy) -N-methylformamido | -butyric acid were dissolved in 200 ml of tetrahydrofuran. The mixture was cooled, and 13 ml (128 mmol) of triethylamine and 12 ml (91.5 mmol) of hydrochloric acid isobutyl ester were added dropwise at -15 ° C. After 2.5 hours, 10.3 g (95 mmol) of o-phenylenediamine in 85 ml of tetrahydrofuran was added dropwise at -10 ° C for 30 minutes. After stirring at room temperature for one hour, the solvent was evaporated under reduced pressure. Water was added thereto and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After drying over magnesium sulfate and dissolving the solvent, 27.05 g of crude product are obtained which is chromatographed on silica gel using ethyl acetate as the elution agent. Pipers were obtained with 20.1 g (71%) of benzyl- [3- ((2-aminophenyl) -carbamoyl] propyl] -methylcarbamate.

MS: M ⁺ 341.

20.1 g (59 mmol) Benzyl- | 3- | (2-aminophenyl) -carbamoyl | -propyl | -methylcarbamate was dissolved in 450 ml of toluene and mixed with 7 g (37 mmol) of p-toluenesulfonic acid. The reaction mixture is then heated under reflux for a period of 2 hours, whereby the recovered water is removed from the non-reaction mixture by a water extractor. After settling and dissolving the residue in ethyl acetate, it is washed twice with saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated. A silica gel crude product chromatography with ethyl acetate as the elution medium gave 11 g (58%) of benzyl- | 3- (2-benzimidazolyl) -propyl | methylcarbamate, m.p. 83-86 ° C.

20.

11.0 g (34 mmol) of Benzyl- | 3- (2-benziroidazolyl) -propyl | -methyl carbamate is reduced to 150 ml of methanol in the presence of 2.5 g of palladium on charcoal (5% catalyst) as a hydrogen catalyst . 5.45 g (85%) of 2- | 3- (methylamino) -propyl | -benzimidazole, m.p. 134-136 ° C.

Example 2

6.2 g (14.6 mmol) | 1S, 2S | -2- | 2- || 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluon-1,2,3, 4-Tetnahid-1-isopnopyl-2-naphthalinol was formed in 50 ml of chloroform. To this was added, at 0 ° C, 2.5 ml (15 mmol) of N-ethyldiisopropylamine and 5 ml (55 mmol) of methoxyacetyl chloride. The reaction mixture was stirred overnight at room temperature. and then mixed with 100 ml of 1 N sodium hydroxide solution in water, and extracted with chloroform. After drying over magnesium sulfate and evaporating the solvent, the residue is chromatographed on silica gel using a mixture of (6: 1) methylene chloride and methanol as the eluting agent. For this, 6.2 g of an oil are obtained which is dissolved in 30 ml of ethanol and mixed with 15 ml of hydrochloric acid saturated ether. The reaction mixture was then evaporated and the residue crystallized from a mixture of ethanol 1 diethyl ether. Pipernic was obtained 5.4 g (65%) of 1S, 2S | -2- | 2- | 3- (2-benzimidazolyl) propyl | -methylamino | -ethyl | -6-fluoro-1,2,3 , 4-Tetrahydro-1 isopropyl-2-naphthylmethoxyacetate dihydrochloride, m.p. 128 ° C

Example 3

A mixture of 4.2 g (10.35 mmol) of 2- (6-fluoro-1,2,3,4-tetrahydro2-hydroxy-1 H -isopropyl-2 H, -naphthyl) -ethyl-p-toluenesulfonate.

and 4.5 g (20.7 mmol) of 2- | 5- (methylamino) -pentyl] -benzimidazole were heated at 100 ° C for 30 minutes. Then 100 ml of chloroform is added first, then after cooling of 100 ml of ether and finally 100 ml of 1 N aqueous hydrochloric acid. After stirring the reaction mixture for 30 minutes, this was made basic with a concentrated aqueous sodium hydroxide solution and the organic phase was decanted, dried and evaporated. Chromatography on silica gel using a mixture of (6: 1) methylene chloride and methanol as the elution medium afforded 2.7 g (58.2%) of 1S, 2S | -2- | 2- || 5- (2-benzimidazolyl). ) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrabidro-1-isopropyl-2-naphthalinol, | o6 | ggg = + 36.8 ° (c = 0.25; methanol).

Example 4 g (13.2 mmol) | 1S, 2S | -2- | 2- | 5- (2-Benzimidazolyl) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, 20 ml methoxyacetic acid anhydride and 1.05 g (13.3 mmol) of pyridine was heated to 70 ° C with stirring. After two hours, it was cooled and mixed with 500 ml of 3 N sodium hydroxide solution and 500 ml of methylene chloride and stirred vigorously. The organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in ethanol and mixed with 16 ml of ether saturated with hydrogen chloride. Evaporation and crystallization from an ethanol / ether mixture afforded 6.2 g (78.5%) of dihydrochloride | 1S, 2S | -2-12- || 5- (2-benzimidazolyl) -pentyl | methylamino | -ethyl | - 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl2-naphthylmethoxyacetate, m.p. 196-198 ° C.

22.

Example 5

In a manner analogous to that described in Examples 1 and 3, the following compounds were obtained:

Starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-e6-isopropyl-2H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 4- (methylamino) -butyl | -benzimidazole obtained 11S, 2S | -2- | 2 - || 4- (2-benzimidazolyl) -butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2naphthalinol, MS: M ⁺ 437;

starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-6-isopropyl-2 H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 7- (methylamino) -heptyl | - of benzimidazole gives | 1S, 2S | -2- | 2- || 7- (2-benzimidazolyl) -heptyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2-naphthalenol dihydrochloride, | αi || gg = + 32.9 ° (c = 1%; methanol);

derived from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy N-isopropyl-2 H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 11- (methylamino) -undecyl | -benzimidazole gives | 1S, 2S | -2- | 2- || 11- (2-benzimidazolyl) -undecyl | methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthalinol;

starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy Ιού-isopropyl-2β-naphthyl) -ethyl-β-toluenesulfonate and

5,6-dimethyl-2- | 7- (methylamino) -heptyl | -benzimidazole is added 11S, 2S | -2-12-1 | 7- (5,6-dimethyl-2-benzyridazolyl) -heptyl | -methylamino | - ethyl 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, lodgg = + 33.6 ° (c = 0.5%; methanol);

23.

starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1 '> 0-isopropyl-2 H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 5- (dodecylamino) -pentyl | -benzimidazole gives | 1S, 2S | -2- | 2- || 5- (2-Benzimidazolyl) -pentyl | dodecylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro- 1isopropyl-2-naphthalinol, MS: M 606;

starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy).

- 1H-isopropyl-2H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 7- (methylamino) -heptyl | -1H-imidazo | 4,5-c | -pyridine give | 1S, 2S | - 6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | 7- (1H-imidazo | 4,5-c | pyridin-2-yl) heptyl | methylamino | -ethyl | - 2-Naphthalinol, MS: M ⁺ 480.

Benzimidazole derivatives used as starting materials were prepared analogously to the method described in Example 1.

Example 6

In the same manner as described in Examples 2 and 4, with the use of methoxyacetylation, the corresponding hydroxy derivatives of the following compounds were obtained:

| 1S, 2S | -2- | 2- || 4- (2-Benzimidazolyl) -butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2- naf ti Toxiace tat name a-dihydrochlor id, | cs6j ² g ₉ = + 28.6 ° (c = 1%; methanol);

| 1S, 2S | -2- | 2- | 7- (2-benzimidazolyl) -heptyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride,

Ic ^ lfgg = + 25.4 ° (c = 1%; methanol);

24.

| 1S, 2S | -2- | 2- || 11- (2-Benzimidazolyl) -undecyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- naphthylmethoxyacetate dihydrochloride, oJ || g ₉ = + 23.7 ° (c = 1%; methanol);

| 1S, 2S | -2- | 2- || 7- (5,6-Dimethyl-2-benzimidazolyl) heptyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1 -isopropyl-2-naphthylmethoxyacetate hydrochloride, (1: 1.85), IO / I589 = + 26.5 ° (c = 1%; methanol);

| 1S, 2S | -2- | 2- || 5- (2-Benzimidazolyl) -pentyl | -dodecylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- naphthylmethoxyacetate dihydrochloride, | o0 || gg = + 22,0 ° (c = 0.25%; methanol);

| 1S, 2S | -6-Fluon-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 7- (1H-imidazo | 4,5-c | pyridin-2-yl) -heptyl | -methylamine | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, m.p. 112-115 ° C.

Example 7

0.79 g (3.8 mmol) 2- | 3- (methylamino) -propyl | -benzthiazole, 1.54 g (3.8 mmol) 2- (6-fluoro-1,2,3,4-tetrahydro) -2-hydroxy-1 <Z-isopropyl-2.Pr-naphthyl) -ethyl | -p-toluenesulfonate and 0.49 g (3.8 mmol) of Hunig's base were stirred for 2.5 hours at 120 ° C. After cooling and dissolving the precipitate with little methylene chloride, the reaction solution was chromatographed on silica gel using a mixture (12: 1 ) methylene chloride and methanol as eluent. 1.12 g (76%) of 1S, 2S | -2- | 2- || 3- (2-benzthiazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2 were obtained. 3,4-tetrahydro-1-isopropyl-2-naphthalinol, MS: M ⁺ 440.

25.

In the manner analogous to the above, the following compounds were obtained:

Starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1CZ-isopropyl-2H-naphthyl) -ethyl | -p-toluenesulfonate and 2- | 5- (methylamino) -pentyl | -benzythiazole give | 1S, 2S | -2- | 2- || 5- (2-benzthiazolyl) -pentyl | -methylamino | ethyl 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, MS: M ⁺ 468;

starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-N-isopropyl-2 H -naphthyl) -ethyl | -p-toluenesulfonate and 2- | 7- (methylamino) -heptyl | -benzythiazole give | 1S, 2S | -2- | 2- || 7- (2-benzthiazolyl) -heptyl | -methylamino | -ethyl | - 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2naphthalinol, MS: M ⁺ 496.

2- | 3- (Methylamino) -propyl | -benzthiazole, which was used as starting material, was obtained as follows:

5.0 g (19.9 mmol) of 4- | 1- (bezyloxy) -N-methylformamido | -butyric acid were dissolved in 175 ml of tetrahydrofuran. To the solution, which was cooled to -20 ° C, was added 2.95 ml (2.1 g;

mmol) of triethylamine and 2.95 ml (22 mmol) of hydrochloric acid isobutyl ester. The reaction mixture was then stirred for 1 hour at this temperature. 2.45 g (19.6 mmol) of 2-aminothiophenol are then added and the reaction mixture is stirred for 20 hours at room temperature. 250 ml of water are then added and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. Chromatography on silica gel using a mixture of (1: 1) ethyl acetate and hexane as eluent afforded 1.7 g (25.1%) of benzyl- | 3- (2-bentiazolyl) propyl | -methylcarbamate as an oil, MS: M ⁺ 340.

