DE3315467A1 - AZEPINOINDOLS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME - Google Patents

Description

- 8 - 500-5596

AZEPINOINDOLES, METHOD OF MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE

The present invention relates to azepinoindoles, their preparation and medicaments containing them.

European patent application 80 106 550.9 discloses a new class of compounds, the 1,2,3,4,5,6-hexahydro-6-phenyl-azepino [4 _s 5-b] indoles, which are used as neuroleptics, antidepressants and antiallergics can be. In this application, various 1,2,3,4,5,6-hexahydro-6-phenyl-azepino [4,5-b] indoles are explained as examples, which are in the fused benzene ring and the 6-phenyl radical as well as in 3- Position on the nitrogen and in the 2-position of the tricycle are substituted.

It has now been found that 1-alkyl-1,2,3,4,5,6-hexahydroazepino [4,5-b] indoles particularly interesting pharmacological Have effects, e.g. neuroleptic and especially antidepressant effective and well tolerated.

The present invention thus relates to 1-alkyl-1,2,3,4,5,6-hexahydro-azepino [4,5-b] indoles and their acid addition salts, hereinafter referred to as "compounds according to the invention". the Compounds according to the invention can be substituted in any desired position, for example by an unsubstituted one or substituted phenyl radical in the 6-position.

In particular, the present invention relates to compounds of formula I,

• e> ο φ α a *

a * α a ο ο ρ ö ö <* ■ β <α

ff A ϋ »ή» ς

- 9

500-5596

wherein

R, and 1 * 2 independently of one another are hydrogen, halogen with an atomic number of 9 to 35, (CJ _-4 ) alkyl, (C · ^) alkoxy, (Ci J alkylthio or trifluoromethyl, Rj ¹ and R ₂ ^{1 are} independently of one another Hydrogen halogen with an atomic number of 9 to 35 _S (C-j_ ₄ ) alkyl or (Cj ^) alkoxy,

R _{3 is} hydrogen, (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _4-3 ) cycloalkyl alkyl, (C _3-5 ) alkenyl, (C _3-5 ) alkynyl or a group of the formula Ii ₅

II

means in which

m stands for 1, 2 or 3,

X is a bond, -CHOH- or -CO-, Rr for hydrogen, halogen with an atomic number of

- 10 - 500-5596

9 to 35, (C _1-4 ) alkyl, (C _1-4 ) alkoxy or trifluoromethyl and R. (Ci ₄ ) alkyl, and their acid addition salts.

A group of compounds according to the invention consists of compounds of the formula I in which R-, and R ₂ independently of one another are hydrogen, halogen with an atomic number from 9 to ³⁵ > ( ^c i_4) alkyl, (C _1-4 ) alkoxy, (C _{1- 4} ) Alkylthio or trifluoromethyl, R ·, ¹ and Rp 'are hydrogen, R _{3 are} hydrogen or (C _1-4 ) alkyl and R _{4 are} (C _1-4 ) alkyl and their acid addition salts.

A further group of compounds of the invention consists of compounds of formula I wherein R ₁ is hydrogen, halogen having an atomic number of from 9 to 35, (C _1-4) alkyl or _(C-j-4) alkoxy, R ₁ ¹ is hydrogen or halogen , R2 is hydrogen, halogen, (C _1-4) alkyl or (C _1-4) -alkoxy, R ₂ 'is hydrogen or halogen, R ₃ is hydrogen or (C, _ ₄₎ alkyl and R ₄ is (C _1-4) AlKyI mean, and their acid addition salts.

In formula I, R- and R-, ^{1 are} preferably in position 8 or 9 of the ring system. R ₂ and R ₂ 'are preferably in position 3 or 4 of the phenyl radical. Halogen is preferably chlorine or fluorine, in particular chlorine. Alkyl, alkoxy and alkylthio preferably have 1 or 2 carbon atoms, in particular 1 carbon atom.

The compounds according to the invention contain in the! Position an asymmetric carbon atom. They therefore appear in the form of optically active isomers. The inventive Compounds and the compounds of the formula I accordingly include the optically active isomers and racemates. The optical isomers can be obtained in a manner known per se, for example by reaction with an optical active acid, such as tartaric acid, and fractionated

- η

500-5596

Crystallization of the diastereomeric salts. It is also possible to use optically active starting materials from the outset, in which case the end product is a correspondingly pure one optically active form is obtained.

