IL32740A - Basically substituted indolines,their preparation and pharmaceutical compositions containing them - Google Patents

Description

BASICALLY SUBSTITUTED INDOLINESV THEIR PREPARATION 4KD PHARMACEUTICAL : COMPOSITIONS CQiTTAINIHG THEM This invention relates to indolines having basic sub- stituents which have interesting physiological, activities and processes for the preparation thereof.

According to one feature of the present invention there are provided compounds of the general formula therein R^ represents an alkyl group containing from 1 to 5 carbon atoms; R2 and j, which may be the same or different, each represents a hydrogen or chlorine atom or a lower alkyl or alkoxy group containing 1 or 2 carbon atoms; R^ and R^, which may be the. same or different, each represents an alkyl group containing from 1 to 5 carbon atoms (which may, if desired, be substituted by a cyclo- alkyl group)an alkenyl group containing from 5 to 5 carbon atoms, or a cycloalkyl group containing from 5 to 7 carbon atoms; or R^ and R^ together with the adjacent nitrogen atom form a saturated monocyclic heterocyclic 5- or 6- membered ring which may if desired contain an oxygen atom or a further nitrogen atom and/or may if desired be substituted by a lower alkyl group containing from 1 to 5 carbon atoms or a phenyl group; η represents 1 or 2/ and acid addition salts thereof. The compounds according to the invention include cis-compounds in which the phenyl group at 3-position and the radical R1 at 2-position are in cis-relationshi , and trans-compounds in which the phenyl group at 3-position and the radical. R^ at 2-p sition are in trans-relationshi , as well as mixtures of the cis- and trans- compounds . Both the cis- and trans- compounds may be in the form of optical isomers.

The compounds of general formula I and physiologically acceptable acid addition salts thereof show interesting physiological properties. They exhibit antiphologistic and antitussive activities and in particular analgesic activity0 The dextrorotatory cis- and trans-indolines in general show the stronger analgesic activity together with very good antitussive properties 0 - ··?·' The particularly preferred compounds according to the invention by virtue of their interesting physiological . activities include those wherein represents a methyl, ethyl or propyl group. At least one of R2 and advantageously represents a methyl or methoxy group. The substituents R^ and R^ preferably each represent a methyl, ethyl, propyl, butyl, amyl, cyclohexyl methyl, cyclohexyl, allyl or 2-methyl allyl group. When R^ and ^ together with the adjacent nitrogen atom form a heterocyclic ring, this ring__conveniently is a pyrrolidine , iperidine , piperazine or morpholine ring which may be substituted by a methyl, ethyl or phenyl group to form, for example, a 2-ethylpiperidine , 4—phenylpiperidino , —methylpiperazino invention by virtue of their especially interesting physiological activities include :-racemic cis-3-(2-dimethylamino-l-propyl)-2-methyl-3- phenylindoline and acid addition salts thereof; dextrorotatory cis-3-(2-dimethylaminp-l-propyl)-2-methyl- 3-phenylindoline and acid addition salts thereof; racemic trans-3-(2-dimethylamino-l-propyl)-2-methyl-3- phenylindoline and acid addition salts thereof; dextrorotatory trans-3-(2-dimethylamino-l-propyl)-2-methyl- 3-phenylindoline and acid addition salts thereof; racemic cis-3-(2-dimethylaminoethyl)-2-methyl-3-phenyl- indoline and acid addition salts thereof; dextrorotatory cis-3-"(2-dimethylaminoethyl)-2-methyl-3- phenylindoline and acid addition salts thereof; racemic cis-2-methyl-3-phenyl-3-[2-( -phenylpiperidyl)- ethyl]-indoline and acid addition salts thereof; racemic cis-3-[2- (N-ethyl- -methyl)-aminoethyl ]-2-methyl- 3-phenylindoline and acid addition salts thereof; racemic . cis-3- 2-[' -methyl-N-(2-methylprop-2-enTl-yl) ]- amino-ethyl -2-methyl-3-phenylindoline and acid addition salts thereof; racemic cis-2-ethyl-3-[2-(N-isopropyl-N-methyl)-amino- ethyl]-r3-phenylindoline and acid addition salts thereof; racemic cis-2-ethyl-3-(2-diethylaminoethyl)-3-phenylindoline and acid addition salts thereof; racemic cis-3-C2- (N-allyl-N-isopropyl)-aminoethyl1-2- methyl-3-phenylindoline and acid addition salts thereof. compounds of the formula I (as hereinbefore defined) wherein a pseudoindole of formula (wherein R- R2, R^, ^, R^, A and n are as hereinbefore defined) is reduced and the compound of formula I is, if desired, converted into an acid additive salt thereof0 The reduction may, for example, be effected using nascent hydrogen, which may conveniently be obtained in a conventional manner such as by the action of an acid, preferably a dilute mineral acid on a non-noble metal such as zinc, tin, iron or aluminium0 The process is generally carried out in water or in a mixture of water with a water-miscible solvent such as a lower alcohol. Advantageously the reaction is effected at a temperature between 20°C and 150°C, preferably while heating under reflux.

The reduction may also be carried out for example by the reaction. of an alkali metal or an alkaline earth metal such as sodium or magnesium with an alcohol such as ter ,-butanol conveniently at a moderately elevated · tem-perature such as between 20°C to 150°C, the compounds of formula II advantageously having previously dissolved in the carbinol. e.g. sodium amalgam, for effecting the reduction.

If a compound of formula II wherein and/or represent chlorine atoms is reduced with an alkali metal, alkaline earth metal or an amalgam thereof in the presence of an alcohol, these chlorine atoms are generally split off. This method is therefore not appropriate for the preparation of compounds where ¾2 and/or represents chlorine .

Aluminium has also been shown to be suitable as a reducing agent when its surface is amalgamated, aqueous methanol or ethanol or moist ether conveniently serving as reaction medium.

The pseudoindoles of formula II may also be converted into indolines of formula I for example by treat-ing them with a complex metal hydride advantageously in a suitable solvent, the, reducing agent conveniently being tised in excess. This method is generally carried out in a solvent for example, one conventionally used when using these reducing agents and advantageously at ambient tem-perature or a moderately elevated temperature.

A further method for the conversion of the pseudoindoles of formula II into compounds of formula I consists in subjecting them to electrolytic reduction preferably using lead electrodes in an aqueous acid solution.

The reduction of the pseudoindoles of formula II or an acid addition thereof to form indolines of formula I may also be effected using catalytically activated hydrogen, generally also reduced during the action of catalytically activated hydrogen. When ]¾2 and/or R^ are chlorine atoms in compounds of formula II either or both of these chlorine atoms generally will be split off under the action of catalytically activated hydrogen. This method is- therefore not expropriate for the preparation of compounds wherein 1¾2 and/or or compounds wherein R^ and/or R^ represent alkenyl groups.

Catalysts suitable for effecting reduction with catalytically activated hydrogen may conveniently contain a metal of Group VIII of the Periodic Table. These metals may take conventional form for such catalyst such as platinum black, platinum dioxide, palladium on a carrier material, Raney nickel, Raney cobalt or Adkins copper-chromium oxide catalyst.

When using a noble metal catalyst , the process may conveniently be effected under a slight hydrogen pressure for example up to approximately 5 atmospheres, at a temperature advantageously between 20°C and 100°C, preferably at 20°C to 40°C and preferably in aqueous acidic solution, for example in dilute hydrochloric acid.

When Raney nickel or copper-chromium oxide are used as catalysts, a hydrogen pressure of 100 to 200 atmospheres may conveniently be used and a temperature of 100 to 200°C is generally required. The reaction is then preferably effected in an organic solvent, for example in an alcohol such as methanol or ethanpl, in an ether such as dioxan or tetrahydrofuran or in an ester such as ethyl acetajte. and the alkyl group in the 2-position are arranged in a cis- and trans- relationship to one another respectively, these mixtures may be separated for example by a conventional physical method, the most simple method generally being the fractional crystallisation of their salts, for example of, their oxalates or salicylates „ Quite; unexpectedly, it has been found that if A in the compound of formula II represents a branched or straight chain ethylene group, the reduction with zinc or tin in the presence of a dilute mineral acid, with surface amalgamated aluminium or by electrolytic reduction leads in the main to indolines wherein the phenyl group in the 3-ppsition and the : alkyl group in 2-position have a cis-relationship. The reduction with palladium on animal charcoal leads to indolines .wherein these two groups have a trans-relationship. These coir-pounds are designated herein as cis- and trans-indolines respectively.

In these reactions, the cis- and trans-indolines always appear as mixtures of their optically active isomers. The cis- and the trans-indolines possess two assymetric centres being the carbon atoms in the 2- and 3-positions of the indoline ring. When A represents a; branched aliphatic hydrocarbon group containing 3 or A-carbon atoms, a further asymmetric centre or when A represents a chain branched in two places, two further asymmetric carbon atoms occur in group A. The compounds may, if desired, be separated into their optically active laevo- and dextrorotatory forms. fractional crystallization of their diastereomeric salts conveniently with D-(-)-tartaric acid. A solution containing an equimolar quantity of D-(-)-tartaric acid, for example, may be added to a solution of the racemic mixture in a suitable solvent, for example in water0 The solution in some cases may be partially evaporated to aid crystallisation,, Generally, the diastereomeric salt with D(-)-tartaric acid of the dextrorotatory indoline base crystallisesfirst „ In most cases it proved to be suffi-cient to recrystallise the tartrate from a solvent only once, for example from water. Subsequently, the optically active base may, if desired, be liberated from its salt by means, for example, of a stronger base such as sodium hydroxide solution. The base which separates may be ex-tracted with an organic solvent, for example with ether, benzene or chloroform and the base liberated from this extract conveniently by evaporating the solvent.

