IL43218A - 2-n-phenyl-n-aminoalkyl-aminoindanes their preparation and pharmaceutical compositions containing them - Google Patents

Description

This invention relates to new nitrogenous organic compounds and to pharmaceutical compositions containing said compounds as active ingredients.

French patent specification No. 2,081,383 describes, among others, dialkylamino analogues of the compounds' according to the invention. It has surprisingly been found that the compounds according to the invention, in which one of the alkyl groups is replaced with a hydrogen atom, show considerably better activity than their dialkyl analogues.

The new nitrogenous organic compounds according to this invention are derivatives of 2-arainoindane of the general formula : wherein n is equal 'to 2, 3 or 4, the (CH2)n group having a . straight or branched chain in which one or more hydrogen atoms • may be replaced by a hydroxy radical, represents a lower alkyl or hydroxyalkyl radical- containing 1 to- 4 carbon atoms or a lower • alkenyl or alkynyl radical containing 2 or 3 carbon atoms, A is ■a phenyl radical, as well as the acid addition 'salts of said derivatives of formula (I).

Examples of .preferred compounds of formula I are as follows : ' -phenyl-N-(T-ethylaminopropyl)-2-aiQinoindane as well as roono-and di-hydrochloride thereof (formula I ; A = phenyl ; = C^H^ ; n = 3), ' ·.

N-phenyl-N-( Y-methylaminopropyl)-2-aminoindane monohydrochloride (formula I ; A = phenyl ; = CH^ ; n = 3), N- hen l- -(T- ro lamino ro l)-2-aminoindane monohydrochloride N-phenyl-N- (β-ethylaminoethyl)-2-aminoindane inonohydrochloride (formula I ; A = phenyl ; = ; n = 2), N-phenyl-N-(6 -ethylaminobutyl)-2-aminoindane monohydrochloride (formula I ; A = phenyl ; = C^H^ ; n = 4), N-phenyl-N-(allylarninobutyl)-2-aminoindane hydrochloride (formula I ; A = phenyl ; = allyl ; n = 4), N-phenyl-N-(β-methyl-Y-ethylaminopropyl)-2-aminoindane hydrochloride (formula. I .; A = phenyl ; R1 = C2H"5 ; (CH2)n = H2C-CH-CH2), • " N-phenyl-N-(Y-hydroxyethylaminopropyl)-2-aminoindane hydrochloride (formula I A = phenyl ; R1 = C^OH ; n = 3), N-phenyl-N- Y-propargylaminopropyl)-2-aminoindane oxalate ( formula I A = phenyl ; R^ = propargyl ; n = 3), N-phenyl-N- Y-allylaminopropyl)-2-aminoindane hydrochloride ( formula I A = phenyl ;■ R^ = allyl ; n = 3), N-phenyl-N- Y-tert .butylaminopropyl)-2~raminoind3j.ie hydrochloride ( formula I A = phenyl ; R^ = t.butyl ; n 3), N-phenyl-N-(β-hydroxy-Y-eth laminopropyl )-2-aminoindane hydrochloride (formula I ; A = phenyl ; (CH2)n = CH2-CH0K-CH2 ; R. I C2H5), N-phenyl-N-(Y-butylaminopropyl)-2-aminoindane hydrochloride (formula I ; A = phenyl ; R^ = C^H^ ; n = 3), N-phenyl-N- (Y-isopropylaminopropyl)-2-aminoindane hydrochloride (formula I ; A = phenyl ; R^ = isopropyl ; n = 3).

This invention also relates to pharmaceutical compositions namely for the treatment of heart arrhythmMxcontaining at least one compound of the general formula (I) together with a pharmaceutically acceptable excipient or carrier.

It has surprisingly been found that the compounds , of the general formula I are very active for the treatment of^-heart arrhythmia. ^ Said compounds can be used for the treatment of various heart diseases such as premature heart contractions, ventricular and surpraventricular tachycardias either idiopathic or subsequent to a cardiopathia or to a coronary disease, cardiac arrhythmias due to digitalin intoxication, as well as atrial fibrillation and flutter, particularly in the early stage.

It is known (see Koch-Weser, J. Arch. Int. Med. 129; 763, 1972) that none of the presently available antiarrhythmic agents are satisfactory for the prophylaxis of tachycardias and fibrillation of ventricular origin.

The oral activity of the known antiarrhythmic agents, such as procainamide or lidocaine, is either too short leading to multiple- day and night administration (for example with-procalnamide) or too low to be of some pratical utility (for example with lidocaine) or their therapeutic activity is conjugated with frequent and dangerous side effects, such as hypotension (with procainamide), sudden death, agranulocytosis or idiosyncrasy.

The compounds of general formula I according to this invention are very active when orally administered, although they may also be administered parenterally. They have also a long activity duration and are not depressant for the myocardial function.

Applicants do not know any orally active antiarrhythmic agent which does not act at the same time as a depressant of the myocardial function The oral antiarrhythmic activity of the compounds of formula I has "been proved by tests on rats using aconitine which is a compound causing premature heart contractions and death of the animals.

