US3105836A - Certain 3-(pyridyl lower alkyl)-2-(tertamino-lower alkyl)-indene quaternary salts - Google Patents

Description

United States Patent 3,105,836 CERTAIN 3-(PYRDYL LOWER ALKYL)-2-(TERT- lggiilgg-LfiWER ALKYLHNDENE QUATERNARY Charles Ferdinand Hnebner, Chatham, NJ., assignor to Ciba Corporation, a corporation of Delaware No Drawing. Filed Feb. 9, 1961, Ser. No. 88,029 12 Claims. (61. 260296) The present invention relates to quaternary ammonium derivatives of tertiary amino-lower alkyl-indenes. Primarily, it concerns quaternary ammonium derivatives of S-(pyridyl-lower a1kyl)-2-(tertiary amino-lower alkyl)- indenes.

The quaternary ammonium derivatives of this invention may be either monoor poly-quaternary ammonium compounds depending on the condition of the quaternization reaction and/ or the number of tertiary amino groups present in the molecule. Therapeutically acceptable quaternary ammonium compounds are particularly those with lower aliphatic hydrocarbon halides, sulfates or sulfonates, primarily those with lower alkyl halides, e.g. methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-propyl iodide, isopropyl bromide, nbutyl iodide and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl methane sulfonate, ethyl methane sulfonate, methyl ethane sulfonate, ethyl ethane sulfonate and the like, lower alkyl lower hydroxyalkane sulfonates, e.g. methyl Z-hydroxy-ethane sulfonate and the like, lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate, ethyl p-toluene sulfonate and the like, as well as those with the corresponding monocyclic carbocyclic aryl-lower alkyl, especially phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2- phenylethyl and the like, halides, sulfates or sulfonates. Also included as quaternary ammonium compounds are the corresponding quaternary ammonium hydroxides, and the salts of such hydroxides with acids, particularly with organic carboxylic acids, e.g. acetic, propionic, maleic, tartaric, citric, benzoic acid and the like.

A pyridyl group in the above compounds represents primarily Z-pyridyl, but may also stand for S-pyridyl or 4-pyridyl. These pyridyl radicals are preferably unsubstituted, or may be substituted by lower alkyl, e.g. methyl, ethyl and the like. Other substituents of pyridyl groups are, for example, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or any other suitable functional groups.

The lower alkyl portion of the pyridyl-lower alkyl radical, which connects the pyridyl group with the indene nucleus, may be represented by a lower alkylene radical having from one to seven, especially from one to three, carbon atoms, e.g. methylene, 1,1-ethylene, 1,2-ethylene, l-methvl-l,2-ethylene, 2-methyl-l,2-ethylene, 1,2-propylene, 1,3-propylene or 2,2-propylene, as well as 1,1-butylene, 2,2-butylene, 2,3-butylene, 1,4-butylene, 1,5-pentylene and the like.

The lower alkyl portion of the tertiary amino-lower alkyl group attached to the 2-position of the indene nucleus, may be represented by a lower alkylene radical containing from one to seven, preferably from two to three, carbon atoms; such radicals are, for example, 1,2- ethylene, l-methyl-l,2-ethylene, 2-methyl-l,2-ethylene or 1,3-propylene, as well as methylene, l,l-ethylene, l-methyl-l,3-propylene, 1,4-butylene, 1-methyl-1,4-butylene, 1,5- pentylene and the like. The lower alkylene radical or a portion of it may also be part of a heterocyclic ring sys tem, such as a saturated or partially saturated azacyclic ring system, containing the tertiary amino group as the aza-ring member. Preferably, the lower alkyl portion of the tertiary amino-lower alkyl group contains from two to three carbon atoms and separates the tertiary amino group from the 2-position of the indene nucleus by from two to three carbon atoms.

Di-substituted amino groups, which represent the tertiary amino portion, are, for example, N,N-di-hydrocarhon-amino groups, in which hydrocarbon represents, for example, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, monocyclic carbocyclic aryl, such as phenyl, or monocyclic carbocyclic aryl-lower alkyl, such as phenyl-lower alkyl. Such radicals contain from one to ten carbon atoms, and may be represented, for example, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, neopentyl, allyl, methylallyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, phenyl, benzyl, lphenylethyl, 2-phenylethyl and the like. These hydro carbon radicals, particularly lower alkyl, may contain further substituents; free hydroxyl, lower alkoxy, e.g.

methoxy, ethoxy and the like, lower alkylmercapto, e.g. methylmercapto, ethyhnercapto and the like, or any other suitable functional group may be attached to the such hydrocarbon radicals. N,N-di-lower hydrocarbon-amino groups are primarily represented by N,N-di-lower alkylamino, in which lower alkyl contains from one to four carbon atoms, e.g. N,N-dimethylamino, N-methyl-N- ethylamino, N,N diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, N-cycloalkyl-N-lower alkyl-amino, in which cycloalkyl contains from five to seven ring carbon atoms and lower alkyl contains from one to four carbon atoms, e.g. N-cyclopentyl-N-methylamino, N-cyclohexyl-N-methyl-amino, N-cyclohexyl-N- ethyl-amino and the like, or N-lower alkyl-N-phenyl-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, e.g. N-benzyl-N-methyl-amino, N- benzyl-N-ethyl-amino, N-methyl-N-( 1-phenylethyl)-ami no, N-methyl-N-(2-phenylethyl)-amino and the like, or any other N,N-di-hydrocarbon-amino group. N,N-di-hydrocarbon-amino groups, in which hydrocarbon contains functional groups as substituents are, for example, N- hydroxy-lower alkyl-N-lower alkyl-amino, e.g. N-(Z-hydroxy-ethyl)-N-methyl-amino and the like, N,N-di-hydroxy-lower alkyl-amino, e.g. N,N-di-(2-hydroxy-ethyl)- amino and the like.

