Journal of Medicinal Cheniisirii, l W 1 , Vol. 14, iYo. 10 1005
NOTES
-Aminch---1%1,
I
Yield,"
n
KO.
____ Hydrochlorides----
(rnrri),
%
A1 I > ,
'
nip, o
"(
c
110- 11I
14M-144 ( 2 . 0 ) 134-1:3*i ( 0 .1.7) 130-131 ( 1 . 0 ) 150-1?52 ( 0 . 2 ) 16S-169(0.3)
104-10.5 82-8:3 82-44 rT 123-126 XO 89-90 11 130- 131 109-110 71 I1 127-128 7.i 107-108 II 133- 134 76h 106-107 TI 117-1 18 80* 82-83 1% 126-127 134-136 (0.3) 113-114 90 '3 CIT3 l,52-lfi3 ( 0 . 3 ) 102-103 93 96-98 9 cIf3 127-128 131-132(0.4) 95 109-111 IO crr3 132-133 162-164 (0.3) s4 120-121 11 CTI3 120-121 8 .i 177-179(0.4) 92-93 12 CHS 131-132 143-144(0.6) 93 118-119 13 C1 10.5-106 15.5-1.56 (0.4) 84 96-97 14 C1 13.5- 136 173-17.5 (0.3) 76 132-133 15 C1 195-197 ( 0 . 6 ) 122-123 71 146-147 16 C1 16 3- 166 86* 108-109 17 '2113 Purified bases. * Unpiirified bases. c Oxalates were arialysed for C, H, N and hydrochlorides for N, S, C1. obtained for those elements were within &0.4% of the theoret value. Calcd for total C1. x7 X2
I1
1 2 3 4 .i 6 7
TIELF: PI1I.LIMIN IRY PH.LRM.lCOLOGIC
Major overt effect
Motor deficit, ataxia, CXS depression Motor deficit, ataxia, CNS depression Motor deficit, ataxia, CNS depression Motor deficit. ataxia, CNS depression Motor deficit, ataxia, CNS depression, decreased muscle tone CNS depression, decreased locomotion CNS depression, decreased locomotion CNS depression, ataxia CNS depression, ataxia CNS depression, ataxia CNS depression, ataxia CNS depresqion, motor deficit Ilecreased locomotion Decreased muscle tone Low carriage, ataxia CNS depression, motor deficit Decreased locomotion
..i 6
4 5
> 100 > 100
6 7 8 9 10 11 12 13
> 100
> 10
>loo > 100 > 100 89.1 > 100 > 100
>10 >.i.6 >17.6 50.1 >10 >17.8 >.i.6 >3.2 >d.6 >17.8 >5.6
79.4
10 10 17.8 5 .6 1.8 10 5 .6 17.X 14 > 100 31.6 1.5 > 100 1.8 16 > 100 .i .6 > 100 17.8 17 ]lose levels are in mg/kg of body wt.
>\lOUSl: SCREKiX'
>17.8 > 10 2A.1 > 10 >5.6
nIEDso
> 100 > 100
10.0 3.2 10.0 17.8
I1
ACTIVITY. PItIMARY
L Dso/l\l E Dsa
LDso
1 2 3
NO.
FormulaC
CizH&lN02S CiaHv2ClNOzS Ci3HzoClNOzS CijH,zClNO,S CiaHzoClN03S CizHi sClN20S Ci4Hz3ClNzOS Ci3HzoClNOzS Cr5H24ClNOzS CI4Hz2CINOzS C~~HZ~C~NO~S CijHzzClN03S Ci3HigClzN02Sd Ci,HziClzNOzSd CijH2iC12N0zSd C14Hi9Cl N03Sd C13HziClN20S The anal results
Duration of effect, min
60 60 60 60 30 60 60 30 30 30 60 60 60 60 60 60 60
was employed to calc the minimal effective dose (MEI)50). The ratio of the median lethal dose ( L 1 ) j O ) to the lfEl)~o was detd for each cvmpd. Preliminary pharmacologic evaluations are listed i n Table 11.
we were attracted by published data's2 on certain 1-azaphenothiazine derivative^.^ In particular 2-(diisopropy1amino)ethyl I-azaphenothiazine-lO-thiolcarboxylate (1, Table I) was reported to have an anticholinergic activity 8 t'imes that of atropine and a spasmolytic activity 9 times that^ of p a p a ~ e r i n e . ~ Neuropharmacological Profile of In addition to establishing a pharmacological profile 1-Azaphenothiazine-10-thiolcarboxylates of 1 we studied the compds 2-6, which were derived ";DW.ZRD R . ATKINSON, * P,\MI.:L.\ L. ItLTSS, ?Vl.\RG.\RET A. TUCIWR, from other a,minothiols,and also 4 substitution products (7-10) of 1. The substituent groups in 7-9 were Arthur D. Little, Znc., Cambridge, ,llassachusetts .\ND FR.\NIOH
7
x 9 10'
\nalb best'
c', IT, iY,s c, H, N , s
CH~CIT~J(Z-C~H~)~ CH2CH2NHCOCII3 CHzCH2COSHNIICOCH1 CH&II2CON(NHCOCH,CH,)H
c, IT, s,s IT, N , s
(*,
F, IT, N , s
u
(3,
rr, CI, s,s
c, 11, s,s
CH,CH2N(i-CaH,), CH2CHzN(i-C3H7)? CHZCHAN (i-C3Hi)? CHzCITJ (i-C3Hi)?