The method used for these tests is described here-after : Animals : ■ · Male or female rats with a body-v/eight ranging from 380 to 450 g„ Aconitine solution : 3 o 12 μβ aconitine nitrate/1 ml physiological saline.

Solution of the compound to be tested : 0 .75 % in distilled water.

Method : Six random selected animals are required for each compound to be tested. The compound is administered by oral route at the dose--of 75 mg/kg ( 1 'ml of the- 0.75 % solution/ 00 g of body-weight) 75 minutes before the intravenous perfusion of the aconitine solution is initiated.

Control groups of animals are treated only with distilled v/ater ( 1 ml/100 g) . ' Sixty minutes after the administration of the compound to be tested, the animals are anesthesized by an intraperitoneal injection of Pentobarbital ( 50 mg/kg) and the jugular vein is dissected.

A catheter is introduced in the vein and fixed by a ligature.

The ECG (D II derivation) is then continuously recorded.

The perfusion of the aconitine solution is started 75 minutes after the administration of the compound to be tested. J The volume delivered by the injection device being 0.287 ml/nl'i-nute, the dose of aconitine nitrate administered is 0.895 g/mi-nute (0.20 - 0.24 g/100 g/min. according to the minimal and maximal weight of the animals).

The experience is stopped as soon as the first extrasystoles are appearing and the time elapsed from the beginning of the perfusion is noted.

The results are expressed as the mean total dose of aconitine injected in a group of animals.

The relative activity between a tested compound and a reference substance (lidocaine, procainamide) is computed in the following way : A (x) = 3L J_ x 100 - C Avhere A(x) = activity of tested compound X (in %) X" = mean dose of aconitine in the animals treated by compound X l ~C = mean dose of aconitine injected in the untreated animals (controls) IT = mean dose of aconitine injected in the animals treated by the reference substances. The following table gives the results of the evaluation of the antiarrhythmic activity by oral route of a great number of acid addition salts of compounds of formula I, compared to the activity of two vrell known antiarrhythmic agents (procainamide and lidocaine) : TABLE 1 The compounds of the formula I may be administered orally or parenterally.

Oral preparations may be administered under the form of capsules, tablets, pills and the like. Each capsule, tablet or pill may contain from 10 to 200 mg of a compound of formula I as active ingredient, together with pharmaceutically acceptable excipients or carriers.

Parenteral preparations may consist in a solution for perfusion or for intravenous or intramuscular injection. Such a solution may contain from 0„2 per thousand to 2 per thousand of a compound of formula I.

The parenteral preparation may be either a solution which may be directly used for the perfusion and contains a proportion of the active ingredient within the above limits, or a. concentrated solution containing 1 to 10 % of the active ingredient, said concentrated solution being diluted when administered to a patient.

The initial dose of active ingredient may be of 200 to 800 mg cper day during 2 or 3 days, the maintenance dose being of about 25 mg to 300 mg per day.

If a single dose is sufficient for ,obtaining the therapeutic effect, this dose is generally comprised between 50 and 300 mg.

The active ingredient may be administered at the same time by the parenteral route (for example by perfusion) and by the oral route .

According to a further aspect of this invention, the compounds of the general formula (I)' may be prepared by the following processes.

First, process. process involves the reaction of a N-phe •aminoindane of the formula : in which A has the above meanings v/ith sodium amide (HaNH9) and v/ith a halogenated amine of the formula in v/hich Hal represents a halogen atom, preferably a chlorine or bromine atom, v/hereas n and R.j have the above meanings.

S.ec njd rocess . ·· .

This process involves the acylation of compound of formula (II) v/ith an acid chloride of the formula : CI ( H2)n, C0C1 (IV) in v/hich n' = 1, 2 or 3, so as to obtain an acylated compound of the formula : the subsequent reduction of the acylated compound of formula ( by means of aluminum lithium hydride into a compound of the follov/ing formula : in which η' has the above meanings, the obtained compound of formula (VI) being finally alkylated by means of a primary amine of the formula : /R H - N (VII) H Third process.

This process involves the acylation of a compound of formula (II) with an acid chloride of the formula : CI (CH2)n, C0C1 (IV) in which n ' = 1 , 2 or 3 , so as to obtain an acylated compound of the formula : the subsequent N-alkylation of the acylated compound of formula (V) with a secondary amine of the formula : so as to obtain a compound of the formula : the latter compound bein finally reduced into a compound of formula (I) by means of aluminum lithium hydride.

Fo'urth process, This process involves the N-alkylation aniline monohydrochloride of the formula whereas n and have the above meanings, by means of indanol mesylate of the- formula : Fifth process .

This process involves the reaction of a N-phen 2-aminoindane of the formula (II) : ¾ "in which A has the above meanings v/ith a broraochloroalkane of the formula' : Br (CH2) CI . (XI) in which n = 2, 3 or 4, so as to obtain an intermediate compound of the formula :. which is then reacted, possibly without isolation, with a f i darv amine of the formula (VI"X) : H - N (VII) Sixth process.

