DE2229359A1 - NEW 1-BENZOYLOXY-2-LOWER ALKYLAMINOBENZOCYCLOALCANDERIVATES - Google Patents

Description

DR. WALTER NIELSCH

Patent attorney

2 Hamburg 70 · P.O. Box 10914 Telephone: 652 97Of

Yamanouohi Pharmaceutical Co., Ltd. Tokyo / Japan

New l-benzoyloxy-2-lower-alkylaminobenzocyclo-

alkane derivatives

The present invention relates to new benzocycloalkane derivatives. More specifically, the invention relates to 1-benzoyloxy ~ 2-lower-alkylaminobenzocycloalkane derivatives with the formula

O CO

(III) 1

wherein R is a hydrogen atom or a lower alkyl group

2 -χ Ij.

means; R represents a lower alkyl group; .R, R and R "* are the same or different from one another and each means a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a phenyl group, an amino group, a lower alkylamino group, an acylamino group or a nitro group; η is a value of 1-3; and (T) and (g) of the formula is the numbering that will find use in describing this invention

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as well as the non-toxic mineral acid salts thereof.

The 1-benzoyloxy-2-lower-alkylaminobenzocyoloalkane derivatives of formula (III) and their non-toxic mineral acid salts which make up the compounds of this invention are new compounds and have excellent local anesthetic effects. In particular, the connections of this invention maintain the local anesthetic effect even in the pH range of gastric juice and this makes them very suitable for the treatment of gastritis and duodenitis. Additionally the compounds have an effect on the stimulation of the stomach and so they are also for the Suitable for therapeutic treatment, especially for the treatment of dizziness in the stomach.

Procaine, lidocaine and the like have heretofore been the known compounds which have a local anesthetic effect, but it has heretofore been difficult to remove such gastritic symptoms as those caused by acute or chronic gastritis as in stomach pain, feeling one severe stomach, belching, nausea, and the like is to be treated by these known compounds. It is believed that these compounds hardly develop their local anesthetic effect at the gastric juice pH (about 2).

Oxäthazain, which eliminates this evil, has this found widespread use. Because the oxethazain has a high local anesthetic effect in the gastric juice pH possesses, in comparison with the aforementioned compounds, however, the effect has so far been insufficient, if you want to suppress the pain that goes through

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a duodenal ulcer is caused and its local anesthetic effect is also unsatisfactory because it occurs too late (Progress in Medicinal Chemistry, la. 387 (1963)).

Recently, J.M. Glassmann and employees that Ν, Ν-diethyl-ß-benzoyloxyphenethylamine developed which has an excellent local anesthetic effect at gastric juice pH, 'but this connection is so far has not yet appeared on the drug market (cf. USA patent 3 ** 99 O87).

The inventors have carefully studied the present problems, taking into account that even for the In the event that the drugs have a local anesthetic effect, they are not sufficiently suitable to treat the gastric symptoms associated with gastritis. For this purpose it is necessary to provide a drug which has an effect of stimulating gastric movement and As a result of their studies, the inventors have found that the compounds of the formula (III) are these Invention have an excellent local anesthetic effect even at the gastric juice pH, and also one Have analgtefciaeh'e effect and as drugs well are suitable for the treatment of gastritischai symptoms, how these are caused by acute or chronic gastritis, in comparison with the known local anesthetics , such as Ν, Ν-diethylamino-e-benzoyloxyphenethylamine and the same.

With respect to the compounds of this invention represented by the formula (III), J. von Braun et al. Reports that l-hydroxy-2-dimethylaminotetralin by the implementation shown below

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can be obtained.

in the sealed tube

in benzene. 100 ⁰ C

(B)

p-nitrobenzoylation

0 -C

reduction

Furthermore, 2-dimethylamino-1-p-nitrobenzoyloxytetralin having a melting point of 112 ° C are obtained by p-nitrobenzoylation of the above obtained tetraline and also 2-dimethylamino-1-p-aminobenzoyloxytetralin can be obtained by reducing the above product (Ber., j55, 3648 (1921)). However, P. Straus et al. Reported that l-hydroxy-2-dimethylaminotetralin by the process shown below can be produced.

^hn C

CH _r

(Ber., 54, 40 (1921)).

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(B)

In addition, A. Gonzalez et al. Reported that 1-hydroxy-2-dimethylaminotetralin was caused by the following

Process can be produced. ?H

3r HN ^ ^CH "
CH ₃

sen tube in benzene, 120 ⁰ C

HNC "3 in the locked

Benzylation

• HC1

1-Benzoyloxy-2-dimethylaminotetrahydronaphthalene hydrochloride with a melting point of 176 ° C. is obtained by benzoylating the aforementioned tetralin compound (Chemical Abstracts, YJ_ » 3030 (1923) and Anales. Soc. espan.fis. quim., 20, 534 ( 1922)).

From these reports one might assume that at least some of the compounds of the present invention might be known by prior publication. However J. von Braun and co-workers have already expressed doubts about the structure of formula (B) themselves and P. Straus and coworkers have regarding the product obtained by the reaction of the compound (A) with dimethylamine obtained further studies of this reaction and found that the reaction product by an intermediate which has the formula (C),

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is obtained and that this is not the l-hydroxy-2-dimethylaminotetralinj but actually traded around the 2-hydroxy-l-dimethylaminotetraXin has (Ber., 63, 3052 (1930)).

Accordingly, it can be seen that the dimethylamino compound, reported by A. Gonzalez and co-workers actually is 2-hydroxy-l-dimethylaminotetralin is because it was made by reacting the compound (A) with dimethylamine under almost the same conditions as reported by J. von Braun et al. (Only the reaction temperature was slightly different here).

In fact, when the inventors followed the method of A. Gonzalez and coworkers, it was found that they obtained a benzoyl compound which was colored and which decomposed at 178-180 ° C near the melting point of 176 ° C, as in US Pat Report is described. During this reworking, the hydroxydimethylaminotetralin was obtained by reacting the compound of the formula (A) with _m ,, · ■ CH7

ο Χ

in benzene at 120 C in the sealed tube CH- * subjected to benzoylation in accordance with the report. Even if you connect a Subjected to p-nitrobenzoylation, became a p-nitrobenzoyl compound obtained with a melting point of 112 ° C. The melting point of the compound obtained is the same with the melting point of the p-nitrobenzoy! compound that by J. von Braun and co-workers and so on is the l-hydroxy-2-dimethylaminotetralin, which by A, Gonzalez et al., Actually a compound consisting of 2-hydroxy-l-dimethylaminotetralin consists.