26.

1.7 g (4.99 mmol) of benzyl- 3- (2-benzthiazolyl) -propylmethylcarbamate were dissolved at 0 ° C in 40% hydrobromic acid in acetic acid and stirred at room temperature for 20 hours. To this was added 60 ml of ether and after 1.5 hours the precipitate formed was filtered off. Washing the crystalline residue with ether and drying afforded 1.71 g (93.1%)

2- | 3- (methylamino) -propyl | -benzothiazole-dihydrobromide, m.p. Mp 196-197 ° C.

In a manner analogous to that described above, the following compounds were obtained:

2- | 5- (Methylamino) -pentyl] -benzothiazole, MS: M ⁺ 234; 2- | 7- (Methylamino) -heptyl | -benzothiazole, MS: M ⁺ 262.

Example 8

1.12 g (2.54 mmol) 11S, 2S | -2- | 2- || 3- (2-Benzthiazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4 -tetrahydro-1-isopropyl-2-naphthalinol was dissolved in 0.2 g of pyridine. 5 ml of methoxyacetic acid anhydride is added thereto. The reaction mixture was heated at 60 ° C for 2 hours. This was deduced with 100 ml of 1 N sodium hydroxide solution at 0 ° C and extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of (30: 1) methylene chloride and methanol as eluent. 0.9 g of an oily product are obtained, which is dissolved in ethyl acetate and treated with 2 ml of ether saturated with hydrogen chloride. After evaporation to a volume of 20 ml, 40 ml of ether are added and the reaction is reached

27.

the mixture stirred for 1 hour. The precipitated precipitate is filtered off and dried. 0.9 g (64.5%) of 1S, 2S | -2- | 2- || 3- (2-benzthiazolyl) -propyl | -methylamino | -ethyl 1-6-fluoro-1,2 are obtained , 3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride, m.p. 13O-134 ° C

In the manner analogous to the one described above with the application of methoxyacetylation, the corresponding hydroxy derivatives of the following compounds are obtained:

| 1S, 2S | - 2 - | 2 - | 5- (2-Ber.zthiazolyl) -per.til | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate hydrochloride (5: 8), | © 6 | | _g = 27.4 ° (c = 0.5%; methanol);

| 1S, 2S | -2- | 2- || 7- (2-Benzthiazolyl) -heptyl | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate -hydrochloride (4: 5), | o6 || gg - + 25.8 ° (c = 1%; methanol).

Example 9

In a manner analogous to those described in Examples 1 and 4, starting from (S) -6- | 1- (benzyloxy) -N-methylformamido | -heptanoic acid via | 1S, 2S | -2- | -2- | | (S) -5- (2-Benzimidazolyl) -1-methylpentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, yielding | 1S , 2S | -2- | 2- || (S) -5- (2-Benzimidazolyl) -1-methylpentyl | -methylamino | -ethyl | -6- -fluoro-1,2,3,4-tetrahydro-1 -isopropyl 1-2-naphthylmethoxyacetate dihydrochloride, | cZ || _g g = + 20.0 ° (c = 0.7%; methanol).

The starting material used is (S) -6- | 1- (benzyloxy) -N-methylformamido | -hepatic acid was obtained at

28.

as follows:

20C g (1.39 mcl) of 6-Oxoheptanoic acid was dissolved in 1.2 liters of methylene chloride. At -20 ° C, 14 ml of concentrated sulfuric acid is added. Then 0.6 -4 (6.3 mol) of isobutylene is condensed at -4 ° C and this is allowed to distill into the reaction balloon. The reaction mixture was then allowed to react for 6 days at room temperature with the reflux of the reagent. Then 1 liter of saturated aqueous sodium bicarbonate solution is added, which is stirred vigorously. The aqueous phase is extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. In this case, 268.0 g (1.338 mol; 96.4%) of tert-butyl-6-oxoheptanoate are obtained, which is then combined with 162.1 g (1,338 mol) of (S) - (-) - 1-phenylethylamine and 5.8 g (30.5 mmol) of p-toluenesulfonic acid and 1.9 l of toluene were heated for 12 hours with reflux and simultaneous separation of water. Evaporation of the solvent gave 395.5 g (1.3 mol; 97.4%) of tert-butyl- (E / Z) -6- (R) - (R-methylbenzyl | -imino | -heptanoate, which dissolved in 7 l of methanol, 43 g of Raney-nickel was added and hydrogenated at a pressure of 10 bar for 24 hours, then filtered and the solvent was evaporated to give 378.5 g of an oil which was dissolved in

1.1 liters of ethyl acetate and at 0 ° C mixed with 130 ml of 10 N ethanol solution of hydrochloric acid. After stirring at 0 ° C for one hour, the formed crystals were filtered off and dried. Repeated crystallization of 282 g of ethyl acetate crystals three times yielded 172.7 g (38.9%) of tert-butyl- (S) -6- | | (S) -IZ-methylbenzyl | -amino | -hexanate hydrochloride, m.p. Mp 154-155 ° C.

160 g (0.648 mol) of the above hydrochloride was dissolved in 2.4 l of ethanol and hydrogenated in the presence of 20 g of palladium on coal (which is 5%) at a pressure of 10 bar. After filtration

29.

The catalyst was evaporated, and the residue was crystallized from 560 ml of ethyl acetate and 240 ml of hexane. 101 g (90.8%) of tert-butyl (S) -6-aminoheptanoathydrochloride, m.p. Mp 107-109 ° C.

g (374 mmol) of tert-butyl (S) -6-aminoheptanoate hydrochloride was dissolved in 1.3 L of methylene chloride. The solution was saturated with hydrogen chloride and refluxed for 4 hours. Filtration and drying of the precipitated precipitate afforded 60.8 g (89.5%) of (S) -6-aminoheptanoic acid as hydrochloride, m.p. 157-16 ° C.

To a solution of 30 g (166 mmol) of hydrochloride (S) -6-aminoheptanoic acid in 57 ml of water was added 57 ml of 4 N sodium hydroxide solution in water and then, at 10 ° C, 92 ml of aqueous sodium hydroxide solution was added dropwise. 42 ml (294 mmol) of hydrochloric acid benzyl ester such that the pH is constantly between 10 and 12. After separation of the crude product, it is stirred for another two hours at 0 ° C. Then 300 ml of water was added and the reaction mixture was extracted with ether. The aqueous phase was acidified with 20 ml of concentrated hydrochloric acid and extracted with methylene chloride. The methylene chloride phase was dried over magnesium sulfate and evaporated. The crystals obtained were recrystallized from chloroform / hexane to give 33.1 g (72%) of (S) -6- | 1- (benzyloxy) -formamido | -heptanoic acid, m.p. 82-83 ° C.

To a suspension of 3.05 g of 55% sodium hydride (70 mmol) in 200 ml of dimethylformamide was added 6.5 g (23 mmol) of (S) -6- | 1- (benzyloxy) -formamido | -heptanoic acid and allow to react at 40 ° for 30 minutes. 13 g (90 mmol) of methyl iodide are then added dropwise, and the reaction mixture is heated for 1 hour

30.

at 70 °. After evaporation of the solvent, 120 ml of 1 N aqueous sodium hydroxide and 120 ml of ethanol were added, and the reaction mixture was refluxed for 30 minutes. It was then evaporated to half its original volume, added to 100 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase was acidified and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. The residue was chromatographed (5 g) on a silica gel column using a mixture of (12: 1) methylene chloride and methanol as eluent to give 3.5 g (52.2%) of (S) -6-11 from the initial 5 g of residue. - (Ber.Zyloxy) -N-methylformamido | -heptanoic acid, MS: M ⁺ 293 ·

Example 10

To a 55% suspension of 436 mg (10 mmol) of 55% sodium hydride in 20 ml of tetrahydrofuran was added 2.0 g (4.43 mmol) of 1S, 2S | -2- | 2- || 5- ( 2-Benzimidazolyl) -pentyl | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol dissolved in 30 ml of tetrahydrofuran. After stirring at room temperature for 45 minutes, 1.42 g (10 mmol) of methyl iodide was added. After another hour of stirring, water and methylene chloride were added and the reaction mixture was shaken vigorously. The organic phase was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of methylene chloride and methanol (6: 1) as eluent to give 1.2 g (60%) of 1S, 2S | -6-fluoro-1,2,3,4- tetrahydro-1-isopropyl-2- | 2- | methyl- | 5- (1-methyl-2-benzimidazolyl) -pentyl | -amino | -ethyl | -2-naphthalinol, MS: M ⁺ 465.

In an analogous manner as described above, reaction with dodecyl iodide gave | 1S, 2S | -2- | 2- || 7- (1-dodecyl-2benzimidazolyl) -heptyl | -methylamino | -ethyl | -6 -fluoro-1,2,3,4tetrahydro-1-isopropyl-2-naphthalinol.

31.

Example 11

Mixture of 1.2 g (2.58 mmol) | 1S, 2S | -6-fluon-1,2,3,4-tetnahydro-1-isopropyl-2- 12- | methyl - | 5- (1-Methyl-2-benzimidazolyl) -pentyl | -amino | -ethyl | -2-naphthalinol, 206 mg (2.6 mmol) of pinidine and 4 ml of methoxyacetic acid anhydride were heated at 70 ° for 2 hours. Then 100 ml of 3 N aqueous sodium hydroxide solution was added and extracted with 100 ml of methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. The crude product is chromatographed on a silica gel column using (15: 1) mixtures of methylene chloride and methanol as eluent. 550 mg of oil are obtained which is dissolved in 50 ml of ethyl acetate and mixed with 1 ml of ether saturated with hydrogen chloride. After evaporation of the solvent, it was crystallized from ethyl acetate / ether to give 600 mg (41%) of 11S, 2S | -6-fluoro-1,2,3,4tetrahydro-1-isopropyl-2- | 2- | methyl- | 5- (1-Methyl-2-benzimidazolyl) -pentyl | -amino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, m.p. 203-205 °.

In the analogous manner to the one described above, | 1S, 2S | -2- | 2- | was obtained 7- (1-dodecyl-2-benzimidazolyl) -heptyl | methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate dihydrochloride, | o6 | | gg = + 20.4 ° (c = 0.9%; methanol).

Example 12

0.425 g (1 mmol) | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro- 1-Isopropyl-2-naphthylmethoxyacetate was dissolved in 60 ml of methanol and then mixed with 10 ml of 6% hydrogenpenoxide and 50 mg

32.

