US3238199A - Phenothiazine compounds - Google Patents

Description

United States Patent 3,238,199 PHENOTHIAZINE COMPOUNDS Leo Berger, Montclair, Alfred John Corraz, Packanack Lake, and John Lee, Montclair, NJ., assignors to Hoffmann-La Roche Inc, Nutley, NJ., a corporation of New Jersey N0 Drawing. Filed Feb. 27, 1961, Ser. No. 91,603 Claims. (Cl. 260-243) 2: This invention relates to novel phenothiazine compounds which have utility as medicinal agents. The phenothiazine compounds of the invention are characterized by a side chain in the l0-position which, in addition to having an ether linkage, also contains a nitrogen atom. More specifically, the compounds of the invention are of the formula wherein n is a whole integer from 1 to 2; R is selected from the group consisting of hydrogen, halogen, and trifluoromethyl; A and B can be the same or different and are selected from the group consisting of straight and branched chain lower alkylene radicals; and R and R are selected from the group consisting of lower alkyl and, taken together with the nitrogen ring, a 5 to 6 membered heterocyclic ring containing 1 to 2 nitrogen atoms and a lower alkyl substituted 5 to 6 membered heterocyclic ring containing 1 to 2 nitrogen atoms.

As used in this disclosure, the term straight or branched chain lower alkylene refers to such radicals as and the like. 5 to 6 membered heterocyclic rings containing 1 to 2 nitrogen atoms are illustrated by radicals such as piperazinyl, pyrrolidyl, and the like and lower alkyl substituted 5 to 6 membered heterocyclic rings containing l to 2 nitrogen atoms are, for example, 4-methyll-piperazinyl and the like.

The compounds corresponding to Formula I above are basic in character and form acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sul- F fomc acid, toluene sulfomc ac1d, acetic acid, succimc acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, oxalic acid, and the like. These medicinally acceptable acid addition salts are part of the invention.

Side chains Within the scope of the invention, conforming to the grouping Patented Mar. 1, 1966 the invention are those under Formula I above wherein A represents the group Especially preferred are those compounds wherein R and R taken together with the nitrogen atom, represent 4-methyl-1-piperazinyl. Also preferred are those compounds wherein R is trifiuoromethyl.

The novel compounds of the invention can be made by several different methods. One method comprises reacting an alkali metal salt of a 10-hydroxy-lower alkylene-phcnothiazine with a tertiary amino-lower alkylhalide to yield a IO-tertiary amino-lower alkyleneoxylower alkylene-phenothiazine. Another method comprises reacting a l0-halo-lower alkylene-phenothiazine with a tertiary amino-lower alkanol, in the presence of an alkali metal, such as sodium, to yield the desired product corresponding to Formula I above.

The compounds of the invention are valuable medicinal agents, having utility as anti-emetic agents. They can also be used as central nervous system depressants and as potentiators of barbiturate hypnosis. They can be administered internally, with dosages adjusted to individual requirements, either as the free base or as a medicinally acceptable acid addition salt. They can be compounded into conventional pharmaceutical forms such as capsules, .tablets, suspensions, solutions and the like.

The following examples are illustrative of the invention but not limitative thereof. All temperatures are in degrees centigrade.

Example 1 A mixture of 150 ml. of dry toluene, 11.6 g. of sodium amide, and 60 g. of phenothiazine was refluxed and stirred for 16 hours, and the reaction mixture then cooled to 60. 26.1 g. of propylene oxide, dissolved in 150 ml. of dry toluene, was added to the stirring mixture at such a rate as to maintain the temperature near 60. When the addition had been completed, the reaction mixture was heated to reflux. After 2 hours of refluxing and stirring, the reaction mixture was allowed to cool to room temperature and then washed three times with 100 ml. of water and dried over sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under vacuum on a water bath to a viscous residue. The residue was distilled at reduced pressure to give l0-(2 hydroxypropyl)-phenothiazine as a viscous, light yellow oil; B.P. 161-163 at 0.03 mm.