'llhe di-substituted amino group may also be represented by l-N,N alkylene-imino or by 1-N,N-aza-alkyleneimino groups, in which the alkylene portions contain from four to six carbon atoms, as well :as by 1-N,N-oxa-a1kylene-imino and by 1-N,N-thia-alkylene-irnino, in which alkylene contains preferably four carbon atoms. Together with the nitrogen atom such alkylene, aza-alkylene, oxaalkylene or thia-alkylene radicals represent, for example, lN,N- alkylene-imino, in which alkylene contains from four to six carbon atoms, such as l-pyrrolidino radicals, e.g. l-pyrrolidino, Z-methyLl-pyrrolidino and the like, 1- piperidino radicals, e.g. l-pi'peridino, 2-methyl-l-piperidino, 4-methyl-1-piperidirro, 34hydroxy-l-piperidino, 3- acetoxy-l-piperidino, 3-hydroxymethyl-l-piperldino and the like, l-N,N-1,6-hexylene-imino and the like, 1-N,N- (aza-alkylene)-imino, in which alkylene contains from four to six carbon atoms, particularly 1-N,N-(N-lower alkylaza-alkyleneyirnino, in which alkylene contains from four to six carbon atoms, such as 1-N,N-(3-azal,5-pentylene)-imino, particularly -1-N,N-(3-aza-3-lower alkyl-1,5-pentylene)-imino, e.g. 4-methyl-l-piperazino, 4- ethyl-1piperazino and the like, as well as 4-hydroxyet1hyl-l-pip-erazino, 4-acetoxyethyl-l-piperazino and the like, 1-N,N-(3- aza-1,6-hexylene)-i1nino, particularly 1-N,N- (3-aza-3-lower alkyl-1,6-hexylene)-irnino, e.g. l-N,N-(3- aza-3-methyl-L64hexylene) -imino and the like, or 1-N,N- (4-aza-l,7-heptamethylene)-itnino, particularly 1-N,N-

3 (4-aza-4-lower alkyl-1,7-heptamethylene)-imino, e.g. 1- N,I I-(4-aza-4-methyl-l,7-heptamethylene)-imino and the like, l-N,N (3-oxal,5pentylene)aimino, e.g. 4-morpholino and the like, l-N,N(3-thia-1,5-pentylene)-imino, e.g. l-thiamorpholino and the like.

The tertiary amino-lower alkyl radical may also be represented by a heterocyclic or a heterocyclic-lower alkyl radical, in which the di-substituted amino group is part of the heterocyclic nucleus. Such nucleus may be connected through one of its ring carbon atoms or through a lower alkylene radical, e.g. methylene, 1,2-ethylene and the like, with the 2-position of the indene ring. Such radicals are represented, for example, by 1-methyl-3-pyrrolidinome-thyl, l-methyl-3-pipenidinomethyl, 1-rnethyl-4- piperidino and the like.

The l-position of the indene nucleus is preferably unsubstituted, or, if substituted, contains primarily a hydrocarbon radical, particularly lower alkyl, e.g. methyl, ethyl and the like, or monocyclic carbocyclic aryl-lower alkyl, e. g. benzyl and the like.

The six-membered carbocyclic aryl portion of the indene nucleus is preferably unsubstituted or may contain one or more than one substituent, which may be located in any of the four positions available for substitution;

whenever at least two substituents are present, these may be of the same or of different nature. Such substituents may be, for example, lower alkyl, esg. methyl, ethyl and the like, halogeuo-lower alkyl, e.g. trfluoromethyl, etherifled hydroxyl, such as lower alk-oxy, e.g. methoxy, ethoxy and the like, or lower alkylene-dioxy, e.g. methylenedioxy, esterified hydroxyl, such as lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, lower alkanoyloxy, e.g. acetyloxy, propionyloxy and the like, or halogeno, e.g. fluoro, chloro, bromo and the like, acyl, such as lower alkanoyl, e.g. acetyl, propionyl and the like, etherified mercapto, such as lower olkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitno, amino, for example, unsubstituted amino, N-mono-substituted amino, such as N-lower alkyl-amino, e.g. N-methylamino and the like, or preferably N,N-disubstituted amino, for example, N,N-di-lower alkylamino, e.g. N,N-dimethylamino and the like. The sixmembered carbocyclic aryl portion of the indene ring may, therefore, be represented, for example, by an nnsubstituted, lower alkyl-substituted, "a halogeno-lower alkyl-substituted, a lower alkoxy-substituted, Ia lower alkylenedioxy-substituted, a lower alkoxy-carbonyloxy-substituted, alower alkanoyloxy-substituted, a halogeno-substituted, a lower alkanoyl-substituted, a lower ulkyl-mercapto-substituted, a nitro-substituted, an amino-substituted, an N-lower alkyl-amino-substituted or an N,N-di-lower alkyl-amino-substituted six-mem'bered carboeyclic 'aryl portion.

Depending on the number of asymmetric carbon atoms the indene compounds of this invention may be obtained as mixtures of racemates, racemates or antipodes, the separation and resolution of which will be discussed and illustrated hereinbelow.

The new compounds of this invention show anihistaminic effects and are intended to be used as antihistaminic agents to relieve allergic disorders, especially those caused by an excess of histamine; such allergic conditions are, for example, hay fever, urticaria, allergies caused by food, plant pollen or medicinal agents, and the like. In addition, compounds of this invention have a central nervous system depressing effect, thus exert sedative and quieting properties; they can, therefore, be used as sedative agents to counteract states of nervousness, anxiety, stress or shock, as well as local anesthetic effects, which render these compounds useful as local anesthetics, for example, in connection with minor surgery and the like.

