DE2339715A1 - N-substd. 1-amino-3-phenyl-indane derivs. - useful as tranquillisers - Google Patents

Abstract

Phenylindanes of formula (I) and their acid addn. salts are new: (where each R1 and R2 is H, halogen, 1-4C alkyl, OH,acyloxy, 1-4C alkoxy or phenyl-1-4C alkoxy, or 2 neighbouring R1 or R2 gps. can form a fused 5- to 7-membered ring; R3 is H, 1-4C alkyl, phenyl-1-4C-alkyl or hydroxy-alkyl; R4 is H, 1-4C alkyl or phenyl-1-4C-alkyl; R5 is H, 1-4C alkyl, benzyl or phenyl; R6 is (a) a mono- or bi-cyclic aromatic gp. opt. substd. by prim., sec. or tert. amino, phenoxy, 1-2C alkylenedioxy or R7R8NR9O, where R9 is lower alkylene and R7 and R8 are alkyl or NR7R8 is a satd. 5- or 6-membered ring opt. another N or O heteroatom, (b) a mono- or bi-cyclic aromatic gp. opt. substd. by 1-3 OH and/or lower alkoxy gps., (c) a monocyclic 6-membered heteroaromatic gp. with 1 or 2 N atoms, opt. substd. by lower alkyl, or (d) a bicyclic heteroaromatic gp. with 1N atom, opt. substd. by lower alkyl). Cpds. (I) are useful as tranquilisers, e. g., in doses of 5-15 mg./kg. i.p. (mouse).

Description

FARBWERKE HOECHST AKTIENGESELLSCHAFT

formerly Master Lvicius & Brüning <y ο OQ "7 λ ς

File number: fff HOE 73 / P 227

Dr.HG / ka

Date: August 2, 1973

Basically substituted phenylindanes and processes for their Manufacturing

It is known that phenylindanes with a low molecular weight substituted amine residue can have spasmolytic, analgesic and coronary dilatory effects (cf. CR Ganellin in
Advances Drug Res. 4_ (1967) pp 175-180).

The invention relates to basic substituted phenylindanes of the general formula I

R,

wherein R ₁ and R ^ are hydrogen, halogen, alkyl with 1-4 C atoms, hydroxy, acyloxy, alkyloxy with 1-4 C atoms, phenalkoxy with 1-4 C atoms in the alkylene part
where R ₁ and R "can be the same or different and 2 adjacent substituents can also be members of a fused 5-7 membered ring, R" hydrogen,
Alkyl with 1-4 carbon atoms, phenylalkyl with 1-4 alkylene carbon atoms or hydroxyalkyl, R. hydrogen, alkyl with 1-4 carbon atoms,
Phenylalkyl with 1-4 C atoms in the alkylene part, R _{5 is} hydrogen, alkyl with 1-4 C atoms, benzyl or phenyl and R _{6 is an} aunono- or bicyclic aromatic radical, which may be replaced by one to at most 3 hydroxyl groups or lower alkoxy groups, it being possible for these groups to be identical or different, substituted, or by a primary, secondary or tertiary
Amino group, a phenoxy group, an alkylenedioxy group with

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1-2 carbon atoms, or a lower dialkylaminoalkoxy group, where in the latter the two alkyl radicals together with the nitrogen atom also for a saturated, 5- to 6-membered one Ring, which may contain another nitrogen or oxygen atom, or a monocyclic, 6-membered heteroaromatic radical which contains one or two N atoms and optionally through lower alkyl groups is substituted, or a bicyclic heteroaromatic radical which contains an N atom and optionally by is substituted lower alkyl groups, as well as their salts with physiologically acceptable acids.

The invention furthermore relates to processes for the preparation of the compounds of the general formula I according to processes known per se by which compounds of this constitution can be prepared in a customary manner. This includes, for example, all procedures in which

.R. ri

the basic residue Ir GH ~ - ^ _P 5 in a suitable preliminary stage

the formula

introduced or in which the substituents R ₁ fo-is R ^ are introduced into the phenyl rings or the basic radical or are formed from suitable precursors by reactions known per se.

Furthermore, for the preparation of those compounds of the general formula I ₁ in which Rg is a heterocyclic radical, those processes are suitable in which the heterocyclic ring is formed in the last reaction stage from suitable precursors in a manner known per se.

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As further procedures for making the compounds of the general formula I, the methods detailed below come into consideration, but also others here Methods that are not individually listed fall within the scope of the present Ex-invention and are therefore subject to the scope of protection of the patent.

Details of the general methods mentioned above can, for example, the compounds according to the invention be made by one

a) Ketones of the general formula II

with an amine of the formula III

T * -

HN-CH

respectively.

b) an amine of the formula IV

R ₁ .

A-NH

where A is the remainder

(H)

(in) (IV)

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means with a carbonyl compound of the formula V.

