Antihypertensive Agents.
I. Non-diuretic 2M-1,2,4-Benzothiadiazine 1,l-Dioxides
(X = 7-Cl, R2 = 1%.Li 1 = CH3) and of related cwmpoiiiid. Siiifamoyl suhstitiitccl 2H-1 ,L',~-bt,iizotliiadiaziiic.1 I a 5 part of a *tudy to determiiic tlir c#cct of crrttiii diosidrs. inc:luding tlic 3,l-diliydro compounds, arc' a ,triictiiral motlifiratioii. i i i tliia >cries 0 1 1 hiologic.:il \vc~lI kiiowii class of orally effective diuretic agcxiits.' act ivit >- . 1 h 1 yof them also show ai1 aiitiliyperteiisive effect sild are used clinically in the treatment of mild liyperteiiTlic >yiitlicbi- of tlic 211-1 ,"4-beiizolliiadia~iiic I , 1 dioxides (I) was accomplished hy the coiidciisatioii of a sioii.? ;llthough the precise mcchaiiism of this actioii is wbstituted o-aminobenzenesiilfoiiamide (11) n ith t l w not kiiowii, it has geiierally h e m assumed to be related appropriate orthoc.stcr (111).6 to tlic diuretic and iiatriurctic properties of the compoiitids.3 How!ver. it lias brei1 s1ion.n receiitly that tlic iioii-diiirctic $-ehloro-3-met~liyl-~H-l,~,~-~eiizotliiadiaziiic. I , I-dioside4 (1, X = 7-CI. It, = H R3, = CH,) exerts it proiiouiiccd aiitili?.pcrt,c.iisi\.(. cffcct which is thought i o be d i i c ~to tlia direct actioii of the compouiid at tlic \wctiilar l ~ \ - ( \ l . ~'l'liis paper reports tlic syiithesis of I or ~
11) l > o r i t r w r n t revic,\+- see I:. Sclilittlc~r,(1. d e s t e r e n s , and I,. Wernt,r, A n g i w . Cliernie. 74, 317 (lY62). ( 2 ) i\. C:rollmann Clin. I ' i i n i . n ~ .T l c e m p . , 1, 738 (1960). ( 3 ) I'..I. Tapia, FI. P.Dustan, R . 1.Schecklotii, .\, C. Corcoran. a n d I. 11. I'W u r y ,.I. C ; , 'ruijlisb, A i . t l . S1tt.rr b w , and .I. Black, S i . i e r ~ c r ,133, 20B7 (i!jUl); .\. .I. 1iuIii11, I: E. I h t l i , :xiid 31. A I . \ \ . i n h i r y , ~ - a f u w192, 1711 i l 9 U t l .
R 4
AXTIHYPERTESSIVE AGENTS. I
March, 1963
123
TABLE Ia R4
I
0C.b 330-331 276-277 2 78-2 80 264-266 246-247 2G2-263e 267-269 267-268 2 6 6-2 67
Reorsst. solventC EtOH-H20 EtOH-Hex. Trit. ether EtOH EtOH-HzO 95% E t O H EtOH-Hz0 EtOH-Hz0 EtOH-Hz0
333.5-336.5 309-310 325-326 253-255 250-252 290-292 337 dec. 154- 156 >360 269-270 >360 273-275 138-140 115-117 248-249 287-289 232-234
MeOH MeOH-Ac M e 0 H- HzO MeOH-Hz0 MeOH MeOH-HSO MeOH-Hz0 MeOH RleOH-H20 Ac-Hex Ac-Hz0 hfeOH Bz-Hex EtOH Ac-Hz0 XfeOH hfeOH-HnO
M.P., No. 1
X
7-C1 6-C1 3 5-C1 4 8-C1 5 7-C1 6 6-C1 7 7-C1 8 6-C1 9 6-C1 lod H lld H 12 7-Br 13 6-Br 6-CFz 14 15 G-OCH3 16 G-CH3 17Q C,-iiH? 18 6-NHCOCHa 19 7-KOz 2Oe 7-XHz 210 7-S02N(CHa)z 22 G-COzH 230 B-CO~CHI 24 6-C1 25 G-C1 26 6-Cl 27 6-C1 28 7-Cl 2
R? H H H H H H H H H
H H H H H H H H H H H H
H €I CH3 CiH6
R3 CHI CHs CHa CHI H H CnH6 Cds n-CaHi CH3 H CH3 CHa CHI CHJ CH3 CH3 CHI CH3 CHI CH3 CHI CH3 CHd CHa CHa H CH3
R4
CHa CHI CH,
Formula CaH7ClNzOzS CsHiClK?OzS CsH7Clh-~OzS CsHiClXzOnS C7HsClX?O?S C7HaClX~OzS CsHsCIN20zS CgHsClXz02S CioHiiClN202S CeHaN10zs
-n'itroaen. ~. %Calcd. Found 12.15 12.40 12.15 12.15 12.15 12.20 12.15 12.07 12.68 12.94
11.45
10.19 10.00
12.38 13.33 19.89 16.62 19.89 13.80 Il.fi6
11.02 11.43 10.83 11.45 12.15 11.45
11.49
-Chlorine, 70Found Calcd. 15.37 15.41 15.37
15.51
16.37
15.92
14.49 14.49 13.71
14.55 14.20 13.90
29.05'
28.52f
10.08 10.47 12.91 13.20 19.99 1G.77 20.10 13.71 11.42 11.20 10.98 10.66
11.19 12.49 11.55
14.49 15.37 14.49
%-
--Sulfur, Calcd.