The compounds of the invention are prepared by

i) for the preparation of those unsubstituted in the 3-position on the nitrogen 1-alkyl-1,2,3,4,5,6-hexahydro-azepino [4,5-b3 indoles or their acid addition salts, 4-alkyl-l, 2,3,4-tetrahydropyrido [3,4-b] indoles, whose 1-M ethyl radical is substituted by a removable group and the one in the 2-position are unsubstituted on nitrogen, or their acid addition salts are treated with a source of hydrogen ions, or

ii) for the preparation of l-alkyl-l ₉ 2,3,4 _s 5,6-hexahydro-azepinoC4 _i 5 »b] indoles substituted in the 3-position on the nitrogen or their acid addition salts, 1-alkyl-unsubstituted in the 3-position l, 2,3,4,5,6-hexahydro-azepino [4,5-b] indoles or their acid addition salts are substituted,

and the compounds obtained in the form of the free bases or isolated in the form of their acid addition salts.

In particular, compounds of the formula I can be prepared by

a) for the preparation of compounds of the formula Ia,

Yes

50Q-55S6

wherein R-pR-, ', R _23, R ₂ ¹ and R _{4 have the} above meaning, and their acid addition salts, compounds of the formula III,

in

wherein R-. , R, ', R ^, R ₂ ' and R. have the above meaning, and Y means a group which can be split off, or treats its acid addition salts with a hydrogen source, or

b) for the preparation of compounds of the formula Ib,

NO,

Ib

^ S se Λβ β <"·

_Ο {, en «ο β β ο ο O * *

tSIi »Γ. I β * "· '·

- 13 - 500-5596

where Ry, R-, ¹ , R _? , R _? 'and R' have the above meaning, and Rg ^{1 has} the meaning of Rg with the exception of hydrogen, or its acid addition salts, in compounds of the formula Ia or their acid addition salts, introduces a group R ₃ ',

and the compounds of the formula I obtained are isolated in the form of the free bases or in the form of their acid addition salts.

Process i) or a) is expediently carried out in a manner known for analog ring expansions. That The process is conveniently carried out in an inert organic solvent such as a cyclic or aliphatic solvent Ether, preferably in dioxane or tetrahydrofuran, at temperatures between 20 ° C and the boiling point of the reaction mixture, preferably at 60 ° C, carried out. X is e.g. chlorine, bromine, hydroxy or tosyloxy, preferably chlorine.

A complex hydride such as aluminum hydride, sodium borohydride or lithium aluminum hydride is expediently used as the hydrogen ion source. If one of the substituents R- ,, R, ', R _? and R _? 'stands for chlorine, the use of aluminum hydride or sodium borohydride is recommended. An acid addition salt of the compound of the formula III, for example the hydrochloride, is preferably used.

The method ii) or b) can be used in one for the substitution of secondary amines can be carried out in a known manner.

Process b) is, for example, an alkylation reaction.

As such, it can be carried out in a manner known for the alkylation of analogous secondary ring amines. The process can be carried out using, for example, alkyl halides or alkyl sulfates. If desired, can the compound of formula Ia with a corresponding

- 14 - 500-5596

Aldehyde with simultaneous reduction, e.g. catalytic Reduction or in the presence of a reducing agent, e.g. Formic acid. If necessary, the process can be carried out in two or more stages, e.g. one can compounds of formula Ia with a halocarboxylic acid ester, in particular chloro- or bromocarboxylic acid ester, for example the ethyl ester, and the urethane obtained, for example with lithium aluminum hydride in a manner known per se Way to reduce. Optionally, N-alkyl derivatives can through Reduction of corresponding N-acyl derivatives are obtained, which in a manner known per se from compounds of the formula Ia can be produced.

The compounds according to the invention can of course in a manner known per se into other compounds according to the invention be convicted.

The starting compounds of the formula III can be, for example, as follows getting produced:

500-5596

R ₂ ¹ CH ₃ NO ₂

i. or R ₄ Mg Z

LiAlH ₄ or AlH ₃ or, ^^^ ² Raney Ni / H ₂ * ^>

ClCH ₂ -CHO or BrCH ₂ -CHO

III

Z = J, Br, Cl

* if Rj, R-, ', R ₂ and R ₂ ' are not halogen

If the preparation of the starting compounds, for example the 4-alkyl-1 ₅ 2 ₅ 3 ₅ 4-tetrahydropyrido [3,4-b] indoles, which are not included in the formula III, is not described, these can be prepared analogously to known compounds or processes described here.

- 16 -. 500-5595

The compounds according to the invention can be known per se Way can be converted into their acid addition salts and vice versa. Examples of acids are hydrochloric acid, Maleic acid, fumaric acid and succinic acid are suitable.

