US3769299A - 2-methyl-3-aminoalkyl-3-phenylindolines - Google Patents

Abstract

BASIC-SUBSTITUTED INDOLINES OF GENERAL FORMULA I,

2-CH3,3-(R1-N(-R2)-A-),3-(C6H5-)INDOLINE

WHEREIN R1 AND R2 MAY BE IDENTICAL TO OR DIFFERENT FROM EACH OTHER, ARE EACH ALKYL OF 1 TO 5 CARBON ATOMS AND A IS BIVALENT ALIPHATIC HYDROCARBYL OF 2 TO 3 CARBON ATOMS, WHEREIN THE PHENYL SUBSTITUENT IN THE 3-POSITION AND THE METHYL GROUP IN THE 2-POSITION ARE IN CIS- CONFIGURATION WITH RESPECT TO EACH OTHER; OPTICALLY DEXTRO-ROTATORY ISOMERS THEREOF; AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS OF SAID BASIC-SUBSTITUTED INDOLINES AND OF SAID OPTICALLY ACTIVE ISOMERS. ALL OF THESE COMPOUNDS ARE USEFUL AS ANALGESICS AND ANTITUSSIVES IN WARM-BLOODED ANIMALS.

Description

ABSTRACT OF THE DISCLOSURE Basic substituted indolines of'general Formula 1,

wherein R and R may be identical to or different from each other, are each alkyl of 1 to 5 carbon atoms and A is bivalent aliphatic hydrocarbyl of 2 to 3 carbon atoms, wherein the phenyl substituent in the. 3-position and the methyl group in the 2-position are in cisconfiguration with respect to each other; optically dextro-rotatory isomers theerof; and non-toxic, pharmacologically acceptable acid addition salts of said basic-substituted indolines and of said optically active isomers. All of these compounds are useful as analgesics and antitussives in warm-blooded animals.

This is a continuation-in-part of copending application Ser. No. 846,291, filed July 30, 1969, now abandoned.

U i d, W 95 This invention relates to novel basic-substituted indolines and acid addition salts thereof, as well as to a method of preparing these compounds.

More particularly, the .present invention relates to 2-methyl-3-aminoal'kyl 3-phenyl-indolines of general FormulaI,

N CH] I Patented Oct. 30, 197.3

' fiTlie compounds ofjgeneral Formula I'inay e'grep by 'feducine a p d ndole of general Formula 11,

N (11) wherein R R and A have the same meanings as in general Formula I.

The reduction may be performed with nascent hydrogen which is generated in the conventional way by the action of acids, preferably of dilute mineral acids, on non-noble metals, such as zinc, tin or aluminum.

The reduction is carried out in water or in a mixture of water with a solvent miscible therewith, such as a lower carbinol, at temperatures between 20 C. and 150 C., preferably while heating up to reflux.

Furthermore, aluminum has proved to be suitable as a reducing agent, its surface being amalgamated, where aqueous methanol or ethanol or moist either may serve as the reaction medium.

A further method of conversion of the pseudoindoles of general Formula 11 consists of subjecting the same to electrolytic reduction, using preferably lead electrodes, in acid aqueous solution.

Surprisingly, it has been found however, that if A in a compound of general Formula II is branched or straight alkylene, the reduction with zinc or tin in the presence of a dilute mineral acid or with surface-amalgamated aluminum or electrolytical reduction leads predominantly to indolines of general Formula I, wherein the phenyl group in the 3-position and the methyl group in the 2- position are in cisconfiguration with respect to each other.

Hereinafter, these compounds will be designated as cisindolines.

In these reactions the cisindolines are always obtained as mixtures of their optically active isomers. The cisindolines possess two optically active centers, namely the carbon atoms in the 2- and in the 3-positions of the indoline ring; in those cases where A is a branched aliphatic hydrocarbon group with 2 or 3 carbon atoms, there will be a further asymmetric carbon atom in the group A. The compounds may accordingly be separated into their optically active levoand dextro-rotatroy forms.

The isolation of the dextro-rotatory forms of the cisindolines is advantageously effected by fractional crystallization of their salts with D-(- )-tartaric acid. To a solution of the racemic mixture in a suitable solvent, for example in water, a solution containing the equimolar quantity of D-(--)-tartaric acid is added. Subsequently, the solution is in some cases partially evaporated. Generally, the diastereomeric salt of the dextrorotatory indoline base with D-( --)-tartaric acid will first crystallize. In most cases it has proved to be sufiicient to recrystallize the tartrate from a solvent, such as water, only once. Subsequently, the optically active base is liberated from its salt by means of a stronger base, for example by means of a sodium hydroxide solution; the thus separated base is extracted with an organic solvent, for example with ether, benzene or chloroform, and "from this extract the base is liberated by evaporation of the solvent.