(0.15 mmol) of sodium tungstate. After stirring for 20 hours at room temperature, 100 mg of platinum on coal (5% platinum) in 2 ml of water is added and stirred for another hour. It is then filtered, concentrated by filtrate, diluted with a little methylene chloride and chromatographed on silica gel with a mixture of (15: 1) methylene chloride and methanol as the eluting agent. 0.18 g (35.2%) of the first diastereomer of 11S, 2S | -2-12- || 3- (2-benzimidazolyl) -propyl | methyl-N-oxidoamino | -ethyl | -6-fluoro are obtained -1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate with a value = 0.33, | οό || ° ₉ = + 39.4 ° (c = 0.5%; methanol) and 0.276 g (54 %) of another diastereomer of said compound with value = 0.26 (methylene chloride / methanol 6: 1), | cZ | | gg = + 34.8 ° (c = 0.5%; methanol).

Example 13

6.1 g (15 mmol) -1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate and

6.8 g (30 mmol) of 1- | 2- (methylamino) -ethyl | -2-benzimidazolinone hydrochloride were stirred for 4.5 hours at 130 ° in a mixture of 30 ml of dimethylformamide and 30 ml of N-ethyldiisopropylamine. The reaction mixture was poured onto 600 ml of ice water and extracted with 700 ml of methylene chloride. The extract was washed with water, dried over calcium carbonate and evaporated. The crude product thus obtained is chromatographed on a column of 150 g of silica gel using methylene chloride and 0-10% isopropanol as the elution medium to give 5.2 g (72%) of 1- | 2- || 2- || 1S , 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -ethyl-2-benzimidazolinone in the form of an oil.

- | 2- (Methylamino-ethyl | -2-benziroidazolinone hydrochloride which

33.

was used as the starting material was obtained as follows:

To a solution of 24.8 g (150 mmol) of 2- (N-benzyl-N-methylamino) ethanol dissolved in 250 ml of absolute tetrahydrofuran, a solution of 93.8 ml (150 mmol) was added dropwise at 0-5 ° -butillitium (ca. 1.6 M) in hexane. After stirring for 15 minutes at 0 °, 11.7 ml (150 mmol) of methanesulfochloride in 50 ml of tetrahydrofuran was added dropwise at a temperature between 0 and 5 °, then the reaction mixture was stirred for 30 minutes at 0 °.

5.8 g (133 mmol) of a 55% sodium hydride dispersion in mineral oil was washed with hexane to release the oil and suspended in 40 ml of dimethylformamide. Then, 23.1 g (132.5 mmol) of 1- (1-methylvinyl) -benzimidazolin-2-one in 90 ml of dimethylformamide are added dropwise at room temperature and the resulting reaction mixture is stirred for an additional 15 minutes.

This reaction mixture was added dropwise at 0 ° to the reaction solution described above. It is then heated to 70 ° and stirred for 3 hours. The reaction mixture was then poured onto 1 liter of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and evaporated. The crude product thus obtained is chromatographed on a column of 500 g of silica gel using methylene chloride and 0-5% isopropanol as the eluting agent to give 26.8 g (63%) of 1- (1-methylvinyl) -3- | 2 - (N-Benzyl-N-methylamino) -ethyl | -2-benzimidazolinone as an oil.

26.5 g (82.5 mmol) of the above compound was dissolved in 265 ml of ethanol, stirred with 26.5 ml of concentrated aqueous hydrochloric acid and heated for 1 hour under reflux. After cooling the reaction mixture to 5 ° crystallizes

34.

1- | 2- (N-Benzyl-N-methylamino-ethyl | -2-benzimidazolinone as hydrochloride, mp 107-109 °; yield 24.2 g (92%).

22.9 g (72 mmol) of 1- | 2- | N-benzyl-N-methylamino) -ethyl | -2-benzimidazolinone hydrochloride was dissolved in 250 ml of methanol, mixed with 2.5 g (10%). palladium on charcoal and hydrogenates for 90 minutes at room temperature. The residue obtained after filtration and concentration was recrystallized from methanol / ether to give 15.5 g (94%) of 1- | 2- (methylamino) -ethyl | -2-benzimidazolinone hydrochloride, m.p. 177-180 °.

Example 14 /

4.57 g (10.7 mrrol) 1- 12- | 2- | 11S, 2S | -6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -ethyl | -2-benzimidazolinone was dissolved in 15 ml. of methylene chloride, mixed with 2.2 ml of pyridine and 7.0 g (43 mmol) of methoxyacetic acid anhydride and stirred for 20 hours at room temperature. It was then stirred under ice-cooling with 30 ml of 3 N aqueous sodium hydroxide solution and stirred for 15 minutes at room temperature. The reaction mixture was then poured onto 400 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and concentrated. The resultant is 6.9 g of an oil (N, O-diacylated product), which is dissolved in 30 ml of methanol and mixed at room temperature with 11.5 ml of 1 N aqueous sodium hydroxide.

After stirring for 30 minutes, the mixture was poured onto 400 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate, evaporated, treated with hydrogen chloride equivalent in methanol, evaporated again and

35.

finally crystallized from methanol / ether. At the towers it is obtained

3.9 g (72%) | 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl | -2- (2-oxo-1- benzimidazolinyl) -ethyl | -amino | -ethyl | -2-naphthylmethoxyacetate-hydrochloride, m.p. 130-133 ° (decay); | οό | = + 26.0 ° (c = 1%; methanol).

Example 15

Analogous to Example 13, by reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate with 1- | 6- (methylamino) -hexyl | -2-benzimidazolinone, yields 1- | 6- || 2- || 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1 -isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -2-benzimidazolinone as an oil.

- | 6- (Methylamino) -hexyl | -2-benzimidazolinone, used as a starting material, is obtained as follows:

In a solution of 32.7 g (150 mmol) of di-tert-butyldicarbonate in 100 ml of methanol was added 17.6 g (150 mmol) of 6-amino-1-hexanol dissolved in 50 ml of methanol, which was carried out at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was evaporated, yielding 36.6 g of tert-butyl- (6-hydroxyhexyl) -carbamate in the form of an oil, which was directly applied in the next step.

34.8 g of tert-Butyl- (6-hydroxyhexyl) -carbamate were dissolved in 250 ml of methylene chloride and mixed at 0 ° with 24.0 ml (174 mmol) of triethylamine. Then 12.9 ml (166 mmol) of methanesulfochloride in 50 ml of methylene chloride were added dropwise at -60 ° C for 15 minutes and the reaction mixture was then stirred at -60 ° C for 90 minutes. It is then reacted

36.

the solution is poured into 600 ml of ice water and extracted with 800 ml of methylene chloride. The organic extract was washed with water, dried over magnesium sulfate and evaporated. The resultant is 58.6 g of tert-butyl- [6- (methylsulfonyl) -oxy] -hexyl | -carbamate in the form of an oil, which can be further processed without purification.

5.9 g (135 mmol) of a 55% sodium hydride dispersion in mineral oil was washed with hexane to release from the oil and then topped with 100 ml of dimethylformamide. 22.3 g (128 mmol) of 1- (1-methylvinyl) -benzimidazolin-2-one in 100 ml of dimethylformamide were added dropwise to this suspension at room temperature. After stirring at room temperature for 55 hours, 55.0 g of tert-butyl- [6- (methylsulfonyl) -oxy] -hexylcarbamate are added dropwise into 10C ml of dimethylformamide and the reaction mixture is stirred for 18 hours at room temperature. This reaction mixture was then poured onto 1 liter of water and extracted with 750 ml of methylene chloride. The organic extract was evaporated with hydrogen, dried over potassium carbonate and evaporated. The crude residue was chromatographed on a column of 950 g of silica gel using methylene chloride / hexane, pure methylene chloride and (95: 5) methylene chloride / isopropanol mixture as eluting agent to give 45.3 g of tert-butyl- | 6- 3- (1-Methylvinyl) -2-oxo-1-benzimidazolinyl | -hexyl | -carbamate in the form of an oil.

5.3 g (121 mmol) of a 55% sodium hydride dispersion in mineral oil was washed with hexane to release from the oil and then topped with 100 ml of dimethylformamide. 45.0 g (121 mmol) of tert-butyl- | 6- | 3- (1-methylvinyl) -2-oxo-1-benzimidazolinyl] -hexyl | -carbamate were added dropwise to this suspension in 100 ml of dimethylformamide at room temperature and the reaction mixture was stirred at this temperature for 90 minutes. 9.0 ml was then added dropwise

37.

(155 mmol) of methyl iodide in 50 ml of dimethylformamide at 10 ° and the reaction mixture was stirred at 10 ° for 1 hour and at room temperature for 16 hours. The reaction solution was then poured onto 800 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and evaporated. The residue thus obtained is chromatographed on 500 g of silica gel using hexane / ethyl acetate (4: 1 and 1: 1) as the eluting agent to give 39.1 g of tert-butylmethyl- | 6- | 3- (1-methylvinyl) ) -2-Oxo-1-benzimidazolinyl | -hexyl | -carbamate as an oil.

38.8 g (100 mmol) of the last mentioned compound was dissolved in 300 ml of absolute ethanol, treated with stirring with 40 ml of concentrated aqueous hydrochloric acid and heated under reflux for 75 minutes. After cooling to 40 °, the reaction mixture was concentrated under reduced pressure and poured onto 500 ml of ice water. The aqueous phase was adjusted to pH 8-9 by addition of concentrated aqueous ammonia and extracted with methylene chloride. The extract was washed with water and then discarded. The combined aqueous phases were adjusted to pH 10-11 with 3 N aqueous sodium hydroxide solution and extracted six times with 150 ml of methylene chloride / isopropanol (4: 1) each. The combined extracts were dried over potassium carbonate and evaporated to give 21.6 g of 1- | 6- (methylamino) -hexyl | -2-benzimidazolinone as an oil.

Example 16

Analogous to Example 15, by reaction of 11S, 2S | -2-6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate and 1-methyl-3 - | 6- (methylamino) -hexyl | -2-benzimidazolinone is obtained 1- | 6- || 2- | | 1S, 2S | -6-Fluos-1,2,3,4-tetra38.

Hydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -3-methyl-2-benziroidazolinone as an oil.

1-Methyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:

A solution of 9.7 g (44.5 mmol) is added dropwise to a solution of 10.0 g (40.4 mmol) of 1- | 6- (methylamino) -hexyl | -2-benzimidazolinone in 150 ml of methanol at room temperature. of tert-butyldicarbonate in 50 ml of methanol and the reaction mixture was stirred for 16 hours at room temperature. Then 6.9 ml (49.5 mmol) of triethylamine and a further 9.7 g of di-tert-butyldicarbonate in 50 ml of methanol were added and stirred for 16 hours at room temperature. The reaction mixture was then poured onto 200 ml of water and extracted with 400 ml of methylene chloride. The extracts were washed with water, dried over potassium carbonate and evaporated to give 14.1 g of tert-butyl methyl- [6- (2-oxo-1-benzimidazolinyl) -hexyl] -carbamate as an oil.