The compounds according to the invention are distinguished by pharmacological ones Effects and can therefore be used as a remedy. In particular, they have an antidepressant effect and are therefore useful as antidepressants. This effect is shown, for example, in a test in which the cancellation the catalepsy and ptosis caused by tetrabenazine is found in rats [modified method according to Stille, Pharmaceutical Research 1_4, 534 (1964)]. The test is as follows carried out: groups of 6 rats (Sprague-Dawley descent, male and female, 120-160 g, Süddeutsche Tierfarm, Tuttlingen, Federal Republic of Germany) the test substance is administered in a dose of approx. 5 to 20 mg / kg i.p. 30 minutes before the Administration of 10 mg / kg i.p. Tetrabenazine administered. 40 minutes after Tetrabenazi η administration, catalepsy becomes each rat measured by placing the front paws on a 7 cm high wooden block. The time when the animal is in this unnatural position is measured up to a maximum of 45 seconds. Immediately after determining catalepsy the ptosis is rated on a 4-point scale. That Absence of ptosis is rated 1 and complete eye closure is rated 4. The values from the separately assessed eyes are totaled so that the maximum value of 8 is possible. Has catalepsy been observed for 30 seconds or less ;, thus the tetrabenazine-induced catalepsy was regarded as antagonized. Rats with a ptosis score of less than 3 were considered to be protected against the ptotic effects of tetrabenazine. This procedure was 60 minutes after

- 17 - 500-5596

the Tetrabenazi η administration repeatedly.

The dose to be administered for use as an antidepressant depends on the compound used and the mode of administration as well as the type of treatment. Satisfactory results are obtained with a daily dose of approx. 0.5 mg up to approx. 30 mg / kg animal body weight, conveniently administered in several partial amounts 2 to 4 times a day or in sustained release form. For larger mammals, one should be administered daily Amount displayed between approx. 25 and approx. 500 mg. The for the Oral suitable form should be about 6 to about 250 mg of the active ingredient along with suitable pharmaceutical form contain indifferent auxiliaries.

The compounds of this invention also possess a neuroleptic activity and are therefore useful as antipsychotics _s, for example, useful for the treatment of psychotic disorders such as schizophrenia. This effect is shown, for example, in the reduction in paradoxical sleep with rebound after administration of 2-20 mg / kg po of the test substance to rats in the sleep / wake cycle for 48 hours (method according to H. Kleinlogel, "EEG in Drug Research" ed. By Hermann, Gustav Fischer Verlag, Stuttgart, New York, 75-88 (1982)).

The compounds according to the invention have an affinity for H-clozapine binding sites in vitro [modified Test according to D. Hauser et al., Life Science 23_, 557 (1978)]. The test is carried out as follows:

- 18 - 500-5596

Fresh Kaib cortex was added to Tris buffer in 19-fold volumes (50 mM, pH 7.4) homogenized and centrifuged. The sediment was resuspended in 400 times the volume of Tris buffer, and used this suspension for the experiments. The composition of the batches (final volume 2 ml) was as follows:

50 mM Tris buffer pH 7.4, membranes corresponding to 4.5 mg of the original weight of the tissue, 0.65 nM H-clozapine and 1 µM imlabeled clozapine for the detection of the unspecific Binding. To determine the inhibition of the specific binding of H-clozapine, the test compounds in Concentrations of 1 nM to 10 μΜ added (5-9 different Concentrations in duplicate). After incubation at room temperature for 40 minutes it was quickly through Filtered a Whatman GF / B filter, washed the residues 2 times with 5 ml of ice-cold Tris buffer and placed in a scintillator measured.

The dose to be administered for use as a neuro-optic depends on the compound used and the mode of administration as well as the type of treatment. Satisfactory results are obtained with a daily dose of approx. 0.15 mg Appropriately administered up to approx. 50 mg / kg animal body weight in several partial amounts 2 to 4 times a day or in sustained release form. For larger mammals, one should be administered daily Amount displayed between approx. 10 and approx. 600 mg.

The form suitable for oral administration should be about 2 to about 300 mg of the active ingredient together with suitable Contains pharmaceutically inert excipients.

The compounds according to the invention can also be in the form of their pharmaceutically acceptable acid addition salts which have the same level of activity like the free bases.

ft q ϋ * ·> * i si ο Λ (* ■ ο ο β 4, A ύ 4 SD 4'O

- 19 - 500-5596

The compounds according to the invention or their salts can be administered orally in the form of tablets, granules, Capsules or dragees, or parenterally in the form of injection solutions.

