Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
  • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
  • C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D233/22—Radicals substituted by oxygen atoms

Definitions

• 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.
• alkyl 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.
• 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
• 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.
• 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.
• substituents are organic groups having preferably from one to ten carbon atoms.
• groups are, for example, aliphatic radicals, especially lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl,
• 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.
• hydroxy-lower alkyl e.g. 2-hydroxyethyl
• lower alkoxy-lower alkyl e.g. 2-methoxyethy1 or 2-ethoxyethyl
• N-monosubstituted amino groups 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 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,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.
• 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.
• 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.
• 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
• quaternary ammonium compounds include 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.
• 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
• the above starting material is represented by the formula Ar X-Ar in which X and Ar has the previously-given meaning.
• a particularly suitable group representing Re is hydroxyl; its conversion into N-substituted amino-lower alkyl-oxy is carried out according to known procedures.
• 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.
• a strong mineral acid such as a hydrohalic acid, e.g. hydrochloric or hydrobromic acid.
• 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.
• the starting material is preferably used in the form of a salt thereof.
• 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
• 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.
• 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.
• a hydrocarbon e.g. hexane, benzene, toluene or xylene
• an ether e.g. diethyl ether, p-dioxane, tetrahydrofuran or diethyleneglycol
• a carboxylic acid amide e.g. dimethylformamide
• 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.
• 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.
• an N-substituted amino-lower alkanol particularly an N,N disubstituted amino-lower alkanol
• a disubstituted carbonate 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.
• 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.
• the reaction is carried out under the previouslydescribed conditions, i.e.
• 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.
• 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.
• 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.
• a bis-(monocyclic carbocyclic aryl)-sulfide is obtained, for example, by reacting a phenol with sulfur dichloride in the presence of carbon disulfide.
• 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.
• each of the monocyclic carbocyclic aryl groups Ar and Ar is substituted by hydroxyl
• a starting material Ar -X-Ar in which each of Ar; and Ar is substituted by hydroxyl 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.
• a phosphorus halide e.g. phosphorus tribromide
• an organic sulfonic acid halide e.g. mesyl or tosyl chloride, or any other suitable method.
• 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.
• 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,
• an acid addition salt particularly an addition salt with an inorganic acid
• a suitable metal e.g. sodium, barium or silver
• 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.
• 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.
• a suitable N-oxidizing reagent such as hydrogen peroxide, ozone or a peracid, e.g. peracetic, perbenz-oic, monoperphthalic or' pe-rsulfuric acid
• 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 reaction is 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.
• 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 hydroxide is: 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.
• 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.
• 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:
• 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-.
• compositions tion by weight of such compositions.
• 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.
• 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
• Encapsulation may be effected by using, ifdesired, the.
• 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.
• 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,
• 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-.
• 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".
• 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,
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

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• 1964
  • 1964-12-14 US US418279A patent/US3340146A/en not_active Expired - Lifetime
• 1965
  • 1965-04-22 US US450176A patent/US3332958A/en not_active Expired - Lifetime
  • 1965-04-26 BE BE663009A patent/BE663009A/xx unknown
  • 1965-04-26 NL NL6505310A patent/NL6505310A/xx unknown
  • 1965-07-01 FR FR23079A patent/FR4486M/fr not_active Expired
  • 1965-07-01 FR FR23078A patent/FR4641M/fr not_active Expired

Non-Patent Citations (1)

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