^R 6

implemented and then reduced or "at the same time or

cj a compound of the formula VI -

A-X '(Vl)

wherein X is halogen or a sulfonyloxy radical, reacts with an amine of the formula III or

d) an amine of the formula IV with a compound of the formula VII

X-CH. (VIl)

implements or

e) an amide of the formula VIII

ANCR ₅ (VIII)

I! ο

! • reduced or

f) a compound of the formula IX

N-CH (IX)

^R 6

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in the presence of Lewis acids with a possibly through a or 2 radicals R converts substituted benzene or

g) compounds of the formulas X or XI

A-N-C or A-N-CH-R, -

| \ ι

Yo- ι 5

(X) "(χι)

wherein Y is a group which can be removed by reduction, such as halogen or hydroxy and R_ 'is alkyl having 1-3 C atoms or Phenyl mean, reduced or

h) a compound of the formula XII

Ri ₁ n _A
A - N - CH - CO - R (XU)

reduced or
i) a Schiff base of the formula XIII a or XIII b

A - N = CH - R (XIII a)

respectively.

A - N = CH - R ₆ (XIII b)

with organometallic compounds

R ₆ (or R.) - Mg - Hai converts, or

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j) in a compound of the formula XIV

(XIV)

in which X ^{1 is} OH, halogen or a sulfonyloxy radical, under acidic catalysis or in the manner of Williamson's ether synthesis, the N group is a 5- or 6-membered

^v -χι
rigen oxygen-containing "ring closes or

k) a compound of the formula XV

A-N-CII

where Z is a substituent suitable for nucleophilic exchange, including a 5- or 6-membered ring containing 2N atoms or reacts with a primary amine

l) compounds of the formulas XVI and XVII

N ~ x or A-N-CH

(XVI) (XVII)

where W is oxygen _t NH or substituted N, cyclized to a 5- or 6-membered ring or

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-Y-

) a compound of the formula XVIII

A-N-CH

N - ⁰ (XVIIl)

reduced or

n) a compound of the formula IXX

I ¹ * χ- 5

AN - CH, _k ^ NH,

mil: *> iier compound of the formula XX

(IXX)

'Z

(XX)

implements or

o) Compounds of the general formulas XXI - XXIII

respectively.

/ ^R 5 AN-CH, 2T

respectively.

- CH - R.

(XXII)

A-N = C

(XXIII)

wherein ty denotes nitro-, nitroso- or -NHOH, reduced

^odcr 509809/1224

ρ) into a compound of the formula XXIV

VT (1.2)

where T is NH, halogen, hydroxyl or alkoxy groups are introduced by diazotization and elimination of nitrogen or

q) from a compound of the formula XXIV in which T is halogen means that the halogen splits off or reductively

r) a double bond present in the 5-membered ring of the indane system hydrogenated

and optionally compounds of the general formula I in which R ₁ , R "and / or substituents of the radical R are alkoxy groups, treated with ether-splitting agents, or compounds of the formula I in which R ₁ , R" are hydroxyl and substituents of the radical R , Hydroxy or NH_ or HN alkyl mean treated with alkylating agents and, if necessary, the basic compounds obtained are converted into their salts by treatment with physiologically acceptable acids.

The radicals R ₁ and R ₉ are preferably hydrogen. Other preferred substituents are halogen, chlorine or bromine, alkyl, methyl, ethyl, propyl, isopropyl or butyl, or the hydroxy group or methoxy, ethoxy, propoxy, isopropoxy or butoxy-, benzyloxy- ^ phenethoxy groups. If R and R are B, there are possibilities of variation in the acyl part within wide limits. Preference is given to aliphatic alkanoyl radicals such as the radicals of acetic acid, propionic acid, butyric acid or cyclohexanecarboxylic acid, but it can also be advantageous

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be liable to use aromatic carboxylic acid residues such as for example benzoyl, ortho-, metha or para-methoxybenzoyl, para-chlorobenzoyl or toluyl.

As the position of the radicals R ₁ and R_ positions come k in particular for R _1, 5 and 6, for _R? positions 3 ¹ and k * are considered.

The radicals R_ and Rk are preferably hydrogen. if R "means alkyl, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl or sec-butyl are possible. Hydroxyalkyl group for R is, for example, the hydroxyethyl group called.

The radical R_ preferably represents hydrogen. As alkyl radicals methyl, ethyl, propyl, butyl come into consideration.

The aromatic or heteroaromatic radical Ry- can be varied within wide limits without the pharmacological effect of the products being significantly impaired. Mono- or bicyclic aromatic radicals such as phenyl or naphthyl are suitable. Examples of heteroaromatic radicals are pyridyl, quinolyl or indolyl.

The phenyl radical can be substituted in many ways.

The following may be mentioned as possible substituents: amino, monoalkylamino or dialkylamino such as, for example Mono- or dimethyl-, ethyl-, propyl-, isopropyl- or butylamino, Piperidino, morpholino, hydroxy, alkoxy such as methoxy, ethoxy, propoxy or butoxy, methylenedioxy and ethylenedioxy. In the alkyl part of the alkoxy radicals, tertiary amino groups can be substituted, the distance between Oxygen and nitrogen atoms are preferably 2 carbon atoms; the substituents on the nitrogen atom of this tertiary amino group can be methyl or ethyl; also can the tertiary

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Amino group be part of a ring such as piperidine, piperazine or morpholine.

