IL35465A - Basic pyrrole derivatives,their production and pharmaceutical compositions containing them - Google Patents

Description

'Twprn pis" Basic pyrrole derivatives, their production and pharmaceutical compositions containing them CIBA-GEIGY A.G.

C: 33609 4-3179* PROCESS FOR THE PRODUCTION OF NEW BASIC PYRROLE DERIVATIVES The present invention concerns a process for the production of new basic pyrrole derivatives and their acid addition salts, these compounds as new substances having valuable pharmacological properties and pharmaceutical preparations containing them.

Basic pyrrole derivatives of the general Formula I wherein R-^ represents a hydrogen atom, or a methyl or ethyl group R represents a hydrogen or chlorine atom and R^ and R^ represent , independently of each other, a hydrogen atom or a methyl or ethyl group and their acid addition salts have not been previously described.

As has now been found, these new substances have valuable pharmacological properties, in particular mild (i.e. non-narcotic) analgesic, antiphlogistic and antipyretic effects with a favorable therapeutic index, especially a good gastro-intestlnal tolerance. The analgesic activity of the new compounds of general Formula I, in particular? 1- [p- [ 2(dimethylamino) -ethyl ] -phenyl ] -pyrrole ; 1- [p- (2-amino-l-methylethyl) -phenyl ] -pyrrole, 1- [p- (2-aminoethyl) -phenyl ] -pyrrole; and 1- [p- l-(methylamino-methyl) -propyl ] -phenyl ] -pyrrole, can be shown, for example, on the mouse using the method described by E. Siegmund, R. Cadmus and G . Lu , Proc . Soc . Exp . Biol .Med. 9_5, 729 (1957), whereby the amount of substance is determined which is required to prevent the syndrome produced by the intraperitoneal injection of 2-phenyl-l, 4-benzoquinonej as well as according to L.O. Randall and J.J. Selitto, Arch. intern, phar acodyn. Ill, 409 (1957) by the delay of the pain reaction time when pressure is applie to a rat's paw which is inflammed due to an injection of yeast. The antipholgistic activity of the new compounds of the general Formula 1, in particular,- 1- [p- (2-aminoethyl) -phenyl] -pyrrole 1- [p- [ 1 -methyl -2- (methylamino) -ethyl ] -phenyl ] -pyrrole, and 1- [ - (2-aminoethyl) -2-chlorophenyl ] -pyrrolej is, for example, demonstrated on guinea-pigs in the UV-erythema test, described by G.Wilhelmi, Schweiz.Med.

Wochenschrift 79.- 577 (1949) , and also on rats in the bolus alba-edema test, according to G. Wilhelmi, Jap. J.. Pharmacol. L5, 187 (1965). The antipyretic activity of the new compounds of the general Formula I, in particular} 1- [p-(2-aminoethyl) -phenyl] -pyrrole, 1- [p- [ 2- (climethylamino) -ethyl ] -phenyl ] -pyrrole » 1- [4- (2-aminoethyl) -2-chlorophenyl ] -pyrrole* 1- [p- (2-amino-1 -methylethyl) -phenyl ] -pyrrole; and 1 - [p- [ 1 -methyl-2- (methylamino) -ethyl ] -phenyl ] -pyrrole can be demonstrated, for example, on the rat in the "yeast-fever"test by subcutaneous injection of a 15%, yeast suspension followed by the ora]. administration of the test substance in 2% gum arable. The rectal temperature, is then measured hourly for 3 hours and the maximum and minimum temperature differences are noted. The new basic pyrrole derivative of general Formula I and their pharmaceutically acceptable acid addition salts are suitable as active substances for medicaments which can be administered orally, rectally or parenterally for the relief and removal of pains of varying origin and of light and medium severity and for the treatment of rheumatic, arthritic and other inflamma ory diseases.

The new compounds of general Formula I and their acid additio salts are produced by reducing a compound of the general Formula II wherein A represents an oxo radical and at the same time Rg1 corresponds to the definition given for R3, or A represents two hydrogen atoms and at the same time R^' represents an acetyl or formyl radical or a low alkoxy-carbonyl group and R]_, R2 and R^ in both cases have the meanings given under Formula I, by means of a complex hydride and optionally converting the resultant compound of general Formula I into an acid addition salt thereof. The reduction of the compounds of general Formula II can be performed, for example, with lithium aluminium hydride or diborane in an ether-type solvent such as diethyl ether, tetrahydrofuran, dibutyl ether, ethylene glycol dimethyl ether (1 , 2-dimethoxyethane) or di-ethylene glycol dimethyl ether, or with bis- (2-methoxy-ethyl) sodium dihydrogen aluminate in benzene or toluene, at temperatures between about 0° and 100°, or at the boiling temperature of the solvent employed. The diborane is prepared separately either preceding or during the reduction and then introduced, or it is formed in situ, e.g. from sodium or potassium boron hydride and boron trifluoride-etherate. The production of the starting materials of Formula II which in themselves are new will be described further below.

The compounds of general Formula I and their acid addition salts are produced by a second process by reacting a reactive ester of an alcohol of the general Formula III with a compound of the general Formula IV H - N (IV) R, wherein Rj_, R2> 3 and R^ have the meanings given under Formula I, and optionally converting the resultant compound of general Formula I into an acid addition salt thereof.

Suitable as reactive esters of alcohols of general Formula III are, for example, hydrohalic acid esters, in particular bromides, furthermore chlorides or iodides, as well as sulphonic acid esters, in particular arene-sulphonic acid esters or lower alkane-sulphonic acid esters such as p-toluene-sulphonic acid esters and methane-sulphonic acid esters. The reactions are performed preferably in a suitable organic medium, e.g. in an aromatic hydrocarbon such as benzene, toluene or xylene, in a lower alkanol or another aliphatic hydroxy compound such as methanol, ethanol, n-butanol, 2.-methoxy -ethanol , in a ketone such as acetone or 2-butanone, or in an ether-type liquid such as dibutyl ether, ethylene- or diethylene-glycol dimethyl ether, tetrahydrofuran or dioxane and/ or an excess of the compound of general Formula IV to be reacted. An excess of the compound of general Formula IV can at the same time serve as acid-binding agent; however, tertiary organic bases such as, e.g. diisopropyl ethyl amine, pyridine or symmetrical collidine, or inorganic basic substances such as, e.g. potassium carbonate- can also be employed as acid-binding agents . The reactions are performed at roorn temperature or at raised temperatures up to about 180°, preferably between about 90° and 130°C and if necessary in a closed vessel. The alcohols of general Formula III and their reactive esters are in turn new compounds, the preparation of which will be described further below.

The compounds of general Formula I in which and represent hydrogen atoms, and 'their acid addition salts, are obtained according to a third process by reducing a nitrile of the general Formula V wherein and have the meaning given for Formula I , and optionally converting the resultant compound of general Formula I into an acid addition salt thereof. The reduction takes place, for example using hydrogen in the presence of a hydrogenation catalyst such as, e.g., Raney nickel, in an organic solvent such as, e.g., methanol, at raised temperature and raised pressure, e.g. at 50-100°C and about I00r200 atm. , and preferably in the presence of ammonia or by means of a complex hydride such as. e.g. diborane in tetrahydrofuran. Of the nitriles of general Formula V, [p-(l-pyrrolyl) -phenyl ] -acetonitrile is described in French patent No. 1,543,100. The other nitriles can be produced analogously.

Likewise, compounds of general Formula I having hydrogen atoms as R3 and R4, and their acid addition salts, are obtained according to a fourth process by reacting an N-substituted phthalimide of the general Formula VI wherein R^ and R have the meanings given under Formula I, with hydrazine, treating the reaction product with an acid and optionally converting the compound of general Formula I which has been liberated into an acid addition salt thereof. For example, a compound of general Formula VI is first boiled for several hours with hydrazine hydrate in ethanol, then dilute hydrochloric acid is added, and boiling is continued for about 10 -30 minutes for cleavage of the phthalazinone derivative resulting as intermediate product. The starting materials of general Formula VI are obtained, for example, by reacting reactive esters of the alcohols defined above of general Formula III, with potassium phthalimide in known manner. The production of the alcohols of general Formula III and their reactive esters will be described further below.

Compounds of general Formula I in which Rj_ , R3 and R^ represent hydrogen atoms, and their acid addition salts, are produced according to a fifth process by reducing a compound of the general Formula VII wherein R£ has the meaning given under Formula I, and optionally converting the resultant compound of general Formula I into an acid addition salt thereof. The reduction of compounds of general Formula VII takes place, for example, with complex hydrides such lithium aluminium hydride or diborane under the conditions given for the first process, or by catalytic hydrogenation, e.g. in the presence of a palladium/charcoal catalyst, in a mixture of glacial acetic acid and hydrochloric acid. The production of the starting materials of general Formula VII will be described further below.

Compounds of general Formula I in which R^ represents hydrogen, whereas R^ , R and R^ have the meanings given under Formula I, and their acid addition salts, are obtained according to a sixth process by hydrolyzing an amide of the general Formula VIII wherein Ac represents the acyl radical of an organic acid, and ¾, and R3 have the meanings given under Formula I, and optionally converting the compound of general Formula I which is set free, into an acid addition salt thereof.

An acyl radical as Ac is derived, in particular, from a carboxylic acid, from a mono-functional carbonic acid derivative, or from a sulphonic acid, and is, for example, a lower alkanoyl radical, the benzoyl radical, a lower alkoxycarbonyl radical, the phenyloxycarbonyl radical or benz loxycarbonyl radical, the cyano radical, a lower alkane-sulphonyl radical such as the methane-suphonyl radical, or an arene-sulphonyl radical such as the p-toluene-sulphonyl radical. The hydrolysis is preferably performed in an alkaline medium e.g. by boiling for several hours with an alkali hydroxide such as sodium or potassium hydroxide in a preferably aqueous lower alkanol such as methanol, ethanol or n-butanol. Some of the starting materials of general Formula VIII, i.e. those having a lower alkanoyl group as acyl radical Ac, also fall under general Formula II. The production of these and other starting materials will be described further below.

Likewise, compounds of general Formula I having a hydrogen atom as R^, as well as their acid addition sal are obtained according to a seventh process by allowing catal tically activated hydrogen to react on a compound of the general Formula IX wherein R3'1 represents a benzyl group or has the meaning given for R3 above and and R2 have the meanings given under Formula I, or on an acid addition salt of such a compound, until a substantially equimolar amount or double the molar amount, depending on the meaning of R3" , is taken up, and optionally converting the resultant compound of general Formula I into an acid addition salt thereof or, conversely, setting free the base from a resultant salt. The hydrogenolytic cleavage of the benzyl group takes place, for example, by using noble metal catalysts, e.g. a palladium/charcoal catalyst, in a suitable organic solvent such a methanol, ethanol or dioxan; at normal or slightly raised pressure and normal or slightly raised temperature. The production of the starting materials of general Formula IX will be described Compounds of the general Formula I possessing a secondary or tertiary amino group and their acid addition salts are produced by an eighth process by reacting a compound of the general Formula X wherein R3" 1 represents a methyl or ethyl group, and R]_ , R and R^ have the meanings given under Formula I, with monomeric or polymeric succinaldehyde or with an open-chain or cyclic, reactive derivative of the monomeric succinaldehyde, and optionally converting the resultant compound of general Formula I into an acid addition salt thereof. The succinaldehyde is employed either in the monomeric form which is preferably prepared directly before the reaction either being set free from a functional derivative or obtained by distillation of polymeric forms, or it is employed in a polymeric modification [cf.C Harries Ber.3_5_, 1183-1189 (1902)]. Functional derivatives of monomeric succinaldehyde which may be employed are in particular open-chain or cyclic acetals, acylals, a-halogeno ethers, enolic ethers or enolic esters corresponding to the general Formula XI wherein X and X' represent, independently of each other, chlorine or bromine atoms or groups of the formulae R-0- and R-CO-0-, wherein R represents an optionally halogen substituted hydrocarbon group, Y and Y' represent, independently of each other, groups of the formulae R-0 and R-CO-0- as defined above for X and X1, or, together the epoxy group(-O-), or Y' together with X1, represents the oxo group (=0) and Z and ' represent, independently of each other, hydrogen atoms or together with Y and Y' respectively additional bonds as indicated by the dotted lines. in the presence or absence of a diluting and/ or condensing agent.

Of the compounds of general Formula XI which may be employed in place of succinaldehyde , the following examples of open-chain derivatives of monomeric succinald-hyde may be mentioned: the acetals thereof such as succinaldehyde-mono-diethyl acetal , -bis . dimethylacetal , -bis- diethyl acetal, acylals such as succinaldehyde- 1 , 1- diacetate (4 , 4- diacetoxy-butyraldehyde) , enolic ethers such as 1 , - diphenoxy-butadiene , enolic esters such as 1.4- diacetoxy-butadiene , Compounds of general Formula XI in which Y and Y' together form the epoxy radical are ■ formally deriv tives of tetranydrofuran which, depending on the meaning of X and X', react like the" acetals or acylals of succinaldehyde, or like open-chain a-halogeno ethers. Such compounds are e.g. 2 ,5- dialkoxy- tetrahydrofurans and. related compounds such as 2 , 5-dimethoxy- , 2.5- diethoxy- , 2 , 5-dipropoxy- , 2 , 5-dibutoxy- , 2,5-bis-allyloxy- , 2 , 5-bis-- (2-chloroethoxy) - , 2 , 5-diphenoxy- and 2 ,5-bis-(3 , 4-xylyloxy) - tetrahydrofura , furthermore 2 , 5-diacyloxy- tetrahydrofurans such as 2 , 5- diacetoxy-tetrahydrofuran as well as 2 , 5-dihalogeno- tetrahydrofurans such as 2 ,5-dichloro-tetrahydrofuran and 2,5-dibromo-tetrahydrofuran , and finally also compounds which simultaneously belong to two classes such as 2-chloro~5- ■ (2-chloroethoxy) - etrahydrofuran and 2-allyloxy-5-chloro-tetrahydrofuran.