2.6 g (59.6 mmol) of a 55% sodium hydride dispersion in mineral oil were washed with hexane to release from the oil and then topped with 30 ml of dimethylformamide. 13.8 g (39.7 mmol) of tert-butyl-methyl- [6- (2-oxo-1-benzimidazolinyl) -hexyl] -carbamate were added dropwise to this suspension in 90 ml of dimethylformamide over 20 minutes at room temperature. temperature. After stirring for 90 minutes at room temperature, 6.2 ml (99.3 mmol) of methyl iodide in 30 ml of dimethylformamide were added dropwise at room temperature and the reaction mixture was stirred for a further 16 hours at this temperature. For the treatment, the reaction mixture was poured onto 20C ml of water and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over potassium carbonate and evaporated. The residue is chromatographed

39.

on a silica gel column (110 g) using methylene chloride and methylene chloride / isopropanol (99: 1 and 98: 2) as eluant to give 9.0 g of tert-butyl methyl- | 6- (3-methyl -2-Oxo-1-benzimidazolinyl) -hexyl | -carbamate in the form of an oil.

Analogous to Example 15, last paragraph, from the above compound, 1-methyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone was obtained in the form of an oil.

Example 17

In an analogous manner to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- p-toluenesulfonate and 1- {p- | 4- (methylamino) -butyl | -phenyl | -imidazole, 11S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl- 2- | 2- || 4- | p- (Imidazol-1-yl) -phenyl | -butyl | -methylarcino | -ethyl | -2-naphthalinol as an oil.

1- | p- | 4- (Methylamino) -butyl | -phenyl | -imidazole, used as starting material, is obtained as follows:

A) 53.1 g (116 mmol) of 2- (m-Dioxan-2-yl) ethyl | -triphenylphosphonium bromide are suspended in 160 ml of tetrahydrofuran and mixed at -25 ° for 77 minutes with 77.3 ml. (116 mmol) solution of n-butyl lithium (ca. 1.5 M in hexane). It was then stirred for 15 minutes at -25 °. Then 10 ml of a mixture of tetrahydrofuran and 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (1: 1) are added, stirred for 5 minutes at -25 ° C and then in a stream

40.

minutes at -25 ° is mixed with 20 g (116 mmol) of p-imidazol-1-yl-benzaldehyde in 18O ml of tetrahydrofuran / 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (1: 1). After complete addition, the reaction mixture was warmed to room temperature and stirred for 15 minutes at that temperature. The reaction mixture was then poured onto 1 liter of ice water and extracted with 600 ml of methylene chloride. The methylene chloride extract was washed with water, dried over magnesium sulfate and evaporated. The resultant is 42.4 g of semi-crystalline product, which is dissolved in 600 ml of methanol and then exhaustively hydrogenated in the presence of 18 g (5%) of palladium on coal. Filtration of the catalyst and evaporation of the filtrate afforded 36.6 g of semi-crystalline residue, which in turn was dissolved in 700 ml of methanol, mixed with 22.4 g of p-toluenesulfonic acid monohydrate and refluxed for 2.5 hours. After cooling to room temperature, the pH was adjusted to 7 with 36 g of sodium carbonate, the reaction mixture was evaporated, the residue poured into 500 ml of water and extracted with 600 ml of methylene chloride. The methylene chloride extract was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 36.1 g of semi-crystalline residue. This was dissolved in 400 ml of tetrahydrofuran, mixed with 110 ml of 3 N aqueous hydrochloric acid, stirred for 3 hours at room temperature and then concentrated under reduced pressure. The reaction mixture was then poured onto 500 ml of ice water and extracted three times with 200 ml of ether each. The aqueous phase was then adjusted to pH 9 with potassium carbonate and extracted with 600 ml of methylene chloride. The methylene chloride extract was washed with water, dried over potassium carbonate and evaporated. The residue was chromatographed on 240 g of silica gel using methylene chloride and 0-5% isopropanol as the eluting agent. In this case, 13.2 g (53%) of 4- | p- (imidazol-1-yl) -phenyl] butanal are obtained as an oil.

41.

B) 37.8 g (558 mmol) of methylamine hydrochloride is dissolved in 200 ml of methanol and then treated with 45.8 g (558 mmol) of sodium acetate and 3.9 g (62.1 mmol) of sodium cyanide. of borohydride. The reaction mixture was stirred for 15 minutes at room temperature, and then 12.05 g (56.24 mmol) of 4- | p- (imidazol-1-yl) -phenyl | -butanal in 40 ml of methanol was added dropwise over a period of 15 minutes at room temperature and the reaction mixture was then stirred for 3 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, the residue poured into 1 liter of ice water and extracted with 800 ml of methylene chloride. The organic extract was washed with water, dried over magnesium sulphate and evaporated. The residue thus obtained is chromatographed on 100 g of silica gel using methylene chloride / iso propanol / aqueous, 25% ammonia solution (160: 40: 1 and 7: 3: 0,3) to give 3.8 g (29%) 1- | p - ^ - (methylamino) -butyl | -phenyl | -imidazole in the form of oil.

Example 18

In a manner analogous to that described in Example 13, by reaction of 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p -toluenesulfonate and 1- | 4- (methylamino) -butyl | -2-benzimidazolinone to give 1- | 4- || 2— | 11S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | butyl | -2-benzimidazolinone in the form of an oil.

- | 4- (Methylamino) -butyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:

42.

Analogous to the process described in Example 15 from 4- (methylamino) -1-butanol, tert-butyl-methyl- | 4- | (methylsulfonyl) -oxy | -butyl | -carbamate was obtained in the form of an oil, which was then converted into tert-butyl butyl-methyl- | 4- | 3- (1-methylvinyl) -2-oxo-1-benzimidazolinyl | -butyl | -carbamate. This compound, also obtained in the form of an oil, was converted from its Side (again analogous to Example 15) to 1- | 4- (methylamino) -butyl | -2-benzimidazolinone which was separated in the form of an oil.

Example 19

In an analogous manner to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- p-toluenesulfonate and 1-isopropyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, 1 - | 4- || 2 - || 1S, 2S | -6-fluoro-1,2 was obtained. 3,4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl-1-ethyl | -methylamino | -butyl | -3-isopropyl-2-benzimidazolinone in the form of an oil.

1-Isopropyl-3-yl 4- (methylamino) -butyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:

8.14 g (22.6 mmol) of tert-butyl-methyl- | 4- | 3- (1-methylvinyl) -2-oxo-1-benzimidazolinyl | -butyl | -carbamate was dissolved in 80 ml of methanol and after addition 1.6 g (5%) of palladium on charcoal is hydrogenated for 4 hours. The reaction mixture was then filtered 1 evaporated to give 8.5 g of tert-butyl-methyl- | 4- (3-isopropyl-2-oxo-1-benzimidazolinyl | -butyl | -carbamate as an oil. This compound is converted to 1-isopropyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, which is also isolated in the form of an oil, analogously to the method described in the last paragraph of Example 15.

43.

*

Example 20

In a manner analogous to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- of p-toluenesulfonate and 1-butyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, gave 1- J 6 - | 2 - | 11S, 2S | -6-fluoro-1,2,3 , 4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl-methylamino | -hexyl | -3-butyl-2-benzimidazolinone as an oil.

1-Butyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:

In analogy to Example 16, tert-butyl-methyl- | 6- (3-butyl-2-oxo is obtained from tert-butyl-methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -carbamate and butyl iodide -1-Benzimidazolinyl) -hexyl | -carbamate in the form of an oil. This compound is converted to 1-butyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, which is also obtained in the form of an oil, analogously to Example 15.

Example 21

In a manner analogous to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- of p-toluenesulfonate and 1- (2-morpholinoethyl) -3- | 6- (methylamino) -hexyl | -2-benzimidazolinone to give 1- | 6- || 2- || 1S, 2S | -6-fluoro- 1,2,3,4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -3- (2-morpholinoethyl) -2-benzimidazolinone in the form of an oil.

1- (2-Morpholinoethyl) -3- | 6- (methylamino) -hexyl | -2-benzimide44.

zolinone, which was used as the starting material, was obtained as follows:

9.0 g (25.9 mmol) of tert-butyl-methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -carbamate is dissolved in 250 ml of methanol, mixed with 35 g (259 mmol) of potassium carbonate, 0.5 g of potassium iodide and in portions with 16.9 g (90.6 mmol) of chloroethylmorpholine hydrochloride. The reaction mixture was then heated at reflux for 16 hours. After cooling, the reaction mixture was poured onto 1 liter of ice water and extracted with 800 ml of methylene chloride. The extract was washed with water, dried and concentrated. The residue was dissolved in 50 ml of ether and extracted once with 15 ml each and then 5 ml of 3 N methanesulfonic acid in water and once with 5 ml of water. The combined aqueous phases were adjusted with ammonia to pH 8-9 and extracted three times with 100 ml of methylene chloride each. The combined extracts were washed with water, dried over potassium carbonate and evaporated to give 7.8 g (65.4%) of tert-butyl-methyl- | 6- | 3- (2-morpholinoethyl) -2-oxo- 1-Benzimidazolinyl | -hexyl | -carbamate in the form of an oil.

This analogous to Example 15 is then converted to 1- (2-morpholinoethyl) -3- | 6- (methylamino) -hexyl | -2-benzimidazolinone dihydrochloride, m.p. 229-232 °.

Example 22

Analogous to the method of Example 15, by reaction of 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate and 1- benzyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, 1-benzyl-3- | 4- || 2- | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -2-benzimidazolinone as an oil.

45.

1-Benzyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, which was used as starting material, was obtained analogously to Example 16 from 1- | 4- (methylamino) -butyl | -2-benzimidazolinone via tert. -Butyl-methyl- | 4- (2-oxo-1-benzimidazolinyl) -butyl | -carbamate.

Example 23

In a manner analogous to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- of p-toluenesulfonate and 1- | 4- (methylamino) -butyl | -3- (2-pyridylmethyl) -2-benzimidazolinone, to give 1- | 4- || 2- || 1S, 2S | -6-fluoro- 1,2,3,4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -3- (2-pyridylmethyl) -2-benzimidazolinone in the form of an oil.

- | 4- (Methylamino) -butyl | -3- (2-pyridylmethyl) -2-benzimidazolinone, which was used as starting material, was obtained analogously to Example 16 starting from tert-butyl-methyl- | 4- (2-oxo -1-Benzimidazolinyl) -butyl | -carbamate.

Example 24

In a manner analogous to that described in Example 13, by reaction of 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl | -p-toluenesulfonate and 1,3-dihydro-3- | 6- (methylamino) -hexyl | -2H-imidazo | 4,5-c | pyridin-2-one to give 3- | 6- || 2- || 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -1,3-Dihydro-2H-imidazo | 4,5-c | pyridin-2-one as an oil.