If desired, the corresponding laevorotatory indoline base may be isolated by rendering the mother liquor alkaline. The precipitated crude base may if desired be converted into a salt of an optically dctive acid with, for example L-(-)-tartaric acid to form its tartrate which may subsequently be purified by recrystallisation0 The laevorotatory indoline base may be liberated from the purified salt for example by making a solution of the salt alkaline and subsequently extracting the free base with a suitable organic solvent.

The compounds prepared by the process according to the invention may, if desired, be converted into an acid be formed from inorganic or organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, salicylic acid, succinic acid, tartaric acid, citric acid, adipic acid, maleic acid and fumaric acid.

The compounds of formula II used as starting materials for the process according to the invention may be prepared Israel for example, according to the processes described in ,24230 Patents' No./ j'^^^ ^^-^-lA ^Q ^O^ and, Cilia. ·ν∞ ·^ φ^Ο- &-, · ·1>γ cyclization of a phenylhydrazone of formula / (wherein 1*2» Rj, R^> R^'and A are as hereinbefore defined) in the presence of a condensation agent whereby ammonia is split off. If desired, the pseudoindole derivative formed may be separated before reaction, for example by crystallization.

The analgesic activity of certain compounds of formula I and physiologically acceptable acid addition salts thereof has been determined in mice according to 316) o The following values were obtained; racemic 3-(2-dimethylamino-l-propyl)-2-methyl-3-phenyl- 3.1 indoline hydrochloride (cis-form) ED10Q, per os mg/kg; its dextrorotatory form ED100 per os 2„ 3 mg/kg, racemic 3-(2-dimethylamino-l-propyl)~2-methyl-3-phenyl- per os 32.8 mg/kg; its dextrorotatory form ED10Q, per os 12 , 7 mg/kg; its laevorotatory form per OS 30.0 mg/kg, racemic 3-(2-dimethylamino-ethyl)-2-methyl-3-phenyl- indolinehydrochloride (cis-form) ED1Q0, per os 3^ o 5 mg/kg; its dextroro atory form ED100, per os 16o 0 mg/kg, racemic 2-methyl-3-phenyl-3-[ 2-(A—phenyl-piperidyl)- ethyl] -indoline (cis-form) ED10Q, per os 15 mg/kg0 The antiphlogistic activity has been determined on the kaolinoedema in the rat paw, following the method of Wagner-Jauregg, Arzneimittelforschung 12 , 1160 ( 1962) 0 The following compounds showed a greater than 60% re-duction of the swelling, at a dosage of 100 mg/kg per os; 3- 2-[N-methyl-N-( 2-methyl-2-propen-l-yl) ] -aminoethyl¾- 2-methyl-3-phenyl-indolinedihydrochloride (cis-form) 2-ethyl-3- [ 2-(N-isopropyl-N-methyl)-aminoethyl] -3-phenyl- indolinehydr chloride (cis-form) 2-ethyl-3-( 2-diethylaminoethyl)-3-phenyl-indoline hydrochloride (cis-form).

The antitussive activity has been determined with awake white rats0 In each test, 25 mg/kg of the separate compounds under test were administered perorally to each - 12a - - 32740/2 The compounds according to the invention have a better activity than the most closely related, paeudoindoles known from Frenc "Patent No. M 4423.

The therapeutic index LD_.Q/ED10Q of the compounds A, B and C according to the invention was compared with' that of the two known compounds: - D) 2-methyl-3-phenyl-3-(2-dimethylamino-l-propyl)-pseudoindole- hydrochloride (Example 8 of French Patent M 4423) and ' . ': '· E) 2-methyl-3-phenyl-3-(2-dimethylamino-ethyl)-pseudoindoie- hydrochloride (Example 2 *of the French Patent 4423).

•The result is shown in the following table: The compounds according to the invention are generally preferable to other analgesics, for example of the morphine type, by virtue of the absence or reduction of ' respiratory prooon invention cause- respix'afaor^ epression-i is generally inai-giajr -e-an - compared' wrl-^r^^-e—pec^u-ced—by^ ■morphine „ According to yet a further feature of the invention there are provided pharmaceutical compositions comprising at least one compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient0 The compositions may be presented in a form suitable for oral, rectal or parenteral administration,, Thus, for example, compositions for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, syrups, shake-mixtures, emulsions, suspensions or drops such composi-tions comprising carriers or excipients conventionally used in the pharmaceutical art0 Thus, for example , suitable tabletting excipients include lactose, potato and soluble starches and magnesium stearate.

For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e„g0 arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base0 Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient „ Tablets, coated tab?-lets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit for being preferred for children.

The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients: - Example 1 3-(2-Dimethylamino-l-propyl)-2-methyl-5-phenylindoline In a flask equipped with stirrer, cooler, thermometer and dropping funnel, 50 g of 3-(2-dimethylamino-l-propyl)- 2-methyl-3-phenylpseudoindole were dissolved in 250 ml of ethanol and to the solution 70 g of zinc dust were added. With constant stirring, 300 ml of 36% hydrochloric acid were then dropped in maintaining the bath temperature at 80 - 90°C. After about 6 hours the reaction mixture was poured into water and mixed with sufficient concentrated aqueous ammonia solution (or sodium hydroxide solution) to redissolve the solid precipitate formed and to cause separation of an oil which was extracted into benzene. The benzene solution was washed, dried and evaporated. ' The above mentioned base was obtained which was recrystallized from petroleum ether.

Yield: 4-5 g, colourless crystals (cis-form) of m.p. 91°C. M.p. of the hydrochlorides 25 °C.

Example 2 • 3-(2-Dimethylaminoethyl)-2-methyl-3--phenylindoline To a solution of 20 g of 3"-(2-dimethylaminoethyl)-2- methyl-3-phenylpseudoindole in 150 ml of ethanol were added 0.5 S of mercury(II)chloride and 0 g of zinc dust. While stirrin and refluxin 12 ml of concentrated alkaline with sodium hydroxide and the base was extracted with ether. The ether was evaporated and the residue distilled in vacuo. 16 g of the above mentioned indoline deriyate (cis-form) of b.p. 120 - 130°C/0.02 m.m. Hg; m.p. 79 - 80°0 were obtained, m.p. of its hydrochloride: 1SG°C (from ethanol). M.p. of the hydrogen maleate: 123°C.