Found
13.90
13.87
13.90
13.86
14.77 13.10
14.94 13.29
12.39
12.38
11.65 11.65 12.13 14.17 15.25 15.18 12.67
11.50 11.69 12.42 13.95 15.18 15.20 12.70
15.18
15.24
13.35 12.61 13.10 12.39
13.49 12.87 13.47 12.81
14.52 15.41 14.19
RIelting points are a The structural assignments given to compounds reported in this table are fully supported by spectral data. D. 0. Parke and R. T. Williams, J . Chem. SOC.,1760 (1950). A4c for acetone, Bz for benzene and Hex for hexane. uncorrected. Bromine. QForthe preparation of this J. H. Short and U. Biermacher, J . Am. Chem. SOC.,82, 1138 (1960), report m.p. 255-286'. compound see Experimental section. Calcd. for CHBOHof solvation: C, 39.56; H, 4.06. Found: C, 40.17; H, 4.35.
When Rz was other than hydrogen (R, = H), the reaction did not usually proceed directly to the benzothiadiazine (I) but gave the imino ether (11') .' Vpon heating at 200-220°, the imino ether yielded the expected 2substituted benzothiadiazine when Rzwas methyl or ethyl (I, R3 = CHs, X = 6-Cl). However, when Rz was isopropyl, the group R2 was eliminated in the cyclization step giving I (Rz = H , R3 = CH,, X = 6-C1).*
The use of the orthoester reaction for the preparation of 4-subst'ituted benzothiadiazines proved satisfact'ory in the one case investigated (11,X = 3-C1, Rz= H, R3 = CH3,R, = CH3) the reaction proceeding directly to the benzothiadiazine (Ia, X = 7-C1, R3 = R4 = CH3). The synthesis of 4-substituted benzothiadiazines was also accomplished by the alkylation of a benzot'hiadiazine in the presence of base. For example, I (X = 7-C1 R2 = H , R3 = CH,), n-hen treated with methyl iodide in the presence of sodium methoxide yielded an Kmethyl derivative (Ia, X = 7-C1, R3 = R, = CH3) identical n-it'h that synthesized by t,he unequivocal orthoester synthesis thus est,ablishing the site of alkylat,ioii as position 4.g X number of substituted 2H-1,2,4(7) Not isolated in the pure state in all cases. (8) This interesting reaction will be discussed in iiivre detail in a fvrtllcominn publication. (9) Similar findings have been rei~ortedby .I. Ekbuiii, Biliang till Suenska Vet. A k a d . H a n d . , 27, 11, No. 1. 3 (1902); Beilstein, 27, 571: and F.C. Novello, S. C. Bell, E . L. .I..Ibraiiis, C. Ziegler, and J. M. Sprague, J . O w . C h e n . , 26, 970 (1960).
beiizothiadiazine I , 1-dioxides synthesized according to the foregoing methods are listed in Table I. I n order to determine the effect on antihypertensive activity of saturation of the 3,4-double bond in this series, a number of substituted 3,4-dihydro-2H-1,2,4beiizothiadazine I ,1-dioxides (V) were synthesized from the o-amiiiobenzeiiesulfoiiamide (11, R, = H) and an aldehyde R3CH0.6 The condensations, which involved low molecular weight aliphatic aldehydes, mere carried out using a large excess of the aldehyde in acetonitrile as solvent in the absence of acid catalyst.10 Some 3J-disubstituted 3,4-dihydrobenzothiadiazines, T'I (X = 8-C1, R2 = H), TI (X = 6-C1, Rz = H ) and VI (X = 8-C1, RS = CH3) were synthesized by coiidensatioii of the appropriate o-aminobenzenesulfonamide with acetone. The position of the chlorine atom was found to have an important effect on the reactivity of the substituted o-aminobenzenesulfonamide in this reaction. Thus 2-amino-6-chlorobenzenesulfonamide (11,X = 6-C1, Rz= R,= H) and 2-amino-6-chloro-Kmethylbenzenesulfonamide (11, X = 6-C1, Rz= CH3, R, = H ) upon warming with a large excess of acetone on the steam bath for 0.3 hr. gave VI (X = 8-C1, R2 = H) and T71(X = 8-C1, RP = CH,), respectively, in high yield. The condensation of 2-amino-4-chlorobenzenesulfonamide with acetone to give T'I (X = 6-CI, R, = H) required an additional 5 days of reaction time at room temperature. However, no reaction of 2-aminohhlorobenzenesulfonamide with acetone was observed either aftcr warming on the steam bath, or after an additional 18 days of reaction time at room temperature.. (IO) J G Topliss, 11 H. Sherlock. F H Clarke, 31 C i)dly, B. 1%'. Pettersen, J. Lipski, and N. Sperber, J . O r y Cliem., 26, 3842 (1961)
v
11. RL=H
VI
The substituted 3,4-dihydro-l ,t2,-l-helizothiadiasjilc I , 1 dioxidcs prepared acrordiiig to tlie foregoing metliodh :ire listed in Table 11.
NaOH, MeOH, H,O 25'
I , X = 7 - C1 K?- H R s = C H ~
II,Rd=H
hl.p, El).
s
29 ;30 31 32 33 34
7-Cl 7-c1 7-C1 Cj-CI
35
6-Cl
8-C1 8-C1
112
TI IT 11 I1 I1 11 CICa
113'
123
I1
Cli3 I1
I1
c2irS n-CaII7 CH, CI13 CIIJ
II 11 CIh CII~ CHI
0C.h
213-214 197-199 183-184 191-1W
188-191 241-244
190-193
Recryst. solventC
EtOH EtOH-1190 MeOH-CIIC'13 I
