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Publication numberUS3340146 A
Publication typeGrant
Publication dateSep 5, 1967
Filing dateDec 14, 1964
Priority dateApr 27, 1964
Also published asUS3332958
Publication numberUS 3340146 A, US 3340146A, US-A-3340146, US3340146 A, US3340146A
InventorsWerner Lincoln Harvey
Original AssigneeCiba Geigy Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Taeniacidal compositions of bis-arylsulfides
US 3340146 A
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Description  (OCR text may contain errors)

Patented Sept. 5, 1967 3,340,146 TAENIACIDAL COMPOSITIONS OF BIS-ARYLSULFIDES Lincoln Harvey Werner, Summit, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 14, 1964, Ser. No. 418,279

' 3 Claims. (Cl. 167-55) This is a continuation-in-part application of my application Ser. No. 362,937, filed Apr. 27, 1964, now abandoned.

The present invention concerns bis-aryl-sulfides. More particularly, it relates to compounds of the formula Ar XArin which X stands for thio (S), sulfinyl (S) or sulfonyl (S0 and each of the groups Ar, and Ar is monocyclic carbocyclic aryl substituted by N-substituted amino-lower alkyl-oxy, in which the N-substituted amino group is separated from oxy by at least two carbon atoms, salts, N-oxides, salts of N-oxides and quaternary ammonium compounds thereof, as well as a procedure for the preparation of such compounds. The above compounds are, more especially, represented by the formula Ar X-Ar in which X and Ar have the above-given meaning.

The monocyclic carbocyclic aryl groups Ar and Ar have preferably one N-substituted amino-lower alkyl-oxy substituent, but may have more than one. Such groups may substitute any of the positions available for substitution; one of it preferably substitutes the 4-position. Ar; and Ar may be otherwise unsubstituted or may contain one or more than one additional 'substituent, which may be attached to any position available for additional substituents. These are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl or Z-methyl-butyl-(Z), or substituted lower alkyl, such as halogenomethyl, e.g. trifluoromethyl, or N,N-disubstituted amino-methyl, such as N,N-di-lower alkylamino-methyl, e.g. N,N-dimethylaminomethyl or N,N-diethylaminomethyl, N,N-alkyleneimino-methyl, in which alkylene has from four to seven chain carbon atoms, e.g. pyrrolidinomethyl or piperidinomethyl, 4- lower alkyl-piperazinomethyl, e.g. 4-methyl-piperazinomethyl, 4-morpholino-methyl, or any other analogous substituted lower alkyl group, such as phenyl-lower alkyl, e.g. benzyl, cycloalkyl having from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyl or cyclohexyl, halogeno, e.g. fluoro, chloro or bromo, or, as mentioned above, further N-substituted amino-lower alkyl-oxy having the meaning given below.

The N-substituted amino-lower alkyl-oxy substitutent may be represented by the formula O(C,,H )Am, in which the portion (C H stands for lower alkylene having at least two carbon atoms (i.e. the letter n is an integer greater than one) and separating the N-substituted amino group Am from the oxygen atom by at least two carbon atoms.

The portion (C,,H stands for lower alkylene, which has preferably from two to three carbon atoms (n=2 or 3) and separates Am from the oxygen atom by at least two, preferably by two to three carbon atoms. Such alkylene group, for example, is 1,2-ethylene, 1,2- 2,3- or 1,3-propylene, as well as 1,3-, 2,3-, 3,4-, or 1,4- butylene, 1,4- or 1,5-pentylene, 1,5- or 1,6-hexylene or 1,7-heptylene.

. A11 N-substituted amino group Am is an N-monosubstituted or an N,N-disubstituted amino group, in which the substituents are organic groups having preferably from one to ten carbon atoms. Such groups are, for example, aliphatic radicals, especially lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl,

pentyl or neopentyl, lower alkenyl, e.g. allyl or methylallyl, cycloaliphatic or cycloaliphatic-aliphatic radicals, such as cycloalkyl or cycloalkyl-lower alkyl having from three to seven, preferably five or six ring carbon atoms, e.g. cyclopentyl or cyclohexyl, cyclopentylmethyl or 2- cyclohexylethyl, carbocyclic aryl radicals, such as monocyclic carbocyclic aryl, e.g. phenyl, carbocyclic arylaliphatic radicals, such as monocyclic carbocyclic aryllower alkyl, for example, phenyl-lower alkyl, e.g. benzyl, l-phenylethyl or Z-phenylethyl, or lower alkyl having functional groups, such as hydroxy-lower alkyl, e.g. 2-hydroxyethyl, lower alkoxy-lower alkyl, e.g. 2-methoxyethy1 or 2-ethoxyethyl, lower alkyl-mercapto-lower alkyl, e.g. 2- methylmercaptoethyl or 2-ethylmercaptoethyl, or any other analogously substituted organic group.

N-monosubstituted amino groups Am are, for example, lower alkylamino, e.g methylamino, ethylamino or n-propylamino, cycloalkylamino, e. g cyclopentylamino or cyclohexylamino, cycloalkyl-lower alkyl-amino, e.g. cyclopentylmethylamino or 2-cyclohexylethylamino, monocyclic carbocyclic aryl-amino, e.g. phenylamino, monocyclic carbocyclic aryl-lower alkylamino, such as phenyllower alkylamino, e.g. benzylamino or 2-phenylethylamino or any other analogous N-monosubstituted amino group.