This process involves the dealkylation of a N-phenyl-2- [N- (γ-dialkylaminoalkyl) ] -aminoindane of the formula : in v;hich A and have the above meanings and has the meanings indicated for , by means of cyanogen bromide.

The compounds of formula (II) used as starting materials in the above described processes may be prepared by various methods.

First method.

This method involves the two following, steps : 1°) reaction of 2-keto-3-cyanoindane of the formula H with aniline, (as described in J.C.S. 1961, page 178) so as obtain a 2-phenyl amino-3-cyanoindane of the formula 2°) reduction of the 2-phenyl-amino-2-cyanoindane (XV) into the compound Of formula II by the Bouveault-Blanc method.

Second method.

This method involves the reaction of the ester methane sulfonic acid and 2-indanol of the following formula : v/itb aniline.

Third method.

This method comprises the two following steps 1°) reaction of 2-indanone of the following formula with aniline, so as to obtain a N-phenyl-2-iminoindane of the following formula : (XVIII) 2°) reduction of the N-phenyl-2-iminoindane by means of sodium borohydride.

In the various formulae II to XVIII, the substi-tuents have the above meanings.

The invention is further illustrated by the following examples : EXAMPLE 1 Preparation of -phenyl-N- ( Y-ethylaminopropyl) -2-aminoindane as well as mono- and di-hydrochloride thereo , (formula I : A = phenyl ; = C2H ί n = 3) ' I - By applying the third process disclosed above.

A.- Preparation of N~(fj-chloropropionyl)~N-phenyl-2-amino-- indane . 0.04 mol of N-phenyl-2-aminoindane are acylated by means of 0.06 mol of β-chloropropionyl chloride in 50 cc of benzene e After 5 hours of reflux, the conversion is complete „ The reaction medium is evaporated to dryness and the residue is recrystallized from petroleum ether. M.P. 85 °C.

Analysis : % calculated : C 72.11 ; H 6.05 ; CI 11.8 % found : C 72.39 ; H 6.01 j CI Ϊ1.82 Be~ Preparation of -N-( -ethylaminopropionyl)- --phenyl-2- aminoindane . 17.8 g of N~( -chloropropionyl)-N-phenyl-2~amino-indane and 100 cc of an. etlianol solution containing 12 by weight of ethylamine are heated at 78°C during 21 hours in an autoclave. After evaporation of the solvent, the residue is extracted by means of 6N hydrochloric acid. A precipitate of the hydrochloride is obtained by cooling in a refrigerator. By recrystallization from acetone, 19.34 g (yield : 88 ) of the hydrochloride melting at 180°C are obtained.

Analysis : % calculated : C 69.65 ; H 7.3 ; CI 10.28 ; N 8.12 % found : C 69.67 ,* H 7.1 5 CI 10. ; N 8.21 The free base is obtained by alkalinization and extraction by means of ether. The residue of the ether phase is used directly in the following step. c»~ Preparation of N-phenyl-N-( Y-ethylaminopropyl)-2—-a—mino- . ··. indane and the dihydrochloride thereof, "' 18.9 g of N-(p-ethylaminopropionyl)-N-phenyl-2-aminoindane (0.063 raol) are dissolved in 200 cc of anhydrous ether. The obtained solution is then poured drop by drop on 0.126 mol (4.8 g) of lithium aluminum hydride suspended in 100 cc of anhydrous ether. The obtained reaction medium is then refluxed during 2 hours. After cooling at 0°C, 50 cc of water are added drop by drop. The ether phases are brought together and dried.

After evaporation of the ether, 15 g (yield : 77 %) of a colourless oil are obtained. This product is the free base.

This free base is converted into the dihydrochloride by the usual method, using an aqueous acid medium. The aqueous phase is evaporated to dryness and the residue is extracted by means of 1N hydrochloric acid. The acid aqueous solution is then, evaporated and the residue is recrystallized from a mixture of methanol and acetone. M.P. 239-240°C.

Analysis of the dihydrochloride : % calculated : C 65.39 ; H 7.68 ; N 7.61 ; CI 19.3 % found : C 65.21 ; H 7.71 ; N 7.63 ; CI 19.18 D*~ Preparation of the monohydrochloride of N-phenyl-N- ( Y- ethylaminopropyl)-2-aminoindane . .

This compound is obtained by the same method as used for preparing the dihydrochloride, except that the pH of the acid aqueous solution is adjusted at 6. The product obtained after recrystallization from methylethylketone melts at 38- 9°C. Analysis : % calculated : C 72.59 ; H 8.23 ; N 8.47 % found : C 72„78 ; H 7.90 j N 8.51 II - By applying the first method disclosed above, i.e. by direct alkylation of the sodium salt of 2-phenylaminoindane it ^ an amine of the type H The following reactants are used : . g of 2-phenylaminoindane ; 4.20 g of 1-bromo-3-ethylaminopropane hydrobromide ; .33- g of aNH2.