The compounds obtained accordingto the hereinbefore mentioned methods may be converted, if desired, into non-toxic pharmaceutically acceptable acid addition salts thereof with inorganic or organic acids. Examples of such salts are those formedwith'hydrochloric acid, hydrob9 aq dr u1fii ila P P' PPQ iQEF Q. sal id succimc acid, tartaric acid, citric acid, adipic acid, maleic" acid, fumaric acid, 8-chlorotheophylline or the like.

The compounds of general 'Formula I I, use d as starting materials, may be obtained, for instance, by cyclizati n of a phenylhydrazone of general Formula III, i

EXAMPLE 1 Racemic cis-3-(2-dimethylamino-1'-propyl)-2-methyl- 3-phenyl-indoline In a flask equipped with a stirrer, cooler, thermometer and dropping funnel, 50 gm. of '3-('2-dimethylamino-1'- propyl)-2-methyl-3-phenyl-pseudoindole were dissolved in 250 ml. of ethanol, and 70 gm. of zinc dust were added to the solution. Then, while constantly stirring, 300 ml. of aqueous 36% hydrochloric acid were added dropwise while maintaining the external temperature at 80-90" C. After about 6 hours the reaction mixture was poured into water and the mixture was admixed with concentrated aqueous ammonia (or sodium hdyroxide) until the formed solid precipitate redissolved and an oil separated out, which was taken up in benzene. The benzene solution was washed, dried and evaporated, whereby the above mentioned indoline base was obtained, which was recrystallized from petroleum ether.

Yield: 45 gm., colorless crystals (cis-form), M.P. 91 C.-M.P. of the hydrochloride: 254 C.

EXAMPLE 2 Racemic cis-3-(2'-dimethylamino-ethyl)-2-methy1- 3-phenyl-indoline 0.5 gmpof mercury (11) chloride and 40 gm. of zinc dust we re added to a solution of 20 gm. of 3-( 2'-dimethyl amino ethyl) 2 methy1 3-phenyl-pseudoindole in 150 ml;

(a) 3-[2'-(N-isopropyl 1- N methyl amino) ethyl1-2- methyl 3 phenyl 4 indoline (cis form), M.P.: 9496 C. (from :petroleum ether); yield of theory.

(b) 3-(2'-diethylamino ethyl) 2 methyl 3 phenyl- "indoline (cis form), B.P.: 157-159 C./0.04 mm. Hg; yield: 66% of theory. M.P. of its dihydrochloride: 176 C. (decomp.).

(c) 3-[2'-(N-tert.-butyl N methyl amino) ethyl]-2- methyl-3-phenyl-indoline (ciskform), B.P.: 156 C./ 0.1 mm. Hg; yield: 78% of theory. M.P. of its dihydrochloride: 163 C. (decornp.).

(d) 3-(3'-dimethylamino 1' 'propyl) 2 methyl-3- phenyl-indoline (cis-form), M.P.: @77-78" C. (from petroleum ether); yield: 68% of theory. M.P. of its dihydrochloride: 235 C. (de'comp.).

(e) 3-[2' (N-ethyl N methyl amino)-ethyl]-2- methyl 3 phenylindoline (cis-form), B.P. 161 C./ 0.07 mm. Hg; yield: 73% of theory. M.P. of itssalicylate: 147 C. r

(f) 3-[2(N-isoamyl N methyl amino) ethyl] 2- methyl 3 phenyl-indoline (cis-form), M.P.: 98-29 C. (from petroleum ether); yield: 70% of theory.-

(g) 3-[2'-(N n butyl N methyl amino) ethyl]- 2-methyl 3 phenyl-indoline (cis-form), M.P.: 80- 81 0.; yield: 71% of theory.

(h) 3 [2 N methyl N n propyl amino)-ethyl]- 2 methyl 3 phenyl-indoline (cis-form), B.P.: 142 143 C./0.05 mmpl-lg (M.P.: 54-56 0.); yield: 80%

of theory. a

(i) 3 [2' (N isobutyl N methyl --amino) -ethyl]- 2 methyl 3 phenyl-indoline (cis-form), B.P.: 157 C./0.04 mm. Hg (M.P.: 68 C-); yield: 81% oftheory.