Example 2 220 g. 2-trifiuoromethylphenothiazine was added rapidly to a fine suspension of 20 g. of sodium in 1200 ml. of dry toluene. While stirring, the mixture was carefully heated to reflux temperature. After 6 hours at reflux with stirring most of the sodium had reacted, and the mixture was cooled to 80 g. of propylene oxide in ml. toluene was added slowly with stirring at such a rate that reaction temperature was maintained around 80. With the last third of the addition, external heating had to be used to maintain 80. After the addition was completed, the reaction mixture was heated with stirring to 100 and held at that temperature for an additional 2 /2 hours. For approximately 18 hours, the reaction mixture Was allowed to remain at room temperature. It was then cooled to +10 with stirring and 60 ml. of ethanol added, followed by 300 ml. of water and 500 ml. of ether. The organic portion was separated, washed with 300 ml. of water 5 times, and the solvent layer separated again and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate concentrated to dryness on a water bath at reduced pressure and the residue was 3 distilled yielding Z-trifluoromethyl-l-(2-hydroxypropyl) phenothiazine, B.P. 172-175/0.2 mm.

2-chloro-10-(Z-hydroxypropyl)phenothiazine, 10 (2- hydroxyethyl)phenothiazine, and 2-chloro-10-(2-hydroxyethyl) phenothiazine were also made by the procedure illustrated in Examples 1 and 2 above.

Example 3 A mixture of 100 ml. of dry toluene, 20 g. of 10-(2-hydroxyethyl)phenothiazine, and 1.9 g. sodium was refluxed and stirred until all the sodium had reacted, ca. 3 hours. 8.7 g. of dimethylaminoethyl chloride in 50 ml. of dry toluene was added dropwise at reflux temperature. After the addition was complete, the reaction mixture was refluxed and stirred for an additional 13 hours, cooled to room temperature, and filtered. The filtrate was extracted with dilute hydrochloric acid. In turn, the acid extract was washed two times with ether and then saturated with potassium carbonate. The alkaline mixture was then extracted with chloroform. When the chloroform extract had been dried over sodium sulfate for 24 hours, it was filtered and the filtrate was concentrated to a syrupy residue under vacuum. The residue was distilled at reduced pressure to give l0-[2-(Z-dimethylaminoethoxy) ethyllphenothi-azine as a viscous oil; BrP. 191-199 at 0.15 mm.

The product was made into an oxalate by dissolving it in ether and adding an excess of an ether-oxalic acid solution. The precipitate formed was crystallized from isopropyl alcohol, M.P. 9496.

Example 4 1.0 g. of sodium was added to a solution of 10.6 g. of 10-(2-hydroxyethyl)phenothiazine dissolved in 100 ml. of dry toluene. The mixture was refluxed and stirred until all the sodium had reacted, ca. 2 hours. 7.0 g. of diethylaminoethylchloride in 50 ml. of dry toluene was added dropwise at reflux temperature, with stirring. After the addition was completed, the reaction was refluxed and stirred for an additional 6 hours, cooled to room temperature and filtered. The filtrate was concentrated to dryness and the residue was dissolved in 300 ml. of ether. Dry hydrogen chloride was bubbled into the solution. The supernatant mother liquor was decanted and the oily residue was washed 3 times with ether, then was dissolved in water and the resulting solution saturated with potassium carbonate and extracted with chloroform. When the chloroform extract had dried over sodium sulfate, it was filtered and concentrated. The residue was distilled at reduced pressure to give 10-[2-(Z-diethylaminoethoxy)ethyl]phenothiazine as a yellow viscous oil; B.P. 193221 at 0.1 mm.

A citrate was made by dissolving the distillate in ether and adding a slight excess of a concentrated citric acidalcohol solution. The precipitate was collected and crystallized from acetone and ether, M.P. 6768.

Example 20 g. N-(Z-hydroxyethyl)-N'-methyl-piperazine was added dropwise, very slowly, to 100 ml. of stirring thionyl chloride. After the addition was complete, the reaction was heated cautiously to reflux and held there for 1 hour. The excess thionyl chloride was removed under vacuum on a water bath. 200 ml. of water was carefully added, with stirring, to the residue. The solution was then cooled, saturated with potassium carbonate, and extracted with ether. After the ether solution had dried over sodium sulfate for several hours, it was filtered and the filtrate concentrated under vacuum on a water bath. The residue was dissolved in 50 ml. of dry toluene and the solution was added to a refluxing and stirring mixture of 16.3 g. of the sodium salt of -(2-hydroxyethyl)phenothiazine in 100 ml. of dry toluene. After the reaction had refluxed and stirred for 16 hours, it was cooled to room temperature and washed by extraction with water. The

reaction was then extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether and saturated with potassium carbonate. The alkaline mixture that formed was then extracted with ether. After the ether solution had been dried over sodium sulfate, it was filtered, and a slight excess of an ether solution of maleic acid was added. The precipitate was filtered and recrystallized from ethanol to give 10-{2-[2*(4-methyl1- piperazinyl)ethoxy]ethyl}phenothiazine dimaleate, M.P. l64-166 (uncorr.).