Furthermore, compounds of this invention also exert analgesic properties, which can be utilized to raise the threshold of pain, for example, in connection with surgery, antihypertensive effects, which are useful in lowering :blood pressure in states of hypertension, such as renal or essential hypertension, or, particularly, autispasmodic properties, which make such compounds useful as agents to counteract spastic conditions.

Compounds with particularly outstanding effects are the lower alkyl quaternary ammonium halides, sulfates and sulfonates of the indene compounds of the formula:

in in which R attached to any of the positions available for substitution, represents hydrogen, lower alkyl containing from one to lfOllI carbon atoms, e.g. methyl, ethyl n-pnopyl, isopropyl, n-butyl and the like, lower alkoxy containing from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, or halogeno having an atomic Weight below 80, e.g. fluoro, chloro or bromo, R represents hydrogen or lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, A stands for alkylene containing from one to three carbon atoms, e.g. methylene, 1,1-ethylene, 1,2-ethylene, 1,1- propylene, l,2-propylene 1,3-propylcne or 2,2-propylene, Py-represents pyridyl or lower alkyl-substituted pyridyl,

A stands for lower alkylene containing from one to three 7 carbon atoms, particularly for lower alkylene, which contains from two to three carbon atoms and separates the group Am from the 2-position of the indene nucleus by from two to three carbon atoms, e.g. 1,2-ethylene, il-

tains from five to seven ring carbon atoms and lower a1 kyl contains from one to four carbon atoms, e.g. N-cyclopentyl-N-methyl-amino, N-cyclopentyl-N-n-propyhamino, N-cyclohexyl-N-ethyl-amino, N cycloheptyl N-methylamino and the like, N-lower alkyl-N-phenyl-lower alkylamino, in which lower alkyl contains from one to four carbon atoms, e.g. N-benzyl-N-methylaam-ino, N benzyl- N-ethyl-amino, N-methyl N-(1-phenylethyl)-amino, N- methyl-N-(Z-phenylethyD-amino, N-methyl-N-(3-phe nylpropyD-amino and the like, 1-N,N-lower alkylene-imino, in which lower alkylene contains from four to seven carbon atoms, e.g. l-pyrrolidino, l-piperidino, 1-N,N-1,6- hexylene-i mino land the like, l-morpholino, l-N,N (N- lower alkyl-azanlkylene)-imino, in which alkylene contains from four to six carbon atoms, particularly 4-lower alkyl-Lpiperazzino, e.g. 4-methyl-l-piperazino, 4-ethyl-lpiperazino, and the like, as well as 1-N,N-(3-aza-3-methyl-1,6-hexylene)-imino, 1-N,N-(4-aza-4-methyl-1,7-heptylene)-imino and the like.

This group of compounds may be represented by the lower alkyl quaternary ammonium halides of 2-(N,N-di lower lalkyl amino-lower alkyl)-3-[ (2-pyridyl)-lower alkyll-indenes, especiallythe 2-(N,N,N-tri-lower alkyl-ammonio-lower alkyl)-3-['(2-pyridyl)-lower alkyll-indene halides, in which lower alkyl of the N,N-di-lower alkylamino, particularly the N,N,N-tri-lower alkyl-ammonio, group contains from one to four carbon atoms, lower alkyl, separating the N,N-di-lower alkyl-amino, particularly the N,N,N-tri-lo-wer alkyl-ammonio, group from the position of the indene nucleus by from two to three carbon atoms, contains from two to three carbon atoms, and lower alkyl of the (2-pyridyl)-lower alkyl portion confects are the lower alkyl quaternary ammonium halides of 2-(N,N-di-lower alkyl-amino-lower alkyl)-3-[(4-pyri dyl)-lower alkyl]-indenes, particularly the 2-(N,N,N-trilower alkyl-ammonio-lower alkyl)-3-[ (4-pynidyl)-lower alkyl]-indene halides, in which lower alkyl of the (4- pyridyl)-lower alkyl group contains from one to three carbon atoms, and in which lower alkyl, separating the N,N-di-lower alkyl-amino, particularly the N,N,N-trilower alkyl-ammonio, group from the 2-position of the indene nucleus by from two to three carbon atoms, stands for an alkylene radical having from two to three canbon atoms, as well as the lower alkyl quaternary ammonium halides of 2-(N,N-di-lower alkyl-amino-lower alkyl)-3- [(3-pynidyl)-lower alkyl] -indenes, particularly the 2- N,N,N-tri-lower alkyl-ammonio-lower alkyl)-3-[(3-pyridyl)-lower alkyl]-indene halides, in which lower alkyl of (3-pyridyl)-l'ower alkyl contains from one to three carbon atoms, and in which lower alkyl, separating the N, N-di-lower alkyl amino, panticularly the N,N,N-tri-lower alkyl-ammonio, group from the 2-position of the indene nucleus by from two to three carbon atoms, stands for an alkylene radical having from two to three carbon atoms.

The new compounds of this invention may be used as medioaments in the form of pharmaceutical preparations, which contain the new quaternary ammonium derivatives, including racemates or antipodes, in admixture with a pharmaceutical organic or inorganic, solid or liquid vehicle suitable for enteral or parenteral administration. To relieve allergic skin troubles, the new indene compounds may also be employed topically. For making up the preparations there may be used substances, which do not react with the new compounds, such as water, gelatine, lactose, starches, lactic acid, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols or any other carrier used in the manufacture of medicaments. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets, dragees and the like, in liquid form, for example, as solutions, suspensions, emulsions and the like, or in the form of selves, cream, lotions for topical administnation and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, huffers etc. They may also contain, in combination, other therapeutically useful substances.

The compounds of the present invention may be prepared by quaternizing a 3-(pyridyl-lower alkyl)-2-(tentiary amino-lower alkyl)-indene compound according to known methods, and, if desired, converting a resulting quaternary ammonium salt into another quaternary ammonium compound.