The sodium salt of 2-phenylaminoindane is first formed by heating the 2-phenylaminoindane with the NaNHg during 15 minutes at 100°C. The mixture is then allowed to cool and the hydrobromide is added thereto at 40°C. The precipitate present in the toluene solution becomes dissolved. By further heating to 70°C, NEj is evolved and a second precipitate is formed. The mixture is refluxed during 22 hours and then subjected to extraction as follows : decant, wash the toluene phase with water, extract with HC1 2N, bring the acid phase to pH 6, extract with CE^Cl^, dry, evaporate.

The residue which is the monohydrochloride of the desired product is recrystallized from ethyl acetate or methylethylketone. M.P. 138~139°C Yield 63 %· III - By desethylation of 2~ ~N-(Y~aiethylaminopropyl)~N-phenyl>_7- aminoindane by means of cyanogen bromide (sixth method described above). 0.155 mol of 2-/lJ~(Y»diethylaminopropyl)-N-phenyl7-aminoindane is dissolved in 100 ml of anhydrous ether. A "suspension of 17 g of BrCN (0.162 mol) in 100 ml of ether is added drop by drop. The mixture is stirred ai: room temperature during 20 hours. The solvents are evaporated. The residue is I hydrolyzed during 20 hours with a mixture of 1000 ml of acetic ' acid, 650 ml of water, 130 ml of HC1 12N. The' mixture is then evaporated to dryness and taken up with 500 ml of water, brought to pH 2 and extracted with CH^C^, giving on the one hand 21 g of an oil containing mainly 2-phenylaminoindane and on the other hand an aqueous phase. Said aqueous phase is adjusted from pH 2 to pH 5.5 and then extracted with CH^C^ which gives about 30 g of oil. Said oil is recrystallized from a mixture of ethyl acetate and methanol giving a product m.p. 1 4- 36°C identical with the monohydrochloride obtained by the other methods 0 EXAMPLE 2 Preparation of the monohydrochloride of -phenyl-N-(Y-methyl-aminopropyl)-2-aminoindane. (formula I : A = phenyl ; = CK-. ; n = 3).

I - A.- Preparation of N-( -methylaminopr pionyl)-N-phenyl~2- aminoindane .

This compound is prepared in the manner described in the' Example 1 (sections I, A and B), except that methylamine is used in place of ethylamine. After recrystallization from methylethylketone, the obtained hydrochloride melts at 202~204°C, Analysis : % calculated : C 68.97 ; K 7.01 ; 8.47 • % found : C 68.95 ; H 6.94 ; N 8.36 onohydrochloride of -phenyl-- - ( Ύ-methylaminopropyl )- 2-aminoindarie .

This compound is prepared in the manner described in the Example 1 (section C) and melts at 181-183°C after recrystallization from isopropanol.

Analysis : % calculated : C 72.01 ; H 7.95 ; N 8.8 % found : C 71.09 ; H 7.75 ; N 8.85 ' * ■ Ύ II - The same product when prepared as in Example 1, section III, is obtained with a better yield.

EXAMPLE 3 Preparation of the monohydrochloride of N-phenyl-N-(Y-propyl-aminopropyl)-2~aminoindane (formula I : A = phenyl ; = ^3^7 ' n = 3).

A.- Preparation of the hydrochloride of N-( -propylaminopropionyl)- N-phenyl-2-aminoindane .

This compound is prepared in the manner described in the Example 1 (sections A and B) except that propylamine is used in place or ethylamine. The obtained hydrochloride melts at 107.6°C after recrystallization from methylethylketone.

Analysis : % calculated : C 70.27 ; H 7.58 ; N 7.81 % found : C 70 ; H 7.5 ; N 7.88 B«~ Preparation of the hydrochloride of N-phenyl-N-(Y-propyl- aminopropyl)-N-phenyl-2~aminoindane .

This compound is prepared in the manner · described in the Example 1 (section C) and melts at 15 °C after recrystal- . lization from isopropanol.

Analysis : % calculated : C 73.12 ; H 8.48 ; N 8.12 % found : C 73.20 ; H 8.20 ; N 8.10 ·· EXAMPLE 4 Preparation of the monohydrochloride of N-phenyl-N-(β-ethylamino-ethy1)-2-aminoindane (formula I : A = phenyl ; = >2^5 » n = 2) . A.- Preparation of N-phenyl-N-chloroacetyl-2-aminoindane .

This compound is prepared as described in Example 1 , section A, chloroacetyl chloride being used as acylating agent.

The obtained compound melts at 63-64°C after recrystallization from cyclohexane. -Analysis : % calculated : C 71.45 ; H 5.64 ; N 4.9 ; CI 12. 1 % found : C 71.62 ; H 5.61 ; N 5.17 ; CI 12.45 B.- Preparation of N-phenyl-N-(ethylaminoacetyl)-2-aminoindane .

This compound is prepared in the manner described in Example 1, section D. The obtained product is recrystallized from acetone-methanol and melts at 223-225°C.