The preferred processes according to a) and b) for the preparation of the compounds according to the invention from a ketone of the formula II and an amine of the formula III or an amine of Formula IV and a carbonyl compound of the formula V can be carried out either in one or in two stages:

In the first case, the reaction conditions correspond to those of a catalytic hydrogenation, the conditions being those of correspond to the second stage of the two-stage process given below.

In the second case one condenses in an indifferent one, with Water-immiscible solvents such as benzene, toluene or xylene add the specified components to Schiff's base or to the enamine. Appropriate reaction temperatures are the boiling temperatures of the solvents used. Of the The progress of the reaction is usually indicated by the amount of water separated on the water separator.

In the second stage, the Schiff base or the enamine is hydrogenated catalytically or by means of complex metal hydrides.

Palladium is preferably used as the catalyst. The reaction conditions are for example 100 at hydrogen, 50 C, 10 hours reaction time; Solvents can be used for Example methanol or ethanol. The reaction temperatures can be between room temperature and 100.degree. Will If complex metal hydrides are used, sodium borohydride is in lower alcohols such as methanol at room temperature advantageous.

The ketones of the formula II to be used as starting material for procedure a) can be used in a known manner, for example by reacting corresponding benzene derivatives with

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speaking citric acids or by cyclization of corresponding β, β-diphenylpropionic acids or their acid halogens in the presence of dehydrating agents or Lewis acids such as anhydrous aluminum trichloride, sulfuric acid or polyphosphoric acid (cf. J. Amer. Chem. Soc. 6 £, 59 (1 ^qZ O); Amer. Chem. J. 21 » ^6Zf 9 Ο9θ4); Amer. Chem. J. kh_, 6h (1910); Ann. 563 (19 ^ 9), 73; J. Chem. ^Soc · '95 ^ ₁ 2928; Zh. Obshch. Climate ^ i » 3hih (1964).

The amines of the formula IV to be used as starting material for process b) can be obtained in a known manner from the ketones of the formula II by reductive amination or by reducing their oximes (cf. J. chem. Soc. 1956 , 2928).

In the preferred expiry modes according to a) and b) it can It may be advantageous to first choose compounds of the formulas III and IV in which R 1 is hydrogen, and optionally the radical Rr subsequently by alkylation in a known manner Way to introduce.

According to procedure c) and d), the implementation of the compounds of formula VI or VII with an amine of formula III or IV in an inert solvent such as benzene, Toluene, xylene, dioxane or dimethylformamide take place, optionally with the addition of a basic auxiliary substance that neutralizes the acid formed during the reaction is suitable, such as alkali or alkaline earth carbonate or tertiary organic amines. As an acid acceptor a corresponding excess of the amines III or IV can also function. In some cases, the reaction product itself serve as an acceptor; one isolates the corresponding one directly Salt of the desired compound I.

The compounds of formula VI and VII are essentially Chlorides or bromides are possible, but corresponding sulfoic acid esters, in particular mesyl and tosyl esters, can also be used will.

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The compounds of the formula VI to be used are obtained by known processes, for example by reducing ketones of the formula II to the corresponding alcohols and this then into the corresponding hydrohalic acid or sulfonic acid ester transferred. Appropriate reagents these include, for example, thionyl chloride, thionyl bromide, phosphorus trichloride or mesyl or tosyl chloride (cf. DBP 912 093).

The amides are reduced by procedure e) of formula VIII "for example with complex metal hydrides, optionally in the presence of a Lewis acid, preferably with lithium aluminum hydride. The amides of Foiroel VIII are obtained, for example by reacting an amine of the formula IV with a carboxylic acid chloride of the formula R ^ COCl in known per se Way. According to method f), a compound of the formula IX is prepared in the manner of a Friedel-Crafts acylation with corresponding Benzene derivatives in the presence of Lewis acids, for example aluminum trichloride, reacted.

The compounds of the formula IX are obtained by, for example an unsaturated halogen compound of the formula XXV

-Shark

(XXV)

(Hai is preferably Br) with an Atnin of the formula III converts and adheres to the reaction conditions described above for procedure c) and d).

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According to procedure g) the compounds of formula X or XI hydrogenated, for example, with the catalysts suitable for removing the Y radicals. Here it can be advantageous to use two-stage process, the first stage of which is to convert the compounds of the formula X or XI into derivatives convert, which facilitate splitting off of Y in the hydrogenation. Such derivatives are, for example, oxazolidones formula XXVI below

(XXVI)

This process gives compounds of the formula I in which R_ is only alkyl with 1-h carbon atoms or benzyl. The reduction of the compounds of the formula XII by process h) can be carried out in the ways customary for carbonyl compounds, in particular 1,3-aminoketones, for example with hydrazine according to the Wolff-Kishner reaction.