Example 6 Phenyl lithium was prepared from 50 g. of brornobenzene and 4.2 g. of lithium wire in 300 cc. of dry ether; 53.7 g. of phenothiazine was then added. The mixture was stirred at room temperature for 1 hour and ether then added to thin the thick mixture which was then cooled with ice-water. When cool 67.0 g. of 3-chloro-n-propy1-ptoluene sulfonate in cc. ether was added. Upon completion of the addition, the reaction mixture was heated toreflux for 2 hours and then cooled, reacted with cold water, and the ether solution separated after washing with water. The ether solution was then dried and concentrated to dryness and the residue crystallized with ethanol to give 10-(3-ch-loropropyDphenothiazine as crystals melting at 63-64".

Example 7 5.9 g. of diethylarn-inoethanol was reacted with 1.2 g. sodium shot in 100 cc. of dry toluene under reflux. 13.7 g. of 3-chloropropylphenothiazine in 50 cc. of warm toluene was then added and the mixture stirred under reflux for 24 hours, cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether and then saturated with potassium carbonate. The product was isolated by extracting the aqueous mixture with chloroform. After the chloroform solution had been dried over potassium carbonate, it was filtered and concentrated under vacuum on a water bath to a viscous oil, which was then distilled to give the product, 10-[3- Z-diethylaminoethoxy)propyl]phenothiazine, as an oil boiling at 200/.02 mm. Conversion to a citrate salt in alcohol-ether, yielded crystals which, after further recrystallization from acetone, melted at 8890.

Example 8 4.5 g. of dimethylaminoethanol was added to 1.2 g. of sodium shot in 100 cc. of dry toluene and the mixture refluxed until the sodium had reacted. To this suspension was added 13.7 g. of 3-chloropropylphenothiazine in 500 cc. of dry toluene and the mixture stirred and refluxed for 24 hours. Alcohol and water were then added and basic material separated with hydrochloric acid solution. The acid solution was made basic and the oil that separated was dissolved in chloroform, Washed with water, the chloroform layer separated and dried. The resulting dried chloroform solution was concentrated to dryness and the residue distilled. An oil boiling at 196/ 0.03 mm. was collected which was dissolved in acetone and converted to a hydrochloride with alcoholic hydrochloric acid. Ether was added to induce crystallization. Crystals of 10[3-(Z-dimethylaminoethoxy)propyl]phenothiazine hydrochloride were obtained.

Example 9 7.2 g. of 1-methyl-4-hydroxyethyl-piperazine was reacted With 1.2 g. of sodium shot in 100 cc. of boiling toluene. 13.7 g. of 3-chloropropylphenothiazine in 50 cc. warm toluene was added and the mixture refluxed and stirred for 24 hours, then cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid, and the acid extract washed with ether and saturated With potassium carbonate. The product was isolated by extracting the aqueous mixture with chlo roform. After the chloroform solution had been dried over potassium carbonate, it was filtered and concentrated under vacuum on a water bath to a thick syrup that did not distill at 0.08 mm. This thick basic residue was converted to a hydrochloride salt in alcohol with alcoholic hydrochloric acid and recrystallized from ethyl acetate-methanol, yielding crystals of -{3-[2-(4-methyll-piperazinyl) ethoxy] propyl}ph-enothiazine dihydrochloride melting at 201202.