As medium for the reaction according to the invention when succinaldehyde is employed, either as the free compound or formed in situ, any solvent desired can be used in which the succinaldehyde . is soluble, for example methanol, aqueous dioxane or acetic acid.

Acetals and acylals of succinaldehyde as well as cyclic, aceta.l-type derivatives are advantageou ly reacted in acetic acid as solvent and condensin a ent. .The reaction of compounds of gerieral Formula XI in which X and/ or X' represent halogen atoms, is performed in an inert organic solvent such as chloroform, benzene or toluene. The reaction temperature is preferably between room temperature and the boiling point of the solvent or diluent employed, the lower range being especially suitable for the last-mentioned halogen compounds.

Compounds of general Formula I having a tertiary amino group and their acid addition salts are obtained according to a ninth process by reacting a compound of the general Formula XII wherein R^, R2 and have the meanings given under Formula which compound of Formula XII is also embraced by Formula I, with a reactive ester of methanol or ethanol in a molar ratio corresponding at least to the number of hydrogen atoms bound to the nitrogen atom of the side chain, in the presence of an acid-binding agent, and optionally converting the resultant compound of general Formula I into an acid addition salt thereof.

As reactive esters of methanol and ethanol, halides , in particular bromides or iodides, as well as arenesulphonic acid esters or disulphates are employed. The reactions are performed for example in organic solvents such as acetonitrile, methanol or dimethylf rmamide, or also without solvent in the presence of an acid-binding agent such as sodium or potassium carbonate at room temperature or raised temperatures e.g. at the boiling point of the solvent employed.

The starting materials needed for the various processes can be produced by various reaction sequences.

These may be divided into two groups, namely those which start with known compounds which already contain the P- (l-pyrrolyl) group and those in which during the course thereof this group is introduced by ring closure analogously to the eighth process for the production of compounds of general Formula I.

Belonging to the first group of methods of preparation is the reaction of lower alkyl esters of [p- (l-pyrrolyl) -phenyl ] -acetic acids which may be substituted corresponding to the definition of and R and which are described in French patent No. 1,543,100, or of mixed anhydrides of the said acids, e.g. the anhydrides of the carboxylic acid-mono- isobutyl esters or of pivalic acid, with ammonia or amines of general Formula IV to giva amides, of general -Formula wherein A represents the oxo radical-. . The aforesaid* [ p- ( l-pyrrolyl) -phenyl ] -acetic acids and their alkyl esters can also be reduced analogously to the amides of general Formula II with complex hydrides to obtain alcohols of general Formula III. These alcohols can be converted by conventional methods into their reactive esters, for pyridine into their p-toluene-sulphonic acid esters.

By acylation of the primary amines falling under general Formula I obtained by the third process, with reactive functional derivatives of formic or acetic acid or with lower chloroformic acid alkyl esters, e.g. with acetanhydride or with ethyl chloroformate, and optionally by subsequent introduction of a methyl or ethyl group into the amide group, e.g. by conversion of the amides into their alkali metal compounds, e.g. sodium compounds, and reaction of the latter with reactive esters of methanol or ethanol e.g. with the halides thereof, starting materials of general Formula II are obtained in which A represents two hydrogen atoms and R-¾ ' represents a formyl or acet}^ radical or a lower alkoxycarbonyl group, and which at the same time can be employed as starting materials of general Formula VIII for the sixth process. Starting materials of general Formula IX are obtained for example analogously to the second process for the production of compounds of general Formula I when instead of compounds of general Formula IV, benzylamine, N-methyl-or N-ethyl-benzylamines or dibenzylamine are employed, or analogously to the first process, when instead of amides of general Formula II, the corresponding N-benzyl- or N, -dibenzyl -amid which can be prepared analogously, are used.

Some individual compounds of the starting materials of general Formula X have been described by K.Kindler and K. Schrader, Arch . Pharmazie 283, 184 (1950), and others can be . , produced analogously to the known compounds as well as by processes mentioned further below.

As has already been mentioned, ring closure analogous to the eighth process can be used for the production of starting materials for some of the other processes as well as for some intermediate products leading to such starting materials. For example, phenethyl halides , β-alkyl- phenethyl halides as well as N-phenethyl acetamides, N- (a-alkylphenethyl) acetamides, N-alkyl- -phenethyl acetamides and N-alkyl -N- (a-alkylphenethyl) acetamides wherein the -and a-alkyl groups are methyl or ethyl can be nitrated to the corresponding p-nitro compounds, which can be reduced, e.g. with tin and hydrochloric acid, to the corresponding amino compounds from which, by ring closure analogous to the eighth process, reactive esters, i.e. halides, of alcohols of general Formula III or amides of general Formula II having 2 hydrogen atoms as A and the acetyl group as ' are obtained; said amides are also starting materials of general Formula VIII.

If tne afore-mentioned p-nitro derivatives of phenethyl halides and /3-al.kyl phenethyl halides are first reacted with compounds of general Formula IV and then afterwards the nitro group is reduced, starting materials of general For ula X for the eighth process are obtained. Furthermore, nitriles of general Formula V can be obtained by condensing p-nitro-chloroben ene with optionally niethyl or ethyl -substituted cyanoacetic acid alkyl esters, or 2 , 4-dichloro-nitrobenzene with 2-cyano-propionic acid alkyl esters with the aid of alkali alcoholates, then hydrolyzing the condensation products with the equimolar. amount of alkanolic/aqueous alkali hydroxide solutions, decarboxyla ing the resultant cyanoacetic acids to 2- (p-nitrophenyl) -alkanoic acid nitriles or to 3-chloro-4-nitro-hydratroponitrile , .. . reducing the nitro group in theses nitriles to the amino group, e.g. again with tin and hydrochloric acid, and finally converting the resultant p-amino compounds, again analogous to the eighth process, into the corresponding p- ( 1-pyrroly1) compounds .

Starting materials of general Formula VII are obtained by converting polymeric p-aminobenzaldehyde or 4-amino- 3-chloro-benzaldehyde analogous to the eighth process into p-- (1-pyrrolyl) -beiizaldehyde or 3-chloro-4- ( 1-pyrrolyl) - benzaldehyde , respectively , and reacting these aldehydes with nitro ethane , for example by boiling in glacial acetic acid in the presence of ammonium acetate or sodium acetate. The aldehydes required can also be produced from the correspondingly substituted benzoic acids, thus, e.g., p- (1-pyrrolyl) -benzaldehyde via , N-ethylene- - ( 1-pyrroly1) - benzamide .

If desired, the new basic pyrrole derivatives of general Formula I obtained according to the processes of the invention are subsequently converted by conventional methods into their acid addition salts. For example, a solvent such as acetone, methanol, ethanol , dioxan, tetrahydrofuran or diethyl ether, is treated wi h an acid of the desired salt component or a solution of said acid, and the salt is separated which precipitates either directly or or after the addition of a second organic liquid, such as diethyl ether to methanol or acetone, For use as active substances for medicaments, if desired, pharmaceutically acceptable acid addition salts, i.e. salts with acids the anions of which in the dosages to be applied have either no pharmacological effect of their own or a desired effect, may be vised instead of the free bases; these are particularly preferred for solutions. For the formation of salts with compounds of general Formula I the following, for example, can be used: hydrochloric acid, hydrobronric acid, sulphuric acid, phosphoric acid, metharie-sulphonic acid, ethane-disulphonic acid, β-hydroxy-ethane-sulphonic acid, acetic acid, malic acid, tartartic acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, ascorbic acid, salicylic acid, mandelic acid, embonic acid or 1 , 5-naphthalene-disulphonic acid.

The new basic pyrrole derivatives of general Formula I and their pbararaceutically acceptable acid addition salts are administered, as mentioned above, orally, rectally or parenterall . The daily doses for mammals range between 1 and 100 mg/kg of body weight. Suitable dosage units such as dragees, tablets, suppositories or ampoules contain as active ingredient preferably 5-500 mg of a 3> acceptable acid addition salt thereof.

In dosage units for oral adminis ration, the amount of active ingredient is preferably between 107. and 90%.

To produce such dosage units, the active ingredient is combined, e.g., with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form. tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which may also contain, e.g. gum arable, talcum and/or . titanium dioxide or they are coated with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. for identification of the various dosage amounts. Further dosage units suitable for oral administration are hard gelatine capsules as well as soft closed capsules made from gelatine and a softener, such as glycerin. The hard capsules contain the active substance preferably as a granulate, e.g. in admixture with lubricants such as talcum or magnesium stearate, and, optionally, stabilizers such as sodium metabisulphite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols , whe eby likewise ■ Suitable as dosage units for rectal adminis ration are, e.g., suppositories consisting of a. combination of an active substance and a suppository base of natui-al or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatine rectal capsules containing a combination of the active substance and polyethylene glycols.

Ampoule solutions for parenteral administration, in particular intramuscular, and also intravenous administra- tion, contain, e.g., an aqueous, preferably 0.5 - 10¾> solutio of a pharmaceutical!)' acceptable, water-soluble acid addition salt of a compound of general Formula I, or a compound of general Formula I in a concentration of preferably 0.5 - 5% prepared as an aqueous dispersion with the aid of conventional solubilizers and/or emulsifying agents as well as optionally of stabilizing agents.

Suitable as other parenteral application forms are, for example, lotions, tincture and ointments prepared with conventional auxiliaries for percutaneous application.

The following prescriptions illustrate the production of various application forms: a) 500 g of active substance, e.g. 1- [p- 11- ( ethy1-amino-methyl) -propyl] -phenyl] -pyrrole hydrochloride are mixed together with 550 g of lactose and 292 g of potato starch. The mixture is moistened with an alcoholic solution of 8 g of gelatine and granulated through a sieve. After drying, 60 g of potato starch, 60 g of talcum, 10 g of ■J? magnesium stearate and 20 g of highly dispersed silicon dioxide are mixed in and the mixture is pressed into ,000 tablets each weighing 1500 mg and each containing 50 g of active substance. Optionally, the tablets can be grooved for finer adjustment of the dosage amount. b) 25 g of active substance, e.g. 1- [p- ( 2-amino- ethyl) -phenyl ] -pyrrole hydrochloride, are well mixed with 16 g of maize starch and 6 g of highlj' dispersed silicon dioxide. The mixture is moistened with a solution of 2 g of stearic acid, 6 g of ethyl cellulose and 6 g of stearin in about 70 ml of isopropyl alcohol and is granulated through a sieve III. (Ph. Helv.'V). The granulate is dried for about 14 hours and is then put through sieve III~IIIa. It Is then mixed with 16 g of maize starch, 16 g of talcum and 2 g of magnesium stearate and the mixture is pressed into 1000 dragee cores. These are coated with a concentrated syrup of 2 g of shellac, 7.5 g of gum arable, 0.15 g of dyestuff, 2 g of highly dispersed silicon dioxide, 25 g of talcum and 53.35 g of sugar, and dried. The dragees obtained each weigh 185 mg and each contain 25 mg of active substance. c) 50 g of 1- fp- [ 2- (dime hy lamino) -ethyl ] -phenyl ] -pyrrole hydrochloride and 1950 g of finely ground suppository foundation substance (e.g. cocoa butter) are thoroughly mixed and then melted. From the melt, maintained homogeneous by stirring, 1000 suppositoties of 2 g each are poured. They each contain 50 mg of active substance.. d) 2.5 g of 1- [4- (2-aminoethyl ) -· 2- chloropheny1 ] - pyrrole, hydrochloride and 0.10 g of ascorbic acid are dissolved in distilled water. and diluted to 100 ml. The solution obtained is used to fill ampoules, each containing e.g. 1 ml, corresponding to a content of 25 rag of active substance. The filled ampoules are sterilized by heating in the usual manner. e) 2 g of 1- [ p- (2-amino- 1-inethylethy1)-· phenyl ] -pyrrole hydrochloride and 4.4 g of glycerin are dissolved in distilled water to give 200 ml and the solution is filled into 100 ampoules each of 2 ml and each containing 20 mg of active substance.

The following examples illustrate the production of the new basic pyrrole derivatives corresponding to general Formula I, but they in no way limit the scope of the invention. Where not stated otherwise, the pyrrole derivatives used as starting materials are described in French patent No. 1,543,100. The temperatures are given in degrees centigrade.

J Example 1 A solution of 22.8 g of , ·- dimethyl- [p- ( 1-pyrrolyl) - phenyl ] -acetamide in 600 ml of absolute ether is added dropwise to a suspension of 7.6 g of lithium aluminium hydride in 150 ml of absolute ether. The reaction mixture is refluxed with stirring for 48 hours. The excess hydride is then decomposed by the dropwise addition of 20 ml of water with cooling. After the addition of 20 ml of concentrated potassium hydroxide solution, the ethereal phase is separated, dried over magnesium sulphate, and concentrated by evaporation. The crude amine is distilled in a bulb tube at 130° under .01 Torr. 19.8g ( 93% of theory) of crystallized 1- [p- [ 2·- (dimethylamino) - ethyl ] -phenyl ] -pyrrole are obtained. After dissolving i 150 ml of ether, 68 ml of 1.4 N ethereal hydrogen chloride solution are added. The hydrochloride is removed by filtration (18.7 g) and recrystallized from ethanol. The pure 1- [p- [ 2- (dimethylamino) -ethyl ] -phenyl ] -pyrrole hydrochloride melts at 228-232°.