According to method i), organometallic compounds which carry the radical R_ or R ^ are used. In particular, organomagnesium compounds are considered which can be reacted in the manner of a Grignard reaction with the exclusion of moisture. You can use the usual solvents, for example ethers and aromatic hydrocarbons such as benzene or mixtures of these solvents. The Schiff bases used as reactants can be obtained, for example, by condensing amines of the formula A-NH ₂ with aldehydes of the formula R_COH or R ^ -COH.

5 6

The ring closure reaction according to procedure j) can be ^{catalyzed in the case of X 1} = hydroxy acid, for example using hydrohalic acids such as hydrobromic acid or a solution of hydrogen bromide in glacial acetic acid

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will. In the event that X »= halogen or sulfonyloxy, can be a base catalysis, for example with alkali or alkaline earth coliolate, in the manner of a Williamson Ätliersynthesis, be advantageous.

The ring closure reactions according to method k), l) and n) can can be carried out in principle analogously to procedures c) and d).

After decay in), the amide-like ones are reduced Grouping in the lactam ring of the compound of the formula XVIII in principle analogous to process e).

Compounds of the formula XVIII which contain such a lactam ring, for example from aminocarboxylic acid esters, can be used of the formula XXVIIE, which can be condensed in a known manner according to Dieckmann to give compounds of the formula XXIX.

A-N A -

- CH ₂ - COOR (XXVIII)

- COOR

(XXIX)

These esters can be saponified by known processes and the resulting carboxylic acids are decarboxylated to the compounds of formula XVIII.

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For the procedure o) come those for nitro-, nitrosoimd Hydroxylamino groups customary reduction methods into consideration. The reductions can be as catalytic ^ hydrogenation also with other reducing agents such as hydrazine, with metals such as zinc or iron, with salts of metals of low oxidation state, for example Tin (il) chloride, or with complex metal hydrides -will. Should also the C = N double bond at the same time a Schiff base can be hydrogenated, for example, catalytically hydrogenated.

According to procedure p) one or more become aniline-like bonded amino groups of the compounds of the formula XXIV are diazotized in the customary manner. You can add both inorganic Use nitrites such as sodium nitrite as well as organic such as alkyl nitrites, depending on the nitrite used, organic or aqueous reaction media can be more advantageous. The elimination of nitrogen and introduction of the desired radicals X is done according to known methods by boiling in aqueous or alcoholic Solution or by adding copper-containing catalysts according to Sandmeyer.

For the reductive splitting off of halogen from compounds of the formula XXIVjin which T is halogen, according to the procedure q) and for procedure r), catalysts such as nickel, palladium or platinum can be used. Other noble metal catalysts can also be used. The reaction conditions correspond to those for catalytic Hydrogenations are customary, but relatively high temperatures and pressures can be advantageous.

The ether cleavage in the radical R ^, which may be carried out subsequently, is carried out in a manner known per se Acid catalysis, for example, with hydrohalic acids such as Hydrobromic acid or a solution of hydrogen bromide in glacial acetic acid or with Lewis acids such as anhydrous

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Aluminum chloride.

For the subsequent alkylation, one or more phenolic Hydroxy groups in a manner known per se with alkylating agents such as dialkyl sulfate or alkyl halides implemented. It can be advantageous to use basic catalysts, such as alkali or Alkaline earth alcoholates or carbonates. A primary or secondary amino group can be alkylated in the usual way. For this purpose, for example, alkyl halides or dialkyl sulfate can be used by choosing conditions that in principle are analogous to those described in method c) and d). If the amino group is to be methylated, it can be used Consider formaldehyde / formic acid as a methylating agent.

The implementation of procedures according to claim h depends on which heterocycle is to be formed in the reaction step. For each heterocyclic type, several known per se can be applied D _a rStellungsmethoden; however, the starting products of the compounds specified in claim h are usually compounds of a bifunctional character which are made to react with a second, likewise bifunctional partner. The types of reactions can be condensations and additions.

For example, if a pyridine ring is to be formed, a glutaconaldehyde derivative of the formula XXX can be mixed with ammonia condense

R _k R.

^A - ^N -

or a ketone of the formula XXXI

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A-N-CH O (XXXl)

CH ₂ R

with aldehydes of the formula XXXII

Alk O

CH ₂ - C, (XXXII)

(Alk = lower alkyl) and ammonia react in a three-component reaction.

Processes are also possible in which the heterocycle can still be modified after ring closure wearing. This is the case, for example, if a condensation of a ß-diketone of the formula XXXIII with ß-> Amino crotonic acid ester chooses.

RTJ I ₁ ■ "■"

A-N-CH. 0 (XXXIIl)

CH ₀ -C

² I.

Alc

The pyridine ring of the formula XXXIV formed by ring closure then also carries an ester group, which can optionally be passed through Can remove saponification and decarboxylation.

^R 4
AN - CH Ι ' _ητ3 (XXXIV)

Alc

Similarly, known methods such as ring closure can be used to construct a quinoline ring

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a compound of the formula XXXV with dehydrating Agents, for example sulfuric acid according to Conrad-Limpach,

A-N-CH

(xxxv)

.N

^CH 2 - f R

or ring closure of a compound of the formula XXXVI with a carbonyl compound of the formula XXXVII according to Friedländer.