(j) 3 [2' (N isobutyl' N isopropyl-aminoyethyll- 2 methyl 3 phenyl-indoline (cis-form), B.P.: 160 162 C./0.01 mm. Hg; yield: 77% of theory.

(k) 3-[2' (N n amyl N methyl amino) ethyl]- 2 methyl 3 phenyl-indoline (cis-form), B.P.: 160 162 C./0.01 mm. Hg; (M.P.: 80-82 C.); yield: 77% of theory.

EXAMPLE 3 Racemic cis-3-(2-dimethylamino-ethyl) -2-methyl- 3-phenyl-indoline 10 gm. of aluminum granules amalgamated with an aqueous 1% solution of mercury (H) chloride were added to a solution of 8 gm. of 3-(2-dimethylamino-ethyl)-2- methyl 3 phenyl-pseudoindole in 80 ml. of methanol. Over a period of 5 hours 10 ml. of water were added dropwise in small portions, while stirring. The reaction mixture was stirred for 8 hours more, admixed with ml. of aqueous-25% sodium hydroxide, filtered and then extractedwith benzene and ether. The organic layers were evaporated;"recrystallization of the residue from petr'oleum ether yielded 5.0 gm. (cis-form) of the hereinbefore mentionedindoline base; M.P.: 78-80 C.

, EXAMPLE 4 Racemic"cis 3 (2'dimethylamino-ethyl)-2- methyl-3 phenyl-indoline .100 mg. of cupric sulfate were added to a boiling solution of 22,.gm. of 3-( 2-dimethylamino-ethyl)-2-methyl B-phenyl-pseudoindole in 180 ml. of concentrated hydrochloric acid .and 90 ml..,of water. Subsequently, 25 gm. of granulated tin were introduced in portions over a period of,7 hours. After adding 50 ml. more of concentratehydrochloric acid, the mixture was refluxed for 2 hours, then madealkaline after cooling, and shaken out with ether. The ether extract was evaporated, and the residue was distilled in vacuo. 11.8 gm. (cis-form) of the hereinbefore mentioned indoline base were obtained; B.P.: 79-80" C. (from petroleum ether).

EXAMPLE 5 Racemic cis-3-(2'-dimethylamino-ethyl)-2- methyl-3-phenyl-indoline A solution of 5.0 gm. of 3-(2'-dimethylamino-ethyl)-2- methyl, 3 phenyl-pseudoindolehydrochloride in 500 m1. of aqueous sulfuric acid was reduced in an electrolysis apparatus with lead cathodes at a voltage of 7-8 volts and at a current of 17 amperes at 5060 C. After completion of the reduction, the progress of which was checked thin-layer chromatographically, the base was precipitated with sodium hydroxide and extracted withether. By adding a solution of salicylic acid in ether, the salicylate (cis-form) of thehereinbefore mentioned indoline precipitated out. M.P.: 156 0.; yield: 3 gm.

Using the same method, the following additional indoline derivative was obtained:

. The optical antipodes of cis-3(2'-dimethylamino-l'- propyl)-2-methyl-3 phenyl-indoline (a) Dex tro-rotatory form of cis 3 (2'-dimethylamino 1'-propyl) -2-methyl-3-phenyl-indoline 44.1-gni. of (i) 3 (2'-dimethylamino 1 propyl)- 2-methyl 3 phenyl-indoline (cis-form) and 22.5 gm. ofD (-')-tartaric acid were dissolved in 600 ml. of hot distilled water; After 7 hours the crystals were sucked "off and recrystallized from 600 m1. of water. After standing overn'ight,'the precipitate (36.5 gm.) was filtered off (M.P.: 98-100 C.) and the base was liberated with aqueous 10% sodium hydroxide and taken up in ether. After drying, filtering and partially evaporating the ether solution 19.2 gm. of optically active (||-)-base precipitated.-"[a] =f,|-3l9 (c.=0.98, ethanol, 1 dm.)

The (+)-base was dissolved in ethanol and converted into its hydrochloride (M.P.: 214-217 C.) by addition of hyrogen chloride gas in ether. [a] ='{+355 (c.=1, ethanol, 1 dm.).