In the examples below, temperatures are in degrees Celsius and are uncorrected.

The following abbreviations are used in the tables:

1) hydrochloride

2) decomposition

3) hydrogen fumarate

4) free base

* * · «Ι * tf

- ²⁰ - 500-5596

Example 1 :! ^, S ^ S ^

[ 4,5-b] indole [method i) or a)]

To a suspension of 14.1 g of lithium aluminum hydride in 140 ml Tetrahydrofuran is added dropwise to a cold solution of 9.9 ml of sulfuric acid monohydrate in 100 ml of tetrahydrofuran at 0 °. After 15 Stirring at 0 ° for minutes, the mixture is heated to 70 ° and 21.4 g of l-chloromethyl-l ^ S ^ -tetrahydro - ^ - methyl-g-phenylpyrido [3,4-b] indole hydrochloride entered in portions. The mixture is then heated to 70 ° for a further 2 hours, then cooled to 0 ° and treated dropwise with 50 ml of a saturated sodium sulfate solution. Then you give 25 ml of a 30% strength sodium hydroxide solution and the mixture is stirred for 1 1/2 hours at 35 °. It is then filtered off, the filtrate concentrated and the oily residue chromatographed on silica gel. Eluent: methylene chloride / ethanol / conc. Anmoniak in the ratio 95 / 4.5 / 0.5. The 1,2,3,4,5,6-hexahydro-l-methyl-6-phenylazepino [4,5-b] indole purified in this way is converted into hydrogen fumarate. Mp. 196-197 ° (from ethanol).

The 1-chloromethyl-1,2,3,4-tetrahydro-4-methyl-9-phenylpyrido [3 ₅ 4-b] indole used as the starting compound can be obtained, for example, as follows:
^a ) 3: {1; Ni

To a suspension of 76.2 g of copper I-iodide in 250 ml Diethyl ether is added dropwise at 0 ° 500 ml of a 5% ethereal Solution of methyllithium and then the mixture is stirred for 1 hour at the same temperature. Dripping on it a solution of 42.3 g of 3- (2-nitro ether, yl ^ -l-p? ienylindb1 in 500 ml of tetrahydrofuran at 0 ° and the mixture is stirred for a further 1 1/2 hours. Then the reaction mixture poured onto a mixture of ice and ammonium chloride and

»OC * · β A ft Ofr ft IS

ο α ο Λοβό οο ο

9 a ο a ο ο e β ο ο ο, ο ο 6

- 21 - 500-5596

extracted with ethyl acetate. After filtering the organic phase through Hyflo and drying over sodium sulfate, is added Completely concentrated under reduced pressure and the residue is chromatographed on silica with toluene. You get so 3- (l-Nitro-2-propyl) -l-phenylindole as a light yellow oil.

A cold solution of 7.7 ml of sulfuric acid monohydrate in 77 ml of tetrahydrofuran is added dropwise at 0 ° to a suspension of 22 g of lithium aluminum hydride in 220 ml of tetrahydrofuran. The mixture is then heated to reflux in an oil bath at 70 ° and a solution of 26.9 g of 3- (l-nitro-2-propyl) -l-phenylindole in 135 ml of tetrahydrofuran is added dropwise. After 4 1/2 hours, the mixture is cooled to 0 ° and the reaction mixture is decomposed with 38.5 ml of a saturated sodium sulfate solution. After adding 19 ml of 30% sodium hydroxide solution, the mixture is stirred for a further 30 minutes at 35 °, filtered off and the filtrate is concentrated. The oily residue, the 3- (l-amino-2-propyl) -l-phenylindole _s , is then converted into the hydrochloride. Mp. 213-215 ° (from ethanol / ether).

20.3 g of 3- (l-amino-2-propyl) -l-phenylindole hydrochloride are heated in 200 ml of water and 70 ml of 2N hydrochloric acid in an oil bath at 110 °, and 18 ml of a 50% chloroacetaldehyde solution are added. After 30 minutes, another 4.5 ml are added and the mixture is heated for a further 15 minutes. The reaction mixture is then cooled to room temperature, the hydrochloride of 1-Chl rmethyl-1 ₃ 2,3,4-tetrahydro-4-methyl-9-phenylpyHc ^! cT ?. ₅ 4-b] i ^ dol precipitates in crystalline form. Mp. 225-228 ° from ethanol / ether.

