Sulfonium Analogs of Pharmacologically Active Amines. The

[CoNTRIBGTIOV FROM THE RESEARCH. 1,ARORATORIES OF AYERST, MCKEYNA & TTARRISOV 1,TD. 1. Sulfonium Analogs of Pharmacologically Active ...
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*4ug.20, 1958









Sulfonium Analogs of Pharmacologically Active Amines. The Synthesis of O- ( 10-Phenothiaziny1)-alkyl-dialkylsulfonium Halides and 2 ’-( 10-Phenothiazinecarb0xy)-ethyldialkylsulfonium Halides BY STANLEY0. WINTHROP AND M.A. DAVIS RECEIVED MARCH31, 1958 A series of w - ( 10-phenothiazinpl) -alkyl alkyl sulfides have been prepared by the interaction of w - ( 10-phenothiazinyl)-alkyl halides with alkylmercaptans. Condensation of 10-phenothiazinecarboxy chloride with 2-hydroxvethyl alkyl sulfides gave 2’-( 10-phenothiazinecarboxy)-ethyl alkyl sulfides. The sulfides were treated with methyl and ethyl halides to produce the sulfonium salts. The pharmacological activities of these compounds are discussed.

Sulfonium compounds have been considered as analogs of both tertiary and quaternary amines, and a number of sulfonium analogs of pharmacologically active amines have been reported.’ In some cases this analogy has proved useful in the search for new drugs. In the present investigation, sulfonium analogs of certain phenothiazine derivatives, amines whose pharmacological properties have been extensively studied as they include some important drugs, have been prepared. These compounds may be represented by structures I and 11.

The 2’-( 10-phenothiazinecarboxy)-ethyl alkyl sulfides were prepared by the condensation of 10phenothiazinecarboxy chloride with 2-hydroxyethyl alkyl sulfides in refluxing benzene. Pyridine was used as an acid acceptor and in one case as the reaction solvent. The sulfonium salts were obtained when the alkyl sulfides were treated with alkyl halides at room temperature. Ether, methanol, nitromethane or an excess of the alkyl halide were used as solvents. Nitromethane was found to give the best yields and pure products. Reaction times ranged from a few hours to a week depending on the reactivity of the alkyl halide. Although heating increased the rate of reaction i t also caused decomposition of the sulfonium salt resulting in lower vields. The 2’-(10I /K I /K phenothiazinecarb0xy)-ethyl-dialkylsulfonium hal(CHz).S+ XCOOCHzCHzS+ Xides were particularly heat-sensitive. I \R I1 \R Methyl iodide, methyl bromide and ethyl iodide &4search of the literature did not reveal any w- reacted normally to give the desired sulfonium com(10-phenothiazinyl)-alkyl alkyl sulfides. An at- pounds. An abnormal reaction occurred, however, tempt to prepare 2’-(1O-phenothiazinyl)-ethyl when isopropyl iodide was allowed to react with 3’methyl sulfide however has been reported.2 Pheno- (IO-phenothiaziny1)-propyl methyl sulfide. The thiazine and 2-chloroethyl methyl sulfide were conproduct was 3‘-( 10-phenothiaziny1)-propyl-didensed together, but only undistillable resins were methylsulfonium iodide and not the expected 3’obtained. It was found that the desired sulfides (10 - phenothiazinyl) -propyl- methylisopropylsulfo could be prepared conveniently by the interaction of W - ( 10-phenothiaziny1)-alkyl halides and sodium nium iodide. Similar anomalies have been reported by other Recently Weiss and O’Donalkyl mercaptides. A second method also was developed which, although longer, circumvented the oghue’ observed that when 1-cyclohexyl-3-methylmercapto-1-phenylpropan-1-01was treated with use of the alkylmercaptan. The preparation of 2‘- propyl, butyl or amyl iodide, the dimethylsulfonium (lO-phenothiazinyl)-l ’-methylethyl methyl sulfide derivative was obtained in each instance. These illustrates this second route. 10-(2’-Bromopropyl)- investigators propose a mechanism which involves phenothiazine (111) was heated under reflux in eth- the formation of the normal sulfonium salt to a anol with thiourea to give the pseudothiouronium limited extent. This salt then functions as an alsalt IV. Alkaline hydrolysis produced the mercap- kylating agent, in competition with the alkyl haltan V which, as its sodio derivative, was treated with methyl iodide t o give the desired sulfide VI (2 ide, to produce the observed dimethylsulfonium salt. This explanation would serve equally well in = 10-phenothiazinyl) . the present case. Pharmacological Activity.-In general the sulS NH fonium compounds exhibited the anticholinergic, I/ NHzCNHz II antihistaminic and antisecretory activities of the Z-CH2CHBr Z-CHzCHSCNH3.Br corresponding tertiary and quaternary amines. I I 111 CHa CHs I V Table I11 shows a comparison of these activities for 2’ - (10 - phenothiazinyl) - 1’ - methylethyldimethylCHSSNa NazCOa amine hydrochloride (Promethazine) ,6 2’-( 10-phenothiazinyl) - 1’ - methylethyltrimethylammonium h’aOCH8 Z-CHZCHSCHI 2-CHzCHSH methyl sulfate (Thiazinamon)6 and 2’-(10-phenoI CHBI I thiazinyl) -1’-methylethyldimethylsulfonium iodide. VI CHI V CH, (3) V. Prelog, el al., Hels. Chim. Acto, 27, 1209 (1944). (1) For a brief review see M. J. Weiss and M. D. O’Donoghue, THIS 4771 (1957). (2) 0. Exner, M. Borovicka and M. Protiva, Coll. Csrch. Chem. C o m m . , 18,270 (1953).