(b) Levo-rotatory form of .cis-3-(2-dimethylamino-l- .propyl)-2-methyl-3-phenyl-indoline After crystallization of the diastereoisomeric salt of the dextro-rotatory base, the mother liquor was made alkaline with aqueous 10% sodium'hydroxide, and the liberated base was taken up in ether. The ether solution was dried with sodium sulfate and then freed from solvent, whereby the enriched ()"-base (13.2 gm.) remained which was admixed with 8.0 gm. of L (+)-tartaric acid in 300 ml. of 'hot water. 21.0 gm. of the precipitated tartrate were recrystallized from 20 ml. of hot water. From 18.0 gm. of pure (+)-tartrate 8.8 gm. of ('-)-base were obtained by addition of sodium-hydroxide, as de- 6 scribed under (a) above. [u] =--314 (c.=1. 08, ethanol, 1dm.). The hydrochloride of this compound had a melting point of 214-216 C. [a] 364 (c.-=l, ethanol, 1

' EXAMPLE7 I The optical antipodes of cis-3-(2'-dimethylamino- 1 ethyl) -2-methyl-3-phenyl-indoline (a) Dextro-rotatory form of cis-3-(2'-dimethylaminoethyl) -2-methyl-3 -phenyl-indoline 28.0 gm. of (i)-3-(2-dimethylamino-ethyl)-2-methyl- '3-phenyl-indoline (cis-form) and 15.0 gm. of D tartaric acid were dissolved in 50 ml. of hot water. After standing for a day in a refrigerator, the solution was inoculated with a small portion of the base's ()-tartrate which had been obtained by a test tube assay, and then it was allowed to stand for further two days in a refrigerator. The precipitate formed thereby (17.5 gm.) was recrystallized from 30 ml. of water. 13.6 gm. of tartrate were obtained, which were then dissolved in water. The solution was made alkaline with an aqueous 10% sodium hydroxide solution. The precipitated oily base was extracted with ether, the ether solution was dried, and after distilling off the ether, 6.5 gm. of (+)-base, M.P. 104-105 C., were obtained. [a] '=-|268 (c.-=l, ethanol, 1 dm.).

By neutralizing of the ethanol solution of the (+)-base with hydrogen chloride gas in ether, the hydrochloride was obtained; M.P.: 161-163 C. [a] =;l-280 (c.=l, ethanol, 1 dm.).

(b) Levo-rotatory form of the cis-3-(2'-dimethylaminoethyl)-2-methyl-3-phenyl-indoline The aqueous mother lye which was obtained when filtering off the precipitated diastereoisomeric salt of the (|)-base with the D-(-)-tartaric acid gave, when treated analogously to Example 6(b), 16 gm. of (-)-raw base to which were added 9.1 gm. of L (+)-tartaric acid in 30 ml. of water. After 24 hours standing in the refrigerator 17.5 gm. of (+)-tartrate were obtained. After recrystallization from 30 ml. of water 12.5 gm. of tartrate remained from which, when treated according to the method described in Example 7(a), resulted 6.4 gm. of --)-base (M.P.: 98-l00 C.). [a] =-268 (c.=1, ethanol, 1 dm.).

The hydrochloride had a melting point of 161-163 C. [on] "'=-280 (c.=l, ethanol, 1 dm.).

EXAMPLE 8 The optical antipodes of cis-3- [2'-(N-methyl N ethylamino)ethyl]-2-methyl-B-phenyl-indoline (a) Racemate of cis 3-[2'-(N-ethyl-N-methyl-amino)- ethyl]-2-methyl-3-phenyl-indoline I-CH;

0.5 gm. of mercury (II) chloride and 40 gm. of zinc dust were added to a solution of 3-[2-(N-ethyl-N-methyl-amino)-ethyl]-2-methyl-3-phenyl-pseudoindole in 160 ml. of ethanol. While stirring and refluxing, ml. of concentrated hydrochloric acid were introduced over a period of 4-5 hours. After cooling, the reaction mixture was made strongly alkaline with aqueous sodium hydroxide, and the base was taken up in ether. The ether extract was evaporated, andthe residue was distilled in vacuo. A mixture of the optically active forms of the above mentioned cis-indoline (B.P. g: 161 C.) was obtained. Yield: 73% of theory.