* Ψ m

* mm η

. 22nd

500-5596

Example 2: 1,2,3,4,5,6-Hexahydro-1,3-dimethyl-6-phenylazepino [4,5-b3indole [method ü) o ^der b)]

To a suspension of 3.65 g of lithium aluminum hydride in 36.5 ml of tetrahydrofuran are added dropwise at 0 ° to -10 ° a cold solution of 2.56 ml of sulfuric acid monohydrate in 25.6 ml of tetrahydrofuran. A solution of 5.58 g of 3-ethoxycarbonyl-1,2,3,4,55 is then added dropwise 6-hexahydro-1-methyl-6-phenylazepino [4,5-b] indole dissolved in 20 ml of tetrahydrofuran. After 30 minutes will be with cooling 13 ml of a saturated sodium sulfate solution and 6.4 ml of a 30% sodium hydroxide solution were added dropwise and the mixture Stirred for 15 minutes at 35 °. It is then filtered off and with Concentrated completely under reduced pressure, whereby the compound named in the title is obtained. M.p. of hydrogen fumarate 195-197 ° (from ethanol). M.p. of the hydrochloride 274-276 °.

The 3-ethoxycarbonyl-l, 2,3,4, used as starting material, 5,6-hexahydro-1-methyl-6-phenylazepino [4,5-b] indole can e.g. can be produced as follows:

A mixture of 4.5 g of 1,2,3,4,5,6-hexahydro-1-metf \ y1-6-phenylazepino [4,5-b] indole and 3.1 ml of ethyl chloroformate in 45 ml of methylene chloride and 15 ml of water is stirred vigorously for 10 minutes. A solution of 1.3 g is then added Add caustic soda in 26 ml of water and stir the mixture for a further 10 minutes. The organic phase is then separated off, twice with a 5% tartaric acid solution, then with water washed j dried and concentrated, the 3-ethoxycarbonyl-1,2,3,4,5,6-hexahydro-1-methyl-6-phenylazepino [4,5-b] indole obtained, which is used without further purification.

3 3 1 b 4 6 V.

0 Φ <ϊ ο $ & © ο «

οο α σ ö * 4 - 'ο Q β ο ©

ΐϊϋ 3 ft O OQ

- 23 -

500-5596

Example 3 ; 1,2,3,4,5,6-Hexahydro-l, S-dimethyl-S-phenylazepino [4,5-b] indole [method ii) or b)]

55.3 g l, 2,3,4,5,6 ~ hexahydro-l-methyl-6-phenylazepino [4,5-b] indole are dissolved in 553 ml of warm ethanol, with 10 g of Raney Nickel and 18 g formaldehyde solution (35%) were added. The reaction mixture is hydrogenated under normal conditions for 2-4 hours. The catalyst is filtered off and the filtrate occurred evaporated. The residue is dissolved in diethyl ether, washed with saturated sodium chloride solution, the ether phase separated, dried and evaporated. The oily residue is dissolved in three times the volume of acetonitrile, seeded and cooled in an ice bath, the title compound having a melting point of 89 ° -92 °.

142 g of the base are dissolved in 750 ml of hot ethanol, in Chilled in an ice bath and shaking with 180 ml of ethanol HCl (3N) added. The hydrochloride precipitates out by inoculation and cooling. The salt is washed with ether and dried and recrystallized from 700 ml of boiling ethanol, melting point 274-276 °.

The starting compound is described as in Example 1, manufactured . Instead of stages la) and Ib), the following can be used proceed:

A Grignard reagent is prepared from 36 g of magnesium turnings, 750 ml of diethyl ether and 212.9 g of methyl iodide. After this Dilute with 1500 ml of toluene and cool to -60 ° in acetone / Dry ice bath is a solution of 132 g of 3- (2-nitroäthenyl) -1-phenylindole in 924 ml of tetrahydrofuran with stirring so added dropwise so that the temperature is between -50 ° and -60 °

- 24 - 500-5596

can be holder. The cooling bath is removed and the mixture is stirred for 30 minutes. The temperature rises to -40 °. The reaction mixture is between 1 kg of ammonium chloride, 5 liters Water and 3 l of ethyl acetate distributed. The organic phase is washed with water, dried and evaporated, the Ti te! compound being obtained as an oil. The crude oil becomes an Chromatographed silica gel with toluene / hexane (2: 1).

55 g of 3- (l-nitro-2-propyl) -l-phenylindole are warm in 550 ml Dissolved ethanol, mixed with 5.5 g of Raney nickel and at 60 ° and hydrogenated at 110 bar for 6-8 hours. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in 100 ml of ethanol, with ethanolic HCl (4N) acidified, cooled in an ice bath, mixed with ether and inoculated, whereby the hydrochloride of the title compound obtained from m.p. 210-213 °.