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In addition, the present inventors through the supplementary investigations found that the benzoyl compound _s having the melting point of 176 ⁰ C (the compound was colored and decomposed at 178 l8O ° C according to the supplementary investigations of the inventors) and by A. Gonzalez and Coworker was confirmed to be actually the 2-benzoyloxy-l-dimethylaminotetralin hydrochloride represented by the following formula

and this formula was verified by nuclear magnetic resonance analysis. and other methods.

As has already been stated above, it has hitherto been assumed that the compound is 1-hydroxy-2-dimethylaminotetralin should be that this is actually the 2-hydroxy-1-dimethylaminotetralin acts. So it is clear that the wrongly designated 1-benzoyloxy-, 1-p-nitrobenzoyloxy-, or 1-p-aminobenzoyloxy-2-dimethylaminotetralin, obtained by the benzoylation of the above compound, in fact 2-benzoyloxy, 2-p-nitrobenzoyloxy or 2-p-aminobenzoyloxy-1-dimethylaminotetralin is.

Accordingly, the names of the compounds of this invention are also of formula (III) by these parts of the literature known, but it is clear from the report by J. von Braun and co-workers in 1930 and by the The inventors' above additional studies revealed that the constitution of the compound was not known and that through these findings the

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Compounds of this invention having formula (III) actually new connections are.

Recently, R. Thrift et al. Has 2-amino-l-hydroxytetralin by reductive acetylation of 2-hydroxyimino «i-tetralone made to obtain 2 ~ acetamido-l-tetralone »by reducing the tetraion compound with NaBHj, 2-Ac et amido-1-hydroxy tetralin was obtained and finally the acetyl group was split off. (J. Chem. Soc, (C), 288 (1-967)).

The inventors actually came up with l-hydroxy-2-dimethylaminotetralin to obtain the 2-amino-l-hydroxytetralin, which is obtained by the above method was reacted with formaldehyde and formic acid, and further l-benzoyloxy-2-dimethylaminotetralin by benzoylation of the obtained 1-hydroxy-2-dimethylaminotetralin manufactured; As already mentioned above, it has also been found that these are manufactured in this way Compounds unexpectedly have a high local anesthetic effect at gastric juice pH and on the The present invention was worked out on the basis of this discovery.

It should be particularly noted that the 1-benzoyloxy-2-dimethylaminotetralin hydrochloride (correct 2-benzqyloxy-ldimethylaminotetralin hydrochloride) which according to the procedure outlined by A. Gonzalez et al has no local anesthetic effect on gastric juice pH and is due to this plague It is also clear that the present invention was not supported by A. Gonzalez and coworkers and J. von Braun and coworkers has been described in some way. In addition, the melting point of l-benzoyloxy-2-dimethylaminotetralin hydrochloride, which by the present

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Invention obtained has been determined at 203-2O4 ° C in the cis ~ Porm (Example 1) and 79 ° C in the trans-Form (Example 2). Furthermore, the melting point of the incorrectly designated 2-dimethylamino-lp-nitrobenzoyloxytetralin (correct: l-dimethylamino-2-p-nitrobenzoyloxytetralin), which has been manufactured by J. von Braun and coworkers, is 112 ⁰ C, while the cis -2-dimethylamino-1-nitrobenzoyloxytetralin (Example 11), which is prepared according to the present invention, is an oily material.

The compounds of this invention having the formula (III) are prepared by reacting the 1-hydroxy-2-lower ones -alkylaminobenzocycloalkane derivatives with the formula

1 2
in which R, R and η have the meaning already mentioned with the benzoic acid which is represented by the formula

0OH

(ID

is shown, wherein R, R and Rr are those already mentioned Have meaning or their reactive derivative on the carboxyl group.

When connecting this finding with the formula (III) The compound of this invention can wherein R is Amino group is, by reducing the compound «, in the

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■ - ίο -

For represents a nitro group, can be prepared by an ordinary method, if necessary.

Practically speaking, the reaction is carried out » by treating the compound of formula (I) with usually an equimolar or slightly excess molar Reacts amount of the compound with the formula (II) or its reactive derivative on the carboxyl group. the The reaction is carried out in water or in a suitable organic solvent. When the benzoic acid (i.e. the compound having the formula (II) is used, the reaction can be carried out at room temperature in an organic Solvents such as methylene chloride, chloroform and the like is carried out in the presence of an almost equimolar amount of a carbodiimido compound such as dicyclohexylcarbodiimide! will. When the reactive derivative of the compound of the formula (II) is an acid halide, such as acid chloride, acid bromide and the like, the Reaction by allowing the reactants to stand in an organic solvent such as benzene, toluene and the like or by heating them in the solvent will. However, a tertiary base such as pyridine, triethylamine and the like can be added to the Reaction batch are added. Furthermore, the reaction can be a so-called Schotten-Baumann reaction be carried out in the presence of an alkali hydroxide in an aqueous solvent. If the reactive Derivative is an acid anhydride or an active: ester, such as p-nitrophenyl ester and the like, the reaction in usually in an organic solvent such as chloroform, benzene and the like at room temperature or can also be carried out with heating.

The compound of the formula (III) represented by the above said reaction has been produced, can in-usual

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Way by a conventional chemical method, such as Filtration, concentration, recrystallization, column chromatography and the like can be isolated.

As a starting material with the formula (I), which in this In the invention, the cis form and the trans form can be used according to the steric configurations of the amino group and the hydroxyl group both in the dl form, in the optically active d-form and in the 1-form can be used. If each of the starting compounds is used, the reaction product has the corresponding steric and optical configuration preserved. The mixture of these isomers can also be used as the starting material in the reaction can be used and the reaction products obtained can by fractional crystallization, column chromatography and separation by means of optically active connections and the like.

In the case where the compound of the formula (III) is obtained, wherein R ^ represents an amino group, and wherein this has been prepared from a compound of the formula (III) in which R · ^ is a nitro group, the compound can can be reduced by a conventional method. For example, the reduction is carried out by Heat the compound together with iron powder and hydrochloric acid in water.

Furthermore, the compounds of this invention represented by the formula (III) can also be obtained by methods other than those described above can be obtained. For example, the connection of the formula (III) also by reacting the 2-amino-1-benzoyloxybenzocycloalkane derivatives, which are divided by the formula (IV)

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2223359

- 12 -

(IV) J

NH ₂ r5

- (CH ₂ ) _n

wherein R, R and R and η have the meaning already mentioned have by treating them with a lower alkylating agent, such as methyl iodide, ethyl iodide, dimethyl sulfate and like obtained by a conventional method ^ Likewise, the compound of the formula (III), wherein R represents a hydrogen atom, can be prepared by reacting the compound with the formula (IV) with a lower aldehyde, such as formaldehyde, acetaldehyde, Propionaldehyde and the like to the appropriate To obtain Schiff's base, which is then subsequently reduced. Furthermore, the compound with the formula (III) wherein R represents a lower alkyl group can be prepared by reacting the compound having the formula

(III), wherein R represents a hydrogen atom by the above method and by means of a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate and the same.