Analysis : % calculated : C 68,97 ; H.7.0 ; N 8.46 ; CI 10.71 % found : C 68.89 ; H 6.85 ; N 8.57 r CI 10.69 Co- Preparation of N--phenyl-- -( -ethylaminoethyl)»2-aminoindane.

This compound is prepared by the method described in Example 1, section C. After recrystallization from water or ethyl alcohol, the obtained product melts at 78- 80°C.

Analysis : % calculated : C 72.01 ; H 7.95 ; N 8.83 ; CI 11.19 % found : C 71.8' ; H 7.8 ; N 8.63 CI 11.6 EXAMPLE 5 Preparation of N-phenyl-M-(6-ethylaminobutyl)-2-aminoindane monohydrochloride (formula I : A = phenyl ; = CgH^ ; n = 4).

Preparation of N-phenyl-N-(S -chlorobutyl)-2-aminoindane hydrochloride 0 To a cooled solution of 13.6 g of lithium aluminum hydride in 300 ml of ether, a solution of 53.37 g of' N-phenyl N-(Y-chlorobutyroyl)-aminoindane in 800 ml of ether is added drop by drop. The obtained mixture is refluxed during 2 hours„ After cooling, 150 ml of water are added drop by drop. The ethe phase is separated, washed, dried and evaporated to dryness.

The obtained oil is treated with 300 ml of iso-propanol and 100 ml of 6N hydrochloric acid. A precipitate is obtained which is recrystallized from methanol. M.P. 198-199°C. Analysis : % calculated : C 67.84 ; H 6.89 ; N 4.27 ;'C1 21.09 % found : C 67.93 ; H 6.80 ; N 4.50 ; CI 20.60 B .- Preparation of N-phenyl-N-(^~ethylaminobutyl)-2-aminoindane hydrochloride . 6.72 g of N-phenyl--N-((5 -chlorobutyl)-2-aminoindane 47 ml of solution ethylamine in alcohol (15.3 g/100 ml) and 50 ml of ethanol are heated in an autoclave at 100°C during 24 hours. After cooling, the volatile materials are removed and the residue is treated with water and made alkaline (pH = 11). The product is extracted with benzene, washed, and dried. An oily residue is obtained when the benzene is removed.

The oily residue to which 1N hydrochloric acid has been added is extracted with dichloromethane. The aqueous phase is brought to a pH of 6 and extracted v/ith dichloromethane. 3.3 g of the desired hydrochloride are obtained. This product melts at 1 8- 60°C after recrystallization from a mixture of methylethylketone and methanol.

Analysis : % calculated : C 73.18 ; H 8.47 ; N 8.12 ; CI 10.28 % found : C 72.70 ; H 8.56 ; N 8.30 ; CI 10.20 ' EXAMPLE 6 Preparation of N-phenyl- -(allylaminobutyl)-2-aminoindane hydrochloride (formula I : A = phenyl ; Ft.,. = allyl ; n = 4). 6.72 g of N-phenyl«N-(6 -chlorobutyl)~2-aminoindane 9.16 g of allylamine and 80 ml of ethanol are heated in an autoclave at 100°C during 24 hours.

Using the method described in Example 5, a mono-hydrochloride is obtained which melts at 1 3-114°C after recrystallization from ethyl acetate.

Analysis : % calculated : C 74.03 ; H 8.19 ; N 7.85 ; CI 9.93 % found : C 73.74 ; H 8.09 ; N 7.82 ; CI 9.76.

EXAMPLE 7 ^ Preparation of N-phenyl-N-(P-methyl-Y-ethylaminopropyl)framingindane hydrochloride (formula I : A = phenyl ;' = C2H^ J (CH2)n = H2C-CH-CH2) .

CH, D A.- Preparation of N-phenyl-N-( -chloro- -methylpropionyl)-2- aminoindane .

To a solution of 15 g of -phenyl-2-aminoindane in 150 ml of benzene, 14.6 g of chloride of 3-chloroisobutyric acid are added. The mixture is refluxed during 4 hours. After cooling, the benzene is removed and the residue is extracted •with petroleum ether. By recrystallization from petroleum ether (B.P. 40-60°C), the obtained product melts at 92-94°C.

Analysis : % calculated : C 72.71 ; H 6.42 ; N 4.46 CI 11.30 % found : C 72.31 ; H 6.20 ; N 4.48 ; CI 10.5 Β·~ Preparation of N-phenyl-N-(Y-chloro-P"meth lpropyl)-2- ,aminoindane .

To 3.14 g of N-pheiiyl-N-(p-chloro- -methylpro- pionyl)-2-aminoindane in 80 ml of anhydrous ether, 0.57 g of lithium aluminum hydride are added. The obtained mixture is re- fluxed during 3 hours and treated in the usual way. The product is purified b conversion into the picrate. M.P. 150-152°C.

Analysis : % calculated : C 56.76 ; H 4.76 ; N 10'.6 ; ' CI 6.70 % found : C 56.64 ; H 4.71 ; N 10.5 ; CI 6.71 By treating the picrate with ammonia, the free base is obtained as an oil which may be used in the follov/ing step.