I α Ο

YY I

JJ

ο β e σ a au α

- 25 -

500-5596

Example 4 :

The following compounds of the formula I, in which R ₁ and R 2 "are hydrogen, are prepared

at
game ^R l R ₂ ^R 3 ^R 4 M.p. Analogue
example a
b
C.
d H
H
9-F
9-Cl H
H
4-F
4-F CH ₃
C ₂ H ₅
CH ₃
CH ₃ C ₂ H ₅
CH ₃
CH ₃
CH ₃ 254-256 ¹ ^
232-23? ¹ ^
285 ¹ ^ ² ^
273-280 ¹ ^ 3
with C ₉ HrBr
alkylfert
2
2 e H H H C ₂ H ₅ 209-212 ¹ ^ ¹ f 8-Cl 3-Cl H CH ₃ 182-187 ³ ^ 1 9 8-Cl 3-Cl CH ₃ CH ₃ 168-170 ³ ^ 2 H H 4-F H CH ₃ 193-198 ³ ^ 1 a H 4-F CH ₃ CH ₃ 283-283 ¹ ^ 2 O H 4-Cl H CH ₃ 250 ¹ ^ ² ^ 1 k H 4-Cl CH ₃ CH ₃ 264-271 ¹ ^ 2 1 H 3-Cl H CH ₃ 164-167 ³ ) 1 m H 3-Cl CH ₃ CH ₃ 254-259 ¹ ^ 2 η
O H
H 4-CH ₃
4-CH ₃ H
CH ₃ CO OO
rc rc
CJ O 200-205 ³ ^
264-274 ^] ) 1
■] ■ P. H 3-CH ₃ H CH ₃ 164-170 ³ ^ 1 q H 3-CH ₃ CH ₃ CH ₃ 254-260 ¹ ^ 2 r 9-Cl 4-F H CH ₃ 220-235 ³ ^ 1 S. 8-CH ₃ H H CH ₃ 23 ^ -240 ³⁾ 1 t 8-CH ₃ H CH ₃ CH ₃ 145-147 ⁴ ^ 2 dd 9-F 4-F H CH ₃ 149-159 ¹ ^ 1

500-5596

At- ι
game ^R l R ₂ ^R 3 R ₄ M.p. Analogue
example U 8-F H H CH ₃ 182-187 ³ ) 1 ν 8-F H CH ₃ CH ₃ 282-292 ¹ ^ ² ) 2 X 9-CH ₃ 4-CH ₃ H CH ₃ 209-214 ³ ) 1 y 9-CH ₃ 4-CH ₃ CH ₃ CH ₃ 130-132 ⁴ ^ 2 ζ 9-CH ₃ H H CH ₃ 133-138 ³ ) 1 rh 9-CH ₃ H CH ₃ CH ₃ 289-293 ¹ ^ 2 ri 9-F H H CH ₃ 182-187 ³ ^ 1 rJ 9-F H CH ₃ CH ₃ 273-277 ¹ ^ 2 rk 9-Cl H H CH ₃ 135-140 ³ ^ 1 rl 9-Cl K CH ₃ CH ₃ 258-278 ¹ ^ ² ^ 2 rm 8-Cl H H CH ₃ 186-188 ² ) 1 rri 8-Cl H CH ₃ CH ₃ 198-200 ⁴ ) 2 ro 9-Cl • 4-Cl H CH ₃ 231-233 ³ ) 1 rp 9-Cl 4-Cl CH ₃ CH ₃ 150-151 ⁴ ^ 2 rs 9-Cl 3-Cl H CH ₃ . 215-228 ³ ) 1 rt 9-Cl 3-Cl CH ₃ CH ₃ 260-270 ¹ ^ ² ^ 2 ru 8-Cl 4-Cl H CH ₃ 223-224 ³ ^ 1 rv 8-Cl 4-Cl CH ₃ CH ₃ 153-155 ⁴ ) 2 rx H 4-OCH ₃ H CH ₃ 213-215 ³ ^ 1 ry H 4-OCH ₃ CH ₃ CH ₃ 132-134 ⁴ ^ 2 rt 9-0CH ₃ H H CH ₃ 208-210 ' 1 ru 9-0CH ₃ H CH, CH _{3 27O} 1) 2) 2 UV H 2-Cl H CH ₃ 190-192 ³ ^ 1 UX H 2-Cl CH ₃ CH ₃ 28O ¹ ) 2

ti Qa -ö. *) a t O Q 0 ) B ti tt £ 3 0 op- O ο y If *

43/1 ö ^ b V

"27-500-5596

Example 5 : (-) - 1,2,3,4,5,6-hexahydro- 1,3-dimethyl-6-phenylaezepino [4,5-b] indole