(b) Dextro-rotatory form of cis-3-[2' (l l-ethyl N rnethyl)-amino-ethyl]-2-methyl-2-phenyl-indoline 39.0 gm. of (i)-3-[2'-(N-ethyl'- N methyl-amino)- ethyl] -2-methyl 3 phenyl-indoline (cis-form) and, 19.5 gm. of D ()-tartaric acid were dissolved in 100 ml. of water. After a day of standing, seed crystals previously obtained in a microtest were added to the solution. Then, the solution was allowed to stand forabout 3 weeks in a refrigerator. The ample precipitate formed thereby was quickly vacuum-filtered off, and thestill moist filter cake (27 gm.) was recrystallized from 30 ml. of water. After two days standing in a refrigerator, the precipitate was filtered off; gm. of (-)-tartrate were obtained, from which 6.0 gm. of (-'+)-3- Z-(N-ethyl-N-rnethyl)-aminoethyl]-2-methyl 3 phenyl-indoline (cis-form) were obtaiued by the same method described in Example 6(a). M.P. of the (--)-tartrate: 60 C. [a] =+251 (c.=1, ethanol, 1 dm.).

(0) Levo-rotatory form of cis-3-[2-(N-ethyl-N-methylamino) -ethyl] -2-methy1-3-phenyl-indoline The mother liquor of the first (-)-tartrate precipitation in ('b) above was made alkaline with an aqueous 10% sodium hydroxide solution, and the precipitated base was extracted with ether and isolated after drying the extract solution and evaporating the ether therefrom.

23.5 gm. of the base were obtained. The base was dissolved in a solution of 12.0 gm. of L (+)-tartaric acid in 60 ml. of water. After two days of standing, 26.0 gm. of moist (+)-tartrate were filtered off and subsequently recrystallized from 50 ml. of water. After separating the precipitated (+)-tartrate, the free levo-rotatory base of cis 3 [2' (N ethyl N methyl amino) ethyl]- 2-methyl-3-phenyl-indoline was isolated as described in Example 6(a).

the US. Pat. No. 3,475,437. The following table contains the values which have been found by the method of Reinhard-De Beer:

1 After peroral application.

Therepeutieal Number Index of test EDmln L1)... in LDso/ Substance animals mg/kg mg./kg. ED

(:t:)-cis-3-(2-dimethyl- 80 4. 05 222 55 amino-1-propyl)-2- (190-260) methyl-3-phenyl-indo line-hydrochloride. (+)-t'orm of the above com.- 30 2. 3 210 91. 5 pound. (180-246)- Prior art compounds:

(:l:)'3-(2'dimethyl- 6. 0 150 25 amino-1-propyl)-2- I (121-186) methyl-lrphenyh pseudoindole-hydro- 7,0 chloride.

(+)-form of the above 30 3.0 122 40.5

compound. (97. 5-

The acute toxicity was determined on 3 groups of ten white mice eachv per dose. The median lethal dose (LD was determined, i.e. the dose which caused the death of 50% of the animals within 14 days after administration of the test compound. The LD b-values' were calculated according to the statistical method of Litchfield and Wilcoxon. a

Besides, the compounds of general Formula I do not change the minute-volume of respiration. By male and female-cats anesthetized with pentobarbital the-minute?- volume of respiration was'estimated-after various intravenous dosages of the tested substances. 7 a

The first compound of theabove table did not change the minute-volume of respiration after 1 to"5 mg./kg. i.v.

The third compound of the above table changed, however, the minute-volume of respiration with a decrease of 8% after a dose of 1 mg./kg. i.v. and of 23% after a dose of 5 mg./kg. i.v.

Thus, the compounds according to, this invention are distinguishable over other analgesics of the morphine type in that they do not produce respiratory depressions of any significance. I i

The substances claimed in claims2 to 5 showed in drug-dependence-experiments on" monkeys (produced in the Dept. of Health, Educ., Welfare, Publ. Health Service, Nat. Inst. of Health, Bethesda, Maryland, U.S.A.) no physical dependence as" shown by morphine'in the same test.

The first two substances of the table did not suppress the morphine-abstinence-symptoms at dosesof 2,- 8, 16, 32 mg./kg. sc., measured on morphine-dependent rhesus monkeys which were withdrawn of morphine.

Therefore, the claimed compounds are morpholine-like agonists in relation to the analgesic activity without exerting the severe side-effects of morphine. v

For pharmaceutical purposes, the compounds according to the present invention are administered to warm-blooded animals perorally or v parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and' one. eflfective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.083 to 5.0 mgrnJkg. body weight, preferably 0.166to 1.67 'mgm./kg.body weight. v.

The following examples illustrate a few dosage junit compositions comprising a compound of the instant invention as an active ingredient and representv the best mode contemplated of putting the invention to practical use. The parts are parts by weight unless otherwisespecified.