By the same method starting frpm the corresponding pseudoindoles the following indolines were obtained: (a) 2-Methy1-3-( iperidinoethyl)-3-phenylindoline (cis- form) m.p.: 116 - 118°C (from petroleum ether); yield 76% of theory. M.P. of its dihydrochlorides 220°C (decomp.). (b) 3-[2-(N-Tsopropyl-N-methyl)-aminoethyl1-2-methyl-3- phenylindoline (cis-form) m.p.: 9' -96°C (from petroleum ether); yield: 75% of theory. (c) 3-(2-Diethylaminoethyl)-2-methyl-3-phenylindoline (cis-form) b.p.: 157-159°C / 0.04 mm Hg; yield: 66% of theory. M.p. of its. dihydrochlorides 176°C (decomp.). (d) 3-[2-(N-tert. -Butyl-N-methyl)-amnoethyl1-2-methyl-3- phenylindoline (cis-form) b.p.: 156°C / 0.1 mm Hg: yield: 78% of theory. M.p. of its dihydrochlorides 163°C (decomp.). (e) 3-(3-Dimethylamino-l-propyl)-2-methyl-3-phenylindoline (cis-form) m.p.: 77~78°C (from petroleum ether); yield: 68% of theory. M.p. of its dihydrochlorides 235°C (decomp.). (f) 2-Methyl-3-phenyl-3-(2-pyrrolidinoethyl)-indoline (cis- form) b.p.: 169-170°C / 0.15 mm Hg (m.p.: 96-98°C ) : yield: 52% of theory. M.p. of its hydrogen maleate: 183°C (decomp.). (h) '5-[2-(N-ethyl-IT-methyl)-aminoethyl1-2-methyl-3-phenyl- indoline (cis-form) b.p,: 161°C / 0.07 mm Hg; yield; 73% of theory,, M.p. of its salicylate; 14-7°C, (i) 5-[2-(N-2-Butenyl-N-methyl)-aminoethyl1-2-methyl-3- phenylindoline (cis-form) b.p.: 160-36^0 / 0.07 mm H ; yield; 71% of theory. (j) 3-[2-(N-Ethyl-N-hut-2-enyl-aminoethyl]-2-methyl-3- phenylindoline (cis-form) b.p.: 155-156°C / 0.06 mm Hg; yield: 77% of theory, M.p, of its diphosphate: 127°C (decomp,), (k) 2-Methyl-3-phenyl-3-[2-( -pfaenylpiperidino)-ethyll- indoline (cis-form) m,p,: 154-155°C; yield: 60% of theory, (1) 3-[2-(N-Isoamyl-N-methyi -aminoethyl]-2-methyl-3- phenylindoline (cis-form) m,p,: 98-99°C (from petroleum ether); yield: 70% of theory, (m) "5-t2- N^n-Buty ^K-methyl)-aminoethyl ]-2-methyl-3-phenyl- indoline (cis-form) m,p,: 80-81°C; yield: 71% of theory, (n) ■ 3-[ 2-(N-Methyl-N-n-propyl)-aminoethyl1-2-methyl-3- phenylindoline (cis-form) b.p.: 14-2-14-3°C / 0.05 mm Hg (m,p.: 5^-56°C); yield: 80% of theory, (o) 3-[2-(N-Isohutyl-N-methyl)-aminoethyl]-2-methyl-3- phenylindoline (cis-form) b.p.; 157°C / 0,04 mm Hg (m.p, 68°C); yield: 81% of theory, (p) 3-[2-(N-Isohutyl-N-isopropyl)-aminoethyl1 ~2^methyl- 3-phenylindoline (cis-form) b,p,: i4-3-14-5°C / 0,01 mm Hg; yield: 77% of theory, (q) 3- [2-(N-n-Amyl-N-metbiyl)-aminoethyl ] -2-me hy1-3-phenyl- (r) 5^[2^CK-Cyclofaexylmethyl-N-metfayl)~amihoethyl1~2-methyl- 3-Phenylindoline (cis-form) b0p0; 182°C / 0,03 mm Hg; yield; 52% of theory; m0p, of its hydrobromide; 157 - 159°C„ (s) 3-[ 2-(N-Allyl-N-methyl)-aminoethyl1-2-me hyl-3-phenyl- indoline (cis-form) b,p„; 152°C / 0,1 mm Hg; yield; 70% of theory,, (t) 3-t2-(IT-Allyl-N-i3opropyl)-aminoethyl]-2~methyl-3- phenylindoline (cis-form) b,p0; 164-165 0 / 0,1 mm Hg; yield; 75% of theory. (u) 3-[2-(2-Ethylpiperidino )-ethyl 1-2-methyl-3-phenyl- indoline (cis-form) b,p0; 172-173°C / 0,01 mm Hg; yields 0% of theory, (v) 3-(2-Piperidinoethyl)-2-methy1-3-(3. ^dimethoxyphenyl)- indoline (cis-form) b0p0; 213°C / 0,5 mm Hg; yield; • 79% of theory0 ΓΊ,ρ, of its dihydrochloride ; 239°C (decornp, ) 0 (w) 2^Ethyl*3-(2-diethylaminoethyl)°3-Phenylindoline (cis- form) b,p,; 166°C / 0,2mm Hg; yield; 69% of theory, (x) 2-Ethyl-3-C2-(N-isopropyl-N-methyl)-aminoethyl1-3- ■ phenylindoline (cis-form) b0p0; 161°C / 0,04 mm Hg; yield; 60% of theor , Mep, of its hydrochloride; 226-228°C, (y) 3-i-2-[N-Methyl-N-(2-methyl-prop-2-ene-l-yl)1-amino- ethyl -2?-methyl-3-phenylindOline (cis-form) b,p,; 179°C / 0,3 mm Hg; yield; 69% of theory, M,p, of its " dihydrochioride; 211°C„ J. (aa) 3-[ 2-(N-Cyclohexyl-N-methyl-aminoe h l 1-2-methyl-3- phenyUndoline (cis-form) b0p„s 164~166°C / 0o05 mm Hg; yields' 71% of theory0 Mep0 of its methane sul- phonates 137-139°0. (bb) 3-C ~Dimethylamino~l°-propyl)-3-phenyl-2~n-propyl- indOline (cis-form) b0pDs 1 9-150°C / 0o06 mm Hg; yields 83% of theor 0 M0p0 of its hydrochlorides 196-198°C0 (cc) 2-Ethyl-3~Γ2-(N-ethyl-N-methyl) -amlnoethyl 1-3- phenylindoline (cis-form) b0p0; 1 5°C / 0„ 0 mm Hg; yields 70% of theory0 M0p0 of its hydrochlorides 193194-°C, (dd) A mixture of 2-Methyl-3-[2-(N-methylpiperazino )-1-propyl ' phenylindoline (cis-form) and 2-methyl-3-i l-(N-methylpiperazino)-2*-propyl phenylindoline (cis-form) b0pos 158-160°C / 0005 mm Hg was obtained by reacting the corresponding mixture of the two pseudoindoles of b0p0s 183- 187°C / 0o 08 mm Hg0 Yields 90% of theory0 (ee) 3-( ~Chlorophenyl)-3-(2~diethylaminoethyl)-2-methyl- indoline (cis-form) b0pos 150-152°C / 0o06 mm Hg; yields 72% of theor 0 (ff) 3-(2-Diethylaminoethyl )-3-( -methylphenyl )-2-methyl- indoline (cis-form) b0p0s 1 2-14-3°C / 0.05 mm'Hg, m0p0s 71-73°C (from petroleum ether); yield: 75% of theory, (gg) ·3-(2-Diethylaminoethyl)-2-methyl-3- ( —methoxyphenyl )- indoline (cis-form) bop0s 173-175°C / 0. 3 mm Hg? 7 % of theory. M.p. of its hydrochloride; 205-207°0 (decomp.). (ii) 5-Chloro-3-(2-diethylaminoethyl)-2-methyl-3-phenyl- indollne (cis-form) b.p„; 13 -139°C / 0.02 mm Hg; yields 61% of theory.

Example 3 , 3-C2-Dimethylaminoethyl)-2-methyl-:3-phenylindoline To a solution of 8 g of 3-('2-dimethylaminoethyl)-2-methyl-3-phenylpseudoindole in 80 ml of methanol were added 10 g of aluminium grit amalgamated and a 1% aqueous solution of mercury(II)chloride. 10 ml of water in small portions were added dropwise over 5 hours with stirring,, The reaction mixture was stirred for a further 8 hours, mixed with 150 ml of 25% sodium hydroxide, filtered and then extracted with benzene and ether. "The organic layers were evaporated and the residue recrystallised from petroleum ether to yield 5.0 g (cis-form) of the above mentioned compound; m.p. s 78-80°C0 Example 3-(2-Dimethylaminoethyl)-2-methyl-3-phenylindoline To a boiling solution of 22 g of 3-(2-dimethylaminoethyl)-2-methyl-3-phenylpseudoindole in 180 ml of concentrated hydrochloric acid and 90 ml of water were added 100 mg of-' cupric sulphate. 25 g of granulated tin were subsequently introduced in portions over 7 hours. After adding a further 50 ml of concentrated "hydrochloric acid, the mixture was refluxed for a further 2 hours, rendered alkaline after cooling and extracted with ether. The ether extract was evaporated and the residue distilled in · vacuo . 11.8 g Example 5 3-(2-DimethylaminOethyl)-2-methyl-3-Thenylindoline A solution of 5.0 g of 3-(2-dimethylaminoethyl)-2-methyl-3-phenylpseudoindole hydrochloride in 500 ml of 10% sulphuric acid was electrolyzed at 50 to 60°C using- a lead cathode at a potential of 7 to 8 Volts at a. current of 17 amps. When complete, the reduction which was monitored thin-layer chromat©graphically, the base was precipitated by addition of-sodium hydroxide solution and the base was extracted wit ether „ Addition of a solution of salicylic acid in ether precipitated the salicylate (cis-form) •of the above-mentioned indoline, M0p0s 156°C; yields 3 g„ By the same method were obtaineds (a) 3^(2-Pimethylamino- -propyl)-2-methyl-3-phenylindOf° line (cis-form) from 3-(2-dimethylamino-l-propyl)-2- methyl-3-phenylpseudoindole. M0p0: 90-9l°C; yield; 65% o (b) 2-Methyl-3-Phenyl-3-[ 2-( -phenylpiperazino)-et g"1-'· indoline (cis-form) ; from- 2-methyl-3-phenyl-3-[2- — phenylpiperazino)-ethyl ]-pseudoindole<, M„p0s 163- 166°C$ yield: 60%.

Example 6 3-(2-Dimethylaminoethyl)-2-methyl-3-phenylindoline 28 g of 3-(2-dimethylaminoethyl)-2-methyl-3-phenyl pseudoindole were dissolved in 150 ml of methanol 0 36 g of Sodium borohydride were introduced portionwise over hours with stirrin 0 The reaction mixture was re-fluxed for a further hour o The batch was then poured into water and the oil which separated extracted into (b.p. 139-1 1°C / 0.1 mm Hg) were obtained consisting in about equal quantities of the cis- and trans-isomers „ Example 7 3-(2-Dimethylaminoethyl)-2-rmethyl-3-phenylindoline (a) 14 g of 3-(2-dimethylaminoethyl)-2-methyl-3-phenyl- pseudoindole were dissolved in 100 ml of anhydrous tetrahydrofuran, 3«6 g of lithium aluminium hydride added 'in small portions with stirring and the mixture warmed for hours at 50°C. After cooling, the batch was poured onto ice, mixed with 20% sulphuric acid until an acid reaction was given and then made alkaline with sodium hydroxide solution,, The oil which separated was extracted with ether and distilled after removal of the solvent , 9 g of the desired . indoline (b,p„ 1 1-1 3°C / 0.15 mm Hg) were obtained consisting of a mixture of the cis- and, trans-isomers,, (b) 2.78 g of this mixture were dissolved in 20 ml of ether and admixed with a solution of 0,72 g of sali-. cylic acid in 5 ml of ether. After standing a short while, the precipitate was filtered off with suction and 2.15 g of the salicylate of the trans-isomer were obtained (m.p,: 17 -177°C from isopropanol) 0 On adding another 0, 72 g of salicylic acid in ml of ether, to the ethereal,filtrate 1„6 g of the salicylate of the cis-isomer precipitated after some hours which recrystallized from isopropanol (m0p,5 152-15 0C)o (c) 2,78 g of the mixture obtained in (a) above were dissolved in 20 ml of ethyl acetate and 0, 9' "g of anhydrous oxalic acid were added, 3 g of the oxalate oxalate of the trans-isomer were obtained (m,p„: 116-118°C).