1,3-Dihydro-3- | 6- (methylamino) -hexyl | -2H-imidazo | 4,5-c | pi46.

ridin-2-one, which was used as starting material, was obtained as follows:

In a manner analogous to that described in Example 15, from

6- (methylamino) -1-hexanol the tert-butyl-methyl- (6-hydroxyhexyl) -carbamate was obtained in the form of an oil, which was then tert-butyl-methyl- | 6- (methylsulfonyl) -oxy | hexyl | -carbamate, which is also isolated in the form of an oil, converted to tert-butyl-methyl- | 6- | - (1-methylvinyl) -1,2-dihydro-2-oxo-3H-imidazo | 4,5-c | pyridin-3-yl | -hexyl | -carbamate; this product is also obtained in the form of oil.

12.2 g (31.4 mmol) of the title compound was dissolved in 100 ml of ethanol, treated with 13 ml of concentrated aqueous hydrochloric acid, and refluxed for 40 hours. Then, under ice-cooling, the pH was adjusted to 9-10 with dilute aqueous sodium hydroxide solution, the reaction solution was saturated with sodium chloride and extracted continuously for 16 hours with chloroform. The extract was dried over potassium carbonate and evaporated to give 7.2 g (92%) of 1,3-dihydro-3- | 6- (methylamino) -hexyl | -2H-imidazo | 4,5-c | -pyridin-2-one in the form of oil, which is further processed without further purification.

Example 25

The following compounds were obtained in an inorganic manner to that described in Example 14:

| 1S, 2S | -6-Fluos-1,2,3,4-tetrahydro-1-isopropyl-2- {2- [methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate hydrochloride,

47.

| o6 | g ° = + 27.8 ° (c = 1%; methanol);

| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 4- (2-oxo-1-benzimidazolinyl) -butyl | -amino | -Ethyl | -2-naphthylmethoxyacetate hydrochloride, 0 ° C = + 28.7 ° (c = 1%; methanol);

| 1S, 2S | -2- | 2- || 6 - (1,2-dihydro-2-oxo-3H-imidazo | 4,5-c | -pyridin-3-yl) -hexyl | -methylamino | - ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride, | ού | = + 26.0 ° (c = 1%; methanol).

Example 26

4.6 g (9.3 mmol) 1- | 6- || 2- || 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2- Naphthyl | -ethyl | -methylamino | -hexyl | -3-methyl-2-benzimidazolinone was dissolved in 15 ml of methylene chloride, mixed with 1.9 ml of pyridine and 6.2 g (38 mmol) of methoxyacetic acid anhydride and stirred for 20 hours at room temperature. It was then treated with ice-cooling with 45 ml of 1 N aqueous sodium hydroxide solution and then stirred at 10-15 ° for 1 hour. The reaction mixture was then poured onto 400 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate, evaporated, treated with one equivalent of hydrogen chloride in ethanol and evaporated. 5.3 g of 11S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 6- (3-methyl-2-oxo) are obtained -1-benzimidazolinyl) -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate-hydrochloride, | </i> = + 27.1 ° (c = 1%; methanol).

48.

Analogous to Example 26, the following compounds were obtained:

| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 "II4- | p- (imidazol-1-yl) -phenyl | -butyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate oxalate (1: 1), μ | ² θ = + 27.6 ° (c = 1%; methanol);

| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 4- (3-isopropyl-2-oxo-1-benzimidazolinyl) -butyl | -Amino | -ethyl | -2-naphthylmethoxyacetate hydrochloride, | oZ | ² θ = + 27.6 ° (c = 1%; methanol);

| 1S, 2SI-6-Fluoro-1,2,3,4-tetrabidro-1-isopropyl-2- | 2- | methyl- | 6- (3-butyl-2-oxo-1-benzimidazolinyl) -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate hydrochloride, | zZl§ ° = + 26.4 ° (c = 1%; methanol);

| IS, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 6- | 3- (2-morpholinoethyl) -2-oxo-1- benzimidazolinyl | -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, | ο /, | ² θ = + 22.4 ° (c = 1%; methanol);

| 1S, 2S | -2- | 2- | 4- (3-benzyl-2-oxo-1-benzimidazolinyl) -butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate hydrochloride, | οέ | ² θ = + 25.6 ° (c = 1%; methanol);

| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 4- | 2-oxo-3- (2-pyridylmethyl) -1- benzimidazolinyl | -butyl | -amino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, I&Z | = + 23.3 ° (c = 1%; methanol).

49.

Example 28

1.3 g (3.1 mmol) 1S, 2S | -2- | 2- | | 3- (2-benzimidazolol) propyl -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol in 10 ml of dimethylformamide was stirred at room temperature with 0.19 g (1.53 mmol) of 4- dimethylaminopyridine,

1.7 ml (12.3 mmol) of triethylamine and a solution of 0.96 ml (9.24 mmol) of isobutyric acid chloride in 5 ml of dimethylformamide and stirred for 2 hours at room temperature. The reaction mixture was then poured into 20 ml of ice water, mixed with 10 ml of 1 N aqueous sodium hydroxide solution, stirred for 10 minutes at 0 ° and extracted with 100 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and evaporated. The crude product thus obtained was dissolved in 20 ml of methanol, treated with 1.5 ml of 1 N aqueous sodium hydroxide solution, stirred at room temperature for 1 hour, poured into 50 ml of water and extracted with 100 ml of methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a column of 30 mg silica gel with methylene chloride and 1-20% isopropanol as elution medium and on a column of 20 g silica gel using methylene chloride / isopropanol / 25% aqueous ammonia (9: 1: 0.1). ) as eluting agents.

Thorne gives 360 mg (21%) of 11S, 2S | -2- | 2- | 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylisobutyrate dihydrochloride.

Example 29

Mixture of 4.67 g (11.5 mmol) 1S, 2S | -2-6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl | - p-toluenesulfonate, 3.5 g (11.5 mmol) of 1-methyl-2- | 3- (methylamino) 50.

-propyl | -4,5-diphenylimidazole, and 1.5 g (11.5 mmol) of N-ethyl-diisopropylamine are stirred at 100 ° for 1 hour. The cooled mass was partitioned between water and methylene chloride, and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The residual oil was chromatographed on a column of 400 g silica gel using methylene chloride / methanol (4: 1) as the elution agent. The purified condensation product (5.3 g of oil) was dissolved in 15 ml of methoxyacetic acid anhydride, mixed with 0.85 ml. of pyridine and the solution stirred for 2 hours at 70 °. The cooled reaction mixture was partitioned between 400 ml of methylene chloride and 400 ml of 3 N aqueous sodium hydroxide and the mixture was stirred vigorously at room temperature for 15 minutes. The separated aqueous phase was re-extracted with 400 ml of methylene chloride, the combined extracts washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The oily residue was chromatographed on 350 g of silica gel using methylene chloride / methanol (9: 1) as the eluting agent. The oil obtained from homogeneous fractions was dissolved in ethyl acetate and treated with excess hydrogen chloride in ether. The crystallizate was filtered off, washed with ether and dried. 4.0 g (51%) of 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 3- (1-methyl-4) are obtained. 5-diphenylimidazol-2-yl) -propyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, m.p. 185-189 °, in the form of an almost colorless crystalline powder.

1-Methyl-2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole was obtained as starting material as follows:

To a solution of 7.0 g (0.024 mol) of 4,5-diphenylimidazole-2-propionic acid and 3.36 ml (0.024 mol) of triethylamine in 80 ml.

of dimethylformamide was added dropwise at -5 ° 3.2 ml of hydrochloric acid isobutyl ester (0.024 mol). After stirring for 30 minutes at 0-5 °, 1.64 g (0.024 mol) of methylamine hydrochloride and 3.36 ml (0.024 mol) of triethylamine in 32 ml of dimethylformamide and 1.65 ml of water were added. Allow the reaction mixture to rise to room temperature and stir for another 20 hours. After concentration under reduced pressure, the residue was dipped in 250 ml of methanol and mixed with 3.6 ml (0.024 mol) of 1,8-diazobicyclo | 5.4.0 | undec-7-one (DBU) to give a clear solution. Cooling in an ice bath crystallized 4.8 g of N-methyl-4,5-diphenylimidazol-2-propionamide, m.p. 195-200 ° (decomposition). From the mother liquor, a further concentration of 2 g of the same product, m.p. 195-200 °. Total yield: 6.8 g (93%).

To a stirred suspension of 2.3 g (0.06 mol) of lithium aluminum hydride in 160 ml of tetrahydrofuran is added portionwise

9.15 g (0.03 mol) of N-methyl-4,5-diphenylimidazol-2-pionamide and then refluxed for 4 hours. At 5-10 ° C, 6 ml of water is added dropwise, then 9 ml of 10% aqueous potassium hydroxide solution and again 6 ml of water. The precipitate was filtered off and three times foamed with 50 ml of tetrahydrofuran each. The combined filtrates were washed with saturated aqueous solution of tri-chloride, dried over sodium sulfate and concentrated under reduced pressure to dryness. The oily residue was chromatographed on 200 g of silica gel, first using a chlonophon / ethanol mixture (9: 1), then with methanol as the elution agent. The first eluted homogeneous fractions gave after digestion and tanning with ether 1.2 g of starting material. The following eluted homogeneous fractions were obtained after the same tnetman

5.5 g (73%) of 2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole as colorless crystals, m.p. 110-113 °.

52.

A solution of 5.25 g (0.018 mol) of 2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole and 3.8 ml (0.028 mol) of hydrochloric acid benzyl ester in 38 ml of dimethylformamide was mixed with 5 g of finely powdered of dry potassium carbonate and then stirred vigorously for 1 hour at room temperature. The inorganic salts are then filtered off, washed with methylene chloride and the filtrate concentrated to dryness under reduced pressure. The oily residue was chromatographed on 500 g of silica gel using ethyl acetate as the eluting agent. Homogeneous fractions gave, after evaporation and rubbing of the residue with hexane

6.5 g (85%) of 2- | 3- (N-benzyloxycarbonylmethylamino) -propyl | -4,5-diphenylimidazole as a colorless crystal, m.p. 105-108 °.

A solution of 6.4 g (0.015 mol) of 2- | 3- (N-benzyloxycarbonylmethylamino) -propyl | -4,5-diphenylimidazole in 120 ml of dimethylformamide was mixed under argon at 15-20 ° with 0.018 mol of sodium hydride (0 , 8 g of 55% dispersion in mineral oil) and then stirred for a further 30 minutes at room temperature. A solution of 1.85 ml (0.03 mol) of methyl iodide in 10 ml of dimethylformamide was added at 15-20 ° C for 15 minutes and stirred for a further 3 hours at room temperature. After concentration under reduced pressure, the residue was partitioned between ice water and ethyl acetate. The organic phase, which was dried over sodium sulfate, was evaporated and the residual oil was chromatographed on 100 g of silica gel using ethyl acetate as the elution agent. The resulting 2- | 3- (N-benzyloxycarbonylmethylamino) propyl | -1-methyl-4,5-diphenylimidazole (6.4 g of oil) was dissolved in 300 ml of methanol and then hydrogenated at room temperature and normal pressure in the presence of 1 g 5% palladium on charcoal. The crude product, which is isolated in the usual way, is chromatographed on 70 g of silica gel using a methanyl / concentrated ammonium hydroxide mixture

53.