Furthermore, the compound represented by the formula (III) can use these

1 2
Invention, wherein R and R represent a methyl group, by heating the compound of the formula (IV) or the oxazoline derivative represented by the formula (V)

> 3

(V)

^{7 N} I ₅

■ <CH ₂ ) _n

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- - 13 -

wherein R, R and R ^ and η have the meaning already mentioned own, be made by putting these together heated with the calculated or excess amount of formaldehyde and formic acid.

Many of the starting compounds of the formula (I) of this invention are new compounds and can be prepared by lower alkylation of the known 2-amino ~ 1-hydroxy-benzocycloalkane derivatives (J. Chem. Soc. (C), 288 (1968) and Ann .Chem., 738 * 79 (1970) ) ₃ which are represented by the formula (VI),

(VI)

in which η has the meaning already mentioned, by a conventional implementation. For example, the starting material having the formula (I) can be prepared by reacting the compound of the formula (VI) with a lower one Alkylating agents such as methyl iodide, ethyl iodide, dimethyl sulfate and the like or reacting the compound of formula (VI) with a lower aldehyde such as formaldehyde, Acetaldehyde, propionaldehyde and the like to form a corresponding Schiff base, which then is reduced. In addition, the connection with

Ί 2
of the formula (I), wherein R and R represent a methyl group, are obtained by heating the compound (VI) together with the calculated or excess amount of formaldehyde and formic acid.

1
The R group of the compound of this invention which

represented by the formula (III), ® & ® · includes hydrogen atom and a lower alkyl group _s such as

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e.g. a methyl group, ethyl group, isopropy group, Isobutyl group, tert-butyl group, amyl group ■ and the like

chen. The R group also includes a lower alkyl group such as methyl group, ethyl group »isopropyl group, isobutyl group, tert-butyl group and amyl group a »The groups R, R and R ^ are equal to or of one another different and each represents a hydrogen atom, a halogen atom such as chlorine, bromine and the like; the lower alkyl groups include, e.g. Methyl group, ethyl group, isopropyl group, tert-butyl group and amyl group, a lower alkoxy group such as methoxy group, Ethoxy group and the like; a substituted amino group, such as monomethylamine group, monoethylamino group, Dimethylamino group, diethylamino group, acetoamino group, Carbobenzoxyamino group; Amino group; Phenyl group; and Nitro group.

Practical examples of the compounds of this invention represented by the formula (III) are for example:

cis-l-benzoyloxy-2-dimethylaminotetralin, trans-l-benzoyloxy-2-dimethylaminotetralin ₅ cis-l-benzoyloxy-2-dimethylaminoindane, trans-l-benzoyloxy-2-dimethylaminoindane, cis-l-benzoyloxy-2-dimethylaminobenzocycloheptane, trans-l-benzoyloxy-2-dimethylaminobenzocycloheptane, cis ~ l-benzoyloxy-2-diethylaminotetralin, cisTl-benzoyloxy-2-diethylaminoindane, cis-l-benzoyloxy-2-methylaminotetralin, cis-l-benzoyloxy-2-methylaminoindane l-Benzoyloxy-2-äthylaminotetralin, cis-l-Behzoyloxy-2 ~ äthylaminoindan _a cis-I-Benzoyloxy-2-propylaminotetralin,

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cis-lp-methylbenzoyloxy-2-dimethylaminotetralin, cis-l ~ p-methylbehzoyloxy-2-diethylaminoindan, · cis-l ~ o-methpxybenzoyloxy-2-dimethylaminotetralin _a cis ~ l- (3 » ¹ i, 5-trimethoxy) ben ! 3oyloxy- ^; 2-diinethylaminotetralin,

cis-l ~ p-chlorobenaoyloxy-2-diethylaminoindane ₉ cis- (3 »^ - dichloro) benzoyloxy - 2-dimethylaminotetralin, cis-lp-nitrobertzqyloxy-2-dimethylaminotetralin, cis-p ~ nitroberizoyloxy-2-diethylaminoindane ₉ cis-lp-nitrobertzqyloxy-2-dimethylaminotetralin lp-dimethylaminobenzoyloxy-2-dimethylaminotefcralin, cie-lp-di3Ilethylaminobenzoyloxy-2-diethylaminoindane, cis-l ~ p-acetylaminobenzoyloxy-2-diethylaminoindane, cis-lp-aminobenzoyloxy-2-dimotetryla | 5-chloro-2-raethoxyberizoyloxy) -2-dimethylaminotetralin,

cis-1- (2-methoxy-4-nitrobenzoyloxy) ~ 2 ~ dimethylaminotetralin ₃

cis -1- (4-amino-2-methoxybenzoxy) -2-dimethylaminotetralin and

cis -2-dimethylaffiino-1- (p-phenylbenzoyloxy) tetralin.

These compounds can be converted into the non-toxic acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or Sulfuric acid, to be transferred ".

The compounds of this invention are administered orally, for example, in the form of tablets, capsules, powders and the like. The clinical administration form of the compound to adults is 10-20 mg and the amount of the compound is administered orally 1 to 3 times a day. The dosage is adjusted accordingly according to the body condition and the age of the patient to be treated.

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In the attempt.;. L: £ :: d§r "is reproduced below, was the excellent local anesthetic effect of cis-i-benzoyloxy-2-dimethylaminotetralin hydrochloride (Sample (A)) and the cis -l-benzoyloxy-2-dimethylaminoindane hydrochloride (Sample (B)), which are the compounds of this invention, compared with those known compounds such as N, N ~ diethyl-3-benzoyloxyphenethylamine hydrochloride (U.S. Patent 3 ^ 99 087) (sample (C)), lidocaine (sample (D)) and the 2-benzoyloxy-1-dimethylaminotetralin hydrochloride (Sample (E)) obtained according to the method reported by A. Gonzalez et al. In '. Anal Soc. eepan. f sharp. quim., 20, 53 ^ (1922).

Attempt I.

