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Syntheses and pharmacological activity of compounds related to the antidepressant, 5-(2-dimethylaminoethyl)-2,3-di-hydro-2-phenyl-1 ...
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Syntheses and Pharmacological Activity of Compounds Related to the Antidepressant, 5-(2-Dimethylaminoethyl)-2,3-dihydro-2phenyl-l,5-benzothiazepin-4(5H) -one (Thiazesim). 1 1 1 ’ ~ ~ JOHX I~HAPCHO, CHESTERF. TURK, ASD JOSEPH J. 1’1.4L.4 Il‘he Squibb Inafitule for JIedzcal Reseat ch, .Yew Briinowicli, ,Yew Jersey

ReceiLecl September 2, 1967

The resolilt ion of thiasesim and t,he preparation of several piperaziiiopropyl analogs are reported. The ayiitheseh of basically substit iited derivatives of 2,3-dihydr0-2-propenyl-l,.i-bellzothiazepiii-4( 3H)-o1ie, 3,4-dihydro2-pheny1-2H-1,4-benzothiazepin-5-one, 2,3-dihydro-2-pheriyl-4H-1,3-be1izothiazin-4-one, and 2’-(betizylthio):tcetauilide (“open-ring” analog of thiazesim) are described. Theie compounds were tested for their ability to inhibit the moiise-killing responhe of selected rats (antimiiricide test). Of the 20 compoiuids of this c;eries, two were $lightly more active than thiazesim in this test procedure.

Aispart of our program to determine a structureactivity correlation in a series of compounds related to the antidepressant, 3-(2-dimethylaminoethj-l)-2,3dihydro-12-phenj-l-l,,j-benzothiazepinI(3H)-one hydrochloride (Ia),3 we TYish to report the Synthebes and

I

1. SOCI, 2. CH,OH

I

R Ia, R = (CHJ,N(CH,),.HCl;

R = C,H,

pharmacological activity of an additional 20 compounds (Table I) which are divided into four classifications. Products of type I are represented by the optical isomers of Ia, as well as analogs containing a substitutedpiperazinopropyl side chain and related compounds having a propenyl group in the 2 position. Compounds of type I1 are 1,4-berizothiazepin-5-ones, materials of type I11 are 1,3-benzothiazin-4-o1ie analogs of type 11,

11, n = 1 111, n = 0

arid type IV products represent “open-ring” modifications of type I.

R

Iv -\Iost of the compounds of Table I n-ere obtained by treatment of the intermediates of types I, 11, arid IT’ (11 = H) with sodamide arid the appropriate basically substituted alkyl halide. The new precursors (R = H) for the compounds were obtained in the following manner: I, by reaction of 2-aminobenzenethiol with sorbic acid; 11, by a four-step procedure (Chart I) involving (1) Paper I1 of this wrirs: .I. Tiraprho a n d C . F. Tnrk, .I. . l f d Chem., 9, 101 (1960).

(2) Presented in p a r t hefore t h e 3rd International 3Ieeting Tlieraperitique, Paris, J u l y 1 9 6 i . (:i) Tliiazeuiin hydrochloride, .lltinil It’.

or

Cliiinie

\130-1&1°

the interaction of thiosalicylic acid with nitrostyrene, conversion of the resulting 2- { [cu-(nitroniethyl)berizyl]thio]benzoic acid to its methyl ester, reduction of thc nitro group to the corresponding amine, followed by thermal cyclization; and IV, by acylation of 2-benzylthioaniline. Most of the products represented by type I11 were obtained by heating thiosalicylic acid with a benzal derivative of the appropriate diamine. In the preparation of 16, the product from thiosalicylic acid arid 3-(benzylideneamino)propanol was treated with thionyl chloride, sodium iodide, and dimethylamine SUCcessively. Resolution of the optical isomers of I a was carried out using (+)-tartaric acid. In the preparation of 3 :md 4. the intermediate of tyl)e I [Ti = (CHJaCl. K’ = C‘aHa] was obtained and then treated with sodium iodide and the appro1)riate substituted piperazine. Compound 5 was obtained ab the product of the reaction of the epoxy intermediate with Smet hylpiperazine. I n our previous studies,’ the coml)ounds IT ere te5ted for their ability to calm a sel’tnl rat. Because of the difficulty in preparing iuch animals arid their ihort period of usefulness, it was desirable to develop a simplified test procedure for screening further members of this series of compounds. Studies in the cat showed that I a affected the amygdala area of the brain.5 Since neurological lesioning of the amygdala of the rat (2) J lirapclio C 13 SyitLmiller, a n d C. F. Turh, I . M e d

Ciiem., 6,

Z44 (1963)

( 5 ) Z 1’. IIoro\It/, 1 It l-urxiuelo, L J BranniLh, J 13. h Crdxer, S u t u r o , 200, ,369 (1963).