The filtrate from preciplliation of the oxalate which contained ethyl acetate was evapprated, a 5% sodium hydroxide solution was added and the base formed extracted with 20 ml of ether. The solution was dried over potassium carbonate and 0.72 g of salicylic acid dissolved in 5 com of ether were added. The precipitated salicylate was reorystallized from ethanol (m.p.: 1'5'5-156'°C) and consisted of the corresponding cis-isomer „ Yield; 0.9 g.

Example 8 3~C2-Dimethylaminoethyl)-2-methyl-3-phenylindoline 13 g of 3-(2-dimethylaminoethyl)-2-methyl-3-phenyi-pseudoindole were dissolved in 200 ml of tert .-butanol and the solution refluxed. Within 7 hours, 8 g of sodium was added with stirring and the mixture was subsequently- re-fluxed for a further hours. The cooled solution was filtered and poured into water. An oil separated which was dissolved in ether. After drying, the solvent was evaporated and the residue distilled. A colourless product (b.p. 1 3°C / 0.2mm Hg consisting of a mixture of the cis- and trans-isomers of the above mentioned indoline was obtained.

Yield: 6.8 g.

Example 9 3- [2-(N-"2-Butenyl-N-methyl) aminoethyl ] -2-methyl-phenyl-indoline with a 1% aqueous solution of mercury(II)chloride. During 5 hours, 10 ml of water were added dropwise in small portions with stirring. The reaction mixture was stirred for another 8 hours, mixed with 150 ml of 25% sodium hydroxide solution and the insoluble products were filtered off. The filtrate was extracted with benzene and ether. The organic extracts were evaporated and distilled in vacuo. 6.6 g of the above mentioned compound (cis-isomer) were obtained. B.p0: 160-165°C / 0.07 mm Hge Example 10 3-(2-Dimethylaminoethyl)-2-methyl-3-phenylindoline 7 g of aluminium grit were amalgamated on the surface and added to a solution of 6 g of 3-(2-dimethylaminoethyl)- 2-methyl-3-phenylpseudoindole in 7Q ml of methanol. 25 ml. of 2N-hydrochloric acid added, dropwise with stirring at a temperature of 20 to 30°C. After stirring for a further 16 hours, the reaction mixture was made alkaline with sodium hydroxide solution and extracted with benzene.

Evaporation of the organic solvent and subsequent re-crystallisation of the solid product from petroleum ether gave 3.9 S the above mentioned compound (cis-isomer) .

M,p. s 80 -81°C.

Example 11 3-(2-Diethylaminoethyl)-5-methoxy-2-methyl-3-phenylindoline 37 g of 3-(2-diethylaminoethyl)-5-methoxy-2-methyl-3-phenylpseudoindole (b.p.: 168-173°c / 0.01 mm Hg) were dissolved in 150 ml of ethanol, mixed with 2 ml of saturated copper sulphate solution and 0 g of zinc powder and heated to reflux temperature. 60 ml of concentrated water and mixed with an excess of ammonia0 The mixture was extracted with ether, the ether solution was dried and the solvent distilled off„ The residue was distilled in vacuo„ Yield; 75% of theory of the indoline (cis-form) . b0p0s 162 - 165°C / 0o01 mm H 0 The dihydrochloride, precipitated from acetone, had a melting point of 209°C (decomp0)„ Example 12 -('2-Dimethylami"noethyl)-2-methyl--3-phenylindoline g of 3-(2-dimethylaminoethyl)-2-methyl~3-phenyl-pseudoindole hydrochloride were dissolved in 200 ml of IN hydrochloric acid and hydrogenated over 3 g of 10% palladium on carbon catalyst in a 500 ml Parr-autoclave at ambient temperature and a hydrogen pressure of 2 to 3 atm until the calculated quantity of hydrogen had been taken up0 After the filtration of the catalyst, the reaction mixture was made alkaline by sodium hydroxide solution, extracted with ether, the ether solution dried and the solvent distilled off0 The residue was recrystallized from petroleum ether„ The product had a melting point of 79°C and consisted of the pure trans-form of the above mentioned indoline0 Yields 1 06 g0 The' dihydrochloride of the compound recrystallized from acetone/ethanol had a melting point of 2 1°C (dec0mp0)e By the same method starting from the corresponding pseudoindoles the following indolines were obtained; (a) 3-(2-Diisopropylaminoethyl)-2-methyl-3-phenylindoline (trans-form) m.p0 s 90-92°C (from ethanol); yields of theory„ (c) 2-Methyl-3-(2-piperidinoethyl)-3-phenylindoline (transform) m.p.s 13 -136°C; yield: 7 % of theory, (d) 2-Methyl-3-[ 2-(N-isopropyl-N-methyl)-aminoethyl1-3- phenylindoline (trans-form) m0p0s 82-84°C; yields 52% of theory. (e) 3-[2-(N-tert0-Butyl-N-methyl)-aminoethyl]-2-iPethyl- 3-phenylindoline (trans-form) m0p0s '99°C; yields 73% of theor . (f) 3-( 3-Dimethylamino-l-propyl)-2-methyl-3-phenylindo- line (trans-form) m,p0: 110-112°C; yields 60% of theory, (g) 2-Methyl-3-(2-morpholinoethyl)-3-phenylindoline (trans-form) m0p„: 122°C; yields 73% of theory0 (h) 3-(2-Dimethylamino-l-propyl)-2-methyl-3-phenylindo- line (trans-form) m0p.s 122~12 °C; yields 81% of theory. (i) 3-(2-Dimethylaminoethyl)-205-dimethyl-3-phenylindo- line (trans-form) b.p.s 158°C / 0o 15 mm Hg; yields 82% of theory. M0p. of its salicylates 206-207°C (decomp,,). (d) 3-(2-Diethylaminoethyl)-5-methoxy-2-methyl-3- phenylindoline (trans-form) b0p.s 162-165°C / 0.01 mm Hg; yields 7 % of therory. M0p0 of its dihydro- chlorides 230°C (decomp,). 3-(2- ethylaminoethyl)-5-roethoxy-2-methyl-3- phenylpseudoindole served as starting material (b.p.s 168-173°C / 0,01 mm Hg). (k) 3-(2-Die'thylami-nOethyl)-2-methyl-3-( -^methylphenyl- Example 13 3-[2-(N-cyclohexyl-N-met ^^ indoline 1,3 S of 3-[2-(N-cyclohexyl-N-methyl)-aminoethyl]-2-methyl-3-phenylpseudoindole were dissolved in 100 ml of IN hydrochloric acid and hydrogenated over 2 g of 10% palladium on carbon catalyst in a 500 ml Parr-autoclave at about 30°C and at a hydrogen pressure of 2 to 3 Atm, until the calculated quantity of hydrogen had been absorbed.

After the filtration of the catalyst, thefiltrate was made alkaline with a base and was extracted with ether.

The ether solution was dried and the solvent distilled off. The remaining oily residue was distilled in vacuo „ 9 g of the trans-form of the indoline were obtained as a yellowish oil (b.p.; 172-173°G / 0.1 mm Hg) . The hydrochloride precipitated from acetone had a melting point of 186 - 188°CC By the same method starting from the corresponding pseudoindoles the following indolines were obtained? (a) 3~(2-I3iethylaminoethyl 2-methyl-3-phenylindoline (trans-form) b.p.s 156°C / 0003 mm Hg; yields 7% of theory. M.p. of its dihydrochloride : 23 °C (decomp0)0 (b) 2-Methyl-3-phenyl-3~(2-pyrrolidinoefhyl)-indoline (trans-form) b.pe; 170 - 175°C / 0.2 mm Hg; yield; 4 of theory. M.p. of its dihydrochloride; 167°C (decomp. ) . (c) 3-['2-(IT-Ethyl-N-methyl-aminoethyl]-2-methyl-3-phenyl- indoline (trans-form) b.p.; 1'57-158°C / 0.08 mm Hg; yield; 95% of theory. M.p. of its dihydrochloride s 215°C (decomp. ). ΓΊ.ρ. of its dihydrochloride : 234- - 236°C0 (e ) 3-[ 2-(N-n-Butyl-N-methyl)-aminoethyl T-2-methyl-3- phenylindoline (trans-form) b0p0s 155-156°C / 0.04· mm Hg; yield: 79% of theory0 (f) 3- Γ2-(N-Methyl-TT-n-propyl)^aminoethyl] -2-methyl-3- phenylindoline (trans-form) b0p0: 14-5°C / 0.08 mm 'Hg; yield: 69% of theory, m0p„ of its diphosphate: 192- 193°Ce (g) 3-[2-(N-Isobutyl-N-methyl)-aminoethyl]-2-methyl-3- phenylindoline (trans-form) 0p0: 153°C / 0„04- mm Hg; yield: 80% of theory. M.p. of its dihydro- chloride: 161°C (decomp.). (h) 3-t'2-(N-Iso¾utyl-:-N-isopropyl)-aminoethyl1-2"met¾ 1- 3-phenylindoline (trans-form) b0p0: 144--1 5°C / 0.02 mm Hg; yield: 81% of theory. M.p. of its hydrochloride: 164-166°C. (i) 3-[2-(N-n-Amyl-N-methyl)-aminoethyl]-2-methyl-3- phenylindoline (trans-form) bop0s 160 - 162°C / 0e01 mm Hg; yield: 83% of theory0 (k) 3-[2-(N-Cyclohexylmethyl-N^methyl )-aminoethyl1-2° methyl-3-phenylindoline '(trans-form) b.p. 180- T82°C / 0.04- mm Hg; yields 55% of theory. M.p. of its hydrogen maleate: 175-177°C. (1) 3-(3-Diethylamino^propyl)-2-methyl-3-phenyl- indoline (trans-form) b0.po: 153-155°C / 0005 mm Hg; yield: 75% of theory. M.p. of its dihydro- chloride: 192°C.