A solution of 71.27 g (+) is added to 55 g of 2,3,4,5,6-hexahydro-1,3-dimethyl-6-phenyl-azepino [4,5-b] indole in 400 ml of ethanol -Dibenzoyl-D-tartaric acid given in 425 ml of ethanol. After stirring for 3 hours at room temperature, the crystalline precipitate is filtered off and washed with diethyl ether. For recrystallization, the salt is dissolved in a hot mixture of methanol and methylene chloride and the methylene chloride is then distilled off. After three recrystallization, the (+) dibenzoyl-D-tartrate of the title ^{compound is obtained, melting point 150 °, [a] [j u} + 50 ° ₅ c = 1 (ethanol).

The methanolic mother liquors are used for isolation of (+) - !, 2,3,4,5,6-hexahydro-l, S-dimethyl-S-phenylazepino [4,5-b] indole (Example 6) was used.

For further purification, the salt is converted into the base by partitioning it between ether and aqueous ammonia. 10 g of base and 5.17 g of (+) L-tartaric acid are dissolved in 250 ml of ethanol. After standing for 24 hours, the (+) L -Tartrate filtered off, m.p. 179-182 °, [a] £ ^u - "9.4, c = 1 (methanol). The salt is dissolved in a hot mixture of methanol / methylene chloride, 60 times the volume of isopropanol is added and the methylene chloride is distilled off. It is recrystallized until it rotates constantly. (+) L-tartrate of the title compound m.p. 185-186 °, [a] ^ -24.1 °, c = 1 (methanol). The salt is converted into the base by partitioning it between ether and ammonia, which with ethanolic HCl the hydrochloride of the Ti! compound results, m.p. 244 ° _s Γ _α ] ^ ° --45.8 °, c = 1 (ethanol).

- 28 - 500-5596

Example 6 : (+) - !, 2,3,4,5,6-Hexahydro-1,3-dimethyl-6-phenylazepino [4,5-b] indole

The methanolic mother liquors of Example 5 are between Diethyl ether and aqueous ammonia distributed. The ether phase is dried over sodium sulfate and the solvent evaporates. 30 g of the base are mixed with 38.87 g of (-) - dibenzoyl-L-tartaric acid added in 600 ml of methanol. The salt obtained is, as described in Example 5, recrystallized twice. Man receives the (-) - dibenzoyl-l-tartrate of the title compound, m.p. 150.5-151 °, [a] p -48.6 °, c = 1 (ethanol).

A further purification is carried out as described in Example 5 using (-) D-tartaric acid. After recrystallization according to the above process up to constant rotation, the (-) D-tartrate of the title compound is obtained, m.p. 185-186 °,

Often O

[oup + 24.0 °, c = 1 (methanol). The salt will be like in the case

game 5 described converted into the hydrochloride, m.p.

? n °
241-242 °, [α] ρ + 45.8 °, c = 1 (ethanol).

Be ispiel 7:

The following compounds of the formula I ^R l H D I
^R l R ₂ R ₂ ' ^R 3 are produced: M.p. analog
example at
game H H 3-C1 4-Cl H R ₄ 130-1354) 1 a 8-Cl H 3-Cl 4-Cl CH ₃ CH ₃ 254-255 ¹ ) 2 b 8-Cl 9-Cl H H K CH ₃ 203-205 ³ ) 1 C. 9-Cl H H CH ₃ CH ₃ 272-275 ¹ ^ 2 d CH ₃

Claims (13)