C. Burke, dnd

Experimental Section 1leltiiig poiiit3 :tie c.ot t c ~ l . Optic.;ii rot:itioit- were iiie:ihitt,vil 1' ; aqireoiib soiiitioii.: ii.ing a Perkin-Elmer 141 pol:trinietci,. The infrared ?peclra Of till of 1 hese conipoltnds were in agreenieii 1 with the assigned strilcttlres, \Vhere analyses arr itrdicatc:tl otily bj- symbols of the elements :uialytical resiilts obtailtecl lor those elements were within =l=0,4:; of the theoretical valiir.. Resolution of Thiazesim (Ia).--A solut ion of 326 g (1. C mole) of the free base of I a I ill BOO ml of 1IeOH n-as treated with :I solutioii of I.iO.0 g (1.0 mole) of ( + ) - t a r t a r i c acid in 600 ml of 1IeOH. After cooling the mixture for several da>-s, the rrystalline product, was filtered and dried iri a desiccator to give X40.0 g of material, [ a ] % +16". Coitcetitration of the filtrate gave l2!I,O y ( i f i i i : i 1 w i ; i l , [,,I% ---82". 13). i q w n t r t l oil

Xarch 1968

C O J I P O U N D S IIELATED T O r ~ H I A Z E b I J l .

111

363

quant,ity of insoluble oil was discarded) and treated with 300 of these solids from water ( 2 ml/g a t 67'), from which the (-)ml of ether containing an equivalent quantity of HC1 to give base (+)-tartrate crystallized as a hydrate, there was obtained an oil. Trituration of this oil wit'h fresh ether arid removal of 199 g of product, [alZ8"o -312". The latter was converted to the remaining solvent under reduced pressure gave 98.5 g of the the HC1 salt (138 g ) and purified by cryst'allizat'ion from 1.6 1. hydrochloride as a foamlike solid. A suspension of this material of E t O H to give 126 g of 2 as a colorless material, [ a I z 8 D -446". in 500 ml of ether was treated with a solution of 45 g of K,COJ After evaporation of the aqueous mother liquors a t reduced in 80 ml of H20 to give 83.7 g (71%) of base. This material pressure and trituration of the residues with EtOH, there was gave a crystalline salt with oxalic acid, mp 153-155' (from obtained 192.5 g of the (+)-base (+)-tartrate. This material AIeCN). 9nal. (C18HlgSO&3) S, S; neut equiv: calcd, 189; was crystallized from 3.1 1. of hIeOH to give 154 g of product, found, 190. [ a ] 2 8 ~+340". The latter was converted to the HC1 salt (117 g) 3,4-Dihydro-2-phenyl-2H-1,4-benzothiazepin-5-one.-The arid purified by crystallization from 1.4 1. of EtOH to give 106 above amine (68.6 g, 0.24 mole) was heated a t 130-180" for 1 hr, g of 1 as a colorless material, [ a ] 2 8 +449". ~ 5 g of JIeOH being collected during this period. The residiie 5-(3-Chloropropyl)-2,3- dihydro- 2- phenyl- 1,5- benzothiazepinwas rapidly distilled [bp 190-240" (0.2-0.3 mm)] and the syrupy 4(5H)-one.-To a solution of K (8.0 g, 0.2 g-atom) in .io0 ml of orange distillate (,50.4 g) was digested with 70 ml of i-PrOH to liquid KH3 was added .?.i.0 g (0.22 mole) of finely divided 2,3give 31.3 g of pale yellow product, mp 180-183'. After crystaldihydro-2-phenyl-I,5-benzothiazepin-4(3H)-one.g The resulting lization from 330 ml of JIeCN, the colorless uroduct weighed pale yellow slurry was rtirred for 1 hr and treated with 40.0 g 3.25, 5.9;, 6.35 p. 2nd. ( 0 . 2 5 mole) of 1-bromo-3-chloropropane. This mistnre was 28.2 g (46%); mp 186-188';' : : :A (C1,Hl-XOS) N. S. ..timed for 3 hr in the cooling bath aiid the solvent was allowed N-Benzylidene-4-(2-aminoethyl)morpholine.