N,N-disubstituted amino groups Am are primarily dilower alkylamino, e.g. dimethylamino, N-methyl-N-ethylamino, di-ethylamino, di-u-propylamino, di-isopropylamino or di-n-butylamino, N-cycloalkyl-N-lower alkylamino, e.g. N-cyclopentyl-Mmethylamiuo, N-cyclohexyl- N-methylamino or N-cyclohexyl-N-ethylamino, N-lower alkyl-N-phenyl-lower alkylamino, e.g. N-methyl-N-benzylamino, N-ethyl-N-benzyl-amino, N-ethyl N (1 phenylethyl)amino or N-methyl-N-(2-phenylethyl)-amino, as Well as N,N-di-substituted amino groups, in which the substituents carry functional groups, for example, N- hydroxy-lower alkyl-N-lower alkylamino or N,N-di-(hydroxylower alkyl)-amino in which hydroxyl is separated from the amino-nitrogen by at least two, preferably by two to three, carbon atoms, e.g. N-(2-hydroxyethyl)-N- methyl-amino or N,N-di-(Z-hydroxyethyl)-amino, or any other equivalent N,N-disubstituted amino group.

In an N,N-disubstituted amino group Am the two substituents may also be taken together and form a divalent radical; such groups are, for example, alkyleneimino, in which alkylene has from four to eight carbon atoms, such as pyrrolidino or 2-methyl-pyrrolidino, piperidino, 2- methyl-piperidino or 4-methyl-piperidino, 1,6-hexyleneimino or 1,7-heptyleneimino, aza-alkyleneimino in which alkylene has from four to six carbon atoms, and the two nitrogen atoms are separated by at least two carbon atoms, particularly N-lower alkyl-aza-alkyleneimino, such as piperazino or, particularly, 4-lower alkyl-piperazino, e.g. 4-methyl-piperazino or 4-ethyl-piperazino, as well as 4-hydroxyethyl-piperazino or '4-acetoxyethyl-piperazino, 3-aza-1,6-hexyleneimino, particularly 3-lower alkyl-3-aza- 1,6-hexyleneimino, e.g. 3-methyl-3-aza-1,6-hexyleneimino, 4-aza-1,7-heptyleneimino, particularly 4-lower alkyl-4- aza-l,7-heptyleneimino, e.g. 4-methyl-4-aza-1,7-heptyleneimino, oxaor thia-alkyleneimino in which alkylene has preferably four carbon atoms and the oxygen or sulfur atom is separated from the nitrogen atom by two carbon atoms, such as 4-morpholino, 3-methyl-4-morpholino, or 4-thiamorpholino, or any other equivalent N,N-disubstituted amino group.

' In an N-substituted amino-lower alkyl-oxy group, the lower alkyl portion, either partially or in toto may form part of a saturated heterocyclic ring system, in which the N-subst-ituted amino group Am represents a ring member, separated from oxy by at least two carbon atoms. Such N- substituted amino-lower alkyl-oxy groups are, for example, l-methyl-piperidyl-(Z)-methoxy, Z-(I-methyl-piperidyl-2)-ethoxy, l-methyl-piperidyl-(3)-methoxy, l-ethylpiperidyl- (4 -oxy or l-methyl-pyrrolidyl- 3 -methoxy.

Salts of the compounds of this invention are acid addition salts, especially those with pharmaceutically acceptable acids such as inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric or phosphoric acid, or organic acids, preferably car-boxylic or sulfonic acids, e.g. acetic, propionic, pivalic, glycolic, lactic, malonic, succinic, maleic, hydroxymaleic, malic, tartaric, citric, benzoic, salicylic, 2- acetoxybenzoic, uicotinic or isonicotinic acid, methane or ethane sulfonic, ethane 1,2-disulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic or naphthalene 2-sulfonic acid. Other addition salts with acids may be useful as intermediates, for example, in the preparation of pharmaceutically acceptable acid addition salts or in the purification of the free compounds, as well as for identification or characterization purposes. Salts, which are prepared primarily for the latter, are, for example, those with certain inorganic acids, e.g. perchloric acid, phosphotungst-ic, phosphomolybdic, chloroplatinic or Reinecke acid or with acidic organic nitro compounds, e.g. picric, picrolonic or fiavianic acid. Monoor poly-salts may be formed depending on the number of salt-forming groups and/or the conditions used for the salt formation;

Salts of the N-oxides of the aforementioned compounds, particularly the acid addition salts thereof are, for example, those with the above-mentioned acids.

Quaternary-ammonium derivatives of the compounds of this invention are those formed with reactive esters of alcohols and strong inorganic or organic acids, particularly those with lower aliphatic halides, sulfates, or organic sulfonates, such as lower alkyl halides, e.g., methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide, di-lower alkyl sulfates, e.g. dimethyl sulfate or diethyl sulfate, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane sulfonate or ethane sulfonate, lower alkyl lower hydroxy alkane sulfonates, e.g. methyl 2-hydroxy-ethane sulfonate, or lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate or ethyl p-toluene sulfonate, as well as those with carbocyclic aryl-aliphatic halides, such as phenyl-lower alkyl halides, e.g. benzyl, l-phenylethyl or 2-phenylethyl chloride, bromide or iodide. Also included as quaternary ammonium compounds are the corresponding quaternary ammonium hydroxides, and the quaternary ammonium salts with acids other than hydrohalic, sulfuric or organic sulfonic acids, particularly those with the organic carboxylic acids mentioned hereinabove.