Analogously, starting from 25.6 g of ,N-diethyl-2- [p- ( 1-pyrrolyl) -phenyl ] -acetamide there are obtained 19.6 g (81% of Theory) of 1- [p- [ 2- (diethylamino)-ethyl ] -phenyl) -pyrrole (b.p. 130- 140° / 0.01 Torr in a bulb tube), which is converted with 9.4 g of fumaric acid, dissolved in 100 ml of methanol, into the furnarate which melts at 123-125° (from isopropanol, 25.1 g).

The amides required as starting mater ials can be produced in the following manner: a) 34.0 g of ethyl [p- (1-pyrrolyl) -phenyl ] -acetate and 50 ml of a 307;. solution of di ethylamine in absolute ethanol are heated for 18 hours in an autoclave at 220°. The reaction mixture is concentrated by evaporation and the residue is recrys aliized from isopropanol. 23.5 g (697a of theory) of N ,N-dimethyl- 2- [p- (1-pyrrolyl) -phenyl ] -acetamide, m.p. 94-96°, are obtained.

Analogously, employing 100 ml of dietl'^lamine and heating to 200° for 15 hours, 25.8 g (67% of theory) of N .N-diethyl-2- [p- ( 1-pyrrolyl) -phenyl ) -acetamide. , m.p. 78-81° (from isopropanol), are obtained.

Example 2 9.1 g of lithium aluminium hydride, suspended in 1.5 liters of absolute ether, are heated with stirring to the boil. Between the reaction flask and the reflux condenser, an extraction device fitted with a glass frit and filled with 33.0 g of 2- f p- ( 1-pyr ol 1 ) -pheny1 ] -butyra ide , has been inserted. During 16 hours the refluxing ether dissolves the difficultly soluble amide in the hydride suspension. Then the reaction mixture is refluxed for 24 hours more with stirring. Then 20 ml of water are carefully added dropwise with ice cooling to the reaction mixture. After the addition of 30 ral of concentrated potassium hydroxide solution, the ether phase is removed, the aqueous phase is again extracted with 200 ml of ether, and the combined ether extracts are dried over potassium carbonate. After the ether has been removed by evaporation, the residual oil is distilled in a bulb tube at 140° under 0.03 Torr . The 1- [p- [ 1- (aminomethyl) -propyl ] -phenyl ) -pyrrole (23.6 g, 76% of theory), obtained as a colorless oil, is converted with the calculated amount of ethereal hydrogen chloride solution into the hydrochloride. After recrystal-lization from absolute ethanol, the hydrochloride melts at 176-181°.

Example 3 7.1 g of N > - diethyl- 2- [p- (1-pyrrolyl) -phenyl ] - butyramide, dissolved. In 50 ml of absolute ether, are added dropwise with stirring to a suspension of 2.0 g of lithium aluminium hydride in 100 ml of absolute ether, whereb ' the reaction comes to the boil. Heating at the boil is con- tinued with stirring and refluxing for 48 hours. After adding 10 ml of water while cooling with ice, 10 ml of concentrated potassium hydroxide solution are added and the phases are separated. The ether phase is dried over potassium carbonate and concentrated by evaporation. 6.8 g of crude, oily 1- [p- [ 1- (diethylaminomethy 1) -propyl ] -phenyl ] -pyrrole are thus obtained. After dissolving in ether, this compound, is added in as small an amount as possible (50 ml) of methanol to a solution of 2.8 g of fumaric acid. The fumarate. which precipitates after condensing the solution and cooling, is recrys tallized from isopropanol and melts then at 140-141° (7.2 g, 74% of theory).

The amide required as starting material is produced as follows : a) 11.5 g of 2- fp- ( 1-pyrrolyl) -phenyl ] -butyric acid are dissolved in 300 ml of dry dioxane, and 7.1 g of triethyl amine are added. Then while cooling at. 10°, 9.6 g of isobutyl chloroformate in 10 ml of absolute dioxane. are. added dropwise. The semifluid reaction mixture is then stirred for 15 minutes more at 10°. After the addition of 5.3 g of diethyl amine at 10-25°, the suspension is stirred mixture is then concentrated by evaporation at 20 Torr and the residue is distributed between 20 τηΐ of water and 200 ml of methylene chloride. The organic phase is washed with 20 ml of 2 N sodium hydroxide solution and 20 ml of water, dried over magnesium sulphate, and concentrated by evaporation. The oily residue is distilled in a bulb tube at 160° under 0.01 Torr. 8.9 g (62% of theory) of N,N- diethyl- 2- [p- ( 1-pyrrolyl) -phenyl ] -butyramide , .p. 122-124° (from isopropanol) , are obtained.

Example. 4 9.5 g of 2- [p- ( 1-pyrrolyl ) -phenyl ) -acetamide are gradually added to 190 ml of an 0.85-molar solution of diborane in tetrahydrofuran . A solution is formed with foaming. This is allowed to s and for 2-3 days at room temperature in the dark,, while excluding moisture. It is then concentrated by evaporation at about 20 Torr, The residue is dissolved in methanol (about 200 ml) and strongly acidified with ethereal hydrogen chloride solution. The reaction mixture is then refluxed for minutes and then concentrated again by evaporation under* reduced pressure. The residue is taken up in about 50 ml of water, made alkaline (pH 10-11) with concentrated potassium hydroxide solution and extracted with a total of 30 ml of ether. The ether phase is separated, washed with 300 ml of water and dried over magnesium sulphate. The ether is removed by evaporation, and the oily residue of 5.8 g of crude base is dissolved in 50 ml of ether and converted with the calculated amount of ethereal hydrogen chloride solution (e.g. 7.3 ml of 4.3 solution) into the hydrochloride. The salt which precipitates as crystals (6.4 g, 60% of theory) is recrystallized from ethanol/water . Pure 1- [p- ( 2-aminoethyl) -phenyl ] -pyrrole hydrochloride, m.p. 290-293° (with decomposition), is thus obtained.

In an analogous manner there- is obtained: using 30.0 g of N-meth 1- 2- [p- ( 1-pyrrolyl) -phenyl ) -acetamide and 450 ml of 0.95-molar diborane solution in tetrahydro- furan, 28.0 g (85% of theory) of crude 1- [p- [2- (methylamino) -ethyl ] - phenyl ] -pyrrole hydrochloride which, after recrysta llization from methanol, melts at 254-256° (18.4 g of pure substance). a) The amides required as starting materials, are obtained by reacting ethyl [p- ( 1-pyrrolyl) -phenyl ) -acetate with a large excess of the appropriate amine in an autoclave at raised temperature arid pressure. If solvents or non-volatile amines are used, the reaction mixture is conceiitrated by evaporation. The crude crystalline product is washed with 30-50 ml of ether and the crude or recrysta llized product is used for the reduction.

Thus there are obtained: from 15.0 g of ethyl [p- ( 1-pyrrolyl) -phenyl ] -acetate and 40 g of pure ammonia (liquid) by heating to 200° for 12 hours , 11.4 g (877a of theory) of 2- fp- ( 1-pyrrolyl) -phenyl ] -acetamide, m.p. 251-252° (from methanol); and from 68.0 g of the same acetate, 190 g of methyl amine and 400 ml of absolute alcohol by heating at 180° for 12 hours, 52.0 g (82% of theory) of N-methyl- 2- [P- ( 1-pyrrolyl) - phenyl ] -acetamide , m.p. 174-176° (from methanol) .

Example 5 Analogously to Example 4. there are obtained: using 7.0 g of p- ( 1-pyrrol 1 ) -hydratropamide and 100 ml of 1.0-molar diborane solution in tetrah drofuran , .7 g (S77o of theory) of crude 1- fp- ( 2-amino- 1-methylethy1 ) - phenyl ] -pyrrole , the hydrochloride of which melts at 228- 231° (from absolute ethanol) , and using 7.9 g of N-methyl-p- ( 1- pyrrolyl ) -hydratropamide and 110 ml of 0.85-molar diborane solution in tetrahydrofuran , 7.7 g of crude oily amine which is converted with the calculated amoun of ethereal hydrogen chloride solution to 6.1 g (70% of theory) of 1- [p~ [ 1-methyl- 2- (methylamino) -ethyl ] -phenyl ] -pyrrole hydrochloride, m.p, 208-212° (from isopropanol) . a) The amides required as starting materials are obtained fully analogously to Example 4a) .

Thus there are obtained: from 10.8 g of methyl p- ( 1-pyrroly1) -hydratropate and 30 g of liquid ammonia by heating for 10 hours at 200°, 7.0 g (69% of theory) of p- ( 1-pyrrol 1) -hydratropa ide , m.p. 161-163° (from isopropanol), and from 18.8 g of the same hydratropate and 50 g of ethylamine, 7.9 g (42% of theory) of N-methyl-p- ( 1-pyrroly 1) -hydratrop-ami'de, m.p. 145-148° (from isopropanol).

Exam le 6 .0 g of N-raethyl- 2- fp- (1-pyrrolyl) -phenyl ] -butyramide are reacted with 700 ml of 0.76-molar diborane solution in tetrahydro uran and further processed fully analogously to Example 4. In this manner, 30.0 g (907o of theory) of crude 1- [p- f 1- (methylamino-iTiethyl) -propyl ] -phenyl ] -pyrrole hydrochloride is obtained, vnich after recrys ta 1 lization from isopropanol melts at 182-185° (19.2 g of pure substance) . a) The amide required as starting material is prepared analogously to Example 4a) by heating 77 g of ethyl 2- [p- ( 1-pyrrolyl) -phenyl ] -butyrate vjith 190 g of methylamine in 300 ml of absolute ethanol for 12 hours at 180° in an autoclave. In this manner 54.5 g (7570 of theory) of -methyl- 2- fp- ( 1-pyrrolyl) -phenyl ]- butyramide , .p. 166-167° , are obtained.

Example 7 By reacting 14.4 g of 2- [ 3-chloro- 4·- ( 1-pyrroly1) - phenyl ] -acetamide with 200 ml of 1.0-molar diborane solution in tetrahydrofuran analogous 1)' to Example 4, 10.0 g (73% of theory) of crude 1- [4- (2-aminoethyl) - 2-chloropheny1 ] - pyrrole are produced, which distills at 120-140° under 0.01 Torr. From the base with 32 ml of 1.4 N ethereal hydrogen chloride solution, the hydrochloride is obtained which, after recrystallization from isopropanol, melts at 203-205°. Yield 10.5 g, 63% of theory.

In an analogous manner there are obtained: using 10.0 g of 2- [3-chloro-4- ( 1-pyrrolyl) -phenyl ) - -methyl-acetamide and 115 ml of 0.85-molar diborane solution in tetrahydrofura , .7 g (53% of theory) of 1- [ 2-chloro-4- [ 2- (methylamino) -ethyl ] -phenyl]-pyrrole hydrochloride, m.p. 173-177° (from isopropanol) , and using 26.5 g of 2- [ 3-chloro-4- ( 1-pyrroly 1) -phenyl ] -N ,N-di-methyl-acetamide and 250 ml of 1.17-molar diborane solu-tion in tetrahydrofuran , .7 g (55% of theory) of 1- [ 2-chloro-4- [ 2- (dimethylamino) -ethyl ] -phenyl ] -pyrrole hydrochloride which, after recrystal-lization from isopropanol and then from absolute ethanol , melts at 210-214°. a) The amides required as starting materials are produced analogously to Example. 4a).

Thus there are obtained: from 30.0 g of ethyl [ 3- chloro-4- ( 1-pyrrolyl) -phenyl ] - acetate and 75 g of liquid ammonia by heating at 200° for 12 hours, 25 g of crude amide as a dark oil. This is distilled in a bulb tube at 180-190° under 0.04 Torr. By recrystalli ing from isopropanol , 14.4 g (540 of theory) of colorless 2- [3-chloro-4- ( 1-pyrrolyl) -phenyl ] -aceta ide , m.p. 95-96°, are obtained; from 30.0 g of the same acetate and 60 g of meth lamine by heating at 180° for 10 hours and distilling in a bulb tube at 170-190°/0.03 Torr, 19.0 g (67% of theory) of 2-[3-chloro-4- ( 1-pyrrolyl) -phenyl ] -N-methyl- acetamide , m.p . 118-121° (from isopropanol) ; and from 30.0 g of the same acetate and 85 g of dimeth la ine by heating at 150° for 15 hours and distilling in a bulb tube at 160-180°/0.1 Torr, 26.5 g (88% of theory) of 2- [ 3-chloro-4- ( l~pyrrolyl) -phenyl ] -N ,N~ dimethyl-acetamide as yellow, cloudy oil, which is used for further processing v/ithout purification.

The acetate required as starting material is obtained by boiling 40 g of the acid in 200 ml of absolute e hanol and 6 ml of concentrated sulphuric acid for 4 hours; b.p. 170-190 /0.1 Torr, m.p. 36-37° (from ligroin) . if Example 8 .6 g of 3-chloro-4- ( 1-pyrrolyl) -hydratropamide are reacted analogously to Example 4 with 67 ml of a 1.0- molar diborane solution in tetrahydrofuran. 4.9 g of the crude base are obtained, which is dissolved in 50 ml of ether and converted with the calculated amount of ethereal hydrogen chloride solution (e.g. 7.0 ml of 3.0 solution) to 3.4 g (56% of theory) of the hydrochloride. After recrys tallization from isopropanol, the pure 1- f4~ ( 2-amin.o- 1-methylethyl) - 2-chlorophenyl ] -pyrrole hydrochloride melts at 183-186°. a) The amide required as starting material can be prepared in the following manner: 6.0 g of 3-cbloro-4- ( 1-pyrrolyl) -hydratropic acid are dissolved in a mixture of 50 ml of dioxane and 100 ml of methylene chloride, 3.4 g of triethylamine are added and cooled to 10° . With stirring and further cooling with ice to 8-12°, 4.9 g of isobutyl chloroformate are added drop-wise. The reaction mixture is stirred for 10 minutes more at 8-12°. Then without further cooling , a strong current of dry ammonia is introduced for 10 minutes. The reaction mixture is then stii'red for 2 hours at room temperature and further processed analogous ly to Example 3a). In this manner, 3-chloro-4- ( 1-pyrrolyl) - hydratropamide is obtained as a yellow oil which distills at 130- 140° /0.01 Torr.