R.

A-N-CH

(XXXVl)

Alc

- C 0

- Alk

(XXXVIl)

An isoquinoline ring can for example by using the Pictet-Spengler reaction can be formed by adding an aldehyde of the formula XXXVIII

A-N-CH

(XXXVIIl)

condensed with an amine of the formula XXXIX

-HC - Alk

H ₂ N - CH ₂

(XXXIX)

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Known indole syntheses can also be considered: for example, a phenylhydrazone of the formula XL according to Fischer close to the ring.

A-N - CH

(XL)

C NR ¹ /% /

R N

For the subsequent formation of the pyrimidine system you can for example amidines of formula XVI

A-N-CH>, NH C

Use NH ₂ and condense with ß-dicarbonyl compounds. For the synthesis of pyrazine and pyridazine systems, methods that are known per se can in principle be used.

In addition to the compounds listed in the examples, following the above analogy procedures, for example Compounds according to the invention are obtained:

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1- (4-PiCoIiIIyI) amino-3- (2, 4, 6-trimethyl) phenyl-.5-chloroindane

dihydrochloride

1- (4-picolinyl) amino-3- (4-bromo) phenylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-methylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-ethylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-n-propylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-i-propylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-n-butylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-4,6-dimethylindane dihydrochloride 1- (4-picolinyl) araino-3- (4-methyl) phenylindane dihydrochloride 1- (4-picolinyl) amino-3- (3-methyl) phenylindane dihydrochloride 1- (4-picolinyl) amino-3- (4-ethyl) phenylindane dihydrochloride 1- (4-picolinyl) amino-3- (3-ethyl) phenylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-hydroxy-indane dihydrochloride 1_ (4-Picolinyi) amino-3- (4-methoxy) phenylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-methoxy-indane dihydrochloride 1- (4-picolinyl) amino-3- (3 j 4-dimethox ^ phenyl-5 »6-dimethoxy-

indan dihydrochloride

1- (4-picolinyl) amino-3- (4-ethoxy) phenylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-ethoxy-indane dihydrochloride 1- (4-picolinyl) amino-3- (4-propoxy) phenylindane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-propoxy-indane dihydrochloride I- (4-picolinyl) amino-3-phenyl-6-benzyloxy-indane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-6-phenethoxy-indane dihydrochloride 1- (4-picolinyl) amino-3-phenyl-5,6-methylenedioxy-indane

dihydrochloride
1- (4-picolinyl) amino-3- (3> 4-methylenedioxy) phenylindan

dihydrochloride

1- (4-picolinyl) amino-3-phenyl-5i6-ethylenedioxyindane dihydrochloride 1- (4-picolinyl) amino-3- (3,4-ethylenedioxy) phenylindane dihydrochloride 1- (4-picolinyl) amino-3-methyl-3-phenylindane dihydrochloride l- (4-picolinyl) amino-3-ethyl-3-phenylindane dihydrochloride 1- (4-picolinyl) amino-3- (2-hydroxyethyl) -3-phenylindane

dihydrochloride

1-N- (4-picolinyl) ethylamino-3-phenylindane dihydrochloride 1- N- (4-picolinyl) n -propylamino-3-phenylindane dihydrochloride, 1- N- (4-picolinyl) i-propylamino-3-phenylindane dihydrochloride

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lN- (4-picolinyl) n-butylamino-3-phenylindane dihydrochloride 1- / 2V (4-pyridyl) eth-2-yl7amino-3-phenylindane dihydrochloride 1- / 3 - (^ - pyridyl) prop-3- yl7amino-3-phenylindan-dihydrochloride 1- / Ji- (^ -pyridyl) but-4-yl7amino-3-plienylindan-dihydroclilorid 1- / F- (4-pyridyl) pent-5-ylJ ^ amino-3-phenylindan dihydrochloride 1- / T-phenyl-2- (4-pyridyl) eth-2-yl7amino-3-phenylindane dihydrochloride

1- / Phenyl- (4-pyridyl) methyJL7amino-3-phenylindane dihydrochloride 1 - ^^ - Naphthylmethyl) amino-3-phenylindane hydrochloride 1- (ß-naphthylmethyl) amino-3-phenylindane hydrochloride 1- (4- Quinolylmethyl) amino-3-phenylindane dihydrochloride 1- (3-quinolylmethyl) amino-3-phenylindane dihydrochloride 1- (2-quinolylmethyl) amino-3-phenylindane dihydrochloride 1- / 5- (2-methyl) quinolylmethylT'amino -3-phenylindane dihydrochloride 1- / 2- (4-methyl) quinolylmethyl7amino-3-phenylindane dihydrochloride 1- / 3- (l-methyl) indolylmethyl7amino-3-pllenylindane dihydrochloride I- / 3- (2-methyl) indolylmethyl7amino-3-phenylindane dihydrochloride 1- (l-isoquinolylmethyl) amino-3-phenylindane dihydrochloride 1- / Γ- (U-methyl) isoquinolylraethyl7amino-3-phenylindane dihydrochloride 1- (3-I- ^s oquinolylmethyl) amino-3 phenylindane dihydrochloride 1- (4-isoquinolylraethyl) amino-3-phenylindane dihydrochloride 1- / 5 "- (l-methyl) isoquinolylraethyl7aniino-3-plienylindane dihydrochloride 1- (2-pyrimidinylmethyl) amino-3-phenylindane dihydrochloride 1- / 2- (4-methyl) pyrimidinyl methyl7amino-3-phenylindane dihydrochloride 1- / 2- (4,6-dimethyl) pyrimidinylmethyl7amino-3-phenylindane dihydrochloride