The quaternization, carried out according to methods known in the art, may be performed by treating the starting material with a reactive ester formed by an organic hydroxylated compound and a strong inorganic or organic acid. Such esters are more especially those with inorganic acids, such as hydrohalic acids, eg. hydrochloric, hydrobromic, hydriodic and the like, sulfuric acid and the like, or with strong organic acids, such as lower alkane sulfonic acids, e.g. methane sulfonic, ethane sulfonic acid and the like, hydroxy-lower alkane sulfonic acids, e.g. Z-hydroxy-ethanesulfonic acid and the like, or monocyclic carbocyclic aryl sulfonic acids, e.g. benzene sulfonic, p-toluene sulfonic acid and the like. Such esters are specifically lower alkyl halides, e.g. methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl iodide, isopropyl bromide, isopropyl iodide, n-butyl bromide and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl methane sulfonate, methyl ethane sulfonate, ethyl methane sulfonate, ethyl ethane sulfonate, n-propyl methane sulfonate and the like, lower alkyl hydroxy-lower alkane sulfonates, e.g. methyl 2-hydroxyethane sulfonate and the like, lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl benzene sulfonate, methyl p-to luene sulfonate, ethyl p-toluene sulfonate and the like, or monocyclic carbocyclic aryl halides, especial-- -ly phenyl-lower alkyl halides, e.g. benzyl chloride, benzyl bromide, benzyl iodide, Z-phenylethyl chloride, Z-phenylethyl bromide and the like, monocyclic carbocyclic aryllower alkyl lower alkane sulfona-tes, particularly phenyllower alkyl lower alkane sulfonates, e.g. benzyl methane sulfonate, benzyl ethane sulfonate, Z-phenylethyl methane sulfonate and the like, monocyclic carbocyclic aryl-lower alkyl monocyclic carbocyclic aryl sulfonates, eg. benzyl benzene sulfonate, benzyl p-toluene sulfonate, Z-phenylethyl p-toluene sulfonate and the like, or any other aliphatic or araliphaltic halide, sulfate or sulfonate suitable for the formation of therapeutically acceptable quaternary ammonium derivatives.

The quaternizing reaction may be performed in the absence or presence of a solvent, under cooling, at room temperature or at an elevated temperature, at atmospheric pressure or in a closed vessel under pressure, and, if desired, in the atmosphere of an inert gas, e.g. nitrogen. Suitable diluents are more especially lower alkane-ls, e.g. methanol, ethanol, n-propanol, isopropanol, tertiary butanol, n-pentanol and the like, lower alkanones, e.g. acetone, ethyl methyl ketone and the like, organic acid amides, e.g. formamide, N,N-dimethylformamide and the like, aliphatic hydrocarbons, e.g. pentane, hexane and the like, halogenated hydrocarbon, e.g. methylene chloride, ethylene chloride and the like, monocyclic carbocyclic aryl hydrocarbon, -e.g. benzene, toluene and the like, or any other suitable solvent.

A resulting quaternary ammonium compound may be converted into the corresponding quaternary ammonium hydroxide, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, or by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysi-s. From a resulting quaternary ammonium hydroxide thene may be obtained a quaternary ammonium salt by reacting the base with acid, for example, with an inorganic acid, e.g. hydrochloric, hydrobromic, nitric, thiocyanic, sulfuric, phosphoric acid and the like, or with an organic acid, such as acetic, propionic, oxalic, hydroxymaleic, dihydroxymaleic, maleic, fu-maric, malic, tartaric, citric, methane sulfonic, ethane su-lfonic, Z-hydroxyethane sulfonic, ethane 1,2-disulfonic, p-toluene sulfonic acid and the like. v

A quarternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of an intermediate qua-ternary ainmonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment of a solution of the former with hydrogen chloride.

Quaternary ammonium compounds may be isolated as hydrates; depending on the conditions for their formation and/ or the number of tertiary amino groups present in the molecule monoor poly-quaternary ammonium compounds may be formed.

The starting materials used in the above quaternizing reaction may be prepared according to the procedure described in my application Serial No. 18,815, filed March 31, 1960, of which the present application is a continuation-in-part application.

Compounds of this invention, as well as the starting materials used for their preparation, which contain more than one asymmetric atom, may be obtained in the form of mixtures of racemates. Such mixtures of racemates may be separated into individual racemic compounds, using known methods, which may be, for example, based on physic'o-chemical differences, such as solubility. Thus, mixtures of racemates may be separated by fractionate 7 crystallization, if necessary, by using a derivative of a mixture of racemates, by'fractionated distillation and the like.

Separated racemates or racemates of compounds which contain one asymmetric carbon atom only, may be resolved into the optically active forms, the levorotatory l-form and the dextro-rotary d-iorm. Such resolution procedure may be carried out according to methods which are suitable for the separation of a racemate. For example, to a solution of the free base of a racemate (a d,lcompound) in an inert solvent or a mixture of such solvents is added one of the optically active forms of an acid, containing an asymmetric carbon atom, or a solution thereof. Especially useful as optically active forms of salt-forming acids, having an asymmetric carbon atom are the d-tartaric acid (L-tartaric acid) and the l tartaric acid (D-tartaric acid); the optically active forms of dibenzoyltartaric, di-p-toluyl-tartaric, malic, mandelic, IG-camphor sulfonic acid, quinic acid and the like, may also be used. Salts, which are formed by the optically active forms of the base with the optically active form of the acid may then be isolated, primarily on the basis of their different solubilities. The free and optically active base may be obtained from a resulting salt according to methods known for the conversion of a salt into a base, for example, by treatment with a basic reagent. An optically active base may be converted into a salt thereof with an acid or may be converted into a quaternary ammonium compound as described hereinbefore. The optically active forms may also be isolated by biochemical methods.

This is a continuation-in-part application of my application Serial No. 18,815, filed March 31, 1960, now Patent No. 3,060,186, which in turn is a continuation-inpart application of my application Serial No. 852,208, filed November 12, 1959 (now abandoned), which in turn is a continuatiofi-in-part application of my application Serial No. 825,886, filed July 9, 1959, now Patent No. 3,036,085, which in turn is a continuation-in-part application of my application Serial No. 810,998, filed May 5, 1959, now Patent No. 2,947,756, which in turn is a continuation-in-part application of my application Serial No. 792,263, filed February 10, 1959, which in turn is a continuation-in-part application of my application Serial No. 771,225, filed November 3, 1958, now Patent No. 2,970,149, which in turn is a continuation-in-part application of my application Serial No. 754,526, filed August 12, 1958 (now abandoned).

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 By treating an acetone solution of the 2-(2-N,N-dimethylaminoethyl)'-3-[(Z-pyridyl)-methyl]-indene with methyl iodide the dimethiodide of 2-(2-N,N-dimethylaminoethyl)-3-[(Z-pyridyl)-methyl1-indene may be obtained.

The starting material may be prepared as follows: 33.2 g. of dihydropyran is slowly added to a stirred mixture of 50 g. of a-benzyl-malonic acid and 0.1 g. of p-toluene snlfon-ic acid in 130 ml. of diethylether kept at 30 during the addition of the dihydropyran. The mixture is stirred for an additional 15 minutes and then poured onto ice. The ether phase is washed with aqueous potassium carbonate, then with water and is dried over magnesium sulfate; the ether is evaporated under reduced pressure by keeping the temperature below 30 to yield the ditetrahydropropyranyl a-benzyl-malonate. A toluene solution of this ester is gradually given to a solution of 4.86 g. of a 50% suspension of sodium Lhydride in mineral oil while heating and stirring for six hours. A solution of 10.8 g. of 2-N,N-dimethylaminoethyl chloride in toluene is added dropwise, and the reaction mixture is refluxed 'for an additional 48 hours. The toluene layer is washed with water, dried over magnesium sulfate and evapo- 8 rated to yield the di-tetrahydropyranyl a-benzyl-e (2- N,N-dimeth3ilamlinoetzhy'l)-nralonate; yield: 32.2 g. of crude material.

A mixture of the resulting di-tetrahydropyranyl mbenzyl-u-(2-N,N-dimethylaminoethyl)-ma1onate in 180 g.

of polyphosphoric acid is stirred at 1l0120 during thirty minutes, and then at during an additional twenty minutes. The reaction mixture is cooled, poured into ice-water, the acidic phase is neutralized with potasafter recrystallization from a mixture of ethanol and ether.

To 650 nil. of an 0.37 molar solution of phenyl lithium in benzene'is added dropwise 24 ml. of dry a-picotline under an atmosphere of nitrogen. After one hour, a solution of 10 g. of 2-(2-N,N-dimethylaminoethyl)indenl-one in 20 m1. of benzene is added while stirring, and the reaction mixture is allowed to stand at room tempera- .ture for several days.

the benzene solution extracted with a solution of 20 ml. of concentrated aqueous hydrochloric acid in 100 ml. of water. The acidic extract, containing 2-(2-N,N-di'- methylaminoethyl) l[(2-pyridyl)-methyl]-indan-1-ol, is heated on the steam bath for one hour, the solution is then cooled, made basic with aqueous ammonia and.

then extracted with ether. The ether solution is dried over sodium sulfate, the solution is removed, and the residue is distilled to yield the 2-(2-N,N-dimethylamino- Example 2 A solution of 2.0 g. of 2-(2-N,N-dimethylaminoethyl)- 3-[1-(2-pyridyl)-ethyl]-indene in 5 ml. of ethyl acetate is treated at room temperature with 0.65 ml. of methyl iodide. The crystalline precipitate is filtered off after 15 minutes to yield the 2-(2-N,N-dimethylaminoethyl)-3-[l- (2-pyridyD-et-hyl] -indene methiodide of the formula:

CH2 which melts at 225-226.

The above-described methiodide is suspendedin 25 ml. of methanol, and hydrogen chloride ,gas is bubbled through the suspension while heating it on steam bath.

9 e CCHaCHzN(CHals I The methanol is then distilled off, the residue is dried for several hours under reduced pressure and at room tempenature. Theamorphous material represents the desired indene methochloride of the formula:

The starting material may be prepared as follows: 26 g.

of Z-ethyl-pyridine is added dropwise to a stirred solution of 650 ml. of an 0.37 molar solution of phenyl lithium in benzene. The addition is carried out in an atmosphere of ntirogen and while cooling to 20. After After wash-.

50 ml. of water is added while. cooling and stirring. The water layer is discarded and ethyl)-3-[(2-pyridyl)'-rnethyl-]indene, B.P. 168-170/0.7

two hours a solution of 10 g. of 2(2-N,N-dimethylaminoethyD-indan-l-one in 50 ml. of dry ether is added over a period of five minutes while stirring and cooling to room temperature. After standing for twenty-four hours the organolithium compounds are decomposed by addition of 50 ml. of water with external cooling. After separating the water phase from the organic solution, the latter is washed several times with 50 ml. of water, and then extracted with a mixture of 40 m1. of concentrated hydrochloric acid and 100 ml. of water.

The acidic solution, containing 2-(2-N,N-dimethylaminoethyl) -1-[ 1- 2-pyridyl) -ethyl] -indan-1-ol, is heated on the steam bath for thirty minutes to eifect complete dehydration to the desired indene derivative. The solution is cooled, made strongly basic with an aqueous solution of ammonia and then extracted with ether. The ether phase is dried over sodium sulfate, filtered, evaporated, and the residue is distilled. At 15 mm. pressure, the excess of 2-ethyl-pyridine is removed, at 120/ 0.5 mm. some unreacted 2-(N,N-dimethylaminoethyl)-indan-1-one distills and at 165-175 0.5 mm. the 2-(2-N,N-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl]-indene is collected.

Example 3 The monomethiodide of 2-(2-N,N-dimethylaminoethyl)-3-[l-(2-pyridyl)-propyl]-indene of the formula:

6B 6 C OHrCHzN (C H3) 3 I MP. 255 (decomposition) after recrystallization from water, is prepared by reacting 0.8 g. of 2-(2-N,N-dimethylarninoethyl)-3-[l-(2-pyridyl)-propyl]-indene in ml. of acetone with 0.5 ml. of methyl iodide; the desired quaternary compound crystallizes within a few minutes.

The starting materials may be prepared as follows: A solution of 17 g. of 2-propyl-pyridine in 50 ml. of ether is added over a period of 15 minutes to a stirred solution of 8 g. of butyl lithium in 50 ml. of hexane in an atmosphere of dry nitrogen. After three hours a solution of 13 g. of 2-(2-N,N-dimethylaminoethyl)-indan-1-one in 50 ml. of ether is added over a period of fifteen minutes while stirring. The reaction mixture is allowed to stand for two days at room temperature; 50 ml. of water is then added dropwise, the aqueous layer is removed and the organic phase is extracted with 60 ml. of 6 N aqueous hydrochloric acid.

The acidic extract, containing 2-(2-N,N-dimethylaminoethyl)-1-[l-(2-pyridyl)-propyl]-indan1-o1, is heated on the steam bath for one hour, cooled, basified with aqueous ammonia and extracted with ether. The ether is removed by distillation and the 2-(2'-N,N-dimethylaminoethy1)-3- [l-(Z-pyridyl)-propyl]-indene is distilled, El. 165- l75/ 0.5 mm.

Example 4 The methiodide of 2-(2-N,N-dimethylaminoethyl)-3- [2-(2-pyridyl)-2-propyl]-indene of the formula:

prepared according to the previously-given procedure, melts at 234 (with decomposition) after recrystallization from ethanol.

The starting materials may be prepared as follows:

.tracted into ether.

in 50 ml. of ether is added; the reaction mixture is allowed to stand for one day at room temperature and is then worked up as described in Example 3. The dehydration product of any intermediarily formed 2-(2-N,N-dimethylaminoethyl) 1-[2-(2-pyridyl)-2-propyl]-indan-1- o l, is distilled to yield the desired 2-(2-N,N-dimethylaminoethyl) 3 [2 (2 pyridyl)-2-propyl]-indene, B1. 155- l/0.4 mm.

Example 5 1 ml. of methyl iodide is added to a solution of 1 g. of 2 (2-N,N-dimethylaminoethyl)'-3-[2-(2-pyridyl)-ethyIJ-indene in 5 ml. of ethanol at room temperature; the reaction mixture is allowed to stand for one hour and the crystalline material is then filtered off. The dimethiodide of 2-(2-N,N-dimethylaminoethyl)-3-[2-(2-pyridyl)- ethyl]-indene of the formula:

CH2CH2 e CH3 is recrystallized from a mixture of ethanol and water, M.P. 235237 (with decomposition).

The starting material used in the above procedure may be prepared as follows: To a solution of 35 g. of 2-(2- N,N-dimethylaminoet-hyl)-indan-1-one in ml. of ethanol is gradually added 10 g. of sodium borohydride while stirring. The reaction mixture is refluxed for two hours, the greater part of the solvent is then removed by distillation and the residue is diluted with water. The

2 (2-N,N-dimethylaminoethyl)-indan-1-ol is extracted with ether and the crude base obtained after removal of the solvent; its picrate melts at 169-170".

A solution of the crude base in 350 ml. of glacial acetic acid and ml. of concentrated hydrochloric acid is refluxed for one-half hour; most of the solvent is then removed by distillation under reduced pressure. The residue is diluted with water, made basic with ammonia and extracted with ether. On addition of 6 N ethanolic hydrogen chloride to the ether, the 2-(2-N,N-dimethylaminoethyD-indene hydrochloride precipitates and is recrystallized from ethanol, Ml. 202-205".

The resulting hydrochloride is converted to the free base by dissolving the salt in a minimum amount of water, adding aqueous ammonia and extracting the free base with ether; the ether solution is dried over sodium sulfate, the solvent is evaporated and the 2-(2-N,N-dimethyl- 'aminoethyD-indene is distilled at 108-115/ 1 mm.

To a solution of potassium tertiary butoxide, prepared by dissolving 4 g. of potassium 300 ml. of anhydrous tertiary butanol, is added dropwise and under an atmosphere of dry nitrogen 15 g. of 2-(2-N,N-dimethylaminoethyl)-indene. After the addition is completed, 17 g. of freshly distilled 2-vinyl-pyridine is given to the solution of the potassium salt; the reaction mixture is then refluxed overnight. The major part of the solvent is removed under reduced pressure, water is added to the concentrated solution, and the separating oil is ex- The ether solution is dried over sodium sulfate, the solvent is evaporated and the residue is distilled under reduced pressure. The excess 2-vinylpyridine is removed first at 15 mm. and the desired 2- 1 1 (2-N,N-dimethylaminoethyl)-3-[2-(2-pyridyl)-ethyl] indene distills at 175-1 80/ 0.7 mm.

Example 6 formula:

HaC-(fH-Q o\ N- crystallizes and is separated by filtration, M.P. 215 (decomposition). The second racemate methiodide, which is non-crystalline, can be collected by evaporating the solvent.

The starting material used in the above reaction may be prepared as follows: 300 g. of diethyl u-benzylmalonate is added over a period of thirty minutes to a refluxing suspension of 66 g. of sodium hydride in mineral oil (50% sodium hydride) in 2000 ml. of toluene. After refluxing for one hour a solution of 2-N,N-dimethylamino-Z-methyl-ethyl chloride in toluene (prepared by dissolving 310 g. of 2-N,N-dimethylarnino-2-methyl-ethyl chloride hydrochloride in 600 ml. of water, basifying the aqueous solution and extracting it 'With 1000 ml. of toluene, which solution is dried over sodium sulfate) is added over a period of one hour. After refluxing overnight, the reaction mixture is cooled and extracted with aqueous hydrochloric acid. The acidic extract is basified with ammonia and the separating oil is extracted with ether. After drying, the ether is evaporated, leaving 396 g. of diethyl a-benzyl-u-(2-N,N-dimethylamino-2- methyl-ethyD-malonate as a residue.

120 g. of diethyl a-benzyl-a-(2-N,N-dimethylamino-2- rnethyl-ethyl)-malonate is added to 840 g. of polyphosphoric acid at 100 while stirring. The temperature is raised slowly to 150-160" and held for thirty minutes. After treatment with ice water, the reaction mixture is made basic with potassium carbonate and extracted with ether. The ether is evaporated to yield a residue containing as thernain constituent the 2-(2-N,N-dimethylarnino-Z-methyl-ethyl)-2-carbethoxy-indan-1- one. 75 g. of this residue is refluxed with 650 ml. of '2 -N aqueous hydrochloric acid for four hours. The acidic solution is made basic with ammonia, the organic material is extracted with ether, the ether evaporated and the residue distilled at 1121l4/0.23 mm. This fraction is converted to the hydrochloride with ethanolic hydrogen chloride and the crystalline material is recrystallized from ethanol, M.P. 194-196". This hydrochloride yields the free 2-(2-N,N-dimethylamino-2-methyl-ethyl) indan 1- one by treatment with ammonia.

A solution of g. of dry 2-ethyl-pyridine in ml. of dry benzene is added to a solution of 60 ml. of butyl lithium in hexane (equivalent to 9 g. of butyl lithium) while cooling to 25 and in an atmosphere of dry nitrogen. After three hours, 12 g. of 2-(2-N,N-dimethylamino-Z-methyl-ethyl)aindan-l-one in 25 ml. of benzene is added at 25. The reaction mixture is allowed to stand for seven days at room temperature, 100 ml. of water is added dropwise to decompose the organic lithium salts and the Water layer is separated. The remaining organic phase is extracted with 75 ml. of 4 N aqueous hydrochloric acid.

The acidic solution, containing 2-(2-N,N-dimethylamino 2 methyl ethyl) l [1 (2 pyridyl) ethyl]- indan-l-ol, is heated on the steam bathfor thirty minutes and is then made basic with aqueous ammonia. After extraction with ether the organic layer is separated, dried over sodium sulfate and then evaporated. The remaining residue is distilled under reduced pressure and the fraction, boiling at 165l70/ 0.2 mm., is collected. This fraction is a mixture of approximately equal amounts of the two racemates of 2-(2-N,N-dimethyIamtiHo-Z-methylethyl -3- 1-( Z-pyridyl) -ethyl] -indene.

Example 7 A solution of 0.8 g. of 2-(2-N,N-diethylaminoethy1)-3- [l-(2-rpyridyl)-ethyl]-indene in 5 ml. of acetone is treated with 0.5 ml. of methyl iodide at room temperature. After fifteen minutes 15 ml. of ethyl acetate, saturated with water, is added. A gummy precipitate which slowly crystallizes is filtered off, and the desired 2-(2-N,N-diethylaminoethyl) -3- 1- (Z-pyridyl) -ethyl] -indene niethiodide of the formula:

CH2 melts at 152-154" after recrystallization from ethanol.

The starting material used in the above reaction may be prepared as follows: To a warm suspension of 22 g. of sodium hydride in 1000 ml. of toluene is given dropwise while stirring 100 g. of diethyl a-benzyl-rnalonate. The reaction mixture is refluxed for one hour after completion of the addition, then a solution of 70 g. of 2-N,N-diethylaminoethyl chloride in toluene is added and the reaction mixture is refluxed overnight. The toluene solution is extracted with aqueous hydrochloric acid, the acidic layer 7 is made basic with aqueous ammonia and the organic material is extracted with ether. The ether solution is washed, dried and evaporated under reduced pressure to yield 136 g. of diethyl a-benzyl-a-(2-N,N-diethylaminoethyl)-malonate, the oxalate of which melts at 117-1 19.

A mixture of 136 g. of diethyl u-benzyl-a-(2-N,N-

diethylaminoethyl)malonate, 65.5 g. of potassium hydroxide, ml. of water and 340 ml. of ethanol is refiuxed for four hours, then concentrated under reduced pressure. The solid residue is dissolved in a minimum amount of water, the aqueous solution is neutralized with acetic acid while externally cooling and the resulting oz- 'benzyl-a-(2-N,N diethylaminoethyl) malonic acid is filtered ofi and Washed with ice Water and ethanol. After drying under reduced pressure, it melts at 128; yield:

minutes and the acid is decomposed by pouring the reaction mixture into ice Water and neutralizing the aqueous solution with potassium carbonate. ethylaminoethyl)-indan-l-one is extracted with ether, the ether solution is washed and dried, and the ether is evaporated. The hydrochloride salt, prepared according to the previously given procedure, melts at 164-166"; yield: 12.3 g. I

To an ether solution of 0.125 mol of phenyl lithium (prepared from 1.75 g. of lithium and 20 g. of brornobenzene) is given While stirring in an atmosphere of nitrogen and at room temperature an other solution of 13.3 g. of Z-ethyl-pyridine.