Exam le 9 A solution of 10.4 g of N- [p- ( 1-pyrrolyl) -phenethyl ] - acetamide in 200 ml of 1 , 2- dime.thoxy- ethane is added dropwise with stirring to a suspension of 5.1 g of lithium aluminium hydride in 200 ml of absolute ether. After completion of the addition, the reaction mixture is refluxed with stirring for 48 hours. The inner temperature gradually rises due to evaporation of the ether from 50 to 85°. Then, while cooling with ice, 10 ml of water are added dropwise to the reaction mixture which, .after the addition of 20 ml of concentrated potassium hydroxide solutioi and 300 ml of ether, is vigorously stirred. The organic phase is separated, dried OVC V C3 lcium chloride, and concentrated by evaporation in a water jet vacuum. After distilling in a bulb tube at 130° /0.01 Torr, 3.0 g (31% of theory) of 1-fp- I 2- (ethylamino) -ethyl ] -phenyl ] -pyrrole are obtained. This is dissolved in 5 ml of ether, and 3.2 ml of a.4.6 N solution of hydrogen chloride in ether is added. In this manner the hydrochloride is obtained, m.p. 265--2680 (from ethanol/methanol) .

The amide required as starting material is prepared in the following manner: a) 20.0 g of 1- fp- ( 2-aminoethyl) -phenyl ] -pyrrole (cf. Examples 4, 12 and 14) are dissolved by slight heating in 50 ml of dioxane; 13. l of acetanhydride are then added. A spontaneous, exothermic reaction commences. After the reaction subsides, the mixture is refluxed for 20 minutes.

On cooling. 18.9 g (77% of theory) of K- [ p- ( 1- pyrroly1) -phenethyl ] -acetamide , rn.p. 174-177° , crys talllzes . After recrys al lizat ion from ethanol , the melting point rises to 177-178°.

Another process for producing the above starting material is described in Example 26 a) .

V Exam le 1Q_ 4.0 g of N-methyl- - (p- (l-pyrrolyl).-phenethyl ) -acet-•amide are reduced analogously to Example 1, using 1.0 g of lithium aluminium hydride in 100 ml of absolute ether. After distilling the crude base in a bulb tube at 130-140°/ 0.02 Tor , there are obtained 2.3 g (6170 of theory) of 1- [ p- [ 2- ( ethy 1-methylamino) - ethy 1 ] -pheny 1 ] - pyrro 1e as a yellowish oil. It is converted v.-ith 2.2 ml of a 4.6 N ethereal hydrogen chloride solution into the hydrochloride which melts at 165-169° (from isopropanol) .

The starting material is obtained by acetylation of 4.2 g of 1- [p- [ 2- (rnethylamino) -ethyl ]-phenyl J-pyrrole (cf. Example 4) v.-ith 3 ml of acetanhyd ide i 10 ml of dioxane analogously to Example 9 a). Yield 907a, m.p. 77-79° (from ether) .

Example 11 Analogously to Example 1, 17g of crude 1- [ρ- (dimethylaminometbyl) -propyl ] -phenyl ] -pyrrole are obtained as an oil which solidifies to crystals starting from 5.7g of lithium aluminium hydride in 2.00 ml of absolute ether and 19.2g of N, N-dimethyl-2- [p- (l-pyrrolyl) -phenyl ] -butyramide , dissolved in 200 ml of absolute ether. The acid fumarate is subsequently prepared by reaction with 8.1g of fumaric acid dissolved in 150 ml of methanol and concen ation of the resulting solution. After recrystalisation from isopropanol 17.5g of the colourless fumarate are obtained m.p. 137-140° (65% of theoretical yield) .

Analogously 24.6g of crude 1- [p- [ 2- (dimethylamino) -1 -methyl -ethyl ] -phenyl ] -pyrrole are obtained starting from 24.6g of ,N-dimethyl-p (l-pyrrolyl-; -hydratropamide dissolved in 100 ml of absolute ether and 7.7g of lithium aluminium hydride suspended in 400 ml of absolute ether.

The hydrochloride is subsequently prepared by dissolving the above product in 300 ml of absolute ether and adding 30 ml of 3-n ethereal hydrogen chloride. 24, Og of the hydrochloride are obtained m.p. 227-230° ( from isopropanol) (89% of theoretical yield) The required amide starting materials can be prepared analogously to Example 3a as follows? a) From 30. Og 2- [p- (1-pyrrolyl) -phenyl ] -butyric acid, IS.5 g triethylamine, 26.8g chloroformic acid-isobutyl.ester and lOg dimethylarnine (Gas) , 19.5g ( 58%. of theory) ,N-dimethyl-2- [p- (1-pyrrolyl) -phenyl ] -butyramide .p. 109-110° (from isopropanol) ,· b) From 23. Og p- (1 -pyrroly1) -hydratropic acid, 13. lg triethylamine, 16.8g pivalic acid chloride and 6g gaseous dimethylarnine, 24g orange coloured N,N-dimethyl-p- (1-pyrrolyl) -hydratropamide as an oil which can be reduced without further purification. 7.0g of 1- [p- [1- (N-carbethoxyaminomethyl ] -propyl ] -phenyl ] -pyrrol in 100 ml of absolute ether are rapidly added dropwise to a suspension of 3.2g of lithium aluminium hydride in 200 ml of absolute ether. The reaction mixture is stirred under reflux for 42 hours.

After cooling 10 ml of water are added followed by ml of concentrated potassium hydroxide solution and the ether phase is separated and dried over potassium carbonate. The ether solution is evaporated to give 3.8g of 1- [p- [1- (methylaminomethyl) -propyl ] -phenyl ] -pyrrol as colourless crystals (67% of theoretical yield) .

The hydrochloride melts at 182-185° ( from isopranol) .

The urethane required as starting material can be prepared as follows; a) .3g of chloroformic acid ethyl ester are added dropwise with stirring and cooling to a solution of 7.6g of 1- [p- [1- (aminomethyl) -propyl ] - phenyl ] -pyrrol (cf. Example 2) and 3.5g of triethylamine in 100 ml of methylene chloride and the mixture is stirred for 3 hours at room temperature. The reaction mixture is then extracted with 10 ml of 2-n hydrochloric acid, washed with 10 ml of saturated sodium bicarbonate solution and dried over magnesium sulphate. After evaporation, cf the solvent the residual oil is distilled in a bulb tube at 150-170° /0, 02 Torr. 7.3g of 1- [p- [ 1- (N-carbethoxyaminomethyl) -propyl ] -phenyl ] -pyrrol are obtained after recrystalisation from isopropanol m.p. 69-70° (73%, of theoretical yield) .

- - Example 13 9.5g of N- [p-methyl-p-(l-pyrrolyl) -phenethyl] -formamide dissolved in a mixture of 80 ml of absolute ether and 30 ml of dioxan are added dropwise within ca. 20 minutes to a suspension of 1.6g of lithium aluminium hydride in 50 ml of absolute ether and stirred for 15 hours under reflux. The reaction mixture is then cooled with ice and 5 ml of water are added. The ether solution is decanted off, dried over magnesium sulphate and evaporated. 9.0g of crude 1- [p- [ 1 -methyl -2 (methyl -amino) -ethyl ] -phenyl ] -pyrrol are obtained (ca. 100% of theoretical yield) . The hydrochloride melts at 208-212° ( from isopropanol) .

The formamide required as starting material can be prepared as follows; a) A mixture of 6 ml of anhydrous formic acid and 14.5 ml of acetic anhydride is warmed for 2 hours at 60° and then cooled. The resulting mixture is then added dropwise to a solution of 14. Og of 1- [p- (2-amino-l-methylethyl) -phenyl ] - pyrrol (cf . Example 5) in 100 ml of ether with ice cooling. After standing overnight at room temperature the mixture is washed! twice with 20 ml of 2-n hydrochloric acid each time and once with ml of saturated sodium bicarbonate solution, dried and evaporated. The oily residue produces, after distillation in a bulb tube at 180-200° /0, 01 Torr, 15g of N- [ -methyl -p- (1 -py rolyl) -phenethyl ] - formamide as a turbid viscous oil (94% of theoretical yield) .

- - Example 14 3 . 4 g of p- ( 1-pyrrolyl) -phenethyl p- toluene-sulphonate , dissolved in 25 ml of dimethyl for amide, are allowed to stand for 6- 8 days at room temperature with 25 ml of a 337o solution of ' dimethylamine in absolute ethanol. After- removal of the solvent by evaporation under reduced pressure, the χ-esidue is dissolved in 50 ml of chloroform and washed with 20 ml each of water and saturated sodium bicarbonate solution. After drying over magnesium sulphate and removal of the solvent by evaporation, the oil which remains is distilled in a bulb tube. After separation of a preliminary run (up to 80° / 12 Torr) , the fraction which distills over at 130- 140° / 0. 01 Torr, containing 1. 5 g of crude 1- [p- [ 2-(dimethylamino)-ethyl]-phenyl]-pyrrolei is dissolved in 5 ml of ether, and then 1 . 5 ml of a 4 . 6 N solution of hydrogen chloride in absolute ether is added. The crystals obtained are suction filtered and recrystallized from ethanol. 0. 9 g ( 36% of theory) of pure 1- [p- [ 2- (dimethyl-amino) -ethyl ] -phenyl ] -pyrrole hydrochloride, m.p. 228- 232° , is obtained.

The toluene-sulphonate required as starting material" is produced as follows : a) A solution of 208 . 0 g of ethyl [p- ( 1-pyrrolyl) -phenyl ] -acetate in 1 . 5 liters of absolute ether is added dropwise with cooling to a suspension of 35 . 0 g of lithium aluminium hydride in 700 ml of absolute ether under nitrogen in such a manner that the reaction is kept stirring for 20 hours.. Then 800 ml of ice-cold, 20% hydrochloric acid are added dropwise with cooling. The ether phase is separated, washed neutral with sodium bicarbonate solution, and dried -with magnesium sulphate. After removal of the ether by evaporation at reduced pressure, 166 g (95% of theory) of p- (1-pyrrolyl) -phenethyl alcohol, m.p. 100-102°, remain which is pure enough for further process ing . b) From 9.0 g of p- ( 1-pyrrolyl) -phenethyl alcohol, dissolved in 50 ml of absolute pyridine, by reaction with 11.5 g of p- toluene-sulfonyl chloride analogous to E. Jenny and S. Winstein, Helv . Chimica Acta 4_1, 820 (1958), there are obtained 14.0 g (82%, of theory) of crude p- ( 1-pyrrolyl) phenethyl p-toluene-sulphonate which, after recrystalliza-tion from isopropanol/ dioxane , melts at 125-127° (10.5 g, 61%, of theory) .

Exam le 15 ; 2.0 g of β-ethyl-p- ( 1-pyrroly1 ) -phenethy1 p-toluene- sulphonate and 20 ml of a 33% solution of meth lamine are heated for 10 hours at 100° in an autoclave. The reaction mixture is concentrated by evaporation, the residue is taken up in water, acidified with a few drops of concentrated hydrochloric acid, and washed with 10 ml of ether. The aqueous phase is made alkaline with concentrated sodium hydroxide solution and extracted with 20 ml of ether. After drying over magnesium sulphate, 1.0 ml of 4.6 ethereal hydrochloric acid are added to the ether phase. The 1- [p- [1- (methylamino ethyl) -propyl ] -phenyl ] -pyrrole hydrochloride (0.7 g, 497o of theory), which precipitates, melts at 183-185° (from isopropanol) .

Iai an analogous manner, using 10 ml of liquid ammonia and 10 ml of absolute ethanol, there is obtained the 1- [p- [1- (aminomethyl) -propyl ] -phenyl ] -pyrrole hydrochloride, .p. 176-181° (from isopropanol).

The p- toluene- sulphonate required as starting material is obtained as follows : a) 42.5 g of ethyl 2- [p- ( 1-pyrrolyl) -phenyl ] -butyrate are reduced with 6.3 g of lithium aluminium hydride in 900 ml of ether analogously to Example 14 a) to obtain 32.0 g (90% of theory) of p-ethyl-p-(l-pyrrolyl)-phenethyl alcohol, m.p. 56-60°. b) 20.0 g of f5-ethyl-p- ( 1-pyrrolyl) -phenethy1 alcohol, dissolved in 100 ml of pyridine, are reacted analogously to Example 14 b) with 23.0 g of p-tcluene-sulphonic acid chloride to yield, after recrys tallization from methanol , 20.2 g (58% of theory) of β- ethy1-p- ( 1-pyrrolyl ) -phenethy1 p- toluene- sulphonate , m.p. 93-95°.

Exam le 16 2.0 g of 1- [p- (2-bromethyl) -phenyl ] -pyrrole and 2.5 g of methylamine are heated together in 70 ml of ■ methanol in an autoclave for 12 hours at 100°. Thecrystal- line residue ( 2.4 g) which remains after removal of the-' solvent by evaporation under reduced pressure is dissolved i 10 ml of water, alkalized with 5 ml of concentrated sodium hydroxide solution, and extracted with 50 ml of chloroform. After drying with magnesium sulphate and removal of the chloroform by evaporation, 1.6 g of crude 1- (p- [2- (methylamino) -ethyl ] -phenyl)-pyrrole remain as oil. The crude base is dissolved in 5 ml of ether and, by the addition of 2 ml of 4.3 N ethereal hydrogen chloride solution, the 1- [p- [ 2- (meth lamino)- ethyl ] -phenyl ] -pyrrole hydrochloride is precipitated, which, after recrystalliza- tion from methanol, melts at 254-256° with decompostion. Yield 0.7 g, 3770 of theory.