r,11, F,s
C, If, F, N, S
Yields reported are those of recrystd prodrict. T o attempt ~ V L A innde to iiiiprove retictioil o r noi,k-rip c ~ o i i c h s . i, \ * d i i e s for the elements indicated were within 0 . 4 q of theoretical. Ala1 = iiialeic acid, C4t1404. I I d e a t e >tilts were pptd from f i : t y O sohitioil.< of the base. Insol in all common solvents; leached with boiling R t O h c . e The free tmse w;i+ n uilorIe>s solid, nip G.1-65" ihextanel. f Obid through t'he courtesy of W.A. Schuler, Cheiniewerk Hanibiirg i I ) e g ~ i . d .l~1
chosen because of their involvement in structureactivity relationships in the plieriothiazine sei iei and in the 1-azaphenothiazine series.6-8 Compd 10. which was commercially available, was chosen as an example of a compd having the same ester group n i 1 and 7-9 but having a substituent in the 3, rather than the S, position. Chemistry.-Compds 1-6 TI ere made by t hr. reaction of 1-azaphenothiazine-lO-carboIiyl chloride* n i t h t h e appropriate thiols. The S-substituted l-azaphenothiazine precursors of 7-9 I\ ere prepared by thionation of the appropriately substituted ariiliriopyridiric~. We believe that thionation proceeded to give the substituent in the S position rather than in the alternative 6 position even though analogous cyclizations in the phenothiazine series are sometimes ltnoirn to give t\r o isomeric p r o d u ~ t s . ~ - lLiterature ~ data shov that a variety of 8-substituted 1-azaphe1iotliiazines hnvc melting points quite similar to those of phenothiazines bearing the same substituents in the analogous 3 position; these himilarities were observed with our 1-azaplienothiazi~ie~.The structures a s q p e d are also supported by ir data Our novel substituted l-azaphenothiazines all sho\ved absorption :it SOO-830 cm-I, which is characteristic of 8-iubstituted l-azaplienothiazines and 3-substituted phenothiazines, but which )
(5) E. F. Domino, R . D. Hudson, and G . Zografi in "Drugs Affecting t h e . E d . . 51. Dekker, S e w York, N. Y., Central Nervous System" .IIiurger, 1968, p 3 2 i , and ref cited therein. (6) J.-P. 13ourciuin, G. Schwarh, G . GamLoni, R . Fisclier, L. R e u d i , S. Guldimann, V. T h e u s , a n d E. Sclienker, Helc. Chim. Acta. 4 2 , 2511 (19.59). (7) Degussa Belgian P a t e n t 630,970 (1963); Chem. Abst?., 61, 43820 (1964). (8) 2. Ledochomski, M. Dogucka, a n d 13. \Vysocka-Jkrzela, Rocz. C h e m . , 38, 311 (1964); Chem. Abstr., 61, 4341 (1964). (9) H. L. Yale, F. Sowinski, a n d J. Bernstein, J . A m e r . Chem. Soc., 79, 4375 (195i). (10) A . R o e a n d \V. F. Little, J . Org. Chem., 20, 1 6 i i (1955). (11) J.-P. Bourquin, G . Schwarb, G. Gamboni, R . Fischer, L. Reuscli, S. Guldimann, V. T h e u s , E. Schenker, a n d J. Renz, H e l r . C h i m . Actii, 41, 1061 (1958).
is not characteristic of the isomeric compds with subst it uent s in the 6 Littempts to prepare S-chloro- arid S-metlioxy-l:Lzaphenothiazines .i\-ere abandoned when \\.e were unable to isolate recognizable products from the thionation of the respective anilinopyridines. Pharmacology.---Compds \\'ere evaluated for iieurop1inrm:icological activity in n modified Irwin mouse profile'3 (Table TI). It was apparent that the t,liiol esters derived from compds ot,her t l i m ?-(diisopropyl:Imino)et'nanethiol (2-6) \Yere considerablj- le, than 1, ivliile 7-10, derived from t h e Same t l retained significant :ictivity in this t e a t . So signific:mt effect on reactive signs or potencj, \vas observed in 10 \\'here the subatiturnt \vas in tlie 3 position; t l i r modest nonspecific activity of 10 wts in contrast to t h e high a t i v i t j . \\-c obberved \vitli :inother 3-chloro-l:tzaphenotlii:izine 1i:iviIig :in ent irel?- different substituent at t h e 10 position (8-cliloro-l0[3- [4-(2-liytlroxyphenyl)piperazin-1-yl ]propyl ]-l-aznpheriotIiiazine tlihydrochloride (cloxgpendyl);I4 ;\IEDjo 0.24 mg/kg (0.1:3-0.42)), I,D,,, 63 mg/lcg (50-70)). Compd 1 had a 1iJ-potensivc JIL.;Djo of 0.:3 mg! lcg in the ariestlietized cat; the effect was not, dose related :ind no effect on respiration or heart rates \vas observed in the dose range studied. Wlien :idministered at 100 kg;'kg iv to rats Fimultaneously n.ith 200 pg/'l