After standing for two hours, the reaction mixture is cooled to -5 with an ice-salt mixture, and a solution of 12.5 g. of 2-(2-N,N-diethylaminoethyD-indan-1-one in ether is slowly added while stirring. The reaction mixture is allowed to stand at room temperature overnight and is then decomposed by carefully adding water. The organic material is extracted with ether, and the ether solution is washed with 15 percent aqueous hydrochloric acid to separate the basic material. The acidic layer, containing 2 (2 N,N diethylaminoethyl) 1 [1-(2-pyridyl)-ethyl]- indan-l-ol, is heated on the steam bath for thirty minutes and, after cooling, is made basic with aqueous ammonia. The organic material is extracted with ether, the ether layer is washed with water and dried over sodium sulfate. The solvent is evaporated and the 2-(2-N,N- diethylamrinoethyl)3-[l-(2-pyridyl)-ethyl]-indene is distilled, BR 178-- 180/0.55 mm.; yield: g.

Other quaternary ammonium derivatives of this invention, such as, for example, the 2-(2-N,N-dimethylam-inoethyl)-3-[1-(2-pyridyl)-ethyl]-iudene methobromide, 2-(2- N,N dimethylaminoethyD-3-[(2-pyridyl)-methyl] indene methochloride, 2 (2 N,N dimethylaminoethyl)-3-[(3- pyridyl)-methyl]-indene methyl methane sulfonate, 2-(2- N,N dimethylaminoethyl)-3-[l-(4pyridyl)-ethyl] indene methiodide, 2-(2-N,N-diethylaminoethyD-3-[(2 pyridyl)- methyl]-indene dimethosulfate, 2-(2-N,N-diethylaminoethyl)-3-[l (2 pyridyl)-ethyl]-indene methochloride, 2- (2-N,N-di-n-propyl-aminoethyl) 3 [(2 pyridyl)-methyl]- indene methiodide, 2-(3-N,N-dimethylaminopropyl)-3-[l- (2-pyridyl-ethyl1-indene ethiodide, 2-(3-N,N-diethylaminopropyl)-3-[(2-pyridyl)-methyl]-indene n-propylbromide, 6- chloro-2-(2-N,N-dimethylaminoethyD-3-[1 (2 pyridyD- ethyl]-indene methiodide, 2-(2-N,N-diethylaminoethyl)-6- methoxy-3-[1-(2-pyridyl)-ethyl]indene methobromide and the like, may be prepared according to the above-described procedure by selecting the appropriate starting materials.

What is claimed is:

l. A member selected from the group consisting of a lower alkyl quaternary ammonium halide, sulfate and sulfonate of a compound of the formula Ar-PY in which R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halogeno, R stands for a member selected from the group consisting of hydrogen and lower alkyl, A stands for alkylene having from one to three carbon atoms, Py is a member selected from the group consisting of pyridyl and lower alkyl-substituted pyridyl, A stands for lower alkylene,

14- and Am stands for a member selected from the group consisting of N,N-di-lower alkyl-amino, N-cycloalkyl-N- lower alkylamino, in which cyeloalkyl has from five to seven ring carbon atoms, N-lower alkyl-N-phenyl-lower alkyl-amino, 1-N,N-alkyleneimino, in which alkylene has from four to seven carbon atoms, 4-morpholino and 4- lower alkyl-bpiperazino.

2. A lower alkyl quaternary ammonium halide of 2- (N,N-di-1ower alkyl-amino-lower alkyl)-3-[(2-pyridyl)- lower alkyl]-indene, the lower alkyl, separating N,N-dilower alkyl-amino from the 2-position of the indene nucleus by from two to three carbon atoms being of from two to three carbon atoms, and the lower alkyl of the (2- pyridyl)-lower alkyl portion being of from one to three carbon atoms.

3. 2 (2 N,N dimethylarninoethyl) 3 [(2-pyridyl)- methylJ-indene dimethiodide.

4. 2 (2 N,N-dimethylarninoethyl) 3 [1-(2-pyridyl)- ethyH-indene methiodide.

5. 2 (2 N,N dimethylaminoethyD-3-[1-(2-pyridyl)- ethyl]-indene methochloni'de.

6. 2 (2 N,N dimethylaminoethyl)-3-[1-(2-pyridyl)- pro-pyl]-indene methiodide.

7. 2 (2 N,N dimethylaminoethyD-3-[2-(2-pwidyl)- 2-propyl]-indene methiodide.

8. 2 (2 N,N dimethylaminoethyD-S-[2-(2-pynidyl)- ethyll-indene dimethiodide.

9. 2 (2 N,N dimethylamino 2-methyl-ethyl)-3-[1-(2- pyridyl)-ethyl]-indene methiodide.

10. 2 (2 N,N diethylarninoethyD-3-[1-(2-pyridyl)- ethyl]-indene methiodide.

11. A lower alkyl quaternary ammonium halide of 2- (N,N-di-lower alkyl-amino-lower alkyl)-3-[(4-pyridyl)- lower alkyl]-indene, the lower alkyl of the (4-pyridyl)- lower alkyl portion being of from one to three carbon atoms, and the lower alkyl, separating N,N-di-lower alkylamino tfrom the 2-position of the indene nucleus by from two to three carbon atoms, being of from two to three carbon atoms.

12. A lower alkyl quaternary-ammonium halide of 2- (N,N-di-lower alkyl-amino-lower alkyl)-3-[(3-pyridyl)- lower aIkyH-indene, the lower alkyl of the (3-pyridy1)- lower alkyl portion being of from one to three carbon atoms, and the lower alkyl separating N,N-di-lower alkylamino from the 2-position of the indene nucleus by from two to three carbon atoms, being of from two to three carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS 2,970,149 Huebner Jan. 31, 1961

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A LOWER ALKYL QUATERNARY AMMONIUM HALIDE, SULFATE AND SULFONATE OF A COMPOUND OF THE FORMULA