In an analogous manner, using 5 ml of liquid ammonia and heating for 20 hours, there is obtained 0.6 g (28% of theory) of 1- [p- ( 2-aminoethyl) -phenyl ] -pyrrole hydrochloride, m.p. 290-293° (decomposition) after crystallization from ethanol/water .

The 1- [ρ- ( 2-broinethyl) -phenyl ] -pyrrole required as starting material is produced as follows: a) p-Nitro-pbenethyl bromide is reduced by the method given by E. Ferber , Ber. 62, 187-188 (1929) for p-nitro-phenethyl chloride with tin chloride to p--amino- phenethylbromide hydrochloride, τη.ρ. 195-200°. b) From 3.5 g of p-amino-pheiethylbromide hydrochloride, the base is set free with concentrated potassium hydroxide solution, extracted with ether and dried over magnesium sulphate. After removal of the ether by distillation in water jet vacuum at 30° bath temperature, the residual crude p-amino-phenethyl bromide (2.7 g) is refluxed for 15 minutes with 30 ml of glacial acetic acid and 1.8 g of 2 ,5-dimethoxy- tetrahydrofuran in an oil bath which has been preheated to 130°. The reaction mixture is then concentrated by evaporation at 12 Torr and the residue is distilled in a bulb tube at 140- 150° /0.002 Torr. The crystalline l-[ p- (2-bromethyl) -phenyl ] -pyrrole is recrystal-liEed from methanol, whereupon it melts at 101-103°.

Example 17_ 7. lg of p-toluene sulphonic acid- [ β -methyl -p- (1-pyrrolyl) -phenethyl ] -ester , 7 ml of liquid ammonia and 100 ml of absolute ethanol are mixed and heated for 14 - 15 hours at 100° in an autoclave. The procedure outlined in Example 15 is then carried out to give 1.9g of 1- [p- ( 2-amino-l -methylethyl) -phenyl ] -pyrrole-hydrochlor-ide m.p. 228-231° ( from absolute ethanol) (40% of theoretical yield) .

Analogously are obtained,- (i) Using, in place of ammonia, 30 ml of . a 33% solution of methylamine in absolute ethanol, 3.1g of 1- [p- [1-methyl-2- (methylamino) -ethyl] -phenyl] - pyrrole-hydrochloride m.p. 208-2.12° (from isopropanol) (62% of theoretical yield) . (ii) Using, in place of ammonia, 30 ml of a 33% solution of dimethylamine in absolute ethanol, 3. g of 1- [ 2- (dimethylamino) -l-methylethyl ] -phenyl ] - pyrrofe-hydrochloride m.p. 227-230° (from isopropanol) (65% of theoretical yield) .

The p-toluene sulphonic acid esters required as starting materials can be prepared as follows,- a) 52. Og of p- (1-pyrrolyl) -hydratropic acid-ethyl ester and 8.2g of lithium aluminium hydride are reacted analogously to Example 14 to give 42. Og (98% of theoretical yield) of crude, β-methyl-p- ( pyrrolyl) -phenethyl -alcohol m.p. 74-76° which is used without further purification in the following reaction step. b) 29. Og of -methyl -p- (1-pyrrolyl) -phenethyl -alcohol are reacted, analogously to Example 14b, in 150 ml of pyridine with 35. Og of p-toluenesulphonyl chloride and then poured into 1 litre of ice-water. After recrystalization from methanol 37.4g of p-toluene sulphonic acid- [ -methyl-p-(l-pyrrolyl) -phenethyl ] -ester m.p. 98-101° (73% of theoretical yield) .

Example 18 2 ml of liquid ammonia are dissolved in 50 ml of absolute ethanol and heated for 10 hours at 100° in an autoclave with 2. Og of p-toluene sulphonic acid- [3-chloro-4- (1-pyrrolyl) -phenethyl ] -ester . The procedure outlined in Example 15 is then carried out to give 0„6g of 1- [4- (2-aminoethyl) -2-chlorophenyl ] -pj^rrole-hydrochloride m.p. 203-205° (from absolute ethanol) (44% of theoretical yield) .

Analogously is obtained using, in place of ammonia, 6 ml of a 33% solution of methylamine in absolute ethanol, 0.95 g of 1- [ 2-chloro-4- [ 2- (methylamino) -ethyl ] -phenyl ] -pyrrole-hydrochloride m.p. 177° ( from isopropanol) (65% of theoretical yield) .

The p-toluene sulphonic acid esters required as starting materials can be prepared as follows; a) 26.3g of [ 3-chloro-4- (1 -pyrrolyl) -phenyl ] -acetic acid-ethyl ester dissolved in 500 ml of absolute ether are added dropwise to a suspension of 4.1g of lithium aluminium hydride in 300 ml of absolute ether so that the reaction mixture boils and the mixture is then refluxed for 4 hours. The resulting mixture is cooled with ice and 20 ml of water and 10 ml of concentrated potassium hydroxide solution are added.

The eher phase is separated and evaporated and the residue is dissolved in 300 ml of ethanol and, after the addition of 25 ml of 2-n sodium hydroxide solution left to stand for one hour at -■ 30° . After evaporating the ethanol at reduced pressure the residue is taken up in 20 ml of water and extracted with 100 ml of ether.

The ether phase is separated, dried over magnesium sulphate and evaporated. The residue is then distilled in a bulb tube at 140° /0.01 Torr to give 13. Og of 3-chloro-4- (1-pyrrolyl) -phenethyl-alcohol as an oil which solidifies to a crystaline mass m.p. 58 - 62° (59% of theoretical yield) . b) 12.6g of 3-chloro-4- (1 -pyrrolyl) -phenethyl-alcohol , 70 ml of pyridine and 14g of p- toluenesulphonic acid chloride are reacted analogously to Example 14b to give 15g of crude oily p-toluene-sulphonic acid- [3-chloro-4- (l-pyrrolyl ] -phenethyl ] -ester (70% of theoretical yield) . A sample chromatographed con 22 silicagel showed n^ 1.590.

Example 19 . Og of p-toluenesulphonic acid- [β-ethyl-p-(1-pyrrolyl) -phenethyl ] -ester (cf. Example 15b) are dissolved in 100 ml of absolute ethanol and heated for 15 hours at 120° in autoclave with 100 ml of a 33%. solution of dimethylamine in absolute ethanol. The procedure outlined in Example 15 is then carried out to give 4.2g of 1- [p- [1- (dimethylaminomethyl) -propyl ] -phenyl ] -pyrrol (63% of theoretical) . Reaction with the equivalent amount of fumaric acid produces the crystaline fumarate m.p. 137-140° ( from isopropanol) .

Example 20 27.8 g of [p- (1-pyrrolyl) -phenyl j -acetonitrile in ' 250 ml of methanol which has been saturated with ammonia at 20° are hydrogenated in an autoclave at 70-80° and 120 atm. in the presence of 5 g of Raney nickel. After 2 equivalents of hydrogen have been taken up, the hydrogenation ceases . The catalyst is removed by filtration and the is removed by evaporation at reduced pressure. The concentrated residue is distilled in a bulb tube at 130-150° and 0.1 Torr. 26.4 g (92% of theory) of 1- [p- (2-aminoethyl) - phenyl ] -pyrrole are obtained as a yellowish oil which solidifies to a crystalline slurry. It is dissolved in 300 ml of ethanol and then 142 ml of 1.0 N aqueous hydrochloric acid are added. A homogeneous solution is obtained by heating, from which upon cooling the 1- [p- (2-aminoethyl) - phenyl ] -pyrrole hydrochloride separates as colorless crystals, m.p. 290-293° (decomposition). Yield 21.8 g, 6 7c of theory.

Example 21 A solution of 3.3g of anhydrous aluminium chloride in 50 ml of absolute ether is added drop ise to a suspension of 0.95g of lithium aluminium hydride in 25 ml of absolute ether. After 5 minutes a solution of 5.25g of oi-ethyl-p- (l-pyrrolyl) -phenylacetonitrile in 100 ml of absolute ether is added dropwise within 15 minutes. The reaction mixture is then stirred for 22 hours under reflux and after cooling with ice 5 ml of water and 3 ml of concentrated potassium hydroxide solution are added. The ether phase is separated, dried, over magnesium sulphate and evaporated. The residual oil is dissolved in 30 ml of ether and neutralised with a solution of hydrogen chloride in ether. 2.35g of crude 1- [p- [1~(. aminomethyl) -propyl ] -phenyl ] -pyrrole-hydrochloride are obtained which melt at 176-181° after recrystalisation from methanol/ ether followed by absolute ethanol (36% of theoretical yield) .

The nitrile required as starting material can be prepared as follows, a) A mixture of 11.4g of 2- [p-- (l-pyrrolyl) -phenyl ] - butyramide, 10.6g of p-toluene-- sulphonic acid chloride and 15g of p3>-ridine are heated for 6 hours at 100° .

The reaction mixture is then cooled and partitioned between 500 ml of ether and 50 ml of water. The ether phase is washed twice with 30 ml of 2-n hydrochloric acid each time followed by 30 ml of After distillation in a bulb tube at 130-140° /0.2 Torr 9.8g of a-ethyl-p- (1-pyrrolyl) -phenylacetonitril are obtained which gradually crystalise rn.p. 35-37° (937o of theoretical yield) .

Example 22 13 ml of a 2-molar solution of diborane in tetrahydrofuran is added dropwise to a solution of .9g of 3-chloro~4- (l-pyrrolyl) -phenyl-acetonitrile in 150 ml of tetrahydrofuran with cooling. The reaction mixture is allowed to stand for 2 to 3 days at room temperature, with the exclusion of moisture and then evaporated under reduced pressure. 50 ml of methanol followed by 15 ml of a 3-n ethereal hydrogen chloride solution are then added carefully to the residue.

The mixture is then refluxed for 20 minutes and again evaporated under reduced pressure. The residue is dissolved in 50 ml of water and extracted once with 50 ml of ether. The aqueous phase is then made basic with concentrated potassium hydroxide, solution and the crude 1- [4- (2-aminoethyl) -2-chlorophenyl ] -pyrrole (3.2g, 53% of theoretical yield) is extracted with 100 ml ether. The hydrochloride thereof melts at 203-205° (from iso-propanol) .

Analogously 3.9g (69% of theoretical yield) of 1- [p- (2-amino-l-methylethyl) -phenyl] -pyrrole are obtained [m.p. of hydrochloride 228-231° (from absolute ethanol] starting from 5.5g of a-methyl-p- (l-pyrrolyl) -phenylaceto-nitrile .

The nitrile required as starting material can be obtained as follows; a) 8.0g of 2- [3-chloro-4- (1-pyrrolyl) -phenyl ] -acetamide (cf. Example 7a), 10.3g of pyridine and 7.2g of p-toluenesulphonic acid chloride are stirred together for 6 hours in a bath at 100°. After cooling, the reaction mixture is partitioned between 200 ml of ether and 50 ml of water. The ether phase is washed twice with 30 ml of 2-n hydrochloric acid, water and saturated sodiumbicarbonate solution each time, dried over magnesium sulphate and evaporated. The residue is distilled in a bulb tube at 150-160°/ 0.1 Torr and 6.5g of 3-chloro-4- (1-pyrrolyl) -phenyl-acetonitrile m.p. 57-61° (88% of theoretical yield). b) Analogously 4.1g of a-methyl-p- (1-pyrrolyl) -phenylacetonitrile m.p. 85-90° are obtained from 7.0g of p- (1-pyrrolyl) -hydratropamide (ef. Example 5a) (64% of theoretical yield) .

Example 23 3.15 g of N- [2- [p-(l-pyrrolyl)-phenyl]-ethyl]- ' phthalimide and 0.53 g of hydrazine hydrate are refluxed in 35 ml of ethanol for 6 hours. Then 3 ml of 207= hydro- chloric acid are added, the mixture is refluxed for 15 minutes more, allowed to cool, the precipitated phthal- hydrazide is suction filtered and rinsed with water. The filtrate is concentrated to dryness by evaporation, the residue is taken up in water, and the solution is made alkaline with 2 1 sodium hydroxide solution. It is extracted with ether, the ether phase is dried over potassium hydroxide and the solution is concentrated. The 1- [p- (2-aminoethyl) -phenyl ] -pyrrole crystallizes (1.2 g) . It is dissolved in 2 ml of ethanol, and 3.2 ml of 2 N aqueous hydrochloric acid are added. The precipitate which separates is dissolved by heating. The i-[p-(2- aminoethyl) -phenyl ] -pyrrole hydrochloride (1.1 g, 50% of theory) which separates on cooling, melts, after recrys tallization from ethanol/water , at 290-293° (with decomposition).

The phthalimide required as starting material is produced as follows : a) A solution of 51 g of p- ( 1-pyrrolyl) -phenethyl p- toluene-sulphonate ,[cf. Example 14 b) ] and 42 g of potassium phthalimide in 1000 ml of dimethyl formamide is heated at 100° with stirring for 15 hours. The dimethyl formamide is substantially removed by dis illation in a rotarary evaporator at 60°, : the residue is taken up in 500 ml of methylene chloride; it is washed once each with dilute sodium hydroxide solution, hydrochloric acid, and water; the methylene chloride phase is dried over sodium sulphate and concentrated to dryness by evaporation. 43 g of crude N- f 2- [p- ( 1-pyrrolyl) -phenyl ]- ethyl ] - ph hal -imide are obtained, which, after recrvstallization from ether, melts at 191-193°. 3.3g of N- [ 2- [p- (1-pyrrolyl) -phenyl] -propyl ] -phtalimi.d . are reacted analogously to Example 23.