Example 14- 3-(2-DimethylaminOethyl)-2-methyl-3-phenylindoline was heated for hours to 150°C at a hydrogen pressure of 150 atm. After cooling, the reaction mixture was filtered free of catalyst and the solvent was evaporated. The residue was distilled at 1 2-14°C / 0,2 mm Hg. The distillate consisted of a mixture of the cis- and trans-isomers of the indoline. Yield: 9 g.

Working by the same method but using 3 g of Raney cobalt instead of Raney nickel and heating for 4 hours under the same conditions gave 1101 g of a mixture of the cis- and trans-isomers.

Example 15 2-Methyl-3"Phenyl-3-[2-( -phenylpiperidino)-ethyl]-indoline g of the methane sulphonate of 2-methyl-3-phenyl-3-[2-( -phenylpiperidino)-ethyl]-pseudoindole were dissolved in a mixture of 50 ml of "2N hydrochloric acid and 50 ml of methanol and hydrogenated using platinum oxide as catalyst at room temperature. After the uptake of hydrogen, the reactio mixture was filtered and evaporated in vacuo.

Sodium hydroxide was then added until the solution was alkaline and the whole was extracted with methylene chloride. After evaporation of the solvent, the cis-form of the above-mentioned indoline remained. Yield; .0 g.

M.p.: 149-151°C (from methanol/ethyl acetate )e Example 16 3-[2-(N-n-Butyl-N-methyl)-aminoethyl]-2-methyl-3-ph'en:ylr indoline .3 S of - 3-[-2-(N-2-butenyl-N-methyl)-aminoethyl]-2- ogenated methyl-3-phenylpseudoindole hydrochloride were hydr^ted. in 100 ml of IN hydrochloric acid using 1 of 10% calculated quantity of hydrogen had been absorbed,, The above mentioned indoline (trans- orm) was obtained. B,p, 155 - 156°C / 0,04 mm Hg; yield; 3.5 g.

By the same method was obtained; 3-ΐ 2-(N-Methyl-N-n-propyl )-aminoethyl1.1 -2-methyl-3-phenylindollne (trans-form) from 3-[ 2-(N-allyl-N-methyl) aminoethyl] -2-methyl-3-phenylpseudoindole. Yield; 70%, The compound had a boiling point of 14-5°C / 0,08 mm Hg, M.p.' of its diphosphate: 192-193°C, Example 17 3-(2-Diethylaminoethyl)-2-methyl-3-(4--methoxyphenyl)-indoline 13A S of 3-(2-diethylaminoethyl)-2-methyl-3-( -methoxyphenyl)-pseudoindole were dissolved in 120 ml of litf hydrochloric acid and hydrogenated in a 500 ml Parr-autoclave over 10% palladium on carbon catalyst at a temperature up to 4-0°C and a hydrogen pressure of 2 to 3 atm until the absorption of the calculated quantity of hydrogen had taken place, 11 g of the above mentioned indoline (b,p0; 160-162°C / 0, 05 mm Hg) were obtained consisting of a mixture of about 80% trans-form and about 20% cis-form.

Example 18 3-(^Chlorophenyl)-3-(2-dimethylaminoethyl)-2-methyl-indoline (cis-form) To a boiling solution of 30 g.l.of 3-(4-chlorophenyl)' 3-( 2-dimethylaminoethyl)-2-methylpseudoindole in 230 ml of ethanol were added 1,6 g of mercury(Il) chloride , 80 g of zinc dust were added in portions over 6 hours with filtered off, the filtrate was made .alkaline with ammonia and the base was extracted with ether „ The organic extract was dried, evaporated and the residue recrystallized from petroleum ether „ 19 5 g of the above mentioned compound (cis-form) were obtained. M„p0: 120-121°Ce Example 19 3-(4--Chlorophenyl)-5-(2-dimethylaminoethyl)-2-methylindoline (cis-form) To a solution of 8 g of 3-( —chlorophenyl )-3-(2-dimethylaminoethyl)-2-methylpseudoindole in 80 ml of methanol were added 10 g of aluminium grit which had been amalgamated immediately before use with a 1% aqueous solution of mercuryClI ) chloride „ 10 ml of water were added dropwise in small portions with stirringe The mixture was stirred for a further 15 hours at ambient temperature and mixed while cooling with excess sodium hydroxide solution. The solution was extracted with ether, the organic phase evaporated and the residue recrystallized from petroleum ether, .2 g of the above mentioned base were obtained (m.p.s 120 - 120.5°C)o Example 20 The optical 1 isomers of cis-3-(2-dimethylamino-l-propyl)-2~ methyl-3~phenylindoline (a) Racemate of 3-(2-dimethylamino-l-propyl)-2-methyl-3- phenylindoline (cis-form) In a flask equipped with stirrer, cooling device, ther-niometer and dropping funnel were placed 50 g of 3-(2-dimethylamino-l-propyl) -2-methyl-3-phenylpseudoindole (m.p.: 102°C) dissolved in 250 ml of ethanol. Then 70 g of zinc dust were added to the solution with constant stirring, 300 ml of 36 hydrochloric acid were added dropwise, the bath temperature being maintained at 80-90°σβ After about 6 hours, the reaction mixture was poured into water and mixed with sufficient concentrated aqueous ammonia solution (or sodium hydroxide solution) to redissolve the solid precipitate formed and to result in separation of oil which was extracted into benzene. The benzene solution was washed, dried and evaporated. The above mentioned base was obtained which was recrystallized from petroleum ether. Yield: 4-5 g of colourless crystals (cis-form) of m.p. 91°C. M.p. of the hydrochloride; 254°C.

Dextrorotatory form of cis-3-( 2-dimethylamino-l-propyl)-2-methyl-3-Phenylindoline 44.1 g of (± )-3-( 2-dimethylamino-l-propyl)-2-methyl-3-phenylindoline (cis-form) and 2275 S of D-(-)-tartaric acid were dissolved in 600 ml of hot distilled water. The solution was allowed to stand for about 7 hours at room temperature. The precipitated crystals were drawn off and then recrystallized from 600 ml of water. After standing over night, the precipitate ( 36. 5 s) was filtered off (m.p. ; 98 -100°C) and the base was liberated with 10% sodium ether solution, 19.2 g of optically active (+)-base precipitated. [o]2£° = +319° (c = 0.98, ethanol, 1 dm) The (+)-base was dissolved in ethanol and converted into the hydrochloride (m..p.: 214'- 217°C) by adding hydrogen chloride gas in ether. [ct]p°° = +355° (c = 1, ethanol, 1 dm) (c) Laevo-rotatory form of cis-3-(2-dimethylamino)-l- propyl)-2-methy1-3-phenylindoline After crystallisation of the diastereoisomeric salt of the dextrorotatory base, the mother liquor was made alkaline with 10% sodium hydroxide solution,, The liberated base was extracted into ether . The ether solution was dried with sodium sulphate and the solvent removed leaving the enriched (-)-base (13.2 g) which was mixed with 8.0 g of L (+)-tartaric acid in 300 ml of hot water. 21.0 g of the precipitated (+)-tartrate were recrystallized from 200 ml of hot water. 8.8 g of (-)-base were obtained from 18.0 g of pure (+)-tartrate by adding an alkali hydroxide solution as described in Example 20 b. [a]p°° = -31 ° (c = 1.08, ethanol, 1 dm) The hydrochloride of this compound had a melting point of 214 - 216°C. [α]ρ0°= -364° (c = 1, ethanol, 1 dm) Example 21 The' optical isomers-0f-trans-3-(2^dimethylamiho-l-propyl)-2-methyl÷3-phenylindoline g of 3-(2-dimethylamino-l-propyl)-2^methyl-3-phenylpseudoindole (see Example 20 (a)) were dissolved in 200 ml of IN hydrochloric acid and hydrogenated using 3 g of 10% palladium on carbon as catalyst in a 500 ml Parr-autoclave at ambient temperature and a hydrogen pressure of 2 to 3 atm until absorption of the calculated quantity of hydrogen had taken place „ After filtration of the catalyst, the reaction mixture was made alkaline by a lye, extracted with ether, the ether solution dried and the solvent distilled offc The residue was recrystallized from petroleum ether 0 The crystals had a melting point of 122-12 °C and consisted of a mixture of the optically active isomers of the pure trans- orm of the above mentioned indolinec Yield; 81% of theory0 Dextrorotatory form of trans-3-(2-dimethylamino-l° propyl )-2-methyl-3-phenylindoline 02- g of (-)-3~(2-dlmethylamino^l-propyl)-2-methyl-3-phehylindoline (trans-form) and 201 g of D-(-)-tar-tarie acid were dissolved in 15 ml of warm water0 The salt crystallized quickly and ,was filtered off. It the base precipitating as an oil. The base was extracted into ether, the solution was dried and the solvent distilled off. The remaining base was converted in ethanolic solution into its hydrochloride by adding hydrogen chloride gas dissolved in ether0 1.0 g of hydrochloride precipitated (m.p.j 228 -231°C). [α]2ρ = +223° (c = 1, ethanol, 1 dm), Laevo-rotatory form of trans-5-(2-dimethylamino-l-propyl)-2-methyl-5-phenylindoline The aqueous mother liquors from the crystallized diastereoisomeric salt of the (+,)-.base with D-(-)-tartaric acid (Example 21 (b)) were made alkaline by addition of a 10% sodium hydroxide solution and the base was extracted with ether. 2.0 g of base remained after evaporating the ether from t¾.e ether solution which was dried over sodium sulphate and 1«5 g of L (+)-tartaric acid in 12 ml of hot water were added. The precipitated crystals were filtered off after a short time and were recrystallized from 10 ml of water. The base was liberated from the (+)-tartrate by adding a 10% sodium hydroxide solution to an aqueous solution of the salt. The oily base was extracted with ether. The ether solution was dried over sodium sulphate and the base was isolated by evaporating the ether. The oily base wai=i converted into its hydrochloride in ethanolic solution with hydrogen chloride gas dissolved in ether. 1.0 g of the hydrochloride was obtained (m.p.s 226-228°C).