Example 10 3.3 g. of diethylaminopropanol was added to 0.06 g. of sodium in 100 cc. of dry toluene and the mixture refluxed until all the sodium had reacted. 6.9 g. of 3- chloropropylphenothiazine in 20 cc. of warm toluene was then added and the mixture stirred and refluxed for 24 hours. 100 cc. of ethanol was then added and the basic oil was extracted with 6 N hydrochloric acid. The acid layer was separated, made basic with excess potassium carbonate, and the basic oil extracted with ether. The ether solution was washed with water, dried, and concentrated to dryness. The thick residue was converted to the citrate, 10-[3-(3-diethylaminopropoxy)propyl]phenothiazine citrate, in alcohol and acetone, and recrystallized from acetone to give crystals melting at 76.

Example 11 5.7 g. of dimethylaminoethoxyethanol was added to 1.2 g. of sodium shot in 100 cc. of dry toluene and the mixture was refluxed until all the sodium had reacted. 13.7 g. of 3-chloropropylphenothiazine in 50 cc. of warm toluene was then added and the mixture stirred under reflux for 8 hours, cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid and the acid extract washed with ether and then saturated with potassium carbonate. The product was isolated by extracting the aqueous mixture with chloro form. After the chloroform solution had been dried over potassium carbonate, it was filtered and concentrated under vacuum on a water bath to a viscous oil, which was distilled to yield an oil boiling at 205207/0.07 mm. This basic oil was converted to a hydrochloride salt with alcoholic hydrochloric acid and recrystallized from ethyl acetate-methanol to yield crystals of 10-{3-[2-(2- dimethylaminoethoxy)ethoxy]propyl}phenothiazine hydrochloride melting at 122.5-123 Example 12 8.1 g. of diethylaminoethoxyethanol was added to 1.2 g. of sodium shot in 100 cc. of dry toluene and the mixture refluxed until all the sodium had reacted. 13.7 g. of 3-chloropropylphenothiazine in 50 cc. of warm toluene was then added and the mixture stirred and refluxed for 8 hours, then cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid and the acid extract washed with ether and then saturated with potassium carbonate. The product was isolated by extracting the aqueous mixture with chloroform. After the chloroform solution had been dried over potassium carbonate, it was filtered and concentrated under vacuum on a water bath to a viscous oil, which was then distilled in vacuum yielding, as a thick oil boiling at 2l2219/0.08 mm., l0{3-[2-(2-diethylaminoethoxy)ethoxy] propyl}pher1othiazine citrate, which gave an amorphous hydrochloride. A crystalline citrate was prepared and when recrystallized from acetone, crystals of the citrate melting at 98l00 were obtained.

Example 13 1.0 g. of sodium was added to a solution of 11.0 g. of 10-(2-hydroxypropyl)phenothiazine in 100 ml. of dry toluene. All the sodium had reacted after the solution had been stirred and refluxed for 1 hour. 5.0 g. of freshly distilled dimethylaminoethylchloride in 50 ml. of dry toluene was then added dropwise, with stirring, at

reflux temperature. The reaction mixture was then stirred and refluxed for an additional 18 hours, cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether and then saturated with potassium carbonate. The product was isolated by extracting the aqueous mixture with chloroform. After the chloroform solution had been dried over potassium carbonate, it was filtered and concentrated under vacuum on a water bath to a viscous oil. The oil was then distilled under vacuum to give 10-[2-(2-dimethylaminoethoxy)propyl]phenothiazine as a viscous light yellow oil; B.P. 190192 at 0.15 mm. An oxalate was made of the product by dissolving the oil in ether and adding a slight excess of an oxalic acid-ether solution. The precipitate that formed was recrystallized from acetone and ether.

Example 14 0.9 g. of sodium was added to a solution of 10 g. of 10-(2-hydroxypropyl)phenothiazine dissolved in ml. of dry toluene. The mixture was refluxed and stirred until all the sodium had reacted, ca. 2 hours. 6 g. of freshly distilled diethylaminoethylchloride dissolved in 100 ml. dry toluene was added dropwise at reflux temperature. After this addition, the reaction mixture was refluxed for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was filtered. The filtrate was concentrated under vacuum on a water bath to a viscous oil, which was distilled; B.P. 187-192" at 0.07 mm., yielding 10[2-(2-diethylaminoethoxy)propyl]-phenothiazine as a light yellow, viscous oil. A solid product was prepared by dissolving the base in ether and adding a slight excess of a concentrated alcoholic solution of citric acid. The citrate was crystallized 2 times from acetone and ether.