The 1 - [ - ( 2 -amino-1 -methyl- ethyl) -phen l ] -pyrrole thus obtained is distilled in a bulb tube at 1 0°/ 0.1 Torr, dissolved in ether and reacted with the calculated amount of hydrogen chloride. The hydrochloride melts at 228-231° ( from absolute ethanol) Analogously can be obtained from 3.5g of N- [2- [p- (1-pyrrolyl) -phenyl] -butyl] -phthalimide 1.2g (48% of theoretical yield) of 1- [p- [1- (aminomethyl) -propyl ] -phenyl ] -pyrrote-hydrochloride m.p. 176-181 from absolute Aethanol) .

The phthalimide derivates required as starting materials are prepared analogously to Example 23 as follows j a^) From 6.0g of p-toluenesulphonic acid- [β-methyl- p- (1 -pyrrolyl) -phenethyl ] teste (cf . Example 17b), 4.7g of phthalimide-potassium and 110 ml dimethylformamide 3.5g (63% of theoretical yield) of N- [ 2- [p- (1-pyrrolyl) -phenyl ] -propyl ] -phthalimide m.p. 161-163° ( from isopropanol) . a2) From 6.2g of p-toluenesulphonic acid- [ β-ethyl- p- (1 -pyrrolyl) -phenethyl ] -ester (cf . Example 15b), 3-.6g (61% :of theoretical yield of N- [ 2- f - (1-pyrrolyl) -phenyl] -butyl ] -phthalimide - ° Example 25 ' 0 . 7 g of /3-nitro-p- ( 1-pyrrolyl) - s tyrene , dissolved in 10 ml of tetra ydro uran , is added dropwise with stirring and cooling with ice to a suspension of 0. 7 g of lithium aluminium hydride in 40 ml of tetrahydrofuran . The reaction mixture is refluxed with stirring over night.

Then after adding 50 ml of ether, 10 ml of water are added. The organic phase is decanted, dried over magnesium sulphate, and concentrated by evaporation in vacuum. The residue ( 0 . 5 g) is dissolved in 2 ml of ethanol and acidified slightly (pH~ 4) with .2 K hydrochloric acid.

The crystals which separate are recrystallized fro methanol with the addition of activated charcoal. 0. 2 g ( 267c of theory) of 1- [p- ( 2-aminoe thyl) -phenyl ] -pyrrole hydrochloride, m.p. 290- 293 ° (with decomposition) is thus obtained.

The starting material is obtained in the following manner : a) A mixture of 4. 8 g of polymeric p-aminobenz-aldehyde, 5 . 4 g of 2 , 5-dimethoxy- tetrahydrofuran and 80 ml of glacial acetic acid are refluxed for one hour. After cooling to about 80° , a large amount of undissolved residue is removed by filtration. The filtrate is concentrated by evaporation in vacuum, and the reaction product is isolated from the black residue by distilling in a bulb tube at 130- 140° / 0. 1 Torr. The partially crystalline, orange-colored distillate is recrystallized p-(l-pyrrolyl)-banzaldi?hyde melts at 95-97°. Yield 2.2 g, 32% of theory, b) 2.2 g of p- ( 1-pyrroly 1 ) -benza Idehyd , 2.2 ml of nitromethane , 0.9 g of ammonium acetate and 9 ml of glacial acetic acid are refluxed together for one hour.

After cooling to 60-70°, the solution is decanted from the precipitated resin and cooled in ice, whereby yellowish brov.ni crystals separate. These are suction filtered, washed with 5 ml of ether and dried in vacuum. 0.85 g (30% of theory) of crude -nitro-p- ( 1-pyrrolyl) -styrcuie , m. . 179-183°, is obtained, which can be used for the following reduction without further purification. - - y Example 26 11.4 g of - 1p- ( 1-pyrrolyl ) -phenethyl ] -acetamide in a mixture of 200 ml of ethanol and 50 ml of 2 N sodium hydroxide solution are refluxed for 15 hours. After removal of the ethanol by distillation under 20 Torr , the aqueous concentrated residue is extracted with 200 ml of chloroform. The chloroform solution is washed with 20 ml of water, dried over sodium sulphate, and concentrated by evaporation in vacuum. The residue of 7 g is dissolved in 50 ml of ethanol, and then 20 ml of 2 N hydrochloric acid are added. The precipitate which separates is brought into solution by heating. On cooling. 8.2 g (7470 of theory) of 1- [p- (2-aminoethyl) -phenyl ] -pyrrole hydrochloride, m.p. 290-293° (decomposition), crystallize.

The starting material can be prepared in the following manner : a) 21.0 g of - (p-aminophenethyl) -acetamide [cf.

Helv.Chim.Acta 42, 1730 (1959)] and 15.5 g of 2 , 5-dimethoxy-tetrahydrofuran are refluxed for one hour in 200 ml of glacial acetic acid. The solvent is removed by distilling at 20 Torr and the residue is distilled in a bulb tube at 160-180°/0.01 Torr. The crystalline - [ p~ ( 1-pyrrolyl) -phenethyl ] -acetamide is recrys tal lized from ethanol and then melts at 177-178°. Yield 16.4 g, 61% of theory.

Example 27 A mixture of 2.0 g of N-methy1-N- Ϊ - ( 1-pyrrolyl) - phenethy1 ] -acetamide , 0.8 g of potassium hydroxide, 2 ml of water and 50 ml of butanol is χ-efluxed for 12-15 hours and then concentrated by evaporation at 12 Torr. The residue is distributed between 100 ml of ether and 10 ml of water. The ether phase is separated, washed with 10 ml of water, dried over magnesium sulphate, and concentrated by evaporation in vacuum. The residual oil is dissolved in 30 ml of ether and then 4 ml of 2.4 N hydrogen chloride solution in ether are added. The crude 1- [p- [ 2- (methy1- amino) -· ethyl ] -phenyl ] -pyrrole hydrochloride which precipitates is recrystallized from methanol; the pure substance melts at 254-256". Yield 0.8 g, 40% of theory.

The starting material is prepared as follows : a) 2.8 g of - [p- (1-pyrrolyl) -phenethyl ] -acetamide fcf. Example 26 a)], dissolved in 35 ml of dimethyl formamide, are treated with 0.7 g of a 50% suspension of sodium hydride in mineral oil, and stirred for 2 hours at 40°. After cooling to 20°, 3.4 g of methyl iodide are added. The slightly exothermic reaction is completed by ' stirring for 4-5 hours without additional heating. The excess sodium hydride is decomposed by the addition of 5 ml of water and neutralized with a few drops of concentrated hydrochloric acid. The residue which is obtained by concentrating by evaporation in vacuum is taken up in 100 ml of ether and washed with 10 ml of water. Concentra ion by evaporating the ether phase which has been dried over magnesium sulphate, yields 3.0 g of crude product. By recrys allization from ether, 2.0 g (67% of theory) of ■ pure N-rne hyl- - [p- (1-pyrrolyl) -phenethy 1 ] -acetamide , .p. 77-79°, are obtained.

Example 28 0.6g of - (β -methyl ~p- (1-pyrrolyl) -phenethyl ] -trifluoroacetamide are dissolved in 10 ml of ethanol and allowed to stand for two hours at room temperature with 2 ml of 2-n sodium hydroxide solution. After acidification with 4 ml of 2-n hydrochloric acid the solution is evaporated under vacuum. The residue is dissolved in ml of water, extracted with 5 ml of ether and the aqueous phase is made basic with 2 ml of concentrated sodium hydroxide. The precipitated base is extracted twice with 20 ml of ether each time. After evaporation of the ether 0.2g of 1 - [p- (2 -amino-1 -me hyl -ethyl) -phenyl ] -pyrrole are obtained. (50% of theoretical yield) , the hydrochloride thereof melts at 228-231° ( from absolute ethanol) .

Analogously can be obtained} (i) From 2.0g of N-methyl-N- [β-methyl-p- (1-pyrrolyl) - ■ phenethyl ] -trifluoroacetamide and 6.5 ml of 2-n sodium hydroxide solution in 30 ml of ethanol, 1.5g (94% of theoretical yield) of crude 1- [ρ- [ 2- (methylamino) -l-methj^l-ethyl ] -phenyl ] -pyrrole- hydrochloride which melts at 208-212° after recrystalisation from absolute ethanol 5 (ii) From 0.9g of N- [ 3-chloro-4- (1-pyrrolyl) - phenethyl ] -trifluoroacetamide and 3 ml of 2n sodium hydroxide solution in 10 ml of ethanol, 0.55g of 1- [4- (2-aminoethyl) -2-chlorophenyl ] -pyrrole- hydrochloride m.p. 203-205° ( from isopropanol) The trifluoroacetamides required as starting materials can be prepared as followsj a]_) 1.4g of 1- [p- (2-amino-l-methylethyl) -phenyl] - pyrrol e(cf. Example 5) and 0,8 ml of triethylamine are dissolved in 20 ml of dioxan and 1.1 ml of trifluoroacetic acid anhydride are added thereto whilst stirring. The reaction mixture is then heated to boiling for 20 minutes, cooled and evaporated under vacuum. The residue is taken up in ether, washed two times each with 10 ml of 2-n hydrochloric acid and water dried over sodium sulphate and the ether solution evaporated. After distillation in a bulb tube at 160-180°/0.oi Torr 0.6g of N- [ β-methyl-p- (1-pyrrolyl) - phenethyl ] -trifluoroacetamide are obtained m.p. 145-149° (297c of theoretical yield.) a ) 2.3g of 1- [p- [l-methyl-2- (metlrylamino) -ethyl ] - phenyl ] -pyrrole (cf. Example 5), 2.5g of trifluoroacetic acid anhydride and' 1.2 ml of triethylamine are. reacted analogously to Example 9, to produce 2.3g of N-methyl-N- [ -methyl-p-(l-pyrrolyl) -phenethyl] - trifluoroacetamide as a yellow oil b.p. 140-150° /0, 01 Torr (bulb tube) ( 68% of theoretical yield) . a*}) From 2.0g of 1- [ 4- (2-aminoethyl) -2-chloro~ phenyl ] -pyrrole (cf . Example 7), 3. lg of trifluoroacetic acid anhydride and 1.5g of ie hy1amine are obtained, analogously to Exampl a]_, 1. g of N- [ 3-chloro-4- (1-pyrrolyl) -phenethyl ] tri luoroacetamide m.p. 105-108° (b.p. 150-160°/ 0.05 Torr) ( 45% of theoretical yield). 2.0g of N-methyl -N- [ /3-rnethyl -p- (1 rpyrrolyl) -phenethyl ] -formamide , l.Og of sodium hydroxide, 2 ml of water and 50 ml of ethanol are refluxed together for 20-24 hours. After treatment of the reaction mixture analogously to Example 27 1.2g of crude 1- [p- [2- (methyl - amino) -1 -methylethyl ] -phenyl ] -pyrrole-hydrochloride are obtained which melt at 208-212° after recrystalisation (58% of theoretical yield) .

The formamide required as starting material can be prepared as follows j a) 2.0g of N- [β-methyl -p- (1-pyrrolyl) -phenethyl ] - formamide (cf. Example 13a) are reacted for 20 hours analogously to Example 27, in 30 ml of anhydrous dimethyIformamide, with 0.5g of sodium hydride suspension (50% in parafin oil) and 2.8g of methyl iodide. Further treatment of the reaction mixture ( according to Example 27) yields 2. Og of -methyl-N- [β-methyl - p- (1-pyrrolyl) -phenethyl ] -formamide as a yellow oil which is distilled in a bulb tube at 140-160°/ 0.1 Torr (94% of theoretical yield).

Example 30 4.5g of N- [ -ethyl -p- (l-pyrrolyl.) -phenethyl j -N-methyl -benzamide (b.p. 180-190° /0, 02 Torr) are heated for 15 hours at 120° in an autoclave together with a mixture of 15 ml of 2-n sodium hydroxide solution and 100 ml of ethanol. The reaction mixture is cooled, made acidic to Congo red with 2-n hydrochloric acid and evaporated under reduced pressure on a rotary evaporator with a bath temperature of 40° . The residue is partitioned between 20 ml of water and 50 ml of ether. The aqueous phase is made alkaline with coiicentrated sodium hydroxide solution and again extracted with 50 ml of ether. The combined ether phases are then dried over magnesium sulphate and evaporated. 1.6g (53% of theoretical yield) of crude, oily 1- [ρ- [1- (methylaminomethyl) -propyl ] -phenyl ] -pyrrole are obtained, the hydrochloride of which melts at 182-185° after recrystalisation from absolute ethanol or isopropanol .0 g of 1- ίρ- { 2- (benzyl-methylamino) -ethyl ] -phenyl ] - pyrrole are dissolved in 150 ml of ethanol, then 23 ml of a 2.5 K solution of hydrogen chloride in ethanol are added, and then hydrogenated in the presence of 1.5 g of palladium/ charcoal (5% Pd) . After the calculated amount of hydrogen has bee taken up, the reaction ceases. The catalyst is removed by filtration and boiled out with 200 ml of methanol. The filtrate and the methanol extract are combined and concentrated to dryness by evaporation under 20 Torr. The residue obtained, almost colorless crystals, is recrystallised from 100 ml of methanol. 7.4 g (60% of theory) of 1- [p- [2- (methyla ino) -ethyl ] -phenyl ] -pyrrole hydrochloride, m.p. 254-256°, are obtained.