A solution of each of the above samples in a buffer solution having a pH of about 6 and 2 was injected into the conjunctiva of the eyes of 8 guinea pigs each constituting a group according to the method of Chance and Lobstein (J. Pharmacol. Exp.Ther ., 82 ^, 203 (19H ² *)). A mechanical stimulus with a constant stimulus value was triggered every 5 minutes after the administration, and the number of losses of the corneal reflex in 30 minutes after the administration of the sample was measured.

The 5Oy? Effective concentration (ECj- ₀ ) was obtained from the dose-response curve of each sample. The results obtained are shown in Tables I and II below.

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(50 $ effective concentration at pH = 6)

Sample 50JS effective concentration (%)

(A) 0.07 (0.03-0.14) *

(B) 0.08 (0.05-0.13) ^v

(C) 0.3 (0.2-0.45) *

(D) 0.8 (0.4 - 1.6) *

(E)> 3

(*): the 95 ^ saturation limit

Table II

(Inhibition percentage if the sample was used with concentration at pH = 2)

Sample inhibition percentage

(A) 86 i 6.3 *

(B) 70 * 3.1

(C) 11 * 2.5

(D) 10 i 3.1

(E) 0

(*): Standard error

In the following Experiment II, the excellent effect of the sample (A) or (B) in stimulating gastric mobility was compared with the effect of the known oxethazaine compound (Sample (P)) in reducing gastric mobility. Experiment II

After anestheticization of a dog that was fasted overnight by intravenous injection of 30 mg / kg pentobarbital 10 mg / kg of the sample was administered intravenously to the dog or 20 mg / kg of the compound in

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the duodenum of the dog was introduced and then the. spontaneous mobility of the stomach with the help of an ink-writing tool Polygraph (RM-15O, manufacturer Nihon Kohdeh K.K.) according to the balloon method (Jap. J. Smooth Muscle Res., 2! " 15 (1966)). The results obtained are shown in Table III below.

In addition, the table shows the stimulating effect the may movement is noted as (+) when the spontaneous movement of the stomach continued for more than 20 minutes and ea is noted as (-) when the movement is not continued.

T able III

Sample Stimulating effect on gastric movement

(a): intravenous injection and (b) administration to the duodenum.

The values for LD ^ ₀ were determined by oral administration to a mouse and were, when cis-1-benzoyloxy-2-dimethylaminotetralin hydrochloride or cis-1-benzoyloxy-2-dimethylaminoindane hydrochloride was administered, 2200 mg / kg and I87O mg / kg.

The examples of the present invention are explained in more detail below.

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Example 1 :

3.8 g of cis-1-hydroxy-2-dimethylamihotetralin was dissolved in 5 ml of benzene. Then 2 ml of a benzene solution containing 3.1 g of benzoyl chloride was added to the solution. The mixture was allowed to stand overnight at room temperature and the se ^ ü refluxed during - ^; ' 4 hours. The reaction skeleton was cooled and the crystals formed were separated by filtration. After washing the crystals with a small amount of Beiizol, they were recrystallized from an ethanol / ethyl acetate solution. 4.3 g of cis-1-benzoyloxy-2-dimethylaminotetralin with a melting point of 203-2O4 ° C. were obtained. (A melting point of 223 ^° C. is measured with the aid of a micro-melting point apparatus).

• Nuclear magnetic resonance spectrum (DpO) hydrogen in the! Position 6: 6.5 ppm (doublet _s J = 2Hz)

Nuclear magnetic resonance spectrum of the free base (CDCl.,) Hydrogen in the! Position δ: 6.65 ppm (doublet, J = 2 Hz).

Elemental analysis as C _{1 QHp 2} NO ₂ Cl:

C (JS) H {%) N {%)

calculated: 68.77, 6.68, 4.22 found: 68.51; 6.75 4.39

Then, the hydrochloride obtained above was dissolved in water, and then potassium carbonate was added in proportions added to the solution. It became cis -l-benzoyloxy-2-dimethylaminotetralin obtained in the form of the free base with a melting point of 74-75 ° C.

Elemental analysis as ^C 19 ^H 2i L ^N0 2 ^: N (% C. (%) - H (S) 4th , 74 calculated: 77 , 26 7.17 4th , 94 found : 77 , 17th 6.91

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Optical separation of cis-l-benzoyloxy-2-dimethylaminotetralin:

Cis-1-benzoyloxy-2-dimethylaminotetralin was dissolved in ethanol. 0,0-dibenzoyl-d-tartaric acid was added and the mixture was allowed to stand to form crystals. [ ^q ] d ° ⁼ " ^l46 > 7 ° < ^c = ¹ » ^li2 > ethanol)

Crystals were also obtained from the mother liquor OGD ° ^{= + 26} » ⁵⁵ ° ^{(c? 1} ^ ⁷⁸ ethanol)

The formed crystals were suspended in water, and after adding potassium carbonate to the suspension, the mixture was extracted with ether. The extract was dried, mixed with ethanol and hydrochloric acid, and then the solvent was distilled off. Recrystallization of the resulting residue from a mixture of ethanol-Äbher l-cis-l-benzoyloxy-2-dimethylaminotetralin hydrochloride was obtained with a melting point of 211- 212 ⁰ C (with decomposition).

JV | j * ⁰ = - 175.27 ° (C = 1.09, ethanol)

Also, by treating the latter crystals similarly to the above, d-cis-1-benzoyloxy-2-dimethylaminotetralin hydrochloride was obtained obtained with a melting point of 210-211 ° C (with decomposition).

J ⁰ = + 177.2 ° (C = 1.728, ethanol)

Production of the raw material:

A mixture of 4.32 g of cis-2-amino-1-hydroxytetralin hydrochloride, 1.69 g sodium formate, 6 g 98% formic acid and 7 g of 37 / s-igeur formalin was on for 14 hours

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90 - 110 ° C heated. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved with 100 ml of water. Then the solution was with Potassium carbonate neutralized. The product was made from the Solution extracted with 120 ml of chloroform. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off. 3.8 g of oily c'is-1-II-hydroxy-2-dimethylaminotetralin were obtained obtain.

Further production of the starting material:

a) 2 g of trans-2-acetamido-1-hydroxytetralin was added to 5 ml of tetrahydrofuran suspended. After adding 2 g of thionyl chloride to the suspension, it was left to cool with ice let the mixture stand for 30 minutes. By severing the The precipitate formed by filtration was 2 g of cis-2-methyl-3a, 4,5,9b-tetrahydronaphtho / 2, l-d.7oxa2ol hydrochloride with a melting point of 148-149 ° C obtain.