Example 15 20.0 g. N-(Z-hydroxyethyl)-N-methyl-piperazine was added dropwise, very slowly at 100 ml. of stirring thionylchloride. After the addition was completed, the reaction was heated cautiously to reflux and held there for 1 hour. The excess thionylchloride was removed under vacuum on a water bath. 200 ml. of water was carefully added, with stirring, to the residue. The solution was then cooled, saturated with potassium carbonate, and extracted with ether. After the ether solution had been dried several hours over sodium sulfate, it was filtered and concentrated, under vacuum, on a water bath. The syrupy residue was dissolved in 50 ml. of dry toluene, and the resulting solution added to a refluxing and stirring mixture of 100 ml. of dry toluene and 11.0 g. of the sodium salt of 10-(2-hydroxypropyl)phenothiazine, previously made by reacting stoichiometric amounts of metallic sodium and 10-(2-hydroxypropyl)phenothiazine in dry toluene. When the reaction mixture had refluxed and stirred 8 hours, it was cooled to room temperature and washed with water. The organic portion was then extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether and saturated with potassium carbonate. The product was collected by extracting the aqueous mixture with ether. After the ether solution had dried over sodium sulfate, it was filtered and concentrated under vacuum on a water bath, to a viscous residue. The crude product was dissolved in dry ethanol, boiled with charcoal and filtered. A slight excess of a citric acid-ethanol solution was added. 'In order to induce precipitation, several volumes of ether were added. The precipitate that formed was filtered off and recrystallized from isopropanol yielding 10-{2-[2-(4-methyl-1-piperazinyl)ethoxy]propyl}phenothiazine citrate, M.P. 87-89 (uncorr.).

Example 16 0.9 g. of sodium was reacted at reflux temperature with 11.4 g. of 2 chloro 10(2 hydroxyethyl)phenothiazine that had been dissolved in 100 cc. of dry toluene. The reaction mixture was refluxed and stirred until all the sodium had reacted, ca. 3 hours. 6.0 g. of diethylaminoethylchloride dissolved in 20 ml. of dry toluene was added dropwise, with stirring, at reflux temperature. After the addition was complete, the reaction mixture was refluxed and stirred for an additional 8 hours, cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid. In turn, the acid fraction was washed with ether and saturated with potassium carbonate. The product was collected by extracting the aqueous mixture with chloroform. After the ether solution had been dried over potassium carbonate, it was filtered and concentrated under vacuum to an oily residue. The oil was distilled at reduced pressure to give 2-chloro-l0- [2-(2-diethylaminoethoxy)ethyl]phenothiazine as a light yellow, viscous oil; B.P. 210214 at 0.15 mm.

A citrate of the reaction product was made by dissolving the distillate in ether and adding a slight excess of a concentrated citric acid-alcohol solution. The precipitate was collected on a filter and crystallized from acetone and ether yielding the crystals of the citrate salt.

Example 1 7 3.8 g. of dimethylaminoethanol was dissolved in 50 ml. of dry toluene. To this solution 1.0 g. of sodium was added. The mixture was refluxed and stirred until all the sodium had reacted, ca. 2 hours. Following the introduction of 15 g. of crude 2-chloro-10-(3-chloropropyl)- phenothiazine dissolved in 50 cc. of dry toluene, the reaction mixture was refluxed and stirred for an additional 16 hours and then allowed to cool to room temperature. 200 ml. of benzene was added and the resulting mixture washed 2 times with water. The organic portion was then extracted with dilute hydrochloric acid. In turn, the acid fraction was washed with ether and then saturated with potassium carbonate. The product was collected by extracting the aqueous mixture with chloroform. After the chloroform solution had been dried over sodium sulfate, it was filtered and concentrated under vacuum on a water bath to a viscous residue. The residue was distilled at reduced pressure to give 2-chloro-l0- [3 (2 dimethylaminoethoxy)propyl]phenothiazine as a viscous oil; B.P. 175200/-0.2 mm. A citrate was made from the product by dissolving the oil in ether and adding a slight excess of a citric acid-alcohol solution. The precipitate formed was crystallized from acetone.