-A mixture of to evaporate. The residue was triturated with ether and filtered 68.0 g (0.64 mole) of PhCHO, 83.5 g (0.64 mole) of 4-(2-amiiiofrom the solid (34 g ; after trituration with HZO, the recovered ethyl)morpholine, and 150 ml of P h H was stirred aiid refluxed for ctarting material weighed 12.0 g, mp 176-1723'). The filtrate 2 hr, 11 ml of HZO being collected during this period. The solwad concentrated iinder reduced pressure and the residue (64 g) vent was distilled and the reiidue was fractionated to give 135.3 crystallized from 20 ml of i-PrOH to give 30 g (54c;C, based on g (97%) of a pale yellow liquid, bp 118-123" (0.1 mm). Anal. recovered starting material) of colorless product, mp 93-98". The analytical sample, mp 102-104", was recrystallized from i( C I ~ H I C T ~N. O) Interaction of eqiiivalent quantities of PhCHO and 3-aminoPrOH. Anal. (ClaH&lSOS) C1, S . propanol gave a 9 3 5 yield of S-benzylidene-3-aminopropanol, Conversion of this material to the corresponding iodo analog, followed by treatment with 1-(2-hydroxyethl-l)- aiid 1-(0bp 127-128" ( 2 mni). dnal. (CloHlrSO) S . The benzylidene derivatives of dimethyl- and diethplamiiiomethoxypheiip1)piperazine in the usual manlier gave 3 and 4 ethylamineu'o were prepared in the bame manlier. of Table I. Alkylatioii of the above iiiicleu? with 3-dimethylaniinopropyl 2,3-Dihydro-3-( morpholinoethyl)-2-phenyl-4H-l ,a-benzothiazin-l-one.-A solution of 80.0 g (0.36 mole) of the above morbromide iising L i s € % , in liqiiid SH, in the above manner gave -?I-(3-dimet hylamiiiopropyl)-2,3-dih~dro-2-phenyl-l,5-be1izo-pholine in 150 ml of xylene was added to a suspension of 56.0 g (0.35 mole) of thiosalicylic acid in 200 nil of xylene and the thiazepin-4( .iH)-one as the only reaction product. T h e HC1 mixture was stirred and refluxed for 2 hr, 5.5 ml of H,O being salt melted at 204-206" (from J l e C N ) . In our previous preparacollected during t>hisperiod. The mixture was cooled, diluted tiorig we obtained this material melting at 127-129" (from biitawith 500 ml of CHCl,, washed (HzO, 5% SaHCOa), and dried iioiie). After recryitallization of the latter product from l I e C S , it melted a t 204-206". (JlgSO,). The solvent was evaporated and the residue was triturated with 200 ml of hexane to give 112.6 g of product. 2,3-Dihydro-2-propeny1-1,5-benzothiazepin 4( 5H)-one.-A After crystallization from 300 ml of i-PrOH, the nearly colorless mixtiire of 250.0 g (2.0 moles) of 2-aminobeiizenethiol, 224.0 g material weighed 108.3 g ( 8 7 % ) ) mp 131-133", '::A; 6.10 p . (2.0 moles) of sorbic acid, 50 ml of DMF, and 1 1. of P h J l e was I n a l . ( C Z o H 2 Z S ~ 0S2 .S )The HC1 salt of this material is 15. stirred and refluxed for 12 hr (about 24 ml of H20 was collected The preparation of 13, [bp 180-185' (0.2 mm)] was carried during this period). About 700 ml of solvent was then distilled, out in a similar manner. In the case of 14, methyl thiosalicylate and the residue was cooled and washed (cold H,O, dilute HC1, and the imine were heated at, 173-180" for 1 hr and the free HeO). The organic phase was dried (JIgSO4) and concentrated base then distilled at 175-185" (0.2 mm). The latter was purified under reduced pressiire, and the residue (398 g ) was digested as a citrate salt, mp 175-177" (from M e C S ) , and then converted with 300 nil of hot hexane and cooled. The semisolid was then tmothe HCI salt (14). tallized from 300 ml of ( i-Pr)ZOt.o give 118 g of pale yellow 2,3-Dihydro-3-( 3-hydroxypropyl)-2-phenyl-4H-1,3-benzothiaprodiict. Sitbseqiient tallizations from AIeC?; and from zin-4-one.-A mixture of equivalent quaiitities of S-benzylii-PrOH gave 71.0 g ( ) of nearly colorless product: mp dene-3-aminopropanol, thiosalicylic acid, and xylene was refluxed 141-142': ':A:: 3.35, 5.99 p . d n d . (Ci,Hi,SOS) N, S. for 3 hr and diluted with CHCl,, and the product was isolated 2-( [a-(Nitromethyl)benzyl]thio)benzoic Acid.