C · " Preparation of N-phenyl-N- ( β-methyl-Y-ethylaminopropyl )-2- aminoindane . .

A mixture of 5 g of N-phenyl-N- ( Y~chloro--p-me1;hyl-propyl)-2-aminoindane , 29.8 ml of a solution of ethylamine in ethanol (20 g/100 ml) and 150 ml of ethanol is heated in an autoclave at a temperature of 100°C during 24 hours. After cooling and evaporation, the residue is treated with 100 ml of 0.1N aOH and extracted with benzene. After evaporation, the oily residue is treated with 100 ml of 2N hydrochloric acid. The obtained mixture is extracted with benzene and the acid phase is brought to a pH of 6 and extracted with dichloromethane , After evaporation, the oil is recrystallized from ethyl acetate. M.P0 137~138°C.

Analysis : % calculated : C 73.12 ; H 8.47 ; N 8.12 CI 10.28 % found : C 73.23 ; H 8.34 ; N 8.03 ; CI 10.35 EXAMPLE 8 Preparation o N-phenyl-N- ( Y-hydroxyethylaminopropyl ) -^-aminoindane^ hydrochloride (formula I : A = phenyl ; = CH CtLOH ; n = 3j . · 6.44 g of N-phenyl-N- (Y-chloropropyl )-2-aminoinda-ne, 9,77 g of monoethanolamine and 50 ml of ethanol are heated in an autoclave at 100°C during 24 hours.

The mixture is then treated as described in Example 7. The obtained monohydrochloride melts at 123-125°C after recrystallization from methylethylketone .

Analysis : % calculated : C 69.24 ; H 7.84 ; N 8.07 ; CI 10.22 % found : C 69.03 ; H 7.70 ; N 7*98 CI 10.08 EXAMPLE 9 Preparation of N-phenyl-N- ( Y-propar ylaminopropyl)-2-aminoindane oxalate (formula I : A = phenyl ; = propargyl ; n = 3). 6,44 g of N-phenyl-N-(Y-chloropropyl)-2-aminoindane, 8.8 g of propargylamine and 50 ml of anliydrous ethanol are aA o-claved at 100°C during 24 hours.

The mixture is then treated as described in Example 7. The oxalate melts at 94- 98°C after recrystallization from methanol.

Analysis : % calculated : C 70.03 ; H 6.64 ; N 7.1 % found : C 70.28 ; H 6.31 ; N 6.87 EXAMPLE 10 Preparation of N-phenyl-N-(Y~allylaminopropyl)-2~aminoindane hydrochloride (formula I : A = phenyl ; = allyl ; n = 3). 6.44 g of N-phenyl-N-(Y-chloropropyl)-2~aminoindane, 9.12 g of allylamine and 50 ml of anhydrous ethanol are heated at 100°C in an autoclave during 24 hours.

After cooling, the solvent and the excess of allylamine are evaporated. The residue is taken, up with 50 ml of NaOH 1N and. then extracted with benzene. The benzene phase is evaporated, taken up with' 20 ml hydrochloric acid 1 , extracted with CELjC-l and dried. The solvent is evaporated, giving 5 g of crystalline residue m.p, 141-143°C (hydrochloride), which after recrys-tallization from isopropanol, melts at 146-148°C.^.

Analysis : % calculated : C 73.55 ; H 7.94 '; N 8.17 ; CI 10.34 % found : C 73.71 ; H 7.98 ; N 8.30 ; CI 10.37 ' EXAMPLE 1 Preparation of N-phenyl-N-(Y-tert.-butylaminopropyl)-2-amino-indane hyd ochloridei (formula I : A = phenyl ; = tert-butyl ; n = 3). 6.44 g of N-phenyl-N-( Y-chloropropyl)-2-aminoir.da-ne, 11.69 g of tert ,-butylamine and 50 ml of anhydrous ethanol are treated in an autoclave at 100°C during 24 hours.

The mixture is then treated as described in Example 7. Recrystallized from methylethylketone, the desired monohydrochloride melts at 180-182°C.

Analysis : % calculated : C" 73.61 ; H 8.70 ; N 7.81 ; CI 9.88 % found : C 73.75 ; Ή 8.78 ; N 8.10 ; CI 10.1 ■ EXAMPLE 12 ' Preparation of 2-/~ -(P-hydrox7\r-T--ethyraminoprop3^l)-N-phenyl 7-aminoindane .hydrochloride (formula .I : = C2H^ ; (CH"2)n = CK2-CH0H-CH2 ; A = phenyl). - A,.- Preparation o 2-/^ -(T-chloro-B-hydroxyi?ropyl)-- -phenyl 7- aminoindane . 0.03 mol of 2-phenylaminoinda?:e and 0.045 mol of epichlorohydrin are heated during 24 hours at 90-95°C in nitrogen medium.