Example 18 g. of 2-chlorophenothiazine was dissolved in 100 m1. of dry toluene. To this solution 4.0 g. of sodium amide was added. The mixture was refluxed and stirred for 6 hours. 10 g. of trimethylenebromochloride was added. The reaction was again allowed to reflux and was stirred for an additional 6 hours. When the reaction had cooled to room temperature, 10 ml. of ethanol was added with stirring followed by 200 ml. of Water and 100 ml. of benzene. The organic layer was separated and washed with water. After the chloropropylphenothiazine solution had dried over sodium sulfate, it was filtered and concentrated to a syrup. The syrup residue was, in turn, dissolved in 50 ml. of dry toluene and added, at a reflux temperature, to a stirring mixture of 8.0 g. of the sodium salt of N-(2-hydroxyethyl)-N-methylpiperazine previously made by reacting stoichiometric amounts of metallic sodium and N-(Z-hydroxyethyl)-N'-methylpiperazine in refluxing dry toluene. After the reaction mixture had stirred and refluxed for 10 hours it was cooled to room temperature. 5.0 ml. of ethanol was then added with stirring followed by 100 ml. of water and 200 ml. of ether. The organic layer was separated and washed with water. It was then extracted with dilute hydrochloric acid. The acid portion was, in turn, saturated with potassium carbonate and the product collected by an ether extraction. After the ether solution had dried over sodium sulfate, it was filtered and concentrated. The filtrate was distilled at reduced pressure to give 2-chloro- 10 {3 [2 (4 methyl 1 piperazinyl)ethoxy1propyl} phenothiazine as a viscous oil; B.P. 120-122" at 0.35 mm.; however, there was considerable decomposition during the distillation. The crude oil was then dissolved in ether and a slight excess of a citric acid-alcohol solution was added. The product formed was crystallized from acetone, M.P. 120122 (uncorr.).

Example 19 10.0 g. of 2-chloro-1-(Z-hydroxypropyl)phenothiazine was dissolved in ml. of dry toluene. To this solution, 0.8 g. of sodium was added. The mixture was refluxed and stirred until all the sodium had reacted, ca. 3 hours. 7.0 g. of dimethylaminoethylchloride dissolved in 50 ml. of dry toluene was added dropwise, with stirring, to the refluxing reaction mixture. After all the dimethylaminoethylchloride had been introduced, the reaction was refluxed and stirred for an additional 11 hours, cooled to room temperature and filtered. The filtrate was extracted with dilute hydrochloric acid. In turn, the acid fraction was washed with ether and then saturated with potassium carbonate. The product was collected by extracting the aqueous mixture with ether. After the ether solution had been dried over potassium carbonate, it was filtered and the filtrate was concentrated under vacuum to give a viscous residue. The residue was distilled at reduced pressure to give 2-chloro-l0-[2-(Z-dimethylaminoethoxy) propyllphenothiazine as a viscous yellow oil; B.P. 191- 200 at 0.08 mm. A citrate was made by dissolving the oil in ether and adding a slight excess of a citric acidalcohol solution. The precipitate that formed was crystallized from acetone; M.P. 9395 (uncorr.).

Example 20 15.0 of 2-chloro-l0-(2-hydroxypropyl)phenothiazine was dissolved in 70.0 ml. of dry toluene. To this solution 2.0 g. of sodium amide was added. The resulting mixture was refluxed and stirred for 2 hours. Then, 23.6 g. of N-(Z-chloroethyl)- I'-methylpiperazine was added with stirring at reflux temperature. After the reaction had refluxed and stirred for 7 hours, it was allowed to cool to room temperature. 200 ml. of water followed by 300 ml. of ether was added to the stirring mixture. The organic portion was separated and extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether and saturated with potassium carbonate. The product was collected by extracting the alkaline mixture with ether. After the ether solution had dried over po tassium carbonate, it was filtered and concentrated under vacuum, on a water bath, to a syrup. The syrup was distilled at reduced pressure to give 2-chloro-l0{2-[2-(4- methyl-l-piperazinyl)ethoxy]propyl}phenothiazine as a light yellow viscous oil; B.P. 200-220 at 0.3 mm. A hydrochloride was made by dissolving the base in ether and saturating the ether solution with dry hydrochloride. The precipitate was crystallized from a combination of methanol and ethyl acetate and gave the hydrochloride salt; M.P. 239-240 (uncorr.).