Example 22 The optical isomers of cis-3-(2-dimethylaminoethyl) -2-methyl-3-phenyl-indoline (a) Rac'emate of cis-3-(2-dimethylaminoethyl)~2-methyl-3~ phenylindoline To a solution of 20 g of 3-(2-dimethylaminoethyl)-2 methyl-3-phenylpseudoindole in 150 ml of ethanol were added 0 „ 5 g of mercury(II)chloride and 4-0 g of zinc dust, 125 ml of concentrated hydrochloric acid were introduced with stirring and refluxing over to 5 hours 0 After cooling, the reaction mixture was made strongly alkaline with sodium hydroxide solution and the base was extracted with ether. The solvent was evaporated and the residue distilled in vacuo„ 16 g of the above mentioned indoline derivative (cis-form) of bop0 129-130°C / 0.Ό2 mm Hg, m0p0 79-80°C, were obtained. M0p„ of its hydrochloride; 189°C (from ethanol) 5 m0p0 of the hydrogen maleates 123°C0 Dextrorotatory form of cis-3-( 2-dimethylaminoethyl) 2-methyl-3-Phenylindoline tartaric acid were dissolved in 50 ml of hot water0 After standing the solution for a day in the refrigerator, the solution was seeded with a small quantity of the (-)-tartrate of the base which had been obtained in a test tube assay and it was then allowed to stand for a further 2 days in the refrigerator. The precipitate obtained (17«5 g) was recrystallized from 30 ml of water0 13.6 g of precipitated (-)-tartrate were then dissolved in water0 The solution was made alkaline with 10% sodium hydroxide solution. The oily precipitated base was extracted with ether, the ether solution was dried and after distilling off the ether, 605 g of (+)-' base (m„p0s 104-105°C) were obtained,, [a]p°° « +268° (c = 1, ethanol, 1 dm) By neutralizing of the ethanolic solution of the (+)-base with hydrogen chloride gas in ether the hydrochloride was obtained (m0p„; 161-163°C)„ [a]p°° = +280° (c = 1, ethanol,. 1 dm) Laevo-rotatory form of cis-3-(2-dimethylaminoethyl)-2-methyl-3-phenylindoline The aqueous mother liquor which was obtained when filtering off the precipitated diastereoisomeric salt of the (+)-bas~e with D-(-)-tartaric acid gave, when treated analogeously to Example 20(c),16 g of (-)-crude base to which were added 901 g of L (+)-tartaric acid in 30 ml of water0 After standing for 24· hours in the refrigerator 17o5 g of (+)- - (m.p.: 98-100°C) were obtained when treated according to the method described in Example 22(b) . [a]p°° = -268° (c = 1, ethanol, 1 dm) The hydrochloride had a melting point of I61-163°C0 [a]p°°= -280° (c = 1, ethanol, 1 dm) Example 23 The optical active forms of cis-3-[2-(N-methyl-N-ethyl)-aminoethyl ] -2-methyl-3-^phenylindoline (a) Racemate of cis-3-[ -(N-ethyl- -methyl)-aminoethyl]- 2-methyl-3-phenylindoline To a solution of 3-[2'-(N-ethyl-N-methyl)-aminoethyl]- 2-methyl-3-phenylpseudoindole in 160 ml of ethanol were added 0.5 g of mercur (II)chloride and 0 g of zinc dust. While stirring and refluxing, 130 ml of concentrated hydrochloric acid were introduced over 4· to hours. After cooling, the reaction mixture was made strongly alkaline with sodium hydroxide solution and the base was extracted into ether. The solvent was evaporated and the residue distilled in vacuo. A mixture of optically active forms of the (b) Dextrorotatory form of cis-3-[ 2-(N-ethyl-N-methyl)~ aminoethyl] -2-methyl-3-phenylindoline 3 o O g of (±)-3-[ 2-(N-ethyl-N-methyl)-aminoethyl]~ 2-methyl-3-phenylindoline (cis-form) were dissolved with 19.5 S of D-(-)-tartaric acid in 100 ml of water „ Seed crystals previously obtained in a microtes.t were added to the solution after a day0 The solution was left to stand for about 3 weeks in a refrigerator. The thick precipitate was rapidly filtered and the still moist mass (27 g) was re- crystallized from 50 ml of water,, After standing for two days in a refrigerator, the precipitate was filtered off; 15 g of (-)-tartrate were obtained from which were obtained by the same method as described in Example 20(b) 6o 0 g of (+)-3-[2-(N-ethyl-N-methyl)= aminoethyl^ -2-methyl-3-phenylindoline (cis-form) 0 M0p0 of the- (-)-tartrates 60°C„ ?n° 1 [o]p = +251A (c = 1 , ethanol, 1 dm)0 (c) Laevo-rotatory form of cis-3-[2-CN-ethyl-N-methyl)- aminoethyl] -2-methyl-3-phenylindoline The mother liquor from the first (-)-tartrate precipitation according to Example 23(b) was rendered alkaline with 10% sodium hydroxide solution, the precipitated base was extracted with ether and isolated after drying and evaporating off the ether0 23 o 5 S °f the base were obtained. The base was dissolved in a solution of 12.0 g of L (+)-tartaric acid in 60 ml of water. After 2 days, 2600 g of ro a ory cis-5-[ 2-(N-ethyl-N-methyl)-aminoethyl]-2- methyl-3-phenylindoline was isolated according to Example 20(b). [a]p°° = -260° ^^-260° (c = 0.5, ethanol, 1 dm) Example 24 The optical Isomers of trans-3-[2-(N-methyl-N-ethyl)-aminoethyl]-2-methyl-3-phenylindoline (a) Racemate of trans-3-[ 2-(N-ethyl-N-methyl)-aminoethyl] -2-methyl-5-phenylindoline 13 g of 3-[2-(N-ethyl-N-methyl)-aminoethyl] -2- methyl-3-phenylpseudoindole were dissolved in 100 ml of 1 N hydrochloric acid and hydrogenated over 2 g of 10% palladium on carbon as catalyst in a 500 ml Parr-autoclave at about 30°C and a hydrogen pressure of 2 to 3 atm until the calculated quantity of hydrogen had been absorbed„ After filtrating off the catalyst, the reaction mixture was made alkaline with a 10% sodium hydroxide solution and was extracted with ether.

The ether solution was dried and the solvent dis isomers (trans-form) of the above mentioned indoline was obtained which was distilled at 157-158°0 / 0.08 nrnHg, . Yield; 95%. (b) Dextrorotatory form of trans-3-[ 2-(N-ethyl-N-methyl)- aminoethyl ] -2-methyl-3-phenylindoline . 25.8 g of (i)-3-[ 2-(N-ethyl-N-methyl)-aminoethyl] -2- methyl-3-phenylindoline (trans-form) and 12 β 9 g of D (-)-tartaric acid were dissolved in 70 ml of hot water. The cooled solution quickly became thick and after 2 hours a crystalline product could be filtered off. 26.0 g of a moist salt were obtained which were recrystallized once more from 30 ml of water. 8.0 g of (+)-base were isolated from 17. 5 g of precipitated (-)-tartrate as described in Example 20(b)0 2·"' ethanol 1 dm) (c) Laevo-rofratory form of trans-5-[ 2-(N-ethyl-N-methyl)- aminoethyl ] -2-methyl-3-phenylindoline The filtrate from the first and second crystallisation of the diastereomeric salt of the (+)-base were com- bined and the base was liberated by the method described in Example 20(b). The second isomer was isolated with the aid of 7.0 g of L (+)-tartaric acid.