1- (4-pyriraidinylmethyl) amino-3-phenylindane dihydrochloride 1- (5-pyrimidinylmethyl) amino-3-phenylindane dihydrochloride 1- (3-Pyi "idazinylmethyl) amino-3-phenylindane dihydrochloride I- / 3- (6-methyl) pyridazinylmethyl7amino-3-phenylindane dihydrochloride

1- (4-pyridazinylmethyl) amino-3-phenylindane dihydrochloride l-pyrazinylmethylamino3-phenylindane dihydrochloride 1- / 2- (5-methyl) pyrazinylmethyl7amino-3-phenylindane dihydrochloride

) 1- (3-indolylmethyl) amino-3-phenylindane dihydrochloride

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1- (4-arainobenzyl) amino-3-phenylindane dihydrochloride 1 - (^ - methylaminobenzyl) amino-3-phenylindane dihydrochloride 1- (4-ethylaminobenzyl) amino-3-phenylindane dihydrochloride 1 - (^ - n-propylaminobenzyl ) amino-3-phenylindane dihydrochloride 1- (4-i-propylaminobenzyl) amino-3-phenylindane dihydrochloride 1- (4-n-butylaminobenzyl) amino-3-phenylindane dihydrochloride 1- (4-piperidylbenzyl) amino-3 -phenylindane dihydrochloride 1- (2-hydroxybenzyl) amino-3-phenylindane dihydrochloride 1- (3-hydroxybenzyl) amino ~ 3-phenylindane dihydrochloride 1- (4-hydroxybenzyl) amino-3-phenylindane dihydrochloride 1- (2 _T methoxybenzyl) amino-3-phenylindane dihydrochloride 1- (3_Methoxybenzyl) amino-3-phenylindane dihydrochloride 1- (^ -. Methoxybenzyl) amino-3-phenylindane dihydrochloride 1- (2-hydroxy-3-methoxy-benzyl ) amino-3-phenylindane-hydr ο chloride 1- (3-hydroxy-4-methoxy-benzyl) amino-3-phenylindane-hydrochloride 1- ( k- ethoxybenzyl) amino-3-phenylindane-hydrochloride l- (4- Propoxybenzyl) amino-3-phenylindane hydrochloride 1- (4-putoxybenzyl) amino-3-phenyl indan hydrochloride 1- (3, ^ - ethylenedioxybenzyl) amino-3-phenylindane hydrochloride 1- ^ / Tf- (2-diethylaminoethoxy) benzyl7amino-3-phenylindane dihydrochloride

1- / 5- (2-Piperidylethox3 ^ benzyl7amino-3-phenylindane dihydrochloride 1 ~ / Ji " (2-morpholinoethoxy) benzyl7amino-3-phenylindane dihydrochloride

The basic substituted phenylindanes according to the invention are preferably used as salts of physiologically compatible Acids used. Suitable acids for salt formation are, for. B. chloric, bromic and hydroiodic acid, phosphoric acid, Sulfuric acid, amidosulfonic acid, methylsulfuric acid, nitric acid, Formic acid, acetic acid, propionic acid, succinic acid, tartaric acid, lactic acid, malonic acid, fumaric acid, citric acid,

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Malic acid, mucic acid, benzoic acid, salicylic acid, aceturic acid, Emboxylic acid, naphthalene-1,5-disulfonic acid, ascorbic acid, Hydroxyethanesulfonic acid, benzenesulfonic acid or synthetic ones Resins containing acidic groups.

The phenylindane derivatives according to the invention have valuable pharmacodynamic properties. In particular, they call at different animal species produce effects that characterize them as psychotropic drugs with tranquilizing effects.

So z. B. 1- (4-picolinyl) amino-3-phenylindane dihydrochloride in the mouse with a dose of 5 mg / kg i.p. p. a pronounced potentiation of the hexobarbital anesthesia, with approx. mg / kg i.p. an antagonism against the metrazol and with 10-15 mg / kg i.p. an antagonism to the electroconvulsive. The compound also inhibits and causes extensor spasm a protective effect against deadly nicotine doses. Thieves-. Movement activity of the animals is inhibited in a dose-dependent manner.