The N-(2-chloroethyl)-N-methylpiperazine used above was made by reacting 25.0 g. of N-(2-hydroxyethyl)-N'- methylpiperazine hydrochloride in a 100 ml. of refluxing thionyl chloride. The excess thionyl chloride was removed under vacuum, on a water bath, and the residue was dissolved in 100 ml. of water, saturated with potassium carbonate, and extracted with ether. After the ether solution had dried over sodium sulfate for several hours, it was filtered and concentrated, yielding N-(2- chloroethyl)-N-methylpiperazine as a syrup.

Example 21 12.0 g. of 2-chloro-l0-(2-hydroxypropyl)phenothiazine was dissolved in 100 cc. of dry toluene. To this solution 1.7 g. of sodium amide Was added. After the reaction mixture had stirred and refluxed for 2 hours, 10.0 g. of dimethylarninoisopropylchloride dissolved in 25.0 ml. of dry toluene was added dropwise at reflux temperature. When the reaction had refluxed and stirred an additional 10 hours, it was allowed to cool to room temperature. 20.0 ml. of ethanol was added with stirring, followed by 200 ml. of water and 200 ml. of ether. The organic layer was separated, washed with ether and extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether and then saturated with potassium carbonate. The product was collected by extracting the aqueous mixture with ether. After the ether solution had dried over potassium carbonate, it was filtered and concentrated under vacuum, on a water bath, to a viscous residue. The residue was distilled at reduced pressure to give 2-chloro-10-[2-(Z-dimethylaminoisopropoxy)propyl]phenothiazine as a viscous oil; B.P. 202- 207 at 0.2 mm. A citrate was made by dissolving the base in ether and adding a slight excess of a citric acidalcohol solution. The precipitate was crystallized by dissolving it in acetone, filtering, and adding several volumes of ethyl acetate; M.P. 7879 (uncorr.).

Example 22 0.85 g. of sodium was added to a solution of 11.2 g. of Z-trifluoromethyl-10-(2-hydroxypropyl)phenothiazine in 50 ml. of dry toluene. The mixture was refluxed and stirred until all the sodium had reacted, ca. 13 hours. Then, 25 g. of N-(2-chloroethyl)-N'-methylpiperazine (made by reacting 44 g. N-(Z-hydroxyethyl)-N'-methylpiperazine hydrochloride with 200 ml. of thionyl chloride at reflux temperature), in 50 ml, of dry toluene, was added at reflux temperature with stirring. The reaction mixture was refluxed and stirred an additional 10 hours. After the reaction had cooled to room temperature, 20 ml. of ethanol was added with stirring, followed by 200 ml. of water and 300 m1. of benzene. The organic portion was separated and in turn washed two times with 100 ml. of water and then extracted with dilute hydrochloric acid. The acid extract was washed once with ether and then saturated with potassium carbonate. Finally, the alkaline mixture was extracted with ether. After the ether solution had dried over sodium sulfate, it was filtered and concentrated. The residue was distilled at reduced pressure to give Z-trifluoromethyl-lO-{Z- [2-(4-methyl-1-piperazinyl) ethoxy]propyl}phenothiazine, B.P. 185190 at 0.25 mm.

A citrate was made by dissolving the base in ether and adding a slight excess of an alcoholic solution of citric acid. The precipitate was crystallized from acetone yielding crystals of the salt melting at 150-152 (uncorr.).

Example 23 N-(Z-chloroethyl)pyrrolidine was made by reacting 67 g. of N-(2-hydroxyethyl)pyrrolidine hydrochloride in 200 ml. of refluxing thionyl chloride. The excess thionyl chloride was removed under vacuum on a water bath. The residue was dissolved in 200 ml. of water plus 100 g. of ice, saturated with potassium carbonate, and extracted with ether. After the solution had dried over sodium sulfate for several hours, it was filtered and concentrated yielding crude N-(2-chloroethyl)-pyrrolidine as a syrup.