The starting material is produced as follows: a) 30.0 g of ethyl [p- ( 1-pyrrolyl) -phenyl ] -acetate and 80 g of benzy1-methylamine are heated at 180° in an autoclave for 15 hours. The reaction mixture is concentrated in a rotary evaporator under 12 Torr in a bath of 90-100°. The residue is distilled in a bulb tube at 190-210° /0.01 Torr and yields 28.9 g (72% of theory) of N-benzyl-N-methyl- 2- [ p- ( 1-pyrrolyl) -phenyl ] -acetamide as a yellowish oil which can be employed in the following reduction without further purification. b) 28.9 g of -benzyl- -methyl-2- [p- ( 1-pyrrolyl) -phenyl ) -acetamide aire reduced analogously to Example 1 with 7.2 g of lithium aluminium hydride in 500 ml of 16.0 g of 1- lp- [2- (bensyl-Tnethylarn3.no) -ethyl ]-pheny pyrrole, m.p. 48-50°, are obtained.

. Og of 1- [p- [ 2- (dibenzylamino) -ethyl ] -phenyl ] -pyrrole are dissolved in 1000 ml of ethanol and bydro-genated with the addition of 3g of palladium charcoal (5%>) , at room temperature and atmospheric pressure until cessation of reaction. The catalyst is filtered off and the filtrate evaporated under reduced pressure. lAg of crude 1- [p- (2-aminoethyl) -phenyl ] -pyrrole are obtained (90% of theoretical yield) , the hydrochloride thereof melts at 290 "293° with decomposition (from ethanol/ water) .

The dibenzyl mine derivat ve required as starting material may be prepared as follows j a) 30. Og of [p- (1-pyrrolyl) -phenyl ] -acetic acid are dissolved in a mixture of 300 ml of dioxan and 600 ml of methylene chloride and 21.2g of triethylamine are added thereto. 27g of pivalic acid chloride are then added dropwise, with cooling at 10° and within minutes. After further stirring 36g of dibenz yl mineare added dropwise at 5-10° within 10 minutes. The reaction mixture is stirred overnight at room temperature and evaporated at 12 Torr. The residue is taken up in 500 ml of ether and washed with 50 of water, 2-n sodium hydroxide solution, 1-n hydrochloric acid and water. After drying over so.dium sulphate the ether is evaporated off under reduced pressure. 57g of crude , -dibenzyl- [p- (1- pyrrolyl) -phenyl ] -acetamide are obtained as an oil which can be reduced without further purification (90% of theoretical yield ) . b) 56g of crude Ν,Ν-dibenzyl- [p- (1-pyrrolyl) -pheny acetamide are reduced analogously to Example 1 using 12g of lithium aluminium hydride in 800 ml of absolute ether. After recrystalization from ethanol 30.8g of IT [p- [ 2- (dibenzylamino) -ethyl ] -phenyl ] -pyrrole are obtained m.p. 84-87° (57% of theoretical yield) . 29. Og of 1- [p- [I -methyl -2- (benzyl methylamino) - ethyl ] -phenyl ] -pyrrole-hydrochloride dissolved in 300 ml of ethanol are hydrogenated, with the addition of two separate ,3g portions of palladium-charcoal (5%) , at room temperature and atmospheric pressure until the calculated quantity of hydrogen has been taken up.

The catalyst is filtered off, the filtrate evaporated and the residue dissolved in 100 ml of water. The resulting soltuio is made slightly basic to pH8 with 20% sodium hydroxide solution and extracted with ether (ca.100 ml). The aqueous phase is then made strongly basic with more concentrated sodium hydroxide solution and extracted with 200 ml of ether. After evaporation of the ether the residual oil is distilled in a bulb tube (100-120°/0,1 Torr) to yield 10.5g(57% of theoretical yield) of 1- [p- [1 -methyl -2- (methylamino) -ethyl ] -phenyl 3 -pyrrole the hydrochloride of which melts at 208-212°.

Analogously is obtained from 7.1g of 1- [ - [ 2~ (benzyl methylamino) -ethyl ] -2-chlorophenyl ] -pyrrole-hydrochloride and 2g of palladium-charcoal (5%) in 150 ml of ethanol, 2.2g of i- [ 2-chloro-4- [ 2- (methylamino) -ethyl] -phenyl] -pyrrole-hydrochloride_ m.p. 173-177° (from absolute ethanol) , (41% of theoretical yield) .

The starting materials may be prepared as follows a]_) 21. Og of ρ·- (1-pyrrolyl) -hydratropic acid, dissolved in a mixture of 170 ml dioxan and 400 ml of methylene chloride are reacted, analogously tc. Example 32a, with 15. Og of triethylamine , 17.9g of pivalic acid chloride and 17.0g of benzyl -methyiamine. 35g of crude N-benzyl -N- methyl -p- (l-pyrroly1) -hydratropamide are obtained as an oil which can be reduced, without further purification, using lithium aluminium hydride. a^) Analogously is obtained from 15. Og of [ 3-chloro-4- (1-pyrrolyl) -phenyl ] -acetic acid, 9.9g of triethylamine, 12. lg of pivalic acid chloride and 11.6g of benzylraethylamine, 25g of the crude amide which is distilled in a bulb tube. The fraction which boils at 180.200°/0, 01 Torr produces oily N-benzyl -N-raethyl- [ 3-chloro-4- (1 -pyrrolyl) -phenyl ] -acetamide (16. g, 76% of theoretical yield) . b ) 35. Og of N-benzyl -N-methyl -p- (1-pyrrolyl) -hydratropamide are reduced, analogously to Example' 1, with 12.5g of lithium aluminium hydride in 1500 ml of absolute ether. The fraction boiling at 150-160° /0.01 in a bulb tube produces 1- fp- [1-methyl -2- (benzylmethylamino) -ethyl ] -phenyl ] pyrrole (26.0g. 76% of theoretical yield). The. oily hydrochloride, prepared using the calculated amount of ethereal hydroge chloride solution, is used, without further purification, as starting material for the debenzylation reaction. t>2.) 16.4g of N-benzyl - -methyl- [ 3-chloro-4- (1-pyrrolyl) -phenyl ] -acetamide are reduced for 20, hours, analogously to Example 1, with 1.9g of lithium aluminium hydride in 300 ml of absolute ether.

After recrystalization from isopropanol 8.2g of 1 - [ 4- [ 2- (benzylmethylamino) -ethyl ] -2-chlorophenyl ] -pyrrole-hydrochloride are obtained, m.p. 189-196° (477c of theoretical yield) . 6. g of 1- [p- [ 1 --benzylmethylareino-methyl) -propyl ] - phenyl J -pyrrole are dissolved in 100 ml of ethanol and hydrogenated , with the addition of 10 ml of 2-n hydrochloric acid and using lg of palladium-charcoal until 1 molecular equivalent of hydrogen is taken up, whereupon the catalyst is filtered off and washed through with 50 ml of warm methanol. The combined filtrates are evaporated under reduced pressure and the residue, recrystalised from isopropanol. 3.1g of 1- [p- [l-(methylaminometlryl) -propyl ] -phenyl ] -pyrrofe-hydrochloride are obtained m.p. 188-185° (587c of theoretical) .

The starting material may be prepared as follows, 11. Og p-toluenesulphonic acid- [β -ethyl -p- (1- pyrrolyl) phenethyl ] -ester . (cf. Example lib) and 20 ml N-methyl-benzylamine in 100 ml of dime h Iformamide are heated for 20 hours in a bath at 60-70°. The solvent is then evaporated under reduced pressure, the residue taken up in 180 ml 2~n hydrochloric acid and extracted with 50 ml ether. The acidic, aqueous phase is separated, made alkaline with concentrated sodium hydroxide solution and extracted with 200ml of methylenechloride . The methylenechloride solution is dried over., sodium sulphate, evaporated and distilled in a bulb tube. After the initial distillation of excess methylbenzylamine at 120°/10 Torr the 1 - [ - [ 1 - (t enzylmethylamino-methyl) -propyl ] -phenyl ] -pyrrole distills at 140-160° /0 , 005 Torr (8.5g 89%, of theoretical yield).

The following may be prepared analogously? a) From 4.8g of 1- [p- [2- (benzylamino) -1- methyl -ethyl ] -phenyl ] -pyrrole , dissolved in 80 ml ethanol debenzylated over palladium-charcoal (5%) with the addition of 8.2 ml of 2-n hydrochloric acid, 1.6g of 1- [p- (2-amino-l-methylethyl) -phenyl ] - pyrrofe-hydrochloride m.p. 228-231° (from absolute ethanol) (43%. of theoretical yield) .

The starting material is prepared from 10g of p-toluenesulphonic acid- [ β-methyl -p- (1 - pyrrolyl) -phenethyl ] -ester and 16 ml of benzylamine (b.p. 150-160° /0.01 Torr).

Example 35 6.7 g of p-amino~N ,N-dimethyl-pheneC!rylamine [Kindler ' et al. , Arch .Pharmasie 283 , 184 (1950)3 are dissolved in 80 mi of glaci l acetic acid and refluxed for one hour with 5.5 g of 2 , 5-dimethoxy- etrahydrofuran. The reaction mi ture is concentrated by evaporation at 12 Torr , Distillation of the black residue in a bulb tube at 140-150/0.02 Torr yields 5..4 g of 1- (p- [ 2- ( dimethylamino) -ethyl ] -phenyl ] -pyrrole as an almost colorless oil which partially crystallizes. It is dissolved in 50 ml of ether and converted with 7.5 ml of 3.3 N ethereal hydrogen chloride solution into the hydrochloride (4.8 g, 46% of theory). After recrystallization from methanol, the l~[p- [ 2- (dimethylaniino) - ethyl ]- phenyl ] - pyrrole hydrochloride melts at 228-232°.

In an analogous manner, using 7.7 g of p-amino-N ,N- diethy1-phenethylam.ine , there are obtained 3.8 g (38% of theory) of 1- [p~ [ 2- (diethyla ino) -ethyl ] -phenyl ] -pyrrole which. is : converted according to Example 1 into the fumarate, m.p. 123-125°.

Exam le 3_6 3.3g of p-amino-N, β-dimethyl-phenethylamine dissolved in 35 ml of acetic acid, are refluxed for 1 hour with the addition of 2.7g of 2 , 5 -dimethoxytetrahydro-furan and the reaction mixture evaporated under reduced pressure. The black residue is partitioned between 100 ml of ether and 20 ml of 2-n sodium hydroxide solution. The ether phase is separated, washed with 10 ml water and dried over sodium sulphate. The oil which remains after evaporation of the ether is distilled in a bulb tube at 120°/0.01 Torr to give 2.4g of 1- [p- [ 1-methyl -2- (methyl -amino) -ethyl ] -phenyl ] -pyrrole ( 55% of theoretical yield). The hydrochloride melts at 208-212°.

Analogously is obtained using 2.5g of j3-ethyl-p-ami.no-N-methyl-phenethylamine, 2.5g of 1 - [p- [1- (methylaminomethyl) propyl ] -phenyl ] -pyrrole (54% of theoretical yield) ( .p. of the hydrochloride 182.185°).

The starting materials may be prepared as follows? a]_) p-aminohydratropic acid. [Liebig's Ann.d.ch. 621 , 34 (1959) ] is esterified in the usual way with absolute ethanol to give the ethyl ester b.p. 110-115°/0.01 Torr. lOg of p-aminohydratropic acid ethyl ester and 20g of methyaraine are heated in an autoclave for 10 hours at 1.80° . After evaporating off the excess methylamine the reaction mixture is distilled in a bulb tube at 150-160°/0.2 Torr. 7.9g of p-amino-N-methyl -hydratropamide are obtained (86% of theoretical yield) .

Analogously is obtained, from 10. Og of 2- (p-aminophenyl) -butyric acid ethyl ester, 7.5g of 2- (p-aminophenyl) -N-methyl-butyramide as a viscous oil. βχ) 7.9g of p-amino-N-methyl -hydratropamide dissolved in 80 ml of absolute tetrahydro uran, are added dropwise, with stirring and ice cooling, to 100 ml of a 2.1 molar solution of diborane in absolute tetrahydrofuran and left standing for three days at room temperature and with the exclusion of moisture. The reaction mixture is then handled as in Example to give 5.0g of -amino-N, β -dimethyl-phenethylamine, which distills at 120-130° /0.1 Torr in a bulb tube (6970 of theoretical yield) . b2) Analogously to Example 6, is obtained from 7.4g of 2- (p-aminophenyl) -N-methyl-butyramide , .2g of β-ethyl-p-amino-N-methyl-phenethylamine (b.p. 135-140°/0.1 Torr in bulb tube) (75% of theoretical yield) .

Analogously to Example 36, 3.0g of p-arnino-N-methyl -phenethylamine and 2.7g of 2 , 5 -dimethoxytetralTydrofuran in 30 ml of glacial acetic acid are reacted and worked up to give. 1.7g of 1- [p- [ 2- (methyl.amino) -ethyl ] -phenyl ] -pyrroleb.p. 120-130°/0.1 Torr (41% of theoretical yield). The hydrochloride melts at 254-256°.