(100: 1) as eluting agents. 2.95 g (64%) of 1-methyl-2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole are obtained as a thick oil.

Example 30

In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate first with 2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole and then with methoxyacetic acid anhydride. 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | 3- (4,5-diphenylimidazol-2-yl) -propyl | methylamino | -ethyl | -2-naphthylImethoxyacetate dihydrochloride, m.p. 160-164 °, in the form of a colorless crystalline powder.

Example 31

In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate first with 2- | 4- | (methylamino) -methyl | -benzyl | -1-methyl-benzimidazole and then with methoxyacetic acid anhydride. 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- ((1-methyl-2-benzimidazolyl) -methyl] -benzyl is obtained | -methylamino | -ethyl | -2-naphthylmethoxyethanol-dihydrochloride, m.p. 130-134 °, in the form of a colorless crystalline powder.

2- | 4- | (Methylamino) -methyl | -benzyl | -1-methylbenzimidazole, which

54.

was applied as a starting material, obtained as follows:

A mixture of 30 g (0.277 mol) of o-phenylenediamine and 150 g of polyphosphoric acid ester (PPE) was heated to 120 °. When the diamine is dissolved, 33 g (0.205 mol) of p-cyanphenylacetic acid are added at once and heated to 120 ° for a further 20 minutes. After cooling to room temperature, the viscous mass is mixed with about 1 liter of water and made weakly basic by the addition of solid sodium bicarbonate. The mixture was extracted with methylene chloride and the extract was washed with water, dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from methylene chloride / ethyl acetate gave 29 g (60%) of 2- (p-cyanbenzyl) -benzimidazole, m.p. 201-203 °, in the form of a colorless crystalline powder.

A solution of 21.9 g of 2- (p-cyanbenzyl) -benzimidazole in a mixture of 140 ml of methanol and 140 ml of liquid ammonia was hydrogenated at room temperature under a pressure of 30 bar in the presence of 5 g of Raney-nickel as a catalyst. The crude product, which was isolated in the usual way, was chromatographed on 400 g of silica gel with methanol as the elution agent. Homogeneous fractions gave after evaporation and rubbing of the residue with ether 14.7 g (66%) of 2- | p- (aminomethyl) -benzyl | -imidazole, m.p. 133-136 °, in the form of a light brown crystalline powder.

A solution of 9.2 g (0.04 mol) of 2- | p- (aminomethyl) -benzyl | -benzimidazole and 8.4 ml (0.06 mol) of hydrochloric acid benzyl ester in 80 ml of dimethylformamide is mixed with 10 g of finely powdered dry potassium carbonate and then stirred vigorously at room temperature for 30 minutes, then 12 ml (0.08 1,8-diazabieiclo | 5.4.0 | undec-7-ene (DBU) was added thereto and stirred further at mol)

55.

room temperature for another 30 minutes. The inorganic salts were filtered off, then washed with methylene chloride and the filtrate concentrated to dryness under reduced pressure. The oily residue was chromatographed on 600 g of silica gel, first with methylene chloride / ethyl acetate (4: 1) and then with chloroform / ethanol (9: 1) as an elution agent. The chloroform / ethanol-eluted fractions after evaporation afforded (after rubbing with ethyl acetate) 10.8 g (73%) of benzyl ester | 4- | 2- (benzimidazolyl) -methyl | -benzyl | -carbamic acid, m.p. 190-194 °, in the form of a colorless crystalline powder.

A solution of 8.9 g (0.024 mol) of benzyl ester | 4- | 2- (benzimidazolyl) -methyl | -benzyl | -carbamic acid in 210 ml of dimethylformamide, under argon at 15-20 °, was mixed with 0.056 mol of sodium -hydride (2.5 g 55% dispersion in mineral oil) and then stirred for 30 minutes at room temperature.

At 15.20 ° for 20 minutes a solution of 7.4 ml (0.12 mol) of methyl iodide in 22 ml of dimethylformamide was added and stirred for 10 minutes at room temperature. After concentration under reduced pressure, the residue was partitioned between ice water and ethyl acetate. The organic phase, which was dried over sodium sulfate, was evaporated and the residual oil was chromatographed on a column of 300 g of silica gel using methylene chloride / ethyl acetate (1: 1) as the elution agent. The first eluted homogeneous fractions, after evaporation and rubbing with ether, afforded 4.5 g (45%) of benzyl ester | 4- | 1- (1-methyl-2-benzimidazolyl) -ethyl | -benzyl-methyl | -methylcarbamic acid , tt 131-133 °, in the form of crystalline powder. The following eluted fractions gave (after concentration) 3.5 g (37%) of benzyl ester | 4- | (1-methyl-2-benzimidazolyl) -methyl | -benzyl | -methylcarbamidic acid, as a thick oil.

56.

3.5 g of benzyl ester] 4 - [(1-methyl-2-benzimidazolyl) -methyl] -benzyl | -methylcarbamic acid are dissolved in 600 ml of methanol and hydrogenated at room temperature and under normal pressure in the presence of 1 g 5 % palladium on activated carbon as catalyst. The crude product, which was isolated in the usual way, was chromatographed on 150 g of silica gel, using a methanol / concentrated ammonium hydroxide (100: 1) mixture as the eluting agent. 2.1 g (90%) are obtained

2- | 4- | (methylamino) methyl | -benzyl | -1-methylbenzimidazole as a thick oil.

Example 32

In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate first with 2- | 1- | 4- | (methylamino) -methyl | -phenyl | -ethyl | -1-methylbenzimidazole and then with methoxyacetic acid anhydride. J1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- | 1- (1-methyl -2-benzimidazolyl) -ethyl | benzyl | -methylamino, -ethyl | -2-naphthylmethoxyacetate-dihydrochloride (mixture of two epimers), m.p. 95-105 °, in the form of an almost colorless crystalline powder.

2- | 1- | 4- | (methylamino) -methyl | -phenyl | -ethyl | -1-methylbenzimidazole, which was used as starting material, was obtained in an analogous manner as described in Example 31 by hydrogenation of benzyl ester | 4- | 1- (1-methyl-2-benzimidazolyl) -ethyl | -benzyl | -methylcarbamic acid.

57.

Example 33

In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate is first 2- | 4 - [(methylamino) -methyl] -benzyl | -benzimidazole followed by methoxyacetic acid anhydride. 11 S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- | (2-benzimidazolyl) -methyl | -benzyl | -methylamino | -ethyl | -2-naphthylmethoxyethyl acetate dihydrochloride, mp 146-150 °, in the form of an almost colorless crystalline powder.

2- | 4- | (Methylamino) methyl | -benzyl | -benzimidazole, which was used as starting material, was obtained as follows:

6.6 g (0.028 mol) of 2- (p-cyanbenzyl) -benzimidazole are heated for 2 hours with reflux in 110 ml of 1 N aqueous sodium hydroxide solution. The resulting solution was cooled and extracted twice with 100 ml of ethyl acetate and twice with 100 ml of methylene chloride each. The aqueous phase was adjusted to Ph 6.0 with 2 N hydrochloric acid and allowed to stand for 30 minutes in an ice bath. The precipitate was filtered off with suction and washed with ether. It does

5.8 g (83%) of p (2-benzimidazolyl) -methyl-benzoic acid, m.p. 265-267 °, in the form of a colorless powder.

To a solution of 5.0 g (0.020'mol) of p- (2-benzimidazolyl) -methyl-benzoic acid and 2.8 ml (0.020 mol) of triethylamine in 68 ml of dimethylformamide at -5 ° was added dropwise 2.8 ml. isobutylether of hydrochloric acid. After stirring for 30 minutes at 0-5 °, 1.32 g (0.020 mol) of methylamine hydrochloride and 2.8 ml (0.020 mol) of triethylamine in 28 ml of dimethylformamide and 1.4 ml of water were added. Allow the reaction mixture to rise to room temperature and stir for an additional 18 hours. After concentration under reduced pressure, the residue is chromatographed at 400 g

58.

of silica gel using chloroform / ethanol (4: 1) as the elution agent. Uniform fractions afforded 2.0 g (38%) of N-methyl-p | (2-benzimidazolyl) -methyl-benzamide, m.p.

250-255 ° (decomposition), in the form of a colorless powder.

1.98 g (0.0075 mol) of N-methyl-p- | (2-benzimidazolyl) -methyl are added dropwise to a stirred suspension of 0.58 g (0.0075 mol) of lithium aluminum hydride in 40 ml of tetrahydrofuran. -benzimide and repression is heated for 4 hours with reflux. At 5-10 ° C, 1.5 ml of water is added dropwise followed by 2.3 ml of a 10% aqueous potassium hydroxide solution and then again 1.5 ml of water. The precipitate was filtered off and boiled three times with 20 ml of tetrahydrofuran each. The combined filtrates were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was chromatographed on 150 g of silica gel using a methanol / conc mixture. ammonium hydroxide (100: 1) as eluting agents. 1.58 g (84%) of 2- | 4- | (methylamino) -methyl (-benzyl | -benzimidazole, mp 157-160 °) are obtained as a colorless crystalline powder

Example 34

In the manner analogous to that described in Example 29, 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p is reacted -toluenesulfonate first with 2- | trans-4- (methylamino) -methyl | -cyclohexyl | -benzimidazole and then with methoxyacetic acid anhydride. 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl | -trans-4- (2-benzimidazolyl) -cyclohexyl | -methylamino | -ethyl-2-naphthylmethoxyacetate dihydrochloride, mp 150-153 °, in the form of a colorless crystalline powder.

59.

2- | trans-4- | (Methylamino) -methyl | -cyclohexyl | -benzimidazole, which was used as starting material was obtained as follows:

A solution of 20.3 g (0.07 mol) of trans-4- (N-benzyloxycarbonyl-aminomethyl) -cyclohexanecarboxylic acid in 380 ml of dimethylformamide, under argon at 15-20 °, was mixed with 0.21 mol of sodium hydride ( 9.35 g of a suspension containing 55% sodium hydride in mineral oil) and then stirred for a further 30 minutes at room temperature for 30 minutes. To this was added at 25-30 ° for a period of 20 minutes a solution of

17.5 ml (0.28 mol) of methyl iodide in 20 ml of dimethylformamide and stirred for an additional 1 hour at 70 °. after concentration under reduced pressure, the residue is partitioned between water and methylene chloride. The organic phase was concentrated and the remaining oil was dissolved in a mixture of 350 ml of ethanol and 350 ml of 1 N aqueous sodium hydroxide solution. It is refluxed for 1 hour, cooled and poured into 700 ml of ice water. The solution was extracted with ethyl acetate and then acidified with 6 N hydrochloric acid. The liberated acid is extracted with methylene chloride, and this extract is dried over sodium sulfate and evaporated. The remaining oil was chromatographed on 270 g of silica gel using methylene chloride / ethyl acetate (4: 1) as eluant. 13.6 g (64%) of trans-4- (N-benzyloxycarbonyl-N-methyl-aminomethyl) -cyclohexanecarboxylic acid are obtained as a thick oil.