After standing for 2 days it was quickly filtered off and the free (-)-base was isolated. [a]p°° = -216° ( c = 2.75 , ethanol, l.dm) M.p. of the tartrate of the L (+)-tartaric acid; 78-80°C.

In Examples 20-24-, the concentration c is given in Example 25 Ampoules with 50 mf of ( -2-methyl-3-phenyl-5-( 2-dimethyl-amino-l-propyl)-indoline hydrochloride (cis-form) Ingredients ; 1 ampoule contains ( + ) -;2-methyl-3-phenyl-3- ( 2-dimethylamino- l-propyl)-indoline hydrochloride 50.0 mg fermentation lactic acid' 90% 9.5 m secondary sodium phosphate . 2H2O 10.5 mg sodium pyrosulphite 2 o 0 mg dist. water ad 2 ml Compounding procedure; In about 90% of the required water were dissolved in succession fermentation lactic acid, sodium phosphate , active substance and sodium pyrosulphite. The solution was diluted to the indicated volume , filtered free from suspended particles under nitrogen-pressure and used to fill colourless 2 ml ampoules with gas protection. The water used must be free of oxygen. All manipulations have to be carried out under an atmosphere of nitrogen.

Sterilisation: 20 minutes at 120°C.

Example 26 ~ Drops with 20 mg of ( -)-2-methyl-3-phenyl-3-(2-dimethyl- ' amino-l-propyl)-indoline hydrochloride (cis-form) per ml0 Ingredients : 100 ml of drop solution contain: ( - )-2-methyl-3-phenyl-3-(2-dime'thylamino- l-propyl)-indoline hydrochloride 2.0 g saccharin sodum 1.0 g methyl p_-hydroxybenzoate 0.1 g sodium pyrosulphite 0.1 g ethanol 10e0 g dist. water ad 100 ml Compounding procedure : The active substance, fermentation lactic acid, disodium hydrogen phosphate, saccharin sodium and sodium pyrosulphit were dissolved one after the other in about 80.0 g of water and a solution of the preservative in ethanol was also added. The mixture was filtered. 1 ml of drop solution contains 20 mg of active ingredient. Example 27 Tablets with 20 mg of )-2-methyl-5-Phenyl-5-(2-dimethyl-amino-l-propyl)-indoline hydrochloride (cis-form) Ingredients : 1 tablet contains: (-)-2-methyl-3-phenyl-3-(2-dimethylamino- l-propyl)-indoline hydrochloride 20.0 mg lactose 90.0 mg potato starch 80.0 mg polyvinylpyrrolidone 10.0 mg cellulose microcrystalline 23.0 mg magnesium stearate 2.0 mg 225.0 mg Compounding procedure: The active substance ,.. lactose and potato starch were mixed and the mixture was granulated by moistening with a 20% aqueous solution of the polyvinyl-pyrrolidone and forcing the moist mixture through a 1.5 mm-mesh screen. The granulate was dried at 5°C and again passed through the Die: 9 mm, flat, partial kerf.

Example 28 Suppositories with 20 mg of (+)-2-methyl-3-phenyl-3-(2-dimethylamino-l-propyl)-indoline hydrochloride (cis-form) Ingredients : 1 suppository contains ί (+)-2-methyl-3-phenyl-3-(2-dimethylamino- l-propyl)-indoline hydrochloride 20.0 mg Witepsol W 5 (suppository base) 1600.0 mg 1620.0 mg Compounding procedure: The suppository material was melted and cooled to 40°Co The finely pulverized active substance was suspended therein and the mixture poured into cooled suppository molds each holding 1.62 g of the composition.

Example 29 Ampoules with 50 mg of (- -2-methyl-3-phenyl-3-(2-dimethyl-amino-l-ethyl)-indoline hydrochloride (cis-form) Ingredients : 1 ampoule contains (+)-2-methyl-3-phenyl-3-(2-dimethylamino- l-ethyl)-indoline hydrochloride 50.0 mg sodium pyrosulphite 2.0 mg sodium chloride ,0 mg dist. water ad 2.0 ml Compounding procedure: The active substance and the two inorganic salts were dissolved in the majority of -the water and the solution subsequently was diluted to the indicated volume with Example 30 Drops with 30.0 mg of ( -2-methyl-3-Phenyl-3-(2-dimethyl-- amino-l~ethyl)-indoline hydrochloride (cis-form) 100 ml of the drop , solution contain; (+)-2-methyl-3-phenyl-3-(2-dimethylamino- l-ethyl)-indoline hydrochloride .0 g saccharin sodium 1.0 g glycerine 15.0 g methyl £-hydroxybenzoate 0.1 g menthol 0.05g ethanol pure 10.0 g dist. water ad 100.0 g Compounding procedure: The active substance and the saccharin sodium were dis- solved in 70 ml of water. The preservative and the menthol were dissolved in ethanol and this solution was added to the aqueous solution. Subsequently, glycerine was added. "The mixture was diluted to 100 ml with distilled water and filtered. 1 ml of drop solution contains 40 mg of active ingredient.

Example 31 Tablets with 50.0 mg of (-)-2-methyl-»3-phenyl-3-(2- dimethylamino-l-ethyl)-indoline hydrochloride (cis-form) Ingredients ; 1 tablet contains: (±)-2-methyl-3-phenyl-3-(2-dimethylamino- 1-ethyl)-indoline hydrochloride lactose potato starch. polyvinylpyrrolidone Compounding procedure: The active substance, lactose and potato starch were mixed and the mixture was granulated by moistening it with a 15% aqueous solution of the polyvinyl-pyrrolidone , forcing the moist mixture through a 1 „ 5 mm-mesh screen, drying the moist granulate at 45°C and again passing the dry granulate through the screen 0 The granulate was admixed with the remaining 255 auxiliary substances and the composition pressed into 240 mg tablets „ Die: 9 mm, flat with partial kerf.

Example 52 Suppositories with 50~mg of (± )-2-methyl-5-phenyl-5-(2-dimethylamino-l-ethyl)-indoline hydrochloride (cis-form) Ingredients : 1 suppository contains: ( - ) -2-methyl-3-phenyl-3-( 2-dimethylamino-1- ethyl)-indoline hydrochloride 50.0 mg cocoa butter 1600.0 mg 1650.0 mg Compounding procedure: The finely pulverized active substance was suspended in the melted cocoa butter and poured into cooled suppository molds each holding le 65 g of the composition.

Example 55 ■ Suppositories with 100 mg of ( -)-2-ethyl-5- [ 2-(N-isoT3ropyl-- N-methyl)-amino-l-ethyl] -5-phenylindoline hydrochloride (cis-form) Ingredients : 1 suppository contains: Compounding procedure; The suppository base material was melted and cooled to 4-0°C0 The finely pulverized active substance was suspended in it and then poured into slightly cooled suppository molds each holding 1 , 7 g of the composition.

Example 3 · Tablets with 100 mg; of C-)-2-ethyl-3-[2-(IT-isopropyl-N-methyl)-amino-l-ethyl1-3-phenylindolinehydrochloride (cis-form) Ingredients ; 1 tablet contains: ( ± ) -2-ethyl-3- [ 2-'(N-isoprbpyl-N-methyl)-amino- l-ethyl] -3-phenylindoline hydrochloride 100 e 0 mg lactose 5, 0 mg potato starch 4-0 , 0 mg polyvinylpyrrolidone 10o 0 mg cellulose microcrystalline 23.0 mg magnesium stearate 2 , 0 mg 220, 0 mg Compounding procedure; The active substance, lactose and potato starch were mixed and the mixture was granulated by moistening it with a 20% aqueous solution of the polyvinyl-pyrrolidone , forcing the moist mixture through a 1 , 5 mm mesh screen, drying the moist granulate at 4-5°C and again passing the dry granulate through the screen. The granulate was mixed with the remaining auxiliary substances and the composition was pressed into 220 mg tablets,^

Claims (1)