(4) T.R. Lewis and S. Archer, THISJOURNAL, 73,2109 (1951). (5) F. D. R a y and I. Levine, J . Org. Chem., 2, 267 (1937). (6) Therapeutic agents for the treatment of hay fever, asthma and other conditions with an allergic basis.

pharniacological data, Mr. \I..J. Turnbull for the analyses and Dr. Gilles Papincau-Couture and Mrs. 7 . Jachner for numerous infrared spwtra. Experimental'


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CH2CH(CHs)?:(CHa)*.HCI 1 1 CHzCH (CH,) N+(CH3)3.CH3SOI2 1 C~1?CH(CH3)St(CHa)2I.0.8 0.3 In vitro; inhibition of the contractions induced lated strips of guinea pig's ileum b y the spasmogenic In viso; using t h e method of S h a ~ . ~


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Most significantly, the sulfoniums did not show any of the central effects of the tertiary amines. Specifically they had no depressant action on the central nervous system and did not exhibit any anti-Parkinson-like activity. In this respect it appears the sulfoniums resemble more closely the corresponding quaternary amines. Acknowledgments.--The authors wish to thank Dr. C. I. Chappel of our laboratories for the (7) H . Shay, C , €7 Stin aad hf. C h i n s t e i n , Gnstroentwol . 26. 906 (106tj

Starting Materials.--Pliciiotlii,rziiie," 2-cliluri1ethyl )toluenesulfonate,' 3-chlnriq~ropyI p - t o l ~ ~ e ~ i e s u l f o n a2te,~ hydrox~etl~plmerc;t~~ta~i~ and l0-phenotliiszinecarbo~~' c11l~1ridelo were available froin ciimmercial sourceh. The f ( 1 1 I i m ing Irere prepared acc,irdi*lg to tnethods descrihed iii t tic literature: l0-(2'-chl1~riiel11~1)-~~l:enotl~iazine,'~ 1i1.1). $17 98' (lit. m.p. 97-98"); 10-(:3'-chltirciprop~lIpIienotlii;i~ir~c.'' m . p . 63-65" (lit. i11.1). (Xi' I ; l ~ ~ - ( ~ ' - h ~ - ~ l r o s y p r ~ ~ ~ ~ ~ l ~ - ~ ~ thiazine,'? b.p. l!JO--19'2° it 0.3 i i i i i i . (lit. 11.p ;92--1!)6" :It 0.3 m n . j ; 10-(2'-lrcinio~i-~1~~~1)-1~l~ericithiazitie,'111 11 12Ii 128' (lit. 1n.p. 125-126O\ 2-hyilros!;ethyl methyl hulFL(Ie, b.p. 1ci5-.16io (lit. b , p . 15; -15!~o');2-h!-drosyeth!-] c.Ili!.I s ~ i l f i d e , h.p. ' ~ 180-181" (lit. b.p. 181'). 3'-(1O-Phenothiazinyl)-propyl Methyl Sulfide.---lll-(:i 'C l i l o r o p r o p y l j - p l ~ c ~ i ~ i t ~ i(20 i ~ ~ ~g i. i, i0.11725 e 1Ilolcj \ ~ a di5\ solved in 400 nil. o f : t h v ~ l u t eCtli:uioI a11(1was added dropwise to a refluxing siilnti,jn $>[ g. in.18 mole) of s~xiium of meth\-lmercaptaii i i i niethoxide and 10.5 g , JII.22 i i 100 nil. of RbsnluIe e i I i : i . n r i I . :ititlition wxs ~ I ~ I I I ~ I I C I ( : .~ . . .

(8) All melting points are iincotrecrr'l. ( 8 ) Eastman Kodak C!o. w h i t e la!)el '10) Delm