Elemental analysis as

C (JO H (*) N (% calculated: 64.43 6th , 31 6th , 26 found : 64.61 6th , 38 6th , 34

b) 2.24 g of cis-2-methyl-3a, 4,5,9b-tetrahydronaphtho / * 2, l- & 7oxazole hydrochloride were dissolved in a mixture of 3 ml of 85? formic acid and 3 ml of formalin. After the addition of 0.7 g of sodium to the solution, the mixture was heated for 8 hours at 100 -105 ⁰ C. After completion of the reaction, the reaction mixture was made alkaline by addition of aqueous Katriumhydroxydlösung and the mixture was heated for 30 minutes at 100 ⁰ C. After cooling, the reaction product was extracted 3 times each time with 5M chloroform. The chloroform extracts were

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united. After drying the mixture over anhydrous potassium carbonate, the solvent was distilled off. It was 1.6 g of cis-l-hydroxy-2-dimethylaminotetralin with a " Melting point of 36-38 ° C obtained.

Elemental analysis as C ₁₀ H .. "NO:

C (Z) 8th (%) N {% calculated: 75.35 8th , 96 7.32 found : 75.24 , 83 7 Ü1

Nuclear magnetic resonance spectrum (, τ = 5.23 (doublet, J = 4.0 Hz, CDCl,)

In addition, the absorption of trans-l-hydroxy-2-dimethylaminotetralin not observed.

Example 2:

In 2 ml of benzene was 0.4 l g of trans-1-hydroxy-2-dimethylaminotetralin dissolved. To the solution, 1 ml of a benzene solution containing 0.33 g of benzoyl chloride was added. Then the mixture was refluxed for 4 hours. The reaction mixture was cooled and washed with 10 ml of water extracted. The extract was made weakly basic with potassium carbonate and then extracted with 10 ml of benzene. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off. It was 0.37 g of oily material was obtained. If the product has been purified using silica gel column chromatography, became 0.17 g of oily trans-1-benzoyloxy-2-dimethylaminotetralin obtain. Furthermore, if the product is with Ethanol-hydrogen chloride solution was mixed and then the solvent was distilled off under reduced pressure was, oily trans-l-benzoyloxy-2-dimethylamino-

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"'· ..: - 23 obtained tetralin hydrochloride.

Nuclear magnetic ¹ Hesonance spectrum (CDCl,) hydrogen in

of imposition

δ ': 6 * 45 ppm

-. · ■; (Doublet, J = 8Hz) Elemental analysis as C ₁₉ H ₂

'Cl

Calculated: 69.77 6.68 4.22. Found: '69.92 6.48 4.36.

By recrystallization of the oily product from water crystals with a melting point of 79 ° C were obtained.

Elemental analysis as C ₁₀ H ₀₀ NO ₀ Cl ^ H ₉ O:

C (S) n (%) N (JS) calculated: 65.23 6.91 4.00 found : 65.66 6.42 · 4.13

Manufacture of the starting product:

To 0.45 g of trans-2-amino-1-hydroxytetralin was added 2 ml 8555 formic acid and 2 ml 37/5 formalin were added. Then the mixture was refluxed for 14 hours, excess formic acid and excess Formalin were distilled off from the reaction mixture. The residue obtained was dissolved in 20 ml of water. the The solution was adjusted to be weakly basic with potassium carbonate. The product was extracted with 20 ml of chloroform. Then · the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off. It was 0.4 l g of oily trans-1-hydroxy-2-dimethylaminotetralin were obtained.

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Example 3 :

0.18 g of cis-1-hydroxy-2-dimethylaminoindane was suspended in 1 ml of benzene. Then 1 ml of a benzene solution containing 0.14 g of benzoyl chloride was added to the suspension. The resulting mixture was refluxed for 5 hours. The reaction mixture was cooled and the crystals thereby formed were separated by filtration. They were recrystallized from ethanol-benzene. There was obtained 0.15 g of cis-l-benzoyloxy-2-dimethylaminoindane hydrochloride with a melting point of 22O ⁰ C.

Nuclear Magnetic Resonance Spectrum (CDCl,) Hydrogen in

the 1-position 6: 6.9 ppm (J = 0 - -1 Hz)

Elemental analysis as C ^ gHp ₀ NOpCl:

C (S) H (*) N (%) calculated: 68.03 6.34 4.41 found: 68.21 6.54 4.36

Production of the raw material:

1 ml of 95% was added to 0.2 g of cis-2-amino-1-hydroxyindane Formic acid and 1 ml 37 # formalin added. Then the mixture was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 15 ml of water. Then the solution was neutralized with potassium carbonate. The product was extracted with 20 ml of chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off from the extract.

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There was 0.18 g of oily cis-1-hydroxy-2-dimethylaminoindane obtain.

Example 4;

To 0.55 g of trans-2-amino-1-hydroxyindane was 0.2 g of sodium formate, 2 ml 85% formic acid and 1.5 ml 37% formalin were added. Then the mixture was left for 8 hours held under reflux. The reaction mixture was concentrated under reduced pressure. The residue obtained. was mixed with 10 ml of water. The aqueous solution obtained was adjusted to be weakly basic with potassium carbonate. The product was extracted with 30 ml of chloroform. After drying the extract over anhydrous magnesium sulfate the solvent was distilled off. An oily residue was obtained. The residue was in 3 ml Pyridine dissolved. Then 0.5 g of benzoyl chloride was added to the solution added. The mixture was allowed to stand over night at room temperature. The pyridine was then reduced under Distilled pressure. The obtained residue was mixed with 5 ml of water and then became the product extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then became the solvent is distilled off under reduced pressure. Eventually, ethanol-hydrochloric acid became that residue thus formed was added and the ethanol was distilled off. The residue thus obtained became pus ethanol-benzene mixture and it was recrystallized 0.2 g of trans-1-benzoyloxy-2-dimethylaminoindane hydrochloride obtained with a melting point of 125-127 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl,) Hydrogen in

the 1-position δ: 6.45 ppm

(J = 0 - IHz)

2098 82/1171

- 26 Elemental analysis as C ^ gH ^ NOgCl:

C (Z) H (55) N (JS). calculated: 68.03 5.34 4.41 found: 67.82 6.19 4.57

Example 5:

In 5 ml of dichloromethane, 0.7 g of 1-hydroxy-2-dimethylaminobenzocycloheptane, prepared by dimethylating 2-amino-1-hydroxybenzocycloheptane, was dissolved. Then 0.6 g of benzoyl chloride was added to the solution. The mixture was refluxed for 4 hours. The solvent was distilled off from the reaction mixture and then 10 ml of sodium carbonate solution was added to the residue thus obtained. The product was extracted 3 times with 10 ml of benzene each time. The benzene extract was washed with water and dried over anhydrous potassium carbonate. Then the benzene was distilled off. By purifying the residue obtained using. Silica gel column chromatography gave 0.8 g of oily 1-benzoyloxy-2-dimethylaminobenzocycloheptane.