The compounds of this invention have anti-parasitic, particularly taeniacidal properties, and are, therefore, useful as taeniacides in the treatment of tapeworm infections, caused, for example, by Hymenolepis nana, Dipyliaium canium or Taenia pisiform'is or Moniezia expansa.

Particularly useful are the compounds of the formula Rb Rb in which X has the previously-given meaning, but stands more especially for thio, Am stands primarily for dilower alkyl-amino, as well as alkyleneimino, in which algroup Am from the oxygen atom by two to three carbon atoms, as well as the acid addition salts, particularly the pharmaceuticallyacceptable acid addition salts, thereof.

The compounds of the present invention are prepared according to methods known per se; for example, they are obtained by converting in a compound of the formula Ar XAr in which X has the previously given meaning, and eachof the groups Arf and Ar; is monocyclic carbocyclic aryl substituted by R capable of being converted into N-substituted amino-lower alkyl-oxy, in which N-substituted amino is separated from oxy by at least two carbon atoms, or a salt thereof, the group R1 into said N-substituted amino-lower alkyl-oxy group and, if desired, converting in a resulting compound the group X into another group representing X, and/or, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into an N-oxide or a quaternary ammonium compound thereof, and/or,- if desired, converting a resulting free compound or an N-oxide into a salt thereof, and/or, if desired, converting a quaternary ammonium compound into another quaternary ammonium 'compound, and/ or, if desired, separating a mixture of isomers into the single isomers.

The above starting material, more especially, is represented by the formula Ar X-Ar in which X and Ar has the previously-given meaning. The conversion of R= into N-substituted amino-lower alkyl-oxy is carried out in one step or in stages.

A particularly suitable group representing Re is hydroxyl; its conversion into N-substituted amino-lower alkyl-oxy is carried out according to known procedures. Usually, the starting material, in which each of the groups Ar and Ar is substituted by hydroxyl, or preferably a salt thereof, is reacted with a reactive ester of a N-substituted amino-lower alkanol, particularly a compound of the formula Am-(C H )Y, in which Am and the portion (C H have the previously-given meaning, Am representing primarily an N,N-disubstituted amino group, and Y stands for a reactive esterified hydroxyl group. The latter is above all a hydroxyl group esterified with a strong mineral acid, such as a hydrohalic acid, e.g. hydrochloric or hydrobromic acid. It may also be a hy droxyl group esterified with a strong organic sulfonic acid, such as a lower alkane sulfonic acid, e.g. methane o-rethane sulfonic acid, or a monocyclic carbocyclic arylsulfonic acid, e.g. p-toluene sulfonic acid.

As noted above, the starting material is preferably used in the form of a salt thereof. Such salt, for example, a metal salt, particularly an alkali metal salt, e.g. lithium, sodium or potassium salt, as well as an alkaline earth metal salt, or any other suitable salt, is formed, for exam ple, by treatment of the starting material with a metal salt-forming reagent, such as an alkali metal hydride of amide, e.g. lithium hydride, sodium hydride, sodium amide or potassium amide, an alkali metal or alkaline earth metal lower alkoxide, e.g. lithium, sodium, potassium or barium methoxide, ethoxide, or tertiary butoxide, or an alkali metal compound of a hydrocarbon, e.g. butyl lithium, phenyl lithium or phenyl sodium. The preparation of the salt is usually carried out in the presence of an inert solvent, for example, a hydrocarbon, e.g. hexane, benzene, toluene or xylene, an ether, e.g. diethyl ether, p-dioxane, tetrahydrofuran or diethyleneglycol, or especially a carboxylic acid amide, e.g. dimethylformamide, or any other suitable solvent, such as a lower alkanol, e.g. methanol or ethanol or a solvent mixture, if necessary, while cooling or at an elevated temperature, and/or in the atmosphere of an inert gas.

The reaction of the starting material, particularly a metal compound thereof, with the reactive ester of an N- substituted amino-lower alkanol is carried out in the presence of a suitable diluent, for example, in the solvent or solvent mixture used for the preparation of a metal compound, if necessary, while cooling or at an elevated temperature, and/or, in the atmosphere of an inert gas, e.g. nitrogen. Formation of the metal compound of the starting material may also be achieved in situ; for example, the free starting material and the reactive ester of the N- substituted amino-lower alkanol may be reacted in the presence of a salt-forming reagent, for example, an alkali metal carbonate or an alkaline earth metal carbonate.

The conversion of hydroxy representing Ra into N- substituted amino-lower alkyl-oxy may also be achieved by treating the corresponding starting material with an N-substituted amino-lower alkanol, particularly an N,N disubstituted amino-lower alkanol, in the presence of a disubstituted carbonate. The latter is, for eXample, a di-aryl carbonate, e.g. diphenyl carbonate, or more particularly, a di-lower alkyl carbonate, e.g. dimethyl carbonate, ethyl methyl carbonate, diethyl carbonate or dibntyl carbonate. The reaction is carried out at an elevated temperature, for example, between about 100 and about 210, preferably between about 180 and about 200, and, if desired, in the presence of a transesterification catalyst enhancing the rate of the reaction, such as sodium, potassium, sodium carbonate, potassium carbonate or sodium aluminate, a metal lower alkoxide, e.g. sodium ethoxide or titanium butoxide, or any other analogous reagent. The reaction is usually performed in the absence of an additional solvent and in an excess of the di-substituted carbonate serving as the diluent, but may also be carried out in the presence of a further solvent or solvent mixture, if necessary, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.