- EXAMPLE 9 Hypodermic solution The solution was compounded from the following in gredients:

Distilled water, q.s. ad, parts by vol.: 2000.0.

Compounding procedure.--The lactic acid, the sodium phosphate, the indoline compound and the sodiumpyrosulfite were dissolved successively in about of the required amount of water. The solution. was diluted with distilled water to the indicated volumeQfiltered until free from suspended particles under nitrogen pressure, and .filled into colorless 2 mL-ampuIes under gas-protection.

The water used. had to be free from oxy'gen. All operations were carried out in an atmosphere of nitrogen. The filled ampules were sealed and sterilized for 20 minutes at 120 C. Each ampule contained 50 mgm. of the indoline compound, and when the contents thereof were administered intramuscularly to a warm-blooded animal of about 60 kg. body weight in need of such treatment, very good analgesic and antitussive efiects were obtained.

EXAMPLE Drop solution The solution was compounded from the following ingredients:

1 Parts (:)cis-2-methyl 3 phenyl-3-(2' dimethylamino- 1'-propyl)-indoline hydrochloride 2.0 Saccharine sodium 1.0 p-Hydroxybenzoic acid methyl ester 0.1 Lactic acid, 90% 0.47 Secondary sodium phosphate.2H O 0.53 Sodium pyrosulfite 0.1 Ethanol 10.0 Distilled water, q.s. ad, parts by vol.: 100.0.

Compounding procedures.The indoline compound, the lactic acid, the secondary sodium phosphate, the saccharine sodium and the sodium pyrosulfite were dissolved, one after the other, in about 80.0 parts by volume of water, and a solution of the methyl hydroxybenzate in the ethanol was added thereto. The mixed solution was then filtered. 1 ml. drops) of the solution contained 20 mg. of the indoline compound and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good analgesic and antitussive eifects.

Compounding procedure.The indoline compound, the lactose and the potato starch were intimately admixed with each other, and the mixture was granulated by moistening it with an aqueous 20% solution of the polyvinylpyrrolidone, forcing the moist mixture through a 1.5 mm.- mesh screen, drying the granulate at 45 C. and again passing the dry granulate through the screen. The granulate was admixed with the remaining ingredients, and the composition compressed into 220 mgm.-tablets. Each tablet contained 20 mgm. of the indoline compound and, when administered perorally to a Warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good analgesic and antitussive efiects.

EXAMPLE 12 Suppositories The suppository composition was compounded from the following ingredients:

Parts (:)cis-2-methyl 3 phenyl-3-(2 dimethylamino- -propyl)-indo1ine hydrochloride 20.0 Cocoa butter 1600.0

Total 1620.0

Compounding procedures.The cocoa butter was melted and cooled to 40 C., the finely pulverized indoline compound was suspended in it, and the mixture was poured into cooled suppository molds, each holding 1.62 gm. of the composition. Each suppositor contained 20 mgm. of the indoline compound and, when administered by the rectal route to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good analgesic and antitussive eifects.

Analogous results were obtained when any other compound of the present invention was substituted for the particular indoline compound in illustrative Examples 14 to 17. Likewise, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

We claim:

1. A racemic mixture of a compound of general Formula I,

wherein R and R may be identical to or different from each other, are each alkyl of 1 to 5 carbon atoms and A is alkylene of 2 to 3 carbon atoms, wherein the phenyl substituent in the 3-position and the methyl group in the 2-position are in cis-configuration with respect to each other; an optically dextro-rotatory isomer component thereof; and a non-toxic, pharmacologically acceptable acid addition salt of said compound or of said optically dextro-rotatory isomer.

2. A compound according to claim 1, which is racemic cis-3-(2'-dimethylamino 1' propyl)-2-methyl-3-phenylindoline or a non-toxic acid addition salt thereof.

3. A compound according to claim 1, which is dextrorotatory cis-3-(2'-dimethy1amino-1'-propy1) Z-methyl- S-phenyl-indoline or a non-toxic acid addition salt thereof.

4. A compound according to claim 1, which is racemic cis 3 (2 dimethylamino-ethyl)-2-methy1-3-pheny1- indoline or a non-toxic acid addition salt thereof.

5. A compound according to claim 1, which is dextrorotatory cis-3-(2'-dimethylamino ethyl) 2 methyl-3- phenylindoline or a non-toxic acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,091,568 5/1963 Bub 260325X JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R.