Elemental analysis as C ₂ H ₂ , N0 ":

C (JO HCO N (Ji) calculated: 77.63 7.49 4.52 found : 77.45 7.54 4.63 Example 6:

2 ml of benzoyl chloride were added to 0.5 g of 2-ethylamino-1-hydroxyindane hydrochloride. Then the mixture was 10 minutes l60 - 170 ⁰ C heated. After the mixture had cooled, 15 ml of benzene and 10 ml of water were added to the mixture and then shaken well.

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The aqueous layer formed was separated off and washed twice with 10 ml of benzene each time and concentrated under reduced pressure. The residue obtained was recrystallized from an ethanol-ether-solvent mixture. 0.5 g of 1-benzoyloxy-2-ethylaminoindane hydrochloride with a melting point of 189-19O ⁰ C (with decomposition) was obtained.

Elemental analysis as C _{1 QHp 0} NOpCl:

C (S) Η (ϊ) N (S)

calculated: 68.03 6.34 4.4l found: 67.89 6.55 4.59

Example_iel_X;

In 10 ml of benzene, 1.8 g of 2-diethylamino ~ l-hydroxyindane, produced by ethylation of 2-ethylamino-1-hydroxyindan, dissolved. Then became the solution

1.4 g of benzoyl chloride added. The mixture was refluxed for hours. After the reaction mixture was cooled, crystals were deposited and filtered through severed. They were recrystallized from a mixed solvent of ethanol-ethyl acetate. It was

2.5 g l-benzoyloxy-2-diäthylaminoindan hydrochloride with a melting point of I97 - obtain 198 ⁰ C (with decomposition).

Elemental analysis as Cp ^ HpuNOpCl:

C (S) H (S) N (S) calculated: 69.45 6.99 '4.05 found : 69.36 6.78 4.21

2 0 9 8 8 2/1171

Example, 8jl

In 10 ml of dichloromethane, O _5, 7 g of cis-1-hydroxy-2-dimethyl-aminotetr "älin were dissolved, then 0.8 g of II-dimethylaminobenzoyl chloride hydrochloride was added to the solution. The mixture was refluxed for 8 hours. Then, the solvent was distilled off under reduced pressure, a small amount of water was added to the residue, and the crystals thereby precipitated were separated by filtration to give 0.8 g of cis-2-dimethylamino-1- (4-dimethylaminobenzoyloxy) tetralin hydrochloride was obtained by recrystallization of the product from an ethanol-ethyl acetate -. mixture of solvents the pure "crystals of the product were obtained with a melting point of 215 216 ⁰ C (with decomposition).

Elemental analysis as C ₂₁ H ₂₇ N ₂ O ₂ Cl * 1/2 H ₂ O:

C (SO H (Si) NW calculated: 65.70 7.35 7.30 found : 65.69 7.11 7.34 Example 9:

1.9 g of cis-1-hydroxy-2-dimethylaminotetralin were dissolved in 27.5 ml of dichloromethane. Then 2.8 g of ^t f-acetamino-5-chloro-2-methoxybenzoyl chloride was added to the solution. The mixture was refluxed for 8 hours. The solvent was distilled off under reduced pressure and after adding 100 ml of 0.1 η sodium carbonate solution to the residue, the product was extracted 3 times each time with 20 ml of ethyl acetate. The extract was dried over anhydrous potassium carbonate, and then the solvent was distilled off under reduced pressure. By purifying the residue by silica gel column chromatography, 2 g of oily cis-l - (* J-acetamino-5-chloro-2-methoxybenzoyloxy) -2-dimethylaminotetralin was obtained

209882/1171

obtain.
Elemental analysis as

C (% ) H (SO N (JO calculated: 38 6.04 6.72 found: 63, 46 6.21 6.53 Example 10:

In 13 ml of dichloromethane, O ₅ 9 g of cis-1-hydroxy-2-diraethylaminotetralin was dissolved. Then 1 g of 2-methoxy-4-nitrobenzoyl chloride was added to the solution. The mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure. 1 ml of ethanol and 10 ml of ether were added to the residue obtained. The crystals thereby precipitated were separated by filtration. They were washed with ether. 1.8 g of cis -1- (2-methoxy-4-nitrobenzoyloxy) -2-dimethylaminotetralin hydrochloride was obtained. Recrystallization of the product from ethanol the pure Mstalle were obtained with a melting point of 207 - 208 obtained ⁰ C (with decomposition).

Elemental analysis as C ₂₀ H ₂ ^ NpOf-Cl:

H (Sf) N (Si)

calculated: 59.04 5.70 6.89

found: 59.27 5.51 6.98

Example 11 ;

In 5 ml of dichloromethane, 1 g of cis-l-hydroxy-2-dimethyl-

aminotetralin dissolved. Then the solution became 1 g

p-Toluojlchlorid added. The mixture became overnight

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stand still. The solvent was distilled off under reduced pressure. Then 5 ml of benzene was added to the residue. The crystals thereby formed were separated by filtration. There was 1 _S 5 g cis-2-dimethylamino-lp-toluoyloxytetralin hydrochloride obtained. The pure crystals with a melting point of 187-189 ° C. (with decomposition) were obtained by recrystallizing the product from an ethanol / ether / solvent mixture.

Elemental analysis as C _{20 HpJjNO 2} Cl:

cm H (SO N (SK) calculated: 69.45 6.99 4.05 found : 69.59 6.78 4.21 Example 12:

Following the same procedure as given in Example 11, but using 1 g of cis-l-hydroxy-2-dimethylaminotetralin and 1.1 g of 3,4-diehlorobenzoyl chloride, 1.8 g of cis-l- (3.4 -Dichlorobenzoyloxy) -2-dimethylaminotetralin hydrochloride with a melting point of 182-183 ⁰ C (with decomposition).

Elemental analysis as C ₁ gHp ^ NOpCl ,:

C ( %) H (%) N (Ji) calculated: 56 , 95 5 , 03 3.50 found : 56 , 73 5 , 21 3.43 Example 13:

By using the method as described in Example 11, but using 1 g of cis-l-hydroxy-2-ciimethylaminotetralin and 1.1 g of p-nitrobenzoyl chloride was

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r 31 - "

Hydrochloride with a melting point of 173-175 ° C

1.5 g of cis-2-dimethylamino ~ 1- (p-nitrobenzoyloxy) tetralin hydrochloride with a tendon!
(with decomposition) obtained.

Elemental analysis as C ^ gHp ^ N

C (U) H (Si) N (%) calculated: 60.56 5.62 7th , 43 found : 60.67 5.46 .7 , 58

Then the hydrochloride obtained above was suspended in water. The suspension became alkaline with 2n Sodium carbonate solution and the product was extracted with dichloromethane. After drying the extract the solvent was distilled off under reduced pressure. It became oily cis -2-dimethylamino-1- (p-nitrobenzoyloxy) tetralin obtained in the form of the free base.

Example 1 4:

In 6.4 ml of dichloromethane was 0.44 g of cis-1-hydroxy-2-dimethylaminotetralin dissolved. Then 0.5 g of p-phenylbenzoyl chloride was added to the solution. The received The mixture was refluxed for 4 hours. The reaction mixture was then given as in Example 11, treated. 0.8 g of cis-2-dimethylamino-l- (p- * phenyl · · benzoyloxy) tetralin hydrochloride. The crystals of the product were recrystallized from isopropanol and had a melting point of 210-212 ° C (with decomposition).

Elemental analysis as C _{2t -HpgN0 2} Cl:

CU) H (JK) N (Ji) calculated: 73.61 6.42 3.43 found : 73.74 6.58 3.31

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Example ljji

Using the same procedure as in the example
14, but using 1.6 g of cis-1-hydroxy-2-dimethylaminotetralin and 2.3 g of 3j ** j5-trimethoxybenzoyl chloride, 3.6 g of cis-l- (3,4, 5-trimethoxybenzoyloxy) -2 ~ dimethylaminotetralin hydrochloride with a
Melting point of 147-149 ° C (with decomposition) obtained.

Elementary analysis as CppHpgNCUCl:

N (Jg)

calculated: 62.63 6.69 3.32
found: 62.52 6.75 3.19

Example 16:

0.462 g of cis-1-hydroxy-2-dimethylaminotetralin was dissolved in 5 ml of dichloromethane. Then 0.5 g of o-methoxybenzoyl chloride was added to the solution. The resulting mixture was refluxed for 5 hours. That
Solvent was distilled off from the reaction mixture under reduced pressure. The residue obtained was mixed with 10 ml of benzene, and 10 ml of water were added
and then shaken well. The aqueous layer thus formed was separated off and after making the aqueous layer alkaline by adding potassium carbonate, the product was extracted twice with 10 ml of ether each time. After drying the ether extract obtained over
anhydrous potassium carbonate, the solvent was distilled off under reduced pressure. The residue obtained was purified by means of silica gel column chromatography. As a result, an oily product was obtained ". By
Addition of ethanol-hydrogen chloride to the oily product and distilling off the solvent was 0.4 g of oily cis-l- (o-methoxybenzoyloxy) -2 - dimethylaminotetralin-

209882/1171

Obtain hydrochloride.
Elemental analysis as Cp ₀ H ₂ JjNO, Cl:

H (Si) N (*) calculated: 66.38 6.68 3.87 found: 66.17 6.42 3.5 * »

Example 17:

By using the same procedure as in the case game 16 specified, but using 2 g cis-2-diethylamino-l-hydroxytetralin, which by Ethylation of cis-2-ethylamino-1-hydroxytetralin produced and 1.42 g of benzoyl chloride became 2.5 g of oily 1-benzoyloxy-2-diethylaminotetralin hydrochloride obtain.

Elemental analysis as Cp.HpgNO-Cl:

C (JS) H (SO-N (Si) calculated: 70.08 7.28 3.89 found: 70.26 7.02 3.58

Example 18 :

A mixture of 1 g of cis-2-dimethylamino-1- (p-nitrobenzoyloxy) tetralin, 1 g of iron powder, 10 ml of ethanol, 3 ml of water and 2 drops of concentrated hydrochloric acid were added heated to 80 ° C for 25 minutes with stirring. Then 0.5 g of sodium bicarbonate was added to the mixture and insolubles were filtered off. Then, ethanol was distilled off from the piltrate under reduced pressure. The precipitates thereby separated out were separated off by filtration. It became 0.5 S cis-l- (p-amino benzoyloxy) -2 ~ dimethylaminobetralin. The crystals of the product were made by recrystallization

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Benzene and had a melting point of 160 -

Elemental analysis ^{as c iqH22 N} 2 ° 2 ^:

■ C (%) H (Si) N (JO calculated: 73.52 7.14 9.02 found: 73.66 7.03 9.18

Example 19 :

Using the same procedure as described in the example, but using 1.5 B cis-1- (2-methoxy-4-nitrobenzoyloxy) -2-dimethylaminotetralin hydrochloride became. 0.9 g of 'cis -1- (4-amino-2-methoxybenzoyloxy) -2-dimethylaminotetralin with a melting point of 202-2O3 ° C.

Elemental analysis as ^c po ^H 24 ^N 2 ° V

C (Ji) H (SK) N (SS) calculated: 70.57 7.11 8.23 found : 70.39 7.25 8.04 Example 20:

To a mixture consisting of 2 ml of 85% formic acid and 2 ml of 37% formalin, 2 g of cis-2-phenyl-3a, 4,5,9btetrahydronaphtho / 2, l ~ d / oxazole added. The mixture was heated to 100-105 ° C for 8 hours. The reaction mixture was mixed with 10 ml of water and then became the mixture is alkaline with aqueous sodium bicarbonate solution set. The product was extracted with 20 ml, 10 ml and then with 10 ml of ether successively. The ether extracts were combined and dried over anhydrous magnesium sulfate dried. After adding a mixture of

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Ethanol-hydrogen chloride, the solvent was distilled off. It was 0.97 g of cis ~ l-benzoyloxy-2-dimethyläminotetralin hydrochloride with a melting point of 211 - 212 obtained ^0C.

Elemental analysis as C ₁ QH ₂₂ NO ₂ Cl:

calculated: 68.77 6.68 4.22 found: 68.64 6.61 4.35

The hydrochloride free base obtained above was used as a sample for nuclear magnetic resonance spectral analysis. QCO

Nuclear magnetic resonance spectrum (r- 3.37 (doublet, J = 2 - 3 Hz ₅ CDCl,)

No absorption at τ = 3.56 (doublet, J = 8 Hz, CDCl,) of the transform was observed.

Production of the raw material:

a) 2 g of 2-amino-1-tetralone hydrochloride was added to 20 ml of water dissolved. Then 2 ml of ethyl acetate solution was added to the solution, the 1.7 g of benzoyl chloride contained. The mixture was stirred with the addition of 10 ^ aqueous sodium hydroxide solution, so that the pH of the batch was kept between 4-5. The crystals precipitated were separated by filtration and washed with water and dried. It became 2.5 g 2 ~ Benzoylamino-1-tetralone with a melting point of 180 - 18l ° C.

Elemental analysis as C ₁₇ H ₁

209882/1171

C (Ji) H (SO N (SK) calculated: 76.96 5.70 5.28 found : 76.95 5.75 5.36

b) In 50 ml of methanol was 2.65 g of 2-benzoylamino-itetralone suspended. While cooling with ice water, 0.4 g of sodium borohydride was added to the suspension and stirred. After stirring for a further 2 hours, the reaction mixture was concentrated to 5 ml and the Crystals which separated out were separated off by filtration. 2.4 x g of crude crystalline txans-2-benzoylamino-1-hydroxytetralin were obtained obtain. In addition, the crystals contained 10-205? cis -2-benzoylamino-1-hydroxytetralin.

Nuclear magnetic resonance spectrum (

τ = 4.63 (doublet, J = 8 Hz, pyridine-DpO) trans

τ = 4.82 CDoublet, J = 3 Hz, pyridine-D ₂ O) - ice

202 ⁰ C are obtained - Next the product from methanol trans-2-Benzoylamino-l-hydroxytetralin was by recrystallization with a melting point of two hundred and first

Elemental analysis as C ₁₇ H ^ ₁₇ NO ₀ :

C (Ji) H(*) N (JS) calculated: 76.38 6.41 5.24 found : 76.42 6.38 5.34

c) To 1 g of crude trans-2-benzoylamino-1-hydroxytetralin 1.5 ml of concentrated sulfuric acid was added with ice cooling and stirring for 2 hours. The reaction mixture was emptied into cold aqueous sodium carbonate solution and then with 20 ml and subsequently with 10 ml of chloroform

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extracted. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off. 0.93 g of oily cIs-2-phenyl-3a, 4 _s 5,9b-tetrahydronaphtho / 2 _a , id. / Oxazole was obtained. ·

Elemental analysis as C ^ "EL (-NO:

calculated: Sl, 90 S , 06-5. »62 found: 79.41 5.86 5.71

Example 21 :

2 ml of 85% formic acid, 2 ml of formalin and 0.45 g of sodium formate were added to 2 g of cis "2-AmIno-benzoyla.xytetralIn-Suilfafc, and the mixture was ^{heated to 100-1QS 0} C for 8 hours After making the reaction mixture alkaline by adding aqueous sodium carbonate solution, the product was extracted with 20 ml and then with 10 ml of chloroform. The extracts were combined with one another and dried over anhydrous magnesium sulfate. After the addition of ethanol-hydrogen chloride to the solution, the solvent was distilled off . It has been g kristallines- sis-I-Bensoyioxjr-2- ■ limethylaminotetralin-Hydrochlorld 1.3 with a Scjhmelspunkt of 211 - 212 ^C C obtained.

The free base that comes from the Hydrochloric! ₃ was used as a sample for the nuclear magnetic analysis « ψ, _Γ ^ .- (/ ^v \

^ JOp " Sernmagnetische3 Reeonansspslctrum (I \\ i * '

- = 3.37 (doublet, J = 2 - 3 Hz ₃ € D01 "l! No absorption at τ- Ί_, 5 & (Doi,: slet'3 _s CDCl,) of the transform Wisrcie ob ££ '; rä3 ~ _iJ

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production of the starting material:

9 g of cis-2-phenyl-3a, 4.5> 9b-tetrahydronaphtho / 2, ld / oxazal were dissolved in a mixture of HO ml of 1 normal sulfuric acid and 40 ml of water. The solution was left to stand overnight. The crystals thereby precipitated were removed by filtration. 6 g of cis-2-amino-1-benzoyloxytetralin sulfate was obtained. If the mother liquor was left to stand overnight, an additional 1.5 S of the above-mentioned product was obtained.

The melting point of the product was 1 ^ 8 - elemental analysis as C ₁₇ H ₁₇ MO ₂ * 1/2 H ₂ SO ₁ J-1/2

CCf)

calculated: 62.75 5.89 4.30 found: 62.76 5.6l

~ ""'W Nuclear Magnetic Resonance Spectrum

? = 3.35 (doublet, J = 3.5 Hz _s D ₅ O)

j-s Kurd no absorption aor trans-Fcrn: tcc-fca

r :: l dichloromethane ", ■. ■

i.1t *: s1 ίΐ! ΐι ^: ^ ί under "'^ r ^ riric ^^ i- ^". J ".""_:;■".:; ii: .i; r ReaKT ™ cns- - ^ ifS ^ isoh. "£ .td2Sti21i.3I ^; * J '"".D" C ^r ■: ■ \ _a "''Z^''■ 1 " IC VtU].' iS Γ.ΪΓ 2 llil Εβί: ;; :: 1 _; 2 it! lthylaaGtas, Vl si ^ "'I: ^ rx: i ι: nl water. Me here; absciii-sdsnir. Crystals were

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separated by filtration and washed with ether. It was 3.25 g of cis-1-cinnamoyloxy-2-dimethylaminotetralin-HydrοChlorid obtain. The crystals were recrystallized from water and had a melting point from 100 - 105 ° C.

Elemental analysis as C ^ H ^ NOgCl 'H ₃ O:

C (Ji) H (JS) .N (Jf)

calculated: 67.10 6.97 3.73

found: 66.50 6.57 4.17

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Claims (7)

- 40 patent claims: 1. l-Benzoyloxy ~ 2-lower-alkylaminobenzocycloalkane derivatives with the formula wherein R is a hydrogen atom or a lower alkyl group, 2 "5 4 ^r ) R is a lower alkyl group, R, R and R ^ are the same or are different from each other and each is a hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, phenyl group, amino group, lower Alkylamino groupj an acylamino group or nitro group represents and η has a value of 1-3, as well as its non-toxic mineral acid salts. 2. cis -l-benzoyloxy-2-dimethylaminotetralin. 3. cis -1-benzoyloxy-2-dimethylaminoindane. 4. cis-1-Benzoyloxy-2-dimethylaminotetralin hydrochloride. 5. cis -1-Benzoyloxy-2-dimethylaminoindane hydrochloride. 6. trans -1-benzoyloxy-2-dimethylaminotetralin. 7. Use of the claims 1 to 6 mentioned Compounds as an active ingredient in the manufacture of medicaments for the treatment of the stomach and intestinal tract Human and animal, 209882/1171