Another group R capable of being converted into N- substituted amino-lower alkyloxy is the group of the formula -OC(=O)Z, in which Z represents halogeno or etherified hydroxyl. The group Z is particularly lower alkoxy, e.g. methoxy, ethoxy or n-butoxy, as well as phenoxy or any other analogous etherified hydroxyl group, whereas halogeno, representing Z, is particularly chloro, as well as bromo. Upon reacting a starting material, in Which each of the groups Arf and Ar; is substituted by said group OC(=O)Z, with an N-substituted amino-lower alkanol, particularly an N,N-disubstituted amino-lower alkanol, the compounds of the invention are formed. The reaction is carried out under the previouslydescribed conditions, i.e. at an elevated temperature, preferably between 180 and 200, and, if desired, in the presence of a transesterification reagent, such as one of those previously described; the reaction is preferably performed in the absence of a diluent, but may also be carried out in the presence of a solvent or solvent mixture, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.

A further group R5 capable of being converted into N- substituted amino-lower alkyl-oxy is a reactive esterified hydroxy-lower alkyl-oxy group. The latter is particularly a group of the formula O(C 2n) Y, in which Y and the portion --(C H have the previously-given meaning. The reactive esterified hydroxyl group Y is primarily halogeno, particularly chloro; it may also be a suitable organic sulfonyloxy group, such as one of those mentioned above.

A starting material, in which each of the monocyclic carbocyclic aryl groups An and Ar is substituted by a reactive esterified hydroxy-lower alkyl-oxy group, is reacted with an N-substituted amine, having preferably the formula H-Am, in which Am has the above-given meaning, to yield the desired compound. The reaction is preferably carried out in such manner, that an excess of the amine or of any other suitable acid-neutralizing agent, e.g. potassium carbonate, is present to neutralize the generated acid. If desired, the reaction mixture is diluted with a suitable inert solvent or solvent mixture; if necessary, the reaction is carried out while cooling or at an elevated temperature, and/or in the atmosphere of an inert gas, e.g. nitrogen, and/or in a closed vessel.

The starting material used in the above procedure is known and prepared according to known methods. Thus, a bis-(monocyclic carbocyclic aryl)-sulfide is obtained, for example, by reacting a phenol with sulfur dichloride in the presence of carbon disulfide. In a resulting bis- (monocyclic carbocyclic aryD-suIfide, the thio group may be converted into a sulfinyl group or a sulfonyl group according to known oxidation methods; the oxidation of the thio group into a sulfinyl group is carried out by oxidation with hydrogen peroxide in the presence of glacial acetic acid while cooling, with an organic per-acid, e.g. peracetic, perbenzoic or monoperphthalic acid, at low temperatures, with chromic acid in the presence of acetic acid and under mild conditions, with nitric acid or any other suitable reagent, whereas its conversion into the sulfonyl group is performed by treatment with hydrogen peroxide or organic per-acids at room temperature or preferably at elevated temperatures, with potassium permanganate in the presence of an acid, e.g. acetic or diluted sulfuric acid. Bis-(monocyclic carbocyclic aryl)- sulfoxides may also be obtained by reacting a phenol with aluminum chloride in the presence of carbon disulfide and thionyl chloride, Whereas a bis-(monocyclic carbocyclic aryl)-sulfone may be obtained by reacting the phenol with oleum, i.e. concentrated sulfuric acid containing sulfur trioxide. A resulting bis-(monocyclic carbocyclic aryl)-sulfoxide may be converted into the corresponding sulfide compound by reduction, for example, with zinc and acetic acid or any other suitable reduction procedure.

In a starting material, in which each of the monocyclic carbocyclic aryl groups Ar and Ar is substituted by hydroxyl, the latter may be converted into the group -O-C(=O)Z in which Z has the previously-given meaning, for example, according to any method suitable for the esterification of a phenolic hydroxyl group, such as formation of an alkali metal compound of the phenolic intermediate and reaction of the latter with an ester of the acid of the formula HOC(=O)Z or the halide thereof.

In addition, a starting material Ar -X-Ar in which each of Ar; and Ar is substituted by hydroxyl, the latter may be converted into a reactive esterified hydroxy-lower alkyl-oxy group by treating said starting material or a salt thereof with a corresponding lower alkylene-oxide, a halogeno-lower alkanol or a lower alkylene halide, for example, a chloro-lower alkyl bromide, and, if necessary, converting in a resulting hydroxy-lower alkyloxy compound the hydroxyl group into an esterified hydroxyl group according to known methods, for example, by treatment with a thionyl halide, e.g. thionyl chloride, a phosphorus halide, e.g. phosphorus tribromide or an organic sulfonic acid halide, e.g. mesyl or tosyl chloride, or any other suitable method.

In a resulting compound of the formula Ar -XAr in which Ar Ar and X have the previously-given meaning, a group X may be converted into another group representing X. This conversion is carried out according to known methods, such as those previously described for the starting material, preferably with oxidation reagents that do notfavor the formation of oxidative degradation products or N-oxides.v

A resulting acid addition salt is converted into the free base, for example, by treating it with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate, ammonia or a suitable hydroxyl ion exchange resin.