The mixture is evaporated to dryness. The residue is recrystallized from a mixture of ethylacetate and methyl ' alcohol. M.P. 170-171 °C Analysis : ¾ calculated .: C 63.9 ; H 6.26 ; N 4.14 ; CI 20.9 % found : C 64.03 ; H 6.25 ; N 4.2 ; CI 20.6 B.- Preparation of the desired secondary amine . 2.10~2.moles of 2- ~N-(Y-chloro-p-hydroxypropyl)- -phenyl_7-aminoindane are refluxed during 24 hours in 11 ml of an alcohol solution containing 20 % of ethylamine .

After said heating under reflux,, the plate chromatography tests show that almost no starting product is left. The solvents' are evaporated from the reaction medium, the residue is taken up with water and rendered alkaline by means of sodium hydroxide » The mixture is then extracted with CH2CI2, washed and the organic phase is isolated, dried and its solvent is evaporated, leaving an oily residue. This residue is treated with HC1 to make the hydrochloride, which is recrystallized from a mixture of ethyl acetate and methanol thus giving the desired hydrochloride product. ,M„P. 137-138°C.

Analysis : ¼ calculated..: C 69.24 H 7.84 .; N 8.08 ; CI 10.22. ¼ found : C 68.96 ; II 7.67 ;. N 7.90 ; CI 10.5 EXAMPLE }3: Preparation of 2-/~N-(Y-butylaminopropyl)-N-phenyl 7-aminoindane hydrochloride (formula I : A = phenyl ; = ; n = 3) .

This compound is prepared in the manner described in Example 10, except that n-butylamine is used instead of allyl-amine B The hydrochloride obtained is recrystallized from acetone. M.P. 95-95°C.

Analysis : % calculated : C 73.61 ; H 8.70 ; N 7.80 ; CI 9.88 % found : C 73 ; H 8.50 ; N 7.9 ; CI 10.14 EXAMPLE 14.

Preparation of 2-/~N- (Y-isopropylaminoOropyl )-N-Ohenyl 7-aminoindane hydrochloride (formula I : A = phenyl ; = isopropyl ; n = 3).

This compound is prepared in the manner described in Example 10, except that isopropyiamine is used instead of allylamine .

- The hydrochloride obtained is recrystallized from isopropyl alcohol. M.P. 140-141 °C.

Analysis :. % calculated : C 73.12" ;Ή.8.47 ; N 8.12 ; CI 10.28 % found : C 72.91 ; H 8.30 ; N 8.17 ; CI 10.40 EXAMPLE *5 ' ' Preparation of the hydrochloride of 2-/~N-(^ -ethylaminobutyl)- -phenyl 7-aminoindane (formula I : = C2H^ ; n = 4 ; A = phenyl 1/3.10 moles of 2- ~N-(i-chlorobutyl)-N-phenylJ7-arnino indane and 9 ml of a 10 % alcoholic solution of ethylamine are heated at 100°C during 20 hours in an autoclave .

After cooling the reaction mixture is evaporated to dryness. The residue is treated with 30 ml of 1N NaOH and then extracted with benzene. The benzene phase is dried and evaporated. The oily residue is treated with 1 hydrochloric acid until the pH of the aqueous solution is 0. After extraction with chloroform, the pH of the aqueous solution is brought to 6.

The chloroform phase obtained after a further extraction with chloroform is dried and the solvent is removed.

By trituration with ethyl acetate, a precipitate is obtained. After recrystallization from a mixture of ethyl acetat and methanol, the desired hydrochloride melts at 160-161 °G0 Yield : 60 ¼.

Analysis : % calculated : C 73.12 H 8.47 ; N 8.12 ; CI 10.28 % found : C 72.98 ; H 8.44 ; N 8.25 ; CI 10.04 EXAMPLE 16 Capsule Active ingredient 100 rng Lactose , 120 mg Rice Starch " 30 mg Corn Starch 30 mg Colloidal silica 1 rng for one capsule.

EXAMPLE 17 Tablet Active ingredient 200 mg Potato Starch . 120 rng Lactose 80 mg Starch-sodium glycollate 30 mg Colloidal silica 15 mg Magnesium stearate 5 mg Hydroxypropylcellulose mg Stearic acid 2 mg • EXAMPLE 18 .

Pills . _ Core : Active ingredient 50.0 mg Lactose 67.5 mg Microcrystalline cellulose 32,0 mg Starch-sodium glycollate 8.2 mg Colloidal silica 0.4 mg Magnesium stearate 0.9 mg Coating : Shellac 1.0 mg Sandarac 0.2 rag Castor oil 0.3 mg Gum arabic •7.0 mg Talc 11.2 mg Corn starch ' 1,0 mg Titanium oxide i .3 mg Dyestuff (Patented Blue V) '4.0 mg Sucrose 2.8 mg White v/ax-carnauba wax 0.2 mg for one pill EXAMPLE 19 Solution for perfusion Active ingredient 200 mg Anhydrous sodium sulfite 60 mg Anhydrous sodium metabisulfite 140 mg Sodium chloride 1.7 mg Water for injection ad 200 ml EXAMPLE 20 Solution for perfusion Active ingredient 200 mg Anhydrous sodium sulfite 60 mg Anhydrous sodium metabisuliite 140 mg Sorbitol , , 10 g Water for injection ad 200 ml . · ' EXAMPLE 21' Concentrated solution for dilution prior to injection Active ingredient 200 mg Anhydrous sodium metabisulfite 14 mg Anhydrous sodium sulfite 6 mg' Sodium chloride 130 mg Y/ater for injection ad 20 ml