A solution of 13.6 g (0.044 mol) of trans-4- (N-benzyloxycarbonyl-N-methyl-aminomethyl) -cyclohexanecarboxylic acid and

9.5 ml (0.068 mol) of triethylamine in 110 ml of tetrahydrofuran is mixed at -15 ° for 30 minutes with 6.5 ml (0.049 mol) of hydrochloric acid isobutyl ester. Then at -15 ° u

60.

A solution of 5.8 g (0.053 mol) of o-phenylenediamide was added dropwise over 45 minutes. Stirred for 1 hour at room temperature and allowed to stand for 20 hours. After concentration under reduced pressure, the residue is partitioned between water and ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution and finally with water. The solution which was dried over magnesium sulfate was evaporated and rubbed with ether. The resulting solid product (9.3 g) was dissolved in 200 ml of toluene, 3 g of p-toluenesulfonic acid were added thereto and refluxed for 4 hours using a water separator. The solution was cooled, washed with 2 N aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The solid residue was recrystallized from ethyl acetate. 5.6 g of benzyl ester of trans-4- (2-benzimidazolyl) -cyclohexyl-methyl-methyl-carbamic acid are obtained, m.p. 146-148 °, in the form of a colorless crystalline powder. After chromatography on a silica gel column (250 g), using ethyl acetate / methylene chloride (9: 1) as eluent, the mother liquor gave another 1.1 g of this same product, m.p. 146-148 °. Total Yield: 6.7 g (40%).

6.0 g of benzyl ester Trans-4- (2-benzimidazolyl) -cyclohexyl | -methyl | -methylcarbamic acid are dissolved in 600 ml of ethanol and hydrogenated at room temperature and under normal pressure with the addition of 1 g of 5% palladium on activated carbon as catalyst. The crude product which was isolated in the usual way was recrystallized from methylene chloride / ether. 3.0 g (78%) of 2- (trans-4 -) (methylamino) -methyl-cyclohexyl-benzimidazole are obtained, m.p. 232-235 °, in the form of a colorless crystalline powder.

.

Example 35

In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl, p-toluenesulfonate first with 2- | trans-4- (methylamino) -methyl | -cyclohexyl | -1-methylbenzimidazole and then with methoxyacetic acid anhydride. 11S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- (methyl- | trans-4- (1-methyl-2-benzimidazolyl) -cyclohexyl is obtained | -methylamino | -ethyl | -2-naphthylmethoxyacetate dihydrochloride, mp 148-152 ° as a colorless crystalline powder.

2- | trans-4- | (Methylamino) -methyl | -cyclohexyl | -1-methylbenzimidazole, which was used as starting material, was obtained as follows:

A solution of 7.2 g (0.019 mol) of benzyl ester trans-4- (2-benzimidazolyl) -cyclohexyl-methyl-carbamidic acid in 160 ml of dimethylformamide under argon and at a temperature of 15-20 ° C was mixed with 0.023 mol of sodium hydride (1.0 g of a 55% dispersion in mineral oil) is then stirred for 30 minutes at room temperature. A solution of 2.3 ml (0.038 mol) of methyl iodide in 10 ml of dimethylformamide was added over 15 minutes at 15-20 ° C and stirred for 3 hours at room temperature. After concentration under reduced pressure, the residue was partitioned between ice water and ethyl acetate. The organic phase dried over sodium sulfate was evaporated and the solid was recrystallized from ethyl acetate / ether.

5.9 g (79%) of benzyl ester of tans-4- (1-methyl-2-benzimidazolyl) -cyclohexyl-methyl-methylcarbamic acid are obtained, m.p. 141-142 °, in the form of a colorless crystalline powder.

5.9 g of benzyl ester trans-4- (1-raethyl-2-benzimidazolyl) 62.

-cyclohexyl | -methyl | -methylcarbamidic acid is dissolved in 600 ml of ethanol and hydrogenated at room temperature and under normal pressure with the addition of 1 g of 55% palladium on activated carbon as catalyst. The crude product, which was isolated in the usual way, was chromatographed on 250 g of silica gel using first a mixture of methylene chloride / methanol (1: 1) and then a mixture of methanol / conc. ammonium hydroxide (100: 1) as eluting agents. 3.3 g (85%) of 2- | trans-4- (methylamino) -methyl-cyclohexyl-1-methylbenzimidazole are obtained as a thick oil.

Example 36

In a manner analogous to that described in Example 7, by reaction of 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1 H -isopropyl-2-6-naphthyl) -ethyl | -p of toluenesulfonate and 3,4-dihydro-4-methyl-1- | 4- (methylamino) -butyl | -2H-1,4-benzodiazepine-2,5- (1H) -dione to give 1- | 4- || 2- || 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -3,4 -Dihydro-4-methyl-2H-1,4-benzodiazepine-2,5- (1H) -dione, MS: M ⁺ 509.

In an analogous manner to that described above, starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-6-isopropyl-2-naphthyl) -ethyl | -p-toluenesulfonate 1 ( S) -6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo | 2,1 -c | 11,4 | benzodiazepine-5,11- (10H) -dione gave (S) -6- chlor-10- | 4- || 2- || 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -1,2,3,11a-tetrahydro-5H-pyrrolo | 2,1-c | 1,4-benzodiazepine-5,11- (10H) -dione, MS: M ⁺ 570.

3,4-Dihydro-4-methyl-1- | 4- (methylamino) -butyl | -2H-1,4-benzo63.

diazepine-2,5- (1H) -dione, which was used as starting material, was obtained as follows:

g (40 mmol) of 4- | 1- (benzyloxy-N-methylformamido | -butaric acid was dissolved in 200 ml of ethanol and treated with 1 ml of sulfuric acid. The reaction mixture was then refluxed for 4 hours and then the solvent was evaporated. The reaction product was then extracted with methylene chloride / saturated sodium bicarbonate solution, after drying and evaporating the extract to give 9.24 g of a brown oil, which was dissolved in 200 ml of tetrahydrofuran, mixed with 7.1 ml of a 10 M bormethylsulfide complex and heated for 2 hours. The reaction mixture was then allowed to stand at room temperature overnight and then slowly added enough methanol to it to prevent gas evolution, thus obtaining a clear evaporating solution. The residue obtained (8.09 g) was chromatographed. with a mixture of (1: 1) ethyl acetate and hexane on silica gel, yielding 6.82 g (72%) of benzyl- (4-hydroxybutyl) -methylcarbamate, which is used directly for the next step.

6.75 g (28.4 mmol) of the carbamate obtained above and 10.0 g (52.5 mmol) of p-toluenesulfonic acid chloride were dissolved at 0 ° in 25 ml of pyridine. After standing for 6 hours, ice was added and extracted with ether. The ether extract was washed with 4 N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous brine, dried and evaporated. In this way 9.38 g (84%) of a yellowish oil of benzyl-methyl- | 4- ((p-toluenesulfonyl) -oxy] -butyl | -carbamate are obtained, which is further directly processed.

1.9 g (10 mmol) of 4-Methyl-3H-1,4-benzodiazepine-2,5- (1H, 4H) 64.

-dione was dissolved in 20 ml of dimethylformamide and added to a suspension of 430 mg (10 mmol) of 55% sodium hydride in 50 ml of dimethylformamide. After half an hour after the addition, a solution of 3.91 g (10 mmol) of benzylmethyl- [4- ((p-toluenesulfonyl) -oxy] -butyl] -carbamate in 20 ml of dimethylformamide was added and the whole reaction mixture was stirred for 20 hours at room temperature. . The solvent was then evaporated under reduced pressure at 50 ° and then water was added. After double extraction with methylene chloride, the solvent was re-evaporated and the residue was chromatographed on silica gel using a mixture of (20: 1) methylene chloride and methanol as the eluting agent to give 3.92 g (95.8%) of benzyl methyl- | 4- ( 2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepin-1-yl) -butyl | -carbamate,

MS: M ⁺ 409.

The carbamate obtained above, analogous to the method described in Example 7 (in the last paragraph), is translated into the desired

3,4-Dihydro-4-methyl-1- | 4- (methylamino) -butyl | -2H-1,4-benzodiazepine-2,5- (1H) -dione, which is directly used in the next step.

In a manner analogous to the one described above, starting with benzyl methyl- | 4- | (p-toluenesulfonyl) -oxy | -butyl | -carbamate, reaction with the corresponding benzodiazepine yields (S) -6-chloro-1,2 , 3-11a-tetrahydro-10- | 4- (methylamino) -butyl | -5H-pyrrolo | 2,1-c [| 1,4 | -benzodiazepine-5,11- (1 OH) -dione.

Example 37

In a manner analogous to that described in Example 8, by methoxyacetylation of the corresponding hydroxy derivatives, the following compounds were obtained:

65.

| 1S, 2S 1-6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- (2,3,4,5-tetrahydro-4-methyl-2, 5-dioxo-1H-1,4-benzodiazepin-1-yl) -butyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate hydrochloride, W | gg = + 28.2 ° (c = 0.5%; methanol );

| 1S, 2S | -2- | 2-l | 4- | (S) -6-chloro-2,3,11,11a-tetrahydro-5,11-dioxo-1H-pyrrolo | 2,1-c | 1,4 | benzodiazepine-10 (5H) -yl | butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate hydrochloride, 1 H -gg = + 215.2 ° (c = 0.5%; methanol).

Example A

Pills

Composition

1) 2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1H-isopropyl-

pil-SZ-naphthylmethoxyacetate hydrochloride 75 mg 2) powdered milk sugar 135 mg 3) white corn starch 55 mg 4) povidone K 30 15 mg 5) white corn starch 15 mg 6) talk 3 mg 7) magnesium stearate 2 mg

tablet weight

300 mg

66.

Obtaining process

Stir vigorously 1-3- The mixture is then moistened with aqueous growth with aroma 4 and then flesh-kneaded, and the resulting mass is granulated, dried and aerated. The granulate is mixed with 5-7 and pressed into suitable sized tablets.