The phenylindane derivatives according to the invention can be administered orally or parenterally for the treatment of mental illnesses. For oral application z. B. tablets, dragees or capsules into consideration, in the manufacture of which the usual auxiliaries and carriers such as lactose, starch, tragacanth, talc, magnesium te arate , etc. are used.

Since the new phenylindane derivatives are particularly hydrolysis-stable in comparison with known compounds with a similar direction of action, they are also well suited for the production of aqueous preparations, e.g. B. of injection solutions for subcutaneous or intramuscular application.

The products of the process can be used alone or in a mixture with other active ingredients . For drug combinations, there are, for example, active ingredients from the following classes of pharmacodynamics (see G. Ehrhart and H. Ruschig?. Arzneimittel, Verlag Chemie, Weinheim / T968; 2nd edition 19727)

509809 / 1.224

- 2h -

Consideration: analgesics, hypnotics, antiepileptics, psychotropic drugs, Analeptics, circulatory drugs, spasmolytics, muscle relaxants, Therapeutics with an effect on the gastrointestinal tract, Therapeutics with an effect on the respiratory tract, vitamins, Antiarrhythmics, lipid-lowering agents, anti-Parkinson agents.

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Examples: * —- Z Λ - '

1) 10.5 β 1-amino-3-phenylindane are boiled in 6θΟ ml of benzene with 5 »^ g of pyridine-'f-aldehyde under reflux on 17asserabscheidox" until the theoretical amount of "water (p, 9 ml) is deposited . The Roaktionslüsung is evaporated in vacuo and the residue (Schiff base) in 500 ml of methanol 15 Sfcd without further purification. box 80 ° and 100 at hydrogen hydrogenated with palladium. After the catalyst has been filtered off and the solution has been evaporated in vacuo, an oily residue remains, which is converted into the hydrochloride with no methanolic hydrochloric acid; aI ^τ lino · -3 - phenylindane dihydrochloride with a melting point of 221-223 ° C.

In 'analogous Vei'se one obtains:

2) 1 - (3-picolinyl) amino-3-phenylindan-dihydrochloi "* id vom M.p. 27-275 ° C. '

3) 1- (2-picolinyl) ainino-3-pn «nylindane dihydrochloride from M.p. 2'5-2 ^ 7 ° C.

h) 1 - (^ - Diniethylamiiiobenzy. ^1. ) amino - ^ - phenylindane hydrochloride of m.p. 24i ~ 2 ^ 3 ° C. "". . '\ - . ·

5) 1- (3i'l, 5-trimethoxybenzyi) amino-3-phenylindan-hydrochloride of m.p. 2h6-s

0) 1 - (3 »-t-methylenedioxybenzyl) ainino-3-phenylindane hydrochloride with a melting point of 223-226 ° C.

7) 1 - (^ -I} iäthylaminobenzyl) ainino-3-phenyl-dihydrochloiid, mp 210-212 ⁰ C..

8) 1- (3-methoxy - ^ - hydroxy-benzyl) amino-3-phonylindane hydrochloride of m.p. 259-20 ° C.

) 1 - [^ - (2-DiMethylcimino) ".thox3'benzyl] amino-3-phenylindane dihydrochloride from m.p. 2 * ί9-25ΐ ° 0.

10) 1- [3-l! Ethoxy - ^ - (2-dimethylat.nino) ethoxyben '/ 5yl] ainino-3-

iiydrochloi'id from

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phenylindan-dihydrochloride with a melting point of 225-227 ° C.

1) 1 - ⁽ⁱ l-morpholino-beriKyl) a nino-3 ~ ~ phGnylinclan diliyc] i'ochlorid, mp 231-232 ^o C (dec)!...

12) 1 - [2- (3-methyl) picolinyl] amino ~ 3-phenylindane dihydrochloride of m.p. 266-269 ° C.

13) 12.1 β 3- (p-chlorophonyl) indan-1-one are refluxed in 600 ml of benzene with 5 j ^ g of 4-picolylamine on a water separator until the thooretisohe Henge water (0.9 ml ) is deposited. The reaction solution is evaporated in vacuo and the residue is made to crystallize by trituration. The Schiff base is obtained in a crude yield of 11.0 ^,

The solution of the Schiff base in 700 ial Λν'ΐχ methanol-d under cooling and stirring with 3 E Natriu; r.borhydrid added. After stirring for an hour at room temperature and briefly warming to ^ 0 °, the solvent is evaporated in vacuo and the residue is partitioned between water and ether. Concentration of the organic phase gives a residue which can be converted into the Hydrochloric! is convicted. Recrystallization from methanol / ethyl acetate gives 1 - (^ - Picolin3 ^r l) anij.no-3 - ('l-chloro) pheiiylindan dihydrochloride with a mp. 181 ° C (decomp.).

In an analogous 1 / way one obtains:

^ h) l- (4-picolinyl) ajBin, a-n3 - (^ -; ehlor) phenyl-6-chloroindan-dihydrod of m.p. Z5h - 255 ° (dec.)