Claims (3)

1. 43218/3 OIAIMS; 1. Derivatives of 2-aminoindane of the general fo wherein la equal to 2, 3 or 4» the (CHL) grpup having a - c u or straight ;chain in one/more hydrogen atoms ma he replaced by a hydroxy Radical, represents a lower alk l or hydroiyalkyl radical containin 1 to 4 carbon atoms or a lower alkenyl or alkynyl radical containing 2 or 3 carbo atoms, A is a phenyl radical, as well as the acid addition salts of said derivatives of formula I.

2. Derivatives of 2«-aminoindane according to claim 1, wherein, in the general formula I, n is equal to 2, 3 or 4» represents a lower alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert., butyl or a lower hydroxyalkyl group containing 2 to 4 carbon atoms, A is a phenyl radical, as well as the acid addition salts of said derivatives* 3· Derivatives of 2-aminoindane according to claim 1, wherein, i the general formula I, n is equal to 2, 3 or 4, represents a lower alkenyl group selected from ethenyl, pro-pe yl, allyl and isopropenyl, or a lower alkynyl group consisting of propargyl, A is a phenyl radical, as well as the acid addition salts of said derivatives. 4. N-phenyl-li^(y-eth laminopropyl)-2-aminoindane as well as the acid addition salts thereof. ■ 43218/3 5. N-phenyl-N-(Y-propylaiiiinopropyl)-2-aminoindane as v/ell as the acid addition salts thereof. S . N-phenyl-N-(T-methyiarainopropyl)-2-aminoindane as v/ell as the acid addition salts thereof. 7'. N-phenyl-N-(Y-allylaminopropyl)-2-aminoindane as Avell as the acid addition salts thereof. i 8. - Derivatives of 2raminoindane according to clai wherein, in the general formula I, when A represents a substit ed phenyl radical, the substituent is selected from the group consisting of lover alkyl, . lower alkoxy, hydroxy, trifluoromet halo, and nitrd. 9. Derivatives of 2-aminoindane. according to clai v/herein the aci -d. ad·ditio'n· salts are selected from the group co sisting of the moriohydrochloride, dihydrochloride, oxalate, raaleate and furaarate acid addition .salts. _ 10 · A pharmaceutical composition containing as the act ingredient at least one compound according to any of the prece ing claims together with a pharmaceutically acceptable vehicle or excipient. *_ . /·' · 11. A process for preparing heyj derivatives of 2-amino indane as defined in ' claim 1, which comprises either reacting N-phenyl-2-aminoindane of the formula : in the form of its sodium salt with a halogenated amine of formula :. or reacting a compound of the formula /ith a primary amine of the formula : H - N' (VII) \ H or reducing a compound of the formula : or reacting an aniline monohydrochloride of the formula : with indanol inoculate of the 10 ί or de^alkylating a N-phenyl- i-2-/~N-( Y-dialkylamino-alkyl) /-aminoindane of the formula in which has the meanings indicated for R^, A, and n in the above-indicated formulae; (II) through (XIII) having the mean ings indicated in claim 1 , the compound of formula I obtained being transformed, if ' necessary, into an acid addition salt. 1 · A process according to claim 12, wherein the sodium salt of the compound of formula II is obtained by reactin said compound with sodium amide (Uaili^) . 1

3. A process according to claim 12, wherein the compound of formula VI is obtained by reduction of a compound of the, formula : 0 in v.'hich n1 is equal to .n-1 and A has the meanings indicated in claim . 1 . A process according to claim 12, wherein the compound of formula VI is obtained by reacting a compound of formula II with a. bromochloroalkane of the formula : 43218/2 Br. (GH2)a CI (XI) in which n has the meanings indicated in claim 1. ^ 15· A process according to claim 13» wherein the compound of formula V is obtained by reacting a compound of fonwula II with an acid chloride of the formula: 01 (<2H CJ. IX. qVoci (IV) in which n' is equal to n-1. 16. A process according to claim 11, Wherein the compound of formula VIII le obtained by reacting a compound of the formula: in which n* is equal to h-1, with a primary amine of formula VII. 17. A process according to any of claims 11 and 13 wherein reduction is effected with aluminium lithium hydride. 1Θ. A process according to claim 11, in which the compound of formula XII, as soon as it is obtained, js reacted without isolation with the primary amine of formula VII, 19. A process according to claim 11, wherein the desalky-lation of the compound of formula XIII Is effected by means of cyanogen broraide. 20. Derivatives of 2-amlnolndane and. their process of pre* paration substantially aa described above and more particularl in the Examples 1-15. 21. Pharmaceutical compositions containing as the active Ingredient a compound according to claim 1, substantially as described in Examples 16-21.