Example B

Pills

Composition

1) 2- | 2-R 3- (2-benzimidazolyl) -propyl) -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-6-isopropyl-2-naphthyl Name Toxicity to t-Hydrochlo-

rid 75 mg 60 mg 2) powdered milk sugar 100 mg 100 mg 3) cornstarch 60 mg 60 mg 4) povidone K 30 5 mg 5 mg 5) cornstarch 15 mg 15 mg 6) sodium carboxymethyl starch 5 mg 5 mg 7) talk 3 mg 3 mg 8) magnesium stearate 2 mg 2mg tablet weight 265 mg 250 mg

Obtaining process

Strongly mix 1-3. The mixture was then moistened with aqueous growth with aroma 4 and meat, and the resulting mass was granulated, dried and average The granulate was mixed with 5-8 and pressed into tablets of suitable size.

67.

Example C

Pills

Composition

1) 2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl It has oxyacetate-

hydrochloride 75 mg 90 mg 2) powdered milk sugar 46 mg 46 mg 3) single crystalline cellulose 60 mg 60 mg 4) povidone K 30 10 mg 10 mg 5) sodium carboxymethyl starch 4 mg 4 mg 6) talk 3 mg 3 mg 7) magnesium stearate 2 mg 2 mg tablet weight 200 mg 215 mg

Obtaining procedure:

Strongly mix 1-3. The mixture was then moistened with an aqueous solution of 4 and meat, and the resulting mass was granulated, dried and aerated. The granulate is mixed with 5-7 and pressed into suitable sized tablets.

68.

Example D

Capsules

Composition

1) 2- | 2- {3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-10Z-isopropyl-2-C-naphthylmethyl oxy tat hydrochloride 75 mg

2) crystalline milk sugar 100 mg

3) white corn starch 20 mg

4) talc 9 mg

5) magnesium stearate 1 mg capsule weight 205 mg

Obtaining process

The active substance is strongly mixed with milk sugar. Cornstarch, talc and magnesium stearate are then mixed into this mixture and the resulting mixture is filled into suitable size capsules.

Example E

Capsules

Composition

2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1H-isopropyl-2H-naphthyl69.

methoxyacetate hydrochloride 75 mg 2) microcrystalline cellulose 100 mg 3) sodium carboxymethyl starch 5 mg 4) talk 9 mg 5) magnesium stearate 1 mg weight of capsules 190 mg

Obtaining process

The active substance is strongly mixed with cellulose. Sodium carboxymethylcellulose, talc and magnesium stearate are then mixed into this mixture and the resulting mixture is then filled into suitable size capsules.

Example F

Injection solution ml

- | 2- | 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-th light dro-1 <Z-i zopropyl-2 <Z-naphthylmethoxyacetate hydrochloride 8 mg crystalline sodium chloride (Pure) 8.5 mg water for solution for injection up to 1 ml

70.

Example G

If used according to the methods described in Examples A-F, starting from the following, also suitable compounds and their pharmaceutically acceptable salts, tablets, capsules and injectable preparations can be obtained:

| 1S, 2S | -2- | 2- || 3- (2-Benzylimidazolyl) -propyl) -methyl amino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2 -Naphthymethoxyacetate hydrochloride;

[1S, 2S | -2- | 2- || 5- (2-Benzthiazolyl) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2- naf ti Name toxiace tat -hi dr ohlori d.

Patent application P.229 / 88

-2-ARAN 4029/6 3987

APPLICANTS ON THE BEST WAY FOR A BUSINESS

USING THE RECORDED FINDING

The best way for the commercial use of the invention, to the applicant's knowledge, is as follows:

6.2 g (14.6 mmol) [IS, 2S] -2- (2- [2- [3- (2-benzimidazolyl) propyl] -methylamino] -ethyl] -6-fluoro-1,2, 3,4-Tetrahydro-1-isopropyl-2naphthalenol was dissolved in 50 ml of chloroform. To this is added, at 0 ° C,

2.5 ml (15 mmol) of N-ethyldiisopropylamine and 5 ml (55 mmol) of methoxyacetyl chloride. The reaction mixture was stirred overnight at room temperature and then mixed with 100 ml of 1 N sodium hydroxide solution in water, and extracted with chloroform. After drying over magnesium sulfate and evaporating the solvent, the residue is chromatographed on silica gel using a mixture of (6: 1) methylene chloride and methanol as the elution agent. The crude was obtained 6.2 g of an oil which was dissolved in 30 ml of ethanol and mixed with 15 ml of hydrochloric acid saturated ether. The reaction mixture was then evaporated and the residue was crystallized from a mixture of ethanol and diethyl ether. 5.4 g (65%) of IS, 2S (-2- [2- [3- (2-benzimidazolyl) -propyl] -methylamino] -ethyl] -6-fluoro-1,2,3 are obtained. 4-Tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride, m.p. 128 ° C.

F.HOFFMANN-LA ROCHE & CO. Aktiengesellschaft,

2/20/2005

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Claims (10)

Claims: 1. A process for the preparation of a tetrahydronaphthalene derivative of the general formula? R ³ with * * · · ^ \ / \. I II l \ / \ • · · · _R l / g- (X) nA 1 v in which R denotes lower alkyl, R denotes halogen, R stands for C 1 -C 4 -alkyl, R ^J stands for lower alkylcarbonyloxy or lower alkoxy-lower alkylcarbonyloxy, X stands for -C ₁ g-alkylene, which in this case may be interrupted by 1,4-phenylene or interrupted or extended 1,4 -cyclohexylene, A denotes di- or tri-substituted 2-imidazolyl which is bonded via an ethylene group or optionally substituted benzimidazolyl, benzimidazolonyl, imidazo (4,5-c | pyridinyl, imidazo | 4,5-c | -pyridinonyl. benztiazolyl or benzodiazepine-2,5-dione-1-yl or pyrrolo [2,1-c || 1,4 | benzodiazepine-5,11-dione-10-yl] represents bray 0 or 1, in the form of racerates and optical antipodes as well as N-oxides and pharmaceutically applicable acid addition salts of these compounds, characterized in that a) reacts a compound of the general formula • OH ^ * \ / * \! • · · - · i II iS / \ * v · · · 1 / \ / \ / la £ - ₍ X) _n -A 1 2 in which R, R, R, A, X in have the above meanings, with an acylating agent which gives a lower alkylcarbonyl- or a lower alkoxy-lower-alkylcarbonyl group, in particular with one activated acid derivative such as a halide acids and acid anhydride, or mixtures of acid anhydride, in one, under the reaction conditions with an inert organic solvent, such as an aromatic hydrocarbon, such as benzene, toluene or xylene, with a single chlorinated hydrocarbon such as methylene chloride or chloroform, one ether such as diethyl ether tetrahydrofuran or dioxane, or a solvent mixture, at a temperature between about 0 ° and a reflux temperature, which b) the resulting compound is oxidized with an oxidizing agent such as hydrogen peroxide or peracid, such as persacetic or perbenzoic acid, in a solvent such as alcohol, such as methanol or ethanol, at a temperature between about 0 ° and 50 ° C, primarily at ambient temperature, in the corresponding N-oxide, and / or c) separates the resulting racemate into optical antipodes, and / or d) the resulting compound is converted into a pharmaceutically acceptable acid addition salt. 2. The method of claim 1, wherein A is 2-benzimidazolyl or 2-benzthiazolyl, R is isopropyl, 3 in 1 R is isobutyryloxy or methoxyacetyloxy, R is fluoro R is methyl, X is propylene, butylene, pentamethylene or hexamethylene, and n is number 1. 3 · The process of claim 1, for the preparation of 2- | 2- || 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl [-6 _T fluoro-1,2,3,4tetrahydro-1 &apos; -isopropyl ~ 2a-naphthylmethoxyacetate, which is 2- | 2- | | 3- (2-Benzimidazolyl) propyl | -methylamino | -ethyl-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol is reacted with methoxyacetyl chloride or acetic acid methoxyhydride. 4. The process of claim 1, for preparing | 1S, 2S | -2- | 2- || 5 (2-Benzthiazolyl) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4 tetrahydro-1-isopropyl-2-naphthylmethoxyacetate by providing | 1S, 2S | -2- | 2- || 5- (2-benzthiazolyl) pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthalinol reacts with methoxyacetyl chloride or acetic acid methoxy anhydride. 5. The process of claim 1, for the preparation of 1S, 2S | -2- | 2- || 3- (2benzimidazolyl) -propyl | -emethylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro -1-Isopropyl-2-naphthylmethoxyacetate, characterized in that | 1S, 2S | -2- | 2- || 3- (2-benzimidazolyl) propyl | -methylamino | -ethyl | -6-fluoro-1,2 , 3,4-Tetrahydro-1-isopropyl-2-naphthalinol is reacted with methoxyacetyl chloride or acetic acid methoxyanhydride. 6. Tetrahydronaphthalene derivatives, of the general formula RR ³ A A: • · · 1 in iV / _D l / / \ / R · · in which R denotes lower alkyl, R '' denotes halogen, R ^ denotes C-C-alkyl, R ^ denotes hydroxy,, lower alkoxy, lower alkylcarbonyloxy, lower alkoxy-lower alkylcarbonyloxy, lower alkylaminocarbonyloxy, arylaminocarbonyloxy or arylaminocarbonyloxy or arylaminocarbonyloxy or arylaminocarbonyloxy alkylaminocarbonyloxy ¥ - (X) nA -3-s ^ X stands for C ₁ -Cθ-alkylene, which in this case may be interrupted by 1,4-phenylene or interrupted or extended 1,4-cyclohexylene, A denotes di- or tri-substituted 2-imidazolyl which is bonded via an ethylene group or optionally substituted benzimidazolyl, benz-imidazolonyl, imidazo / 4,5-c / pyridinyl, imidazo / 4,5- c) Pyridinonyl, benzothiazolyl or benzodiazepine-2,5-dione-1-yl or pyrrolo / 2,1-c // 1,4 / benzodiazepin-5,11-dione-10-yl represents the number 0 or 1, in form of racemates and optical antipodes, as well as N-oxides and pharmaceutically acceptable acid addition salts of these compounds. Compounds according to claim 6, wherein R is isopropyl, o R is hydroxy, isobutyryloxy, methoxyacetyloxy or butylaminocarbonyloxy, R is fluoro, R is methyl, X is propylene, butylene, pentamethylene or hexamethylene, A is 2-benzimidazolyl or 2-benzthiazolyl and n is number 1. 8. 2- [2- [3- (2-Benzimidazolyl) -propyl] -methylamino] -ethyl] -6-fluoro-1,2,3,4-tetrahydro-W-isopropyl-2c] -naphthyl- methoxyacetate 9. 1S, 2S / -2- [2- (5- (2-Benzthiazolyl) -pentyl] -methylamino) -ethyl] -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl- 2-naphthyl methoxyacetate. 10. (1S, 2S / -2- / 2 - // 3- (2-Benzimidazolyl) -propyl] -methylamino / -ethyl / -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl-methoxyacetate.