ο ο ο β Ο Ο ι? * C CJ β -S SANDOZ-PATENT-GMBH 500-5596 Loerrach patent claims 1.J l-Alkyl-1 _s 2,3,4,5,6-hexahydroazepino [4,5-b3indoles and their acid addition salts. 2. Compounds of the formula I ₅ - 2 - 500-5596 wherein R ·, and R ~ independently of one another are hydrogen, halogen with an atomic number from 9 to 35, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (Cn λ) alkylthio or trifluoromethyl, R ·, ¹ and R ₂ 'independently represent hydrogen, halogen with an atomic number from 9 to 35, (CJ _-4 ) alkyl or (C ^ _-4 ) alkoxy, R _{3 is} hydrogen, (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _4-9 ) cycloalkylalkyl, (C _3-5 ) alkenyl, (C _3-5 ) alkynyl or a group of the formula II, means in which m stands for 1, 2 or 3, X is a bond, -CHOH- or -CO-, R ₅ - is hydrogen, halogen with an atomic number of ⁹ to 35, (C _1-4 ) alkyl, (C _1-4 ) alkoxy or Trifluonnethyl and ^R 4 are C ^c i_4> alkyl, and their acid addition salts. '- 3 - ■ 500-5596 3. Compounds of the formula I in which R ₁ and R 2 independently of one another are hydrogen, halogen with an atomic number of 9 to ³⁵ > ( ^c i_4) alkyl, (C _1-4 ) alkoxy, (C _1-4 ) alkylthio or trifluoromethyl, ^R ₁ ¹ and R ₂ ¹ is hydrogen, R ₃ is hydrogen or ⁽⁰ IV ^{Alk y], and R} 4 i ^C l-4 ^ ^{alkyl and INRs} acid addition salts. 4. Compounds of the formula I ₃ in which R _{1 is} hydrogen, halogen having an atomic number of from 9 to 35, (C _1-4) alkyl or (C ₁ ") alkoxy, R ₁ ¹ is hydrogen or halogen, R ₂ is hydrogen, halogen, (C ₁ _ ₄₎ Alky1 or (C _1-4) AIk ₀ Xy, R ₂ 'is hydrogen or halogen,' R _{3 is} hydrogen or (C _1-4 ) alkyl and R _{4 is} (C _M ) alkyl, and their acid addition salts. 5. 1,2,3,4,5,6-hexahydro-1,3-dimethyl-6-phenylazepino [4,5-b] indole in the form of the free base or in the form of its acid IS addition salt. 6. A process for the preparation of compounds according to claim 1, characterized in that one i) for the production of in 3-position on the nitrogen unsubstituted tuierten l-alkyl-l, 2,3,4 * 5,6-hexahydro-azepino [4,5-b] ■ indoles or their acid addition salts, 4-alkyl-l, 2,3,4- tetrahydropyrido [3,4-b] indoles, the 1-M ethyl radical of which is substituted by a removable group and which are unsubstituted in the 2-position on the nitrogen, or their acid addition salts ₅ treated with a hydrogen source , or> ü) for the production of substi in the 3-position on the nitrogen tuted 1-alkyl-1,2.3 _s 4,5,6-hexahydrc-azepino [4,5-b] indoles or their acid addition salts, 1-alkyl-1,2,3,4,5 unsubstituted in the 3-position , 5-hex.ahydro-azepino [4,5-b] indoles or their acid addition salts, and the compounds obtained are isolated in the form of the free bases or in the form of their acid addition salts. 500-5596 7. Process for the preparation of compounds of the formula I according to claim 2, characterized in that one a) for the preparation of compounds of the formula Ia ₅ Yes wherein R ,, R, ¹ , Rp, R 'and R- have the above meaning and their acid addition salts, compounds of the formula III, III in which Rj, R-j ', R2, Ro ¹ and R ^ have the above meaning, and Y denotes a removable group, or treats its acid addition salts with a hydrogen source, or O «Ϊ O £ ώ ft Q 500-5596 b) for the preparation of compounds of the formula Ib, Wherein R ₁ , R-j ', R _2> R ₂ ' and R ^ have the above meaning, and Rg 'has the meaning of R ^ with the exception of hydrogen, or their acid addition salts, in compounds of the formula Ia or their acid addition salts, a Group R- / introduces, and the compounds obtained from formula I are isolated in the form of the free bases or in the form of their acid addition salts. 8. Medicinal products, characterized by a content of compounds according to claim 1 or their pharmaceutically usable Acid addition salts. 500-5596 9. Use of compounds according to claim 1 in free Form or in the form of their pharmaceutically acceptable acid addition salts for the treatment of depression and Schizophrenia. 10. 4-Alkyl-1,2,3,4-tetrahydropyrido [3,4-b] indoles, their 1-methyl radical substituted by a removable group and which is unsubstituted in the 2-position on the nitrogen and their acid addition salts. 11. Compounds of the formula III, III wherein R- ,, R, ¹ , Rp, R ₂ 'and R, have the meaning given in claim 2, and Y is a removable group and its acid addition salts. O · DO β 0 ft ft O O ■ a o b O fl * 500-5596 12. Compounds of the formula wherein Rp, Rj ¹ , R ₂ , R ₂ ¹ and R _{4 have} the meaning given in claim 2, and their acid addition salts. 13. Compounds of the formula wherein Rj, R-j ', R ₂ , R ₂ ' and R _{4 have} the meaning given in claim 2, and their acid addition salts.