A resulting acid addition salt can be converted into another salt according to known methods, for example,

by treatment with a suitable anion exchange prepara-'- tion. Furthermore, an acid addition salt, particularly an addition salt with an inorganic acid, may be converted into another acid addition salt, for example, by reacting it with a suitable metal, e.g. sodium, barium or silver, salt. of an acid, preferably'in' the presence of a diluent in which. a resulting inorganic'salt is insoluble and is thus-removed from the reaction medium.

- A free base is converted into. an acid addition salt thereof. according to known methods, for example, by reacting. it one solution thereof in a suitable solvent or solvent mixture with the acid or a solution thereof, or with a suitable anion exchange preparation, and isolating. the desiredsalt. A salt may be. obtained in the formof a hydrate thereof or may include solvent of crystallization.

An N-oxide of the compounds of this invention is prepared; according to known methods, for example, by treating the free base with asuitable N-oxidizing reagent, such as hydrogen peroxide, ozone or a peracid, e.g. peracetic, perbenz-oic, monoperphthalic or' pe-rsulfuric acid, in the presence of a suitable inert diluent. D'uring the'formation of an N-oxide, a thio or a sulfinyl group 'representingthe group X of a resulting compound, maybe converted into sulfinyl and/or sulfonyl, respectively. An- N-oxide is converted into an acid addition salt thereof according to the above procedure.

Quaternary ammonium derivatives of the compounds of this invention are obtained according to known methods,.for example, by reacting the base with the reactive ester ofian alcohol and astrong acid, such as, for example, with one ofthe lower alkyl halides, di-lower alkyl sulfates, lower alkyl organic sulfonates or phenyl-' lower alkyl halides described above. The quaternizing reactionis performed in the presence or absence of a solvent, while cooling or at an elevated temperature, if' necessary, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.

Resulting quaternary ammonium compounds may be converted into other quaternary ammonium compounds, such as the quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternaryammonium salt with a hyd'r'oxyl ion exchange preparation or any other suitable method. A quaternaryammonium hydroxideis: converted into a quaternary ammonium salt by reacting the former with a suitable acid. A quaternary ammonium salt is also converted directly into another quaternary ammonium salt; for example, a quaternary ammonium iodide, when reacted with freshly prepared silver chloride or'with hydrochloric acid in anhydrous methanol, yields the'desired'quaternary ammonium chloride,'.or'a quaternary ammonium salt, when treated with asuitable anion exchange preparation, can be converted into another quaternary ammonium salt. A quaternary ammonium compound may be obtainedin the form of a hydrate thereof or may contain solvent: of crystallization.

A mixtureof: resulting isomeric compounds may be separated: into thesingleisomers. For example, a mixture of diastereoisomers is separated into theindividual racemic' compounds'on the basis of physic-o-chemical differences, such as solubility, for example, by fractional crystallization,-. as well as by fractional distillation. Racemates' are resolved'into' the optically active forms according to known resolution procedures, for example, by forming a salt of the free racemicbasewith one of theoptically active forms of an acid containing an asymmetric. carbon atom. A resulting mixture of salts of the optically active acid with the antipodes of the base racemate' isseparated into the single. salts on the basis of physico-chemical differences, for example, by fractionalcrystallization. From a resulting salt, the free and optically active base is obtained according to the method described above, and a free and optically active base can be converted into its acid addition salt, N-oxide, salt ofan N-oxide'or quaternary ammonium compound according to the procedures described above.

' The invention also comprises any modification of the process wherein a compound formedsasanintermediateat any stage of the process, is used as starting material:

and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting mate-- rials are preferably used which lead to final products mentioned in the beginning as preferred embodiments.

of the invention.

The compounds of this invention are useful in the form of pharmaceutical compositions suitable for enteral, e.g. oral, parental or topical use; essentially, they comprise a pharmacologically effective amount of one of the compounds of this invention in admixture with a: pharmaceutically acceptable, organic or inorganic, solid or liquid carrier, which usually represents the major por-.

tion by weight of such compositions. These peparations are in solid form, for example, as capsules, tablets'or.

dragees, in liquid form, for example, as solutions or suspensions, or in the form of emulsions, e.g. salves or creams. Suitable carrier materials, are, for example,

starches, e.g. corn starch, wheat starch or rice starch, sugars, e.g. lactose, glucose or sucrose, stearic acids or salts thereof, e.g. magnesium stearate or calcium stearate, benzyl alcohol,- stearyl alcohol, cetyl alcohol, petrolatum, talc, gums, acacia, tragacanth, sodium lauryl sulfate, poly 'alkylene glycols or propylene glycol. The quantity and" the nature of the carrier ingredients can'vary widely and depend, inter alia, upon the desired physical appearance or size of the composition or'method of manufacture.

Encapsulation may be effected by using, ifdesired, the.

ture or a granulate. Any compatiblecolor, approved and' certified under the provisions of the Federal Food, 'Drug and Cosmetic Law maybe used for aesthetic purposes or as a means of identification.

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

Example 1 To a solution of 10.8 g. of bis-(4 hydroxy-2fmethyl-5- tert. butyl-phenyl) -sulfide in a mixture of 50 ml. of tolu-- ene and 30 ml. of dimethylformamide is added in portions 2.7 g. of a 53% suspension of sodiumhydride-in mineral oil, while maintaining an atmosphere of nitrogen. After stirring for 10 minutes, a solution of. 8.0 g. of 3-dimethylamino-propyl chloride in toluene, isadded,

and'the reaction mixture is heated to 60 for l' /zhours,v

and then at for 4 /2 hours. After cooling, the in-. organic precipitate is filtered off and the filtrateis concentrated under reduced pressure. The residue is dissolved in diethyl ether, the organic solution is washedwith water, dried and evaporated to dryness. The residue. is

dissolved in ethyl acetate, and the solution containing the bis-[4-(3-dimethylamino-propyl)-oxy-2-methyl 5.. --tert..

butyl-phenyl1-sulfide of the formula acetate, and the resulting crystalline bis-[4-(3-dimethylamino-propyl)-oxy-2-methyl-5-tert. butyl phenyl] sulfide dihydrochloride is filtered off and recrystallizedtwicefrom a mixture of isopropanol and ethyl acetate, M-.P. 209-211-.

Bis- [4-(3-dimetliylamino-propyl)-oxy-2-methyl-5 -'tert. butyl-phenyH-sulfide, when reacted with picric acid or with methyl iodide, yieldsthe bis-[4-(3-dimethylaminopropyl)-oxy-2-methyl-5-tert. butyl-phenyH-sulfide picrate and the bis-[4-(3-dimethylamino-propyl)-oxy-2-methyl-5- tert. butyl-phenyl1-sulfide dimethiodide, respectively.

Example 2 By reacting 10.8 g. of bis-(4-hydroxy-2-methyl-5-tert. butyl-phenyl)-sulfide in a mixture of 50 ml. of toluene and 30 ml. of dimethylformamide with 2.7 g. of a 53% suspension of sodium hydride in mineral oil and then with a solution of 9.8 g. of 1-(2-chloro-ethyl)-piperidine in toluene according to the procedure described in Example 1, yields the bis-[4-(2-piperidino ethyl) oxy 2- methyl-S-tert. butyl-phenyl1-sulfide of the formula 11 0 (HsChN-OHICHiOQS-QO O HrOHnN (CH 3 I l CUT/113): (H0113): is treated with hydrogen chloride in ethyl acetate. The resulting crystalline bis-[4-(2-dimethylamino-ethyl)-oxy- Z-methyl-S-tert. butyl-phenyl1-sulfide dihydrochloride is filtered 0E and recrystallized from a mixture of ethanol and ethyl acetate, M.P. 270-273".

a)a C( a)s which is converted into the dihydrochloride with a solution of hydrogen chloride in ethyl acetate, M.P. 270 (decomposition) after recrystallization from a mixture of ethanol and ethyl acetate.

Example 4 Other compounds of this invention, which are prepared according to the above described and illustrated procedure by selecting the appropriate starting materials, are, for example,

Starting Material Reagents Product Bis-(4-hydroxy-phenyl)-sulfide Z-diethylaminoethyl chloride-l-Nall. .1- (2-ehloroethy1)-pyrrolidine +NaH.

3-dirnethylamino-pr0pyl chlon'de'l-NaH Bis-(2-diethylaminomethyl-3,6-dimethyl-4- hydroxy-phenyD-sulfide.

Bis%1-hydr0xy-2,3,5,6-tetramethyl-phenyD- su c e. Bis-(3-bromo-2-chloro-4-hydroxy-phenyl)-sulfide Bis-(4-hydroxy-2-methyl-5-tertiary butylphenyD-sulfoxide. Bis44-hydroxy-phenyl)-su1fone Bis-(4-hydroxy-2methyl5-tertiary butylphenyD-sulione. Bis-(3,4'dil1ydroxypheuy1)-su1fide 4-(2-chloroethyl) -morpholine+NaH 3-dimethylaminopropyl chloridel-NaH 1(2-chl0r0ethyl) -pip eridine+NaH 2-diethylann'noethyl chloride+NaH 1-(2-ehloroethyl)-4-methylpipera.zine+NaH 3-dimethylaminopropyl chloride-l-NaH 2-dimethylaminoethyl ch1oro+NaH i l-d imethylamino-2chloro-propane +NaH Z-diethylaminoethyl chloride+NaH 3-dimethylaminopropyl chloride+NaH l-(3chl0roethyl) -piperidine-|-NaH 3-dimethylaminopropyl chloride-l-NaH Z-diethylaminoethyl chloride+NaH n-Propylamine 1-(2eh1oroethyl)-pyrrolidine+NaH B Bis-[4-(3-dirnethylamjno-propy1-2)-oxy-2- diethylamino-methyl-3,6-dimethy1-phenyl1- Bis-[4-(3-dimethylamiuo-propyl)-oxy-phenyl]- sulfoxide. Bis-[4-(3-dimethylamino-propyl)-oxy-2-methyl- S-tertiary butyl-phenyH-sulfoxide. Bis-[4-(2-piperidinoethyD-oxy-phenyll-sulfone. Bis-[4-(S-dimethylamino-propyl)-oxy-2-methyl- 5-tertiary butyl-phenylI-sulfone. Bifi-bis-(Z-diethylamino-ethyl)-oxy-phenyl]- Example 3 To a solution of 16.2 g. of bis-(4-hydroxy-2-methyl-5- Example 5 To a mixture of 10.8 g. of bis-(4-hydroxy-2-methyl-5- tert. butyl-phenyl)-sulfide in 45 ml. of dimethylformamide and 75 ml. of toluene is added 4.0 g. of a 53% suspension of sodium hydride in mineral oil while stirring and maintaining an atmosphere of nitrogen, and then a solution of 10.75 g. of '2-dimethylamino-ethyl chloride in toluene. The reaction mixture is stirred for six hours at and is then allowed to stand overnight. After filtering, the solution is concentrated under reduced pressure;

tert. butyl-phenyD-sulfide, 30 ml. of dimethylformamide and 50 ml. of toluene, 2.7 g. of a 53% suspension of sodium hydride in mineral oil is added while stirring and keeping the whole under nitrogen. After stirring for about one hour, 8.95 g. of diethylamino-ethyl chloride, diluted with toluene, is added and the reaction mixture stirred for 6 hours at -80. After cooling, the whole is filtered and the filtrate evaporated under reduced pressure. The

residue is dissolved in ethyl acetate. and the solution.-

residue is taken up in ditliyl ether and water, the 'ethereal' which meltsafter recrystallization fiom' isopropanollayer washed with water, dried and evaporated. The. ethyl acetate at 215-216 mixed with a. solution of hydrogen chloride in ethyl: 'f 9 acetate. The so obtained bis-[4-(2-diethylamino-ethyl)- 2 2 g. of a 5 suspenswmofsodmm hydnde 111 oxy-2-methyl-5-tert. butyl-phenyl1-sulfide dihydrochloride eral oil is-added to a solution of 9.0 g. of bis-(Z-hydroxy,

of the formula 5-methyl-3-tert. butyl-phenyl) sulfide in 25' ml. of di- (EH3 (EH3;

(hem). C(OH is filtered off and recrystallized from methyl ethyl ketoneethyl acetate; M.P. 192-193 methyl-formamide and 45 ml. of toluene and the mixture is stirred for one hour at room temperature and under Example 6 nitrogen. Thereupon a solution of 6.7 g. of 3-dimethyl- Following the procedure shown in Example 5 but subamino-propyl chloride in toluene is added and the prostituting the diethylamino-ethyl chloride by 9.9 g. of 3-dicedure followed as described in Example 5. There is obethylamino-propyl chloride, the bis-[4-(3-diethylaminotained the bis-[2 (3-dimethylamino-propyl)-oxy-5-metliyle propyl)-oxy-2-methyl-5-tert. butyl-phenyH-sulfide dihy- 3- tert. butyl-phenyl] -sulfide dihydrochloride of the drochloride of the formula I formula CH3 CH3 0=He iN(oHe e-o-s0-(om)e-N(on1en -2HC1 is obtained; it melts after recrystallization from isopro- CH3 CH3 panel-ethyl acetate at 178-180. I

Example 7 Substituting in Example 5 the diethylamino-ethyl chlo- (03930 S C(CHQN ride by 10.7 g. of 3-piperidino-propyl chloride and fol- V v lowing the procedure given, the bis-L4- (3 -piperidino- O (CHZ)PN(CH3)I 21101 propyl)-oxy-2-methyl-5-tert.' butyl phenyl] -sulfide dihymelting at 223-225 after recrystallization from isoprodrochloride of the formula panol-ethyl acetate.

CH3 $113 (0He)e0-s--o om)e-Nj -2no1 'K ah C HC Da is obtained; it melts a-fter recrystallization from isopro-- Example 10 peanol at 255458 E l 8 Substituting in Example 9 the starting material by 9.0

ramp e 50 g. of bis-(4-hydroxy-S-methyl-S-tert. butyl phenyl) sul- 2.25 g. of a 53% suspension of sodium hydride in minfide and following the procedure given, the bis-[4-(3-dieral oil is gradually added with stirring to a mixture of methylamino-propyl)-oxy-3-methyl5-tert. butyl-phenylJ- 8.9 g. of bis-(2-hydroxy-3,5-dichloro-phenyl)sulfide, 25 sulfide dihydrochloride of theformula ml. of dimethyleformamide and ml. of toluene kept so melting at 218220, is obtained. under nitrogen. After stirring. for onehour at room temperature a solution of 6.7 g. of B-dimethylamino-propyl Example 11 chloride intoluene isaddedand the whole heated for 8- By r cti n of 10-8 g. of bis-(4-hydroxy-2-methyl-5 hours to 70-80". After cooling, the reaction mixture is terty -ph nyl)- lfide in 30 m1- of dimethyl formamworked up as described in Example 5 in order to obtain ide and ml. of toluene with 2.7 g. of a 53% suspension the bis-[2-(3-dimethylamino-propyl)-oxy 3,5 dichloroof sodium hydride in mineraloilfollowed by 11.7 g. of phenyH-sulfide dihydrochloride of the formul idiethylamino-pentyl chloride in toluene according to the method described in Example 5, thecrude bis-[4-(5- O1 O1 diethylamino pentyl)-oxye2-methyl-5-tert. butyl-phenyl]: l 7O sulfide of the formula CH3 CH3 is obtained. It is converted into its dicitrate by combining an ethereal solution of the crude base with the equivalent amount of citric acid dissolved in ethyl acetate. The dicitrate precipitates and slowly solidifies. It is filtered off and after drying it softens on heating and begins to melt at 105.

Example 12 A solution of 4.7 g. of bis-[4-(3-dimethylamino-propyl)-oxy-2-methyl-5-tert. butyl-phenylJ-sulfide in 25 ml. of methanol is saturated with methyl chloride by bubbling it through the solution for 45 minutes. After standing for 4.5 hours the methanol is removed in vacuo and the residue treated with acetone whereupon it crystallizes. The so obtained bis-[4-(3-dimethylamino-propyl)oxy-2- methyl-S-tert. butyl-phenylJ-sulfide dimet-ho chloride of the formula in which X is a member selected from the group consisting of thio, sulfinyl and sulfonyl, each of Ar and Ar is a member selected from the group consisting of phenylene and phenylene substituted by at most 2 members selected from the group consisting of lower alkyl and halogeno, each of C H and C H is lower alkylene with 2 to 7 carbon atoms and separating the groups Am from the oxygen atoms by at least two carbon atoms and each of Arm and Am is a member selected from the group consisting of lower alkylamino, di-lower alkylamino, cycloalkylamino, cycloalkyl-lower alkylamino and N-cycloalkyl-N-lower alkylamino in which cycloalkyl has 3 to 7 ring-carbon atoms, N-lower alkyl-N-phenyl-lower alkylamino, N-hydroXy-lower alkyl-N-lower alkylamino, N,N- di- (hydroXy-lower alkyl)-amino, alkyleneimino with 4 to 8 carbon atoms, piperazino, 4-lower alkyl-piperazino, 4- morpholino and 4-thiarnorpholino, or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutical carrier.

2. A composition as claimed in claim 1, wherein the active ingredient is the compound having the formula a)s (C a)s is filtered off and dried; it melts at 253-255 Example 14 To a solution of 6.2 g. of bis-(4-hydroXy-phenyl)- sulfone in 25 ml. of dimethylformamide and 45 ml. of toluene, 2.25 g. of a 53% suspension of sodium hydride is stirred in under nitrogen and stirring is continued for one hour at room temperature. Thereupon a solution of 6.7 g. of 3-dimethylamino-propyl chloride in 50 ml. of toluene is added and the reaction mixture stirred for 18 hours at 70 to 80. It is then filtered, concentrated under reduced pressure, the residue taken up in diethyl ether, the solution washed twice with water, dried and evaporated in vacuo. The residue is dissolved in ethyl acetate and mixed with a solution of hydrogen chloride in ethyl acetate. The precipitated bis-[4-(3-dimethylamino-propyl)-0Xy-pheny1]-sulfone dihydrochloride of the formula in which X is a member selected from the group consisting of thio, sulfinyl and sulfonyl, Am is a member selected from the group consisting of di-lower alkylamino, a kyleneimino in which alkylene has from four to seven carbon atoms, 4-morpholino and 4-l0wer alkylpiperazino, the portion (C H stands for alkylene having from two to five carbon atoms and separates the group Am from the oxygen atom by at least two carbon atoms, and each of the groups R and R is a member selected from the group consisting of hydrogen, lower alkyl and halogeno, or a pharmaceutically acceptable acid addition salt thereof.

3. A composition as claimed in claim 1, wherein the is filtered off and recrystallized twice from ethanolacetone; M.P. 216-218.

Example 15 Preparation of 500 capsules each containing 0.50 g. of the active ingredient.

INGREDIENTS AND PROCEDURE G. Bis [4 (3 dimethylamino propyl) oxy 2- methyl 5 tert. butyl phenyl]-sulfide dihydrochloride 250.00 Lactose 65.00 Magnesium stearate 10.00

The ingredients are blended in a suitable mixer, sieved through a No. 40 screen and again mixed. Portions weighing 0.65 g. each of the resulting mixture are filled into No. 0 capsules.

What is claimed is:

1. A pharmaceutical composition comprising essentially a pharmacologically efiective amount of a compound having the formula active ingredient is the compound having the formula Ra Ra Rb b Burger Medicinal Chemistry, 2nd ed., p. 497, 1960.

ALBERT T. MEYERS, Primary Examiner.

JULIAN S. LEVITT, Examiner.

L. B. RANDALL, Assistant Examiner.

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5085410 *Dec 14, 1989Feb 4, 1992Jersey Nuclear-Avco Isotopes, Inc.Modular processing system
US5185757 *Oct 8, 1991Feb 9, 1993Jersey Nuclear-Avco Isotopes, Inc.Modularized replaceable vaporizer and extractor apparatus
US6646012Jan 15, 2002Nov 11, 2003Theravance, Inc.Central nervous system analgesic; hypotensive agents; antiarrhythmia agents; antidiabetic agents
US6756400Aug 30, 2001Jun 29, 2004Theravance, Inc.Diaromatic compound containing 2-amine groups, useful for treating neuropathic pain
US7183323Apr 15, 2004Feb 27, 2007Theravance, Inc.Sodium channel modulators
WO2002018334A2 *Aug 30, 2001Mar 7, 2002Advanced Medicine IncSodium channel modulators
Classifications
U.S. Classification514/651, 514/252.11, 514/253.1, 514/227.8, 514/254.1, 514/237.8
International ClassificationC07C291/04, C07D233/22, C07D295/092, A61K31/135
Cooperative ClassificationC07D295/088, C07C291/04, A61K31/135, C07D233/22
European ClassificationC07D233/22, C07C291/04, C07D295/088, A61K31/135