1. -r Compounds of the general formula ^wherein ^ represents an alkyl group containing from 1 to 5 carbon atoms; R2 and -j,; which may be the same or different, each represents a hydrogen or chlorine atom or a lower alkyl or alkoxy group containing 1 or 2 carbon atoms; ^ and R^, which may be the same or different, each represents an alkyl group containing from 1 to 5 carbon atoms (which may, if desired, be substituted by a cyclo-alkyl group) an alkenyl group containing from 3 to 5 carbon atoms, or a cycloalkyl group containing from 5 to 7 carbon atoms; or R^ and R^ together with the adjacent nitrogen atom form a saturated monocyclic heterocyclic 5- or 6-membered ring which may, if desired, contain an oxygen atom or a further nitrogen atom and/or may if desired be substituted by a lower alkyl group containing from 1 to 3 carbon atoms or a phenyl group; A represents a bivalent aliphatic hydrocarbon group containing from 2 to carbon atoms; and n represents 1 or 2^ and acid addition salts thereof. 20 Compounds as claimed in Claim 1 wherein R^ represents 3. Compounds as claimed in Claim 1 or Claim 2 wherein at least one of ^ and R-j represents a methyl or methoxy group0 4. Compounds as claimed in any of the preceding claims wherein at least one of R^ and R^ represents a methyl, ethyl, propyl, butyl, amyl, cyclohexylmethyl, cyclohexyl, allyl or 2-methylallyl group, or R^ and R^ together with the adjacent nitrogen atom represent a pyrrolidino, piperidino, pipera-zino, morpholino, 2-ethylpiperidino , 4—phenylpiperidino , 4-methylpiperazino or 4-phenylpiperazino group. 5. Compounds as claimed in any of the preceding Claims in which the phenyl group at 3-position and the radical R-^ at 2-position are in cis-relationshi „ 6. Compounds, as claimed in,Claim 5 in the form of optical isomers. 7. Compounds as claimed in any of Claims 1 to in which the phenyl group at 3-position and the radical ^ at 2-position are in trans-relationship„ 8. Compounds as claimed in Claim 7 in the form of optical isomers. 9. Compounds as claimed in any of Claims 1 to in the form of stereoisomeric mixtures of compound as claimed in Claim 5 and compounds as claimed in Claim 7o 10. Racemic ciji-3-(2-dimethylamino-l-propyl)-2-methyl-3-phenylindoline and acid addition salts thereof. 11. Dextrorotatory cis-3-(2-dimethylamino-l-propyl)-2-methyl-3-phenylindoline and acid addition salts thereof. 12. Racemic trans-3-(2-dimethylamino-l-propyl)÷2-methyl- 3-phenylindoline and acid addition salts thereof. 13. Dextrorotatory trans-3-(2-dimethylamino-l-propyl)- salts thereof. 19. Racemic cjUs-2-ethyl-3-[2-CN-isopropyl-N--methyl)-aminoethyl]-3~phenylindoline and acid addition salts thereof. 20. Racemic cis-2-ethyl-3-(2-diethylaminoethyl)-3-phenyl-indoline and acid addition salts thereof. 21. Racemic cis_-3-['2-(N-allyl-N-isopropyl)-aminoethyl]- · 2-methyl-3-phenylindoline and acid addition salts thereof. 22. Compounds as claimed in Claim 1 as herein specifically disclosed with the exception of those as claimed in any of Claims "10 to 21. 23. A process for the preparation of compounds as claimed in Claim 1 wherein a pseudoindole of formula •r is, if desired, converted into an acid addition salt thereof. 24·. A process as claimed in Claim 23 wherein the reduction is effected using nascent hydrogen. 25. A process as claimed in Claim 24- wherein the nascent hydrogen is produced by the action of an acid on a non-noble metal, 26. A process as claimed in Claim 25 wherein the said acid comprises a dilute mineral acid. 27. A process as claimed in Claim 25 or Claim 26 wherein the said non-noble metal comprises zinc, tin, iron or aluminium. 28. A process as claimed in any of Claims 24- to 27 wherein the reduction with nascent hydrogen is effected ·· in water or a mixture of water with a water-miscible solvent. 29. A process as claimed in Claim '28 wherein the water-miscible solvent comprises a lower alcohol. 30. A process as claimed in any of Claims 24· to 29 wherein the reduction is effected at a temperature between 20°C and 150°C. 31. A process as claimed in Claim 30 wherein the reduction is effected under reflux. 32. A process as claimed in Claim '23 (for the preparation of compounds as claimed in Claim 1 wherein neither R2 nor represents a chlorine atom) wherein the reduction is effected by means of an alkali metal or an alkaline earth metal, or an alkali metal or alkaline earth metal amalgam, in the presence of an alcohol. 33. A process as claimed in Claim 32 wherein the alkali metal or alkaline earth metal comprises podium or the alcohol comprises tert-butanol. 35. A process as claimed in any of Claims 32 to wherein the reduction is effected at a temperature of from 20 to 150°C. 36. A process as claimed in Claim 23 wherein the reduction is effected by means of surface-amalgamated aluminium. 37. process as claimed in Claim 36 in which the reduction is effected in the presence of an aqueous lower alcohol or moist ether. 38. A process as claimed in Claim '23 wherein the compound of formula II is reduced using a complex metal hydride, 39. A process as claimed in Claim 38 wherein the reduction is effected in a solvent. 40. A process as claimed in Claim 38 or Claim 39 wherein the reduction is effected at ambient temperature or a moderately elevated temperature. 41. A process as claimed in Claim 23 wherein the compound of formula II is reduced by electrolytic reduction. 42. A process as claimed in Claim 41 wherein the reduction is effected using lead electrodes. 43. A process as claimed in Claim 41 or Claim 42 wherein the reduction is effected in an aqueous acidic solution. 44. A process as claimed in Claim 23 (for the preparation of compounds as claimed in Claim 1 wherein neither R2 nor represents a chlorine atom and neither R^ nor R^ represents an alkenyl group) wherein the compound of formula II or an acid addition salt thereof is reduced using catalytically activated hydrogen. 45. A process as claimed in Claim 44 wherein the catalyst 46. A process as claimed in Claim 45 wherein the catalyst comprises platinum black, platinum dioxide, palladium on a carrier, Raney nickel, Raney cobalt or Adkins copper-chromium oxide catalyst. 47. A process as claimed in Claim 45 wherein the catalyst comprises a noble metal and the hydrogenation is effected under slight hydrogen pressure. 48. A process as claimed in Claim 7 wherein the hydrogenation is effected in aqueous acidic solution,, 49. A. process as claimed in Claim 48 wherein the hydrogenation is effected in dilute hydrochloric acid. 50. A process as claimed in any of Claims 47 to 49 wherein the hydrogenation is effected at a temperature between 20°C and 100°C. 51. A process as claimed in Claim 0 wherein the hydrogenation is effected at a temperature between 20°C and 40°C. 52. A process as claimed in Claim 45 wherein the catalyst comprises a Raney nickel or copper-chromium oxide catalyst and hydrogenation is effected at a hydrogen pressure of from 100 to 200 atmospheres. 55. A process as claimed in Claim 52 wherein the hydro-genation is effected at a temperature of from 100 to 200°C. 54. A process as claimed in Claim 52 or Claim 55 wherein the hydrogenation is effected in an organic solvent. 55. A process as claimed in Claim 54 wherein the organic solvent comprises an alcohol, an ether or an ester. 56. A process as claimed in Claim- 5 wherein the organic solvent comprises methanol, ethanol, dioxan, tetrahydro- of compounds as claimed in Claim 5) wherein the reduction is effected by means of zinc or tin in the presence of dilute mineral acids . 58. A process as claimed in Claim 23 (for the preparation of compounds as claimed in Claim 5) wherein the reduction is effected by means of surface amalgamated aluminium. 59. A process as claimed in Claim 23 (for the preparation of compounds as claimed in Claim 5) wherein the reduction is effected by means of electrolytic reduction. 60. A process as claimed in Claim 23 (for the preparation of compounds as claimed in Claim 7) wherein the reduction is effected by means of palladium on animal charcoal. 61. A process as claimed in Claim 23 wherein a stereomeric mixture as claimed in Claim 9 is first produced and is subsequently separated into acompound as claimed in Claim 5 and a compound as claimed in Claim 7„ 62. A process as claimed in Claim 61 wherein the separation is effected by fractional crystallization of an acid addition salt of the stereomeric mixture. 63. A process as claimed in Claim 62 wherein the said acid addition salt is the oxalate or salicylate. 64-. A process as claimed in any of Claims: 23 to 56 wherein a cis- or trans- compound of formula I in racemic form is first produced and is then separated into its optical isomers. 65. A process as claimed in Claim 64- wherein the separation is effected by fractional crystallization of a diasterioisomeric acid addition salt of the compound of diasterioisomeric acid addition salt is a salt with D(-)-tartaric acid or L-(+)-tartaric acid. 67. A process as claimed in Claim 23 substantially as herein described. 68. A process for the preparation of compounds as claimed in Claim 1 substantially as herein described in any of Examples 1 to 19. 69. A process for the preparation of compounds as claimed in Claim 1 substantially as herein described in any of Examples 20 to 2 . 70. Compounds as claimed in Claim 1 when prepared by a process as claimed in any of Claims 23 to 67 and 68 , 71. Compounds- as claimed in Claim 1 when prepared by a process as claimed in any of Claims 57 to 67 and 69. 72. Pharmaceutical compositions comprising at least one compound οί· formula I (as defined in Claim 1) or a physiologically acceptable acid addition salt thereof as active ingredient in association with a pharmaceutical carrier or exclpient. 73. Compositions as claimed in Claim 72 in a form suitable for oral, rectal or parenteral administration. 7 . Compositions as claimed in Claim 72 or Claim 73 in the form of granules, tablets, coated tablets, capsules, syrups, shake-mixtures, emulsions, suspensions, drops, injectable solutions or suppositories. 75. Compositions as claimed in any of Claims 72 to 74 in the form' of dosage units. 76. Compositions as claimed in Claim 75 for administration to adults wherein each dosage unit contains 5 to dosage unit contains 10 to 100 tag of active ingredient. 78. Compositions as claimed in Claim 75 for administration to children wherein each dosage unit contains 2.5 to 150 mg of active ingredient. 79. Compositions as claimed in Claim 78 wherein each dosage unit contains 5 to 50 tag of active ingredient. 8Q. Compositions as claimed in Claim 72 substantially as herein- described. 81. Pharmaceutical compositions substantially as herein described in any of Examples 25 to 354. For the Applicants DR. NERS