15) 1 - (^ - Dinethylamino-benzyl) amino ~ 3 - ('* - chloro) phenylidandihydrochloride of m.p. 23 "1-236 ⁰ C (dec.).

16) 19.9 g of 1 - ('t ~ picolinyl) amino-3-phenylinclane (Example 1) are mixed with 13.3 ⁿ ' l of a 30% aqueous formaldehyde solution and 12.2 ml of formic acid until the end of the C0 "-Ent ' winding heated on the steam bath. Then vii-cl made the reaction solution alkaline with 2N NaOH and extracted with ether. An oily residue is obtained from the organic phase by evaporation, which is then treated with a methanolic salt

509808 / 122A bad original

acid is converted into the Ilydrochlorid. By Recrystallization from Hethaiiol / ethyl acetate is obtained 12.0 g of 1-N - (^ - picolinyl) i: iethylaiaino-3 ~ phenylindandihydrochloride of m.p. 170 ~ 172 ° C.

In an 'analogous' way one obtains:

17) -1 -N- (31 '' 1 5-trimethoxybenzyl) methylaniino-3-phenylindan-

hydrochloride λόιπ melting point 211-212 ° C.

18) 1-N- (3, Ί-MethylenedioxybensylJmethylamino - ^ - phenylindane hydrochloride of m.p. 196-197 ° C

19) 1 -N - [^ - (2- "Diiuethylaminoethoxy) ben2yl] -nethylamino-3-phenylindane dihydrochloride of m.p. 236 C (decomp.)

ORIGlMAL INSPECTED

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Claims (8)

PATENT CLAIMS (I) where R ₁ and R _{g are} hydrogen, halogen, alkyl with 1-4 C atoms, hydroxy, acyloxy, alkyloxy with 1-4 C atoms, phenalkoxy with 1-4 C atoms in the alkylene part, where R ₁ and R_ can be the same or different and 2 adjacent substituents can also be members of a fused 5-7güedrigen ring, R_ hydrogen, alkyl with 1-4 carbon atoms, phenalkyl with 1-4 alkylene carbon atoms or hydroxyalkyl, R ^ hydrogen, alkyl with 1-4 carbon atoms, phenalkyl with 1-4 carbon atoms in the alkylene part, R_ hydrogen, alkyl with 1-4 carbon atoms, benzyl or phenyl and R, a mono- or bicyclic aromatic radical, which is optionally replaced by a primary, secondary or tertiary amino group, a phenoxy group, an alkylenedioxy group with 1-2 C atoms, a lower alkoxy group which is substituted by a dialkylamino group, the two alkyl radicals together with the nitrogen atom also for a saturated 5- to 6-membered group Ring that may contain another nitrogen or oxygen atom n can, can stand, a mono or bicyclic aromatic radical which is optionally substituted by one to at most 3 hydroxyl groups or lower alkoxy groups, these groups being identical or different, or a monocyclic, 6-membered heteroaromatic radical which is a or contains two N atoms and is optionally substituted by lower alkyl groups, or a bicyclic heteroaromatic radical which contains one N atom and is optionally substituted by lower alkyl groups as well 509809/1224 their salts with physiologically compatible acids. 2. Process for the preparation of the compound according to claim 1, characterized in that these compounds are after Establishes the usual methods for this class of compounds. 3. Process for the preparation of the compounds according to claim 1, characterized in that one of the substituents R ₁ , R ₅₁ , R ", R ^, R_ or R ^ or, if these substituents have the same meaning, several simultaneously in the last reaction stage in connection with the general Formula Ij in which at least one of the substituents R ₁ to R-. Hydrogen means introduces by analogy process. k. Process for the preparation of the compounds according to claim, characterized in that compounds corresponding to formula I in which one or more of the substituents R ₁ to R ^ represent a suitable precursor are converted into the compounds according to claim by methods known per se. 5. Process for the preparation of the compounds of the formula I in which R ₁ to R_ have the above meaning and R ^ denotes a heterocyclic radical, characterized in that a compound of the formula. TJ TJ f * / ⁵ A-N-CH η 509809/1224 where A is the remainder means »according to known ones Methods implemented so that from -C C ^ a ntonocyclic 6-membered heterocyclic radical with 1 ·. or 2 N-Atonieii o, which is formed as a bicyclic heteroaromatic radical with an N atom. 6. Pharmaceutical preparations marked with psychotropic effects by containing a compound according to claim 1. 7. Process for the production of pharmaceutical preparations with psychotropic effects, characterized in that one a compound according to claim 1, optionally with the addition of pharmaceutically customary carriers and / or stabilizers | in a form suitable for therapeutic purposes brings. 8. Pharmaceutical combination preparations characterized by a content of a compound according to claim 1 in combination with one or more pharmaceutics of the classes analgesics, hypnotics, antiepileptics, psychotropic drugs, analeptics, Circulatory drugs, spasmolytics, muscle relaxants, therapeutics with an effect on the gastrointestinal tract, therapeutics with effect on the respiratory tract, vitamins, antiarrhythmics, lipid-lowering agents, anti-Parkinson drugs. 509809/1224