The starting material is prepared as follows; a) 11. g of p-nitrophenethyl bromide are dissolved in a mixture of 20 ml of dioxan and 100 ml of absolute ethanol and allowed to stand for 6 days at room temperature with 25 ml of benzylmethylamine . The reaction mixture is then thoroughly evaporated initially at 20 Torr and subsequently at 0.1 Torr and 80 -100° bath temperature. The residue is partitioned between 150 ml of ether and 30 ml of 2-n sodium hydroxide solution and the ether phase washed with 10 ml of water, dried over sodium sulphate and evaporated. The residue is distilled at 140- 150°/0.05 Torr to give 12.9g of -benzyl-N- methyl-p-nitrophenethylamine . (95% of theoretical yield) . b) 11.7g of N-benzyl-N-methyl-p-nitro-phenethylamine are dissolved in 150 ml of ethanol, 21 ml of 2 n hydrochloric acid are added and the mixture is h dro enated, with the addition of 2g of palladium- charcoal- (5%) at room temperature and atmospheric pressure until cessation of reaction. (4 mol . equiv. taken up). The catalyst is filtered off, the solvent evaporated and the base liberated with concentrated sodium hydroxide solution and extracted with ether. The crude base is distilled in a bulb tube at 100-110° / 0 . 2 Torr to give 4 . 8g of p-amino-N--methyl--phenethylamirie m.p. 84-88 ° (747o of theoretical yield) .

Example 38 Analogously to Ecarople 35 is obtained from 2.3g of -ethyl -p-amino-N, -dimethyl-phenethyl amine, 1.6g of 2 , 5 -dimethoxytetrahydrofura.n and 30 ml of glacial acetic acid, 2.1g of 1 - [p- [ 1 - (di ethylamino-methyl) -prop3'l ] -phenyl ] -pyrrole the acid fumarate of which melts at 137-140° (72% of theoretical yield).

The starting material is prepared as follows, a) 27.0g of 2- (p-aminophenyl) -butyric acid ethyl ester and 80g of dimethylamine give, analogously to Example 36a, 12.9g of 2- (p-aminophenyl) -N, -dimethyl-butyramide m.p. 88-95° (48% of theoretical yield) . b) Reduction of 12.9g of the substituted butyramide with 100 ml of a 2~n diborane solution in tetrahydro uran analogously to Example 36b, gives 7.7g of -ethyl-p-amino-N,N-dimethyl- pheneth lamine, b.p. 120-:125° 0.1 Torr in a bulb tube (64% of""theoretical yield) .

Example 39 A solution of 4.3g of 2.5 -dichloro- etrahydrofuran [H. Gross, Chem.Ber.95_, 83(1962)] in 20 ml of chloroform is added drop ise with stirring to a solution of 4.9g of p-araino- , -dimethyl -phenethylamine and 6 ml of pyridine in 40 ml of chloroform. The reaction mixture is then allowed to stand for 2-3 hours, shaken with ml of 4-n sodium hydroxide solution and the chloroform phase is dried over potassium carbonate. The residue obtained after evaporation of the chloroform is distilled in a bulb tube at 140° /0.02 Torr to give 2.1g of 1- [p- [ 2- (dimethylamino) -ethyl ] -phen l ] -pyrrole the hydrochloride of which melts at 228-232° (from isopropanol) (32% of theoretical yield) . 3-3g of p- amino- , β-dimethyl -phenethylamine (cf. Example 36b), 3.8g of 2 , 5 -diacetoxy- etrahydro-furan and 40 ml of glacial acetic acid are refluxed for 1 hour and worked up according to Example 36 to give 2.1g of 1- [p- [l-methyl-2- ( ethylamino) -ethyl ] -phenyl ] -pyrrole the hydrochloride of which melts at 208-212° (from isopropanol) (48% of theoretical yield) .

Analogously is obtained using 3.3g of p-amino-N, N-dimethyl -phenethylamine, 2. g of 1- [p- [ 2- (dimethylamino) -ethyl] -phenyl] -pyrrole the hydrochloride of which melts at 228-232° (55% of theoretical yield) .

Ex_a—m—*pl—e_ 41 3. Bg of 2.5-diacetoxy-tetrahydrofuran are stirred at room temperature with 20 ml of 0.1-n hydrochloric acid (ca.20 minutes) until a homogenous solution of succinic -dialdehyde is obtained. After the addition of a solution of 3.3g of p-amino-N, N-dimethyl-phenethylamine and 1.2g of glacial acetic acid in 10 ml of dioxan and 5 ml of water the reaction mixture is refluxed for 1 hour. The residue obtained after evaporation under reduced pressure is partitioned between 100 ml of ether and 20 ml of 2-n sodium hydroxide. The ether phase is separated, dried over sodium sulphate and distilled in a bulb tube at 140°/ 0.02 Torr to give 1.9g of 1- [p- [ 2- (dimethylamino) -ethyl ] -phenyl ] -pyrrole the hydrochloride of which melts at 228-232°. (44% of theoretical yield) .

Example 42 A solution of 1.8 g of ethyl iodide in 10 ml of dimethyl formamide is added dropwise with stirring during one hour to a solution of 2.0 g of 1- [ p- [ 2- (methyla ino) - ethyl ] -phenyl ] -pyrrole in 20 ml of dimethyl formamide , in which 2 g of potassium carbonate have been suspended. The reaction mixture is stirred over night, then concentrated by evaporation at 12 Tor , and distributed between 10 ml of water and 100 ml of ether. The organic phase is separated, washed with 10 ml of water, dried over magnesium sulphate, and concentrated by evaporation. The oil obtained (1.5 g) is dissolved in 20 ml of ether and then 2.0 ml of 3,3 N hydrogen chloride solution in ether are added. The 1- [p- [ 2- (ethyl-methylamino) -ethyl ] -phenyl ) -pyrrole hydrochloride which precipitates is suction filtered and, after* recrystallization from is opropanol, melts at 165-169°.

Yield 0.8 g, 30% of theory.

The production of the starting material is described in Example 16 , 2.5g of 1 - [ - [ 1 - (aminometh l) -propyl j -phenyl ] -pyrrole-hydrochloride (cf. Example 2) are stirred for 15 mintues with 7g of potassium carbonate in 35 ml of dimethyl forma ide in order to liberate the free base. 2.8g of methyliodide are then added and the reaction mixture is stirred for 20 hours at room temperature. The undissolved salt is filtered off, the filtrate evaporated and the residue partitioned between 50 ml of ether and 30 ml of water. After evaporation of the ether 1.7g (70% of theoretical yield) of crude 1- [p- [1- (dimethylaminomethyl) -propyl ] -phenyl ] -pyrrole are obtained which are converted into the acid fumarate by addition of the equivalent quantity of fumaric acid. After twice recrystalising from isopropanol or ethanol the fumarate melts at 137-140°. 4-5g of 1 - [p- (2-aminoetbyl) -phenyl ] -pyrrole-hydrochloride are stirred for 30 minutes together with 14g of potassium carbonate in 50 ml of dimethylformamide . 1.2 ml of methyl iodide are then added dropwise and with cooling and after 3 hours of stirring at room temperature a further 1.2 ml of methyliodide are added in the same manner. The mixture is then stirred for a further 3 hours, evaporated under reduced pressure and the residue is partitioned between 20 ml of water and 50 ml of ether. The ether phase is then made slightly acidic with a 3-n ethereal hydrogen chloride solution and the resulting crystals are repeatedly recrystalised from absolute ethanol . 0.65g of 1- [p- [ 2- (dimethylamino) -ethyl] -phenyl] -pyrrofe-hydrochloride are obtained .p. 228-232° (12% of theoretical yield). 17/9/70 JMS/N0R/sk'

Claims (24)

4-3179* WHAT WE CLAIM IS:

1. Basic pyrrole derivatives having the Formula I wherein R represents a hydrogen atom or a mettryl or ethyl group 1 R represents a hydrogen or chlorine atom, and 2 R^ and ^ represent, independently of each other, a hydrogen atom or a methyl or ethyl group.

2. The pharmaceutically acceptable acid addition salts of a basic pyrrole derivative as claimed in Claim 1.

3. 1- [p- (2-Aminoethyl) -phenyl ] -pyrrole .

4. 1- [ - (2-Aminoethyl) -2-chlorophenyl ] -pyrrole .

5. 1- [p- (2-Amino-l-methylethyl) -phenyl ] -pyrrole .

6. 1- [p- [1- (Methylamino-methyl) -propyl ] -phenyl ] -pyrrole .

7. 1- [p- [ 2- (Dimethylamino) -ethyl ] -phenyl ] -pyrrole .

8. 1- [p- [l-Methyl-2-(methylamino) -ethyl ] -phenyl ] -pyrrole.

9. The pharmaceutically acceptable acid addition salts of a basic pyrrole derivative as claimed in any one of claims 3 to 8.

10. Process for the production of basic pyrrole derivatives having the Formula I as defined in Claim 1 and their pharmaceutically acceptable acid addition salts which comprises reducing a compound having the Formula wherein A represents an oxo radical and at the same time ' corresponds to the definition given for R^ in Claim 1 or A represents two hydrogen atoms and at the same time R31 represents an acetyl or formyl radical or a low alkoxy- carbonyl group and R_, R2 and R have the meanings given in Claim 1, by means of a complex hydride and when required converting a basic pyrrole derivative having the Formula I thus obtained into a pharmceutically accepted acid addition salt thereof.

11. Process for the production of basic pyrrole derivatives having the Formula 1 as defined in Claim 1 and their pharmaceutically acceptable acid addition salts which comprises reacting a reactive ester of the corresponding alkanol having the Formula III with an amine having the Formula IV wherein and R ave the meanings given in Claim 1 and when required converting a basic pyrrole derivative having the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

12. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim 1, wherein and R2 have the meanings given in Claim 1 and R3 and R^ represent hydrogen atoms, and their pharmaceutically acceptable acid addition salts which comprises reducing the corresponding nitrile having the Formula V and when required converting a basic pyrrole derivative having the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

13. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim 1, wherein R]_ and have the meanings given in Claim 1 and R3 and represent hydrogen atoms, and their pharmaceutically acceptable acid addition salts which comprises reacting the corresponding N- subs ituted phthalimi.de having the Formula VI with hydrazine and treating the. reaction product thus obtained with an acid and when required converting an acid addition salt of a basic pyrrole derivative having the Formula I thus obtained into the free base or into another, pharmaceutically acceptable acid addition salt thereof.

14. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim wherein R2 has the meaning given in Claim 1 and R-^ , R3 and ^ represent hydrogen atoms and their pharmaceutically acceptable acid addition salts which comprises reducing the corresponding compound having the Formula VII R2 and when required converting a basic pyrrole derivative having the Formula 1 thus obtained with a pharmaceutically acceptable acid addition salt thereof.

15. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim 1 wherein R-^ , R2 a d R^ have the meanings given in Claim 1 and R^ represents a hydrogen atom, and their pharmaceutically acceptable acid addition salts which comprises hydrolysing the corresponding amide having the Formula VIII wherein Ac represents the acyl radical of an organic acid and when required converting a basic pyrrole derivative having the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

16. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim 1 wherein , Rp and 3 have the meanings given in Claim 1 and R represents a hydrogen atom, and their pharmaceu ically acceptable acid addition salts which comprises treating the corresponding compound having the Formula IX wherein R^" has the meaning given for R3 in Claim 1 or it represents a benzyl group, or an acid addition salt of said compound, with catalytically activated hydrogen until substantially the equimolar, or when R^" represents a benzyl group substantially double the molar, amount of hydrogen has been taken up and, when required, converting an acid addition salt of a basic pyrrole derivative having the Formula I thus obtained into the free base or converting a basic pyrrole derivative having the Formula I or an acid addition salt thereof thus obtained into, or into another, pharmaceutically acceptable acid addition salt thereof.

17. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim 1 wherein Rj , R2 and R^ have the meanings given in Claim 1 and R^ represents a methyl or ethyl group and their pharmaceutically acceptable acid addition salts, which comprises reacting the corresponding' compound - having the Formula X wherein R3" 1 represents a methyl or ethyl group with monomeric or polymeric succinaldehyde or with an open-chain or cyclic, reactive derivative of monomeric succinaldehyde and when required converting a basic pyrrole derivative having the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

18. Process for the production of basic pyrrole derivatives having the Formula I as illustrated in Claim 1 wherein R-^ and R2 have the meanings given in Claim 1 and R3 and R^ represent methyl or ethyl groups and their pharmaceutically acceptable acid addition salts, which comprises reacting the corresponding compound having the Formula XII -101- GB. etc. with, when is other than a hydrogen atom, at least the molar amount or, when is a hydrogen atom, at least twice the molar amount of a reactive ester of methanol or ethanol in the presence of an acid-binding agent and when required converting a basic pyrrole derivative having the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.

19. A basic pyrrole derivative having the Formula I as defined in Claim 1 or a pharmaceutically acceptable . acid addition salt thereof whenever prepared by a process as claimed in any one of Claims 10 to 18. 20. Frocess for the production of basic pyrrole derivatives having the Formula I as defined in Claim I or pharmaceutically acceptable acid addition salts thereof substantially as hereinbefore described with reference to any one of the Examples 1 to 10, 14 to 16,

20. 23, 25 to 27, 31 35 and 42.

21. Process for the production of basic pyrrole derivatives having the Formula I as defined in Claim 1 or pharmaceutically acceptable acid addition salts thereof substantially as hereinbefore described with reference to any one of the Examples 11 to 13, 17 to 19, 21, 22, 24, 28 to 30, 32 to 34, 36 to 41, 43 and 44.

22. A basic pyrrole derivative or pharmaceutically acceptable acid addition salt thereof as hereinbefore t described with reference to any one of the Examples I to 10, 14 to 16, 20, 23, 25 to 27, 31, 35 and 42,

23. A basic pyrrole derivative or pharmaceutically acceptable acid addition salt thereof as hereinbefore described with reference to any one of the Examples II to 13, 17 to 19, 21, 22, 24, 28 to 30, 32 to 34, 36 to 41, 43 and 44.

24. A pharmaceutical composition comprising a basic pyrrole derivative having the Formula 1 as defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier therefor. 21st September, 1970 JMS/GSG/sk G.B. etc For * Apffcwiu