-A mixture of 10'3 g (0.66 mole) of thiosalicylic acid, 100 g (0.66 mole) of 8-nias described above to give 535& yield of colorless material: nip 125-127" (from M e C S ) ; A::':"' 2.94, 6.20 p . Anal. (C1;HliSO2S) trostyrene, and 1.50 nil of EtOH was heated and the resulting s,s. solutioii refluxed for 3 hr. The hot solution was diluted with 15 34 3-Chloropropyl)-2,3-dihydro-2-phenyl-4H-l,3-benzothiazin1x11 of H20 and cooled, and the crystalline prodiict was washed with cold 95% EtOH to give 167.7 g (84%) bf colorless material, 4-one.-The above material was added to a solution of SOC1, in CHC1, and refluxed for 3 hr, and the solvent was evaporated mp 150-132". Anal. (C1&H13SO4S) h', S. under reduced pressure. The residue was triturated n-ith hexane Methyl 2-{ [a-(Nitromethyl)ben'zyI]thio)benzoate.-A suspento give a 967, yield of product, mp 134-136". The analytical sion of 167.7 g (0..55 mole) of the above acid, 300 ml of CHC13, sample was crystallized from M e C S ; mp 134-136". Anal. arid 300 ml of SOCl, was refluxed for 3 hr. The bulk of the vola(C1,H1&1SOS) CI. This material wa3 treated with N a I and tile material was distilled, aiid the remainder was removed under HX( CH,), to give 16. reduced pressure leaving 176.1 g of the intermediate acid chloride 2'-(Ben~ylthio)propionanilide.-~4 mixture of 43.0 g (0.18 mole) as a pale yellow solid, mp 89-91". This material was heated with 600 ml of JIeOH and the resulting solution was refluxed for 6 hr of 2-( beiizylthio)aniline11 and 80 ml of propioiiic anhydride was and cooled to give 162.8 g (Y3Fc) of colorless product, mp 100refluxed for 10 min. The propioiiic acid and excess anhydride were removed under reduced pressure and the residue was frac102". : h a l . (ClsHijNOB) S , S. tionated to give 60.0 g (77%) of nearly colorless liquid, bp 180Methyl 2-{ [a-(Aminomethyl)benzyl]thio)benzoate.-A mix183' (0.2 mm). Anal. (C1OH1iNOS) S , S. tiire of 130.0 g (0.41 mole) of the above material, 350 g ( 1 . 5 The acetyl derivative of 2-(beiizylthio)aiiiliiie11 was also moles) of SnC12~2T-~20, 1 1. of JIeOH, and 350 ml of AcOH was prepared in t,he above manner. A small quantity of the diacetyl stirred and refluxed for 3 hr. The reaction mixture was then compound was isolated from the reaction, mp 88-90" (from ipartly concentrated (500 ml collected), cooled, and treated portionwise with a cold solution of 700 g of KLCOI in 1 1. of H 2 0 . PrzO). Anal. (C1iH1&02S) C, H, N. Ether (600 ml) and CHCI3 (200 ml) were added and the mixture wi? shakeii. Tlw I:iyers were separated nrld the aqiieoii:, phase was extracted twice with the same Et2O-CI-ICl~ mixture. The (10) -4. R . Surrey, J . A m . Chem. Soc., 71, 3105 (lY49). organic phases were combined and dried (MgSO4) and the (11) A. Sieglitz a n d H. Koch, Ber.. 68, 78 (3925). \Ye olJtairied this masolvents w-ere removed iiiider reduced pressure to give 110 g terial by alkylation of tile sodiurn salt oi 2-alnilloi,enzerletllioi wit11 benzyl of residue. The latter was dissolved in 700 ml of ether (small chloride i n i-PrOH.

-

Notes 3-l'heiiy Irhodanines as Potential Antimalarial Agents'

: ~ - ( p - C ~ h l c ~ r o p t i e i i ~ l ) - ~ ~ - ~ i c t l i y l r l (1) i ~ ~ dI\ ~a,z i i i irviie ported to exhibit aritirnalarial activity in preliminary bcrcening :gainst Plasi/ioclzurli berghei in mice.2 Thewfore, :III authentic sample of I and sevcxr:il related coni-

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