Example 24 A mixture of 52 g. Z-trifluoromethyl-l-(2-hydroxypropyl)-phenothiazine, 120 ml. dry toluene, and 6.2 g. of sodium amide was stirred at room temperature for 0.5 hour and then heated slowly to reflux. After all the sodium amide had reacted (ca. 2 hours), 58 g. of crude N-(2-chloroethyl)pyrrolidine in 80 ml. of dry toluene was added dropwise with stirring at reflux temperature. After the reaction had refluxed and stirred for 12 hours, it

was allowed to cool to room temperature. 150 ml. of water and 2000 ml. of ether were added to the stirring mixture. The organic portion was separated and extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether, saturated with potassium carbonate, and extracted again with ether. After the ether extract had dried over potassium carbonate, it was filtered and concentrated to a viscous syrup under vacuum. The residue was distilled, giving 2-trifluoromethyl-10- {2-[2-(l-pyrrolidyl)-ethoxy]propyl}phenothiazine as a glassy solid; B.P. 199200/O.2 mm., a 1.5674. The hydrochloride was obtained by dissolving the distillate in ether and bubbling dry hydrogen chloride into the solution. A mixture of ethyl acetate and methanol was used to crystallize the crude hydrochloride; M.P. 164-165" (uncorr.).

Example 25 2.4 g. of sodium amide was added to a solution of 20 g. of 2-trifluoromethyl-10-(Z-hydroxypropyl)phenothiazine in ml. of dry toluene. The resulting mixture was carefully heated (some effervescence), with stirring, to reflux. After the reaction had refluxed and stirred for 2 hours and all the sodium amide had reacted, 20 g. dimethylaminoethyl chloride in 100 ml. of dry toluene was added dropwise. The mixture was allowed to reflux and was stirred for an additional 18 hours. When the reaction mixture had cooled to room temperature, 10 ml. of ethanol was added with stirring, followed by 100 ml. of water and 200 ml. of ether. The organic portion was separated, washed with water, and then extracted with dilute hydrochloric acid. In turn, the acid extract was washed with ether, saturated with potassium carbonate, and again extracted with ether. After the ether extract had dried over sodium sulfate, the desiccant was removed by filtration and the filtrate concentrated under vacuum on a water bath. The syrupy residue was distilled at reduced pressure to give Z-trifluoromethyl-IO- [2-( Z-dimethylaminoethoxy )propyl1phenothiazine as a light yellow, viscous oil, B.P. 176177/0.05 mm. A citrate was made by dissolving the distillate in 300 ml. acetone and adding 8 g. of citric acid in 10 ml. of water. In order to induce crystallization, the solution was concentrated to dryness and 300 ml. of fresh acetone was added. The solution was set in the refrigerator for several days and then filtered; the resulting citrate melted at 102104 (uncorr.).

We claim:

1. 2-trifluoromethyl-10-{2-[(4-lower alkyl 1 piperazinyl -lower alkyleneoxy] -propyl}-phenothiazine.

2. A compound selected from the group consisting of compounds of the formula sisting of straight and branched chain lower alkylene radicals; the moiety is selected from the group consisting of unsubstituted and lower alkyl-substituted l-pyrrolidyl, l-piperazinyl and l-piperidinyl.

3. 2-trifluoromethyl-10-{2-[2-(1-pyrrolidyl)-lower kyleneoxy]propyl}-phenothiazine.

4. 2 trifluoromethyl-lO-{Z-[2-(1-pyrr01idy1)-ethoxy]- propyl}-phenothiazine.

5. Z-trifluorornethyl-lO-{Z-[2-(4-methyl-1-piperaziny1)- ethoxy]-propy1}-phenothiazine citrate.

References Cited by the Examiner UNITED STATES PATENTS Cusic 260243 Von Seemann 260-243 Jacob et a1 260243 Gailliot et a1 260243 Gailliot et a1. 260243 Jacob et a1. 260243 12 2,928,767 3/1960 Gulesich et a1. 260243 2,976,286 3/1961 Schindler et a1. 260243 FOREIGN PATENTS 5 213,402 2/1961 Australia.

786,384 11/1957 Great Britain.

OTHER REFERENCES Schmitt et a1.: Bull. Soc. Chim., France, 1957, page 10 939.

WALTER A. MODANCE, Primary Examiner.

IRVING MARCUS, Examiner.

Claims (2)

1. 2-TRIFLUOROMETHYL-10-(2-((4-LOWER ALKYL - 1 - PIPERAZINYL)-LOWER ALKYLENEOXY)-PROPYL)-PHENOTHIAZINE.

2. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA