Hypotensive 1,2,4-Benzothiadiazines
L'-hrninobenzenesulforlumides were prepared by way of ( I the c.hlorl,sulf~iiIutioii of aiiiiriot)eiizeries, 2 1 tilt, :rrninat.ion of ~-chloro,enzenesulfoiia~~iides and (S) the c~hlorine oxida.tion o f %-l)enzylmercaptcinitrohenzene~. S e w 1,2,1-benxothiadiazine-l,l-dioxideswere obtained by the cayclization of the L'-3iiiinobenzenesulfonaiiii(les with formic acid, ortho esters, mixed anhydrides and with :rldehydes. The hypotensive :ictivities of the endoc.vclic sulfonamides a r e desrrihrd.
Siiict the hypote1isi.i e actii ity oi 6-chloro-i-sulfacids reacted with the ~ - a ~ i i i i i o b ~ ~ i i z e i i e s u l f tooi i i ~ i ~ ~ ~ aiiioyl-1 ,',.l-heiixothiadiaziii~~-l,1-dioxide was recoggive 2-carboxamidobeiizeiie~iilfoiia~iide~.( h i r oi iii.wd cliiiically,' there has hecii a seaich 111 this lab.i-chloro-~-pheiiacetylaii~iiiobciixcl~llf~)ii~riii~l~~, oratory for sulfoiiaiiiides har iiig priiicipally or exclnsively \vas i d a t e d and characterized. The other rrudo 2dfecti\ e hypoteiisil e actir ity Thi. paper describeh c~al.t~oxaniidobciizciiesiilfoiiaiiiides were cyclizcd i i i coiipart 01 thr ~iivestigatioiicoiiceriird with 12-l-heiizowiltrated aiiimoiiiuin hydroxide to yield 3-alkyl (1 o i ' thiadiazitir-l,l-dioxid(~~ iiot coutaiiiiiig ai1 ext raiiiicleai i i i o r ~c8arhoiis) :baralkyl- aiid :3-cycloalkyl-l,2,j - h ( \ i i i-wlf ainoyl group zothiadiaziii+l,l -dioxides (Tahle 11). The iiiixcd C'hlorosulfonatioii of :~-chloro-l-iiiethylaiiilirieaiid of anhydride iiiethod \\'as iiot successful with hciizoic I-chlorotwiizoic acid yielded, rebpectively, 2-aiiiiiio-lacid. a i d ~i-iiirthyl-:~-triflri~~ror~icthyl-l,2,l-hciizothic~hloro-.5-i~icthylhcii~eiie,~ilfoii~l chloride aiid 5-cardiaziiie-1,l-dioxide was ohtaiiicd from the reactioii \vith I~oxy-2-chlorobeiizeiies~il~oiiyl chloride The reaetivc the anhydride of trifluoroawtic acid aiid :3q4,.i-ti,ichlorine atoms of 2~~3-dichloroiiitroheiizeiirmid of 2iiiPthoxy1)ciizoic :wid. Coiidciisatious of aldchydcb (~hloio-.i-iiicthyliiitiobeiizciic n e w dibplaced by heiizylI\ ith the ~-aiiiiiiobc~iizeiies~ilfoiiaiiiides i i i avid g a \ ~ the. thiol 111 alkaliiic Yolutioii C'hloi iiir oxidatioii oi thc L'.X-dihSdro-:~-alkyI-,aralkyl- and cycloalkyl-1.2.k - 1 ~ 1 1 i r d t i i i g 2 - t ~ e i ~ z ~ ~ l i i i c r c a p t o - ~ - ~ h l o r o i i i t r ~ aiid ~ t ~ c i i ~mthiadiaziiie-1, riie I-dioxides (Tahle 111). Thv i i i i i i ~ i i : i l 2-t)riizyliiirrcapto-5-iiiethyliiitro~~eiizciieyielded the aiid iirn adaiiiniitaiie-l-carl)o?raldehydc\I a:. p i c y a r t ~ l (ww3poiidiiig 2-iutroheiizeiicsulf oiiyl chloride. -ill the 1)p thc lithiuiii alriiniiiuiii hydride rcduct i o i i ot a h \ r srilioiiyl chlorides \L ei'c cmivei,ted to sulfoiiariiidcs S-methyl-S-phriiyl-adai~ia~itaii~-l-carboxa~iiid~~ 'Fhi\ ljy t i catiiig thein J\ ith liquid aiiinioiiia. Reactioiii oi amide \vab ohtaiiied from adaiiiantaiir-1-carboxylic, :icicl .i-ehloro-2-iiitroheiizeiir~iilfoiiylchloride nith n-prothimigh the acid chloiklc. pylaiiiiiic arid u ith heiizylamiiir yirltird S-it-proExperimental pyl- a i d S - t ~ c i i x y l - ~ - c h l o r o - 2 - i i i t ~ ~ ~ l ) ~ ~ i i z c i i c s u l ~ o i i a i i i i ~ ~ ~ ~ ~ < 'atalytic redrwtioii oi thc i - i i i t i o1)ciizeucsulfoiiaiiiid~. Chlorosulfonations (Table I).-To 1 hg of ~hl~~ri~bultoiiii 'ii iti :uid di-placrmeiit of the chloiwic oi 2-chloro-3-carboxpmas added carefully 100 g of 3-chloro-4-methylanlline or 100 p tjtiizt~iit.iulfoiiaiiiidc yicldrtl thr 2 - ~ n i i i i o ~ ~ c i i z c i i c ~ ~ i l f oofi i p-chlorobenzoic arid The mixture was stirred mec.hanic:tll\ , ~
:tnd 150-200 g of SaCl \\:is added in small portions The csiiiiiio~~c~ii~ci~~s~ilf~ with ~ i i a ~ i ($aping i i d c ~h>drogeii vhlonde n as conduvted t o a TI ater-wish coluniii
The re:trtion niixtrirr N J S heated in an oil-bath at 160' for 5 hr., then cooled and added to ice vater. The separated sulfon\I acctatc. mid TI ith t m t h y l orthopropioilate yielded 3-I€-, chloride was eutrarted nith ether or collected on a filter, \\aslied :i-iiiethyl- aiid .i-eth~l-l,2,l-l~eii~othiadaziiie-l,l-diox- a i t h water and dried. The product n a s added cautiousl? t o excess liquid ammonia. 111 :in open beaker. After the e u w s idrs ('l'ahlc 11) 11ixed aiihydixides of trifluoroacetic ammonia had evaporated, the solid sulfonamide n as recryst:il: i d I\ ith alkaiir. aralkaiie aiid c~cloalkaiircarboxylic lized from alcohol. 2-Benzylmercaptonitrobenzenes and their Chlorine Oxidation ( 1 ) \\ Ilolldnder and 1Z \\ilhins Boatori Ired Vuart 8 , 04 ( l c ) i 7 i (Table I).-To a cmld solution of KOH (54-108 g.) in 2 1 i l l bins \ e w h n u l a n d J \led 257 I 0 2 b (1c)i7) A 4 Rubin 1 I alcohol was added 100 g. of benzylmercaptan and either 154.5 g 1 T a v l u i dnii H RosenLllde I Phn mar01 Erptl T h e r a p 136. of 2,3-dirhloronitrobenzene or 128 g. of 2-chloro-5-methylnitro-
i oi inic acid, triethyl oi thoforiiiatc, triethyl ortho-
HYPOTENSIVE 1,2,4-BENZOTHIADI.4ZINES
May, 1963
273
TABLEI R.
R1
Ra
R2
Empirical formula
R4
H H
SH2 C1 SO2 SH2 NH,
C1 CHS H CO?H H H H CH3 H H 2" H COiH CsH&Oa H C1 Phenylacetamido.
c1
H
c1 H H
CjHgClK2OzS C,HsC1104S C&C1N204S C7HioN202S C6H7ClS202S CjHsX204S C14HiaClX203S
ALP.,
Yield,
I
OC.
%
C
185 260 144 125 135 283 d. 148
45 TO 70 15 91 42 60
38.09 35.67 30.40 45.14 34.90 38.88 51.75
--
Analyses. % C a 1 c d . p H C N
4.11 2.56 2.13 5.41 3.41 3.72 4.03
7
Found--
H
38.16 35.85 30.37 45.23 35.09 38.96 51.92
12.69 5.84 11.83 15.04 13.56 12.96 8.83
4.28 2.77 2.16 5.68 3.39 3.70 4.06
n12.49 5.73 11.77 15.00 13.42 12.98 8.47
TABLEI1
-Analyses
Ri
Ri
H H H
c1 c1
c1 c1
c1
H H
H
c1
H c1
c1 c1
c1 c1
c1 c1
c1 c1 CFa CFa CF3 CHI CHJ CHI CHI CI
c1
C1
c1
c1
a
SH, NO2 H CH3 CH3 CH3 CH,
c1 c1 c1 c1 H H H H H H H H H H H H
c1 H c1 H H c1 H Cl H c1 c1 H H c1 H c1 H c1 CHI H C02H H Values for S. * 1-Adamantyl.
R3
Empirical formula.
H H H H H H H c1 c1 H H H H H H H H H H H H H H
c1
c1 c1
c1 c1 c1 H H H H H H H H H H 5-Sorbomen-2-yl.
M.P.,
Yield.
OC.
%
-----Calcd.
C
45.18 301 50 325 42.60 io 262 37.00 85 280 48 44.20 304 72 46.42 290 70 63.55 11 285 13 46.81 307 261 41.20 81 44.20 70 229 303 52 33.47 36.26 322 48 311 i o 38.38 310 43 40.96 53.00 >400 21 314 55.25 20 241 34 45.04 40.90 36 326 312 43.17 39 196 32 47.60 56 250 51.47 218 53.57 83 244 46 63.97 191 54 57.80 61 36.26 370 337 38.74 SO 265 57 47.15 230 28 47.90 326 46.80 29 400 52.85 18 327 60 41.60 272 44.17 83 54.40 268 19 240 52.10 31 262 32 54.75 246 52.55 27 312 28 52.20 298 50 45.90 40 40.90 298 390d. 6 44.99 Cyclopent-2-enylmethyl.
7
H
N
%-Found--
7
C
"
3.79 17.65 45.10 3.85 3 . 5 8 21.30 42.56 3 . 9 4 2.22 14.11" 36.50 2.18 12.25 3 . 7 1 11.45 44.14 3.87 4 . 2 6 10.82 46.65 4 . 5 1 4.31 7.06 63.74 4.51 3.40 7 . 2 8 47.08 3.58 3 . 0 6 12.25 41.09 2 . 9 1 3 . 7 1 11.45 44.81 4.15 1.59 11.15 33.66 1 . 4 1 2.28 10.57 36.34 2.49 2.89 10.04 39.04 3.10 3.43 9.56 40.84 3.24 4.71 7.27 52.85 5 . 1 0 3 . 0 9 7.16 55.37 3 . 0 7 2.70 7.50 45.24 2.92 2 . 6 7 10.61 41.36 2 . 9 2 3 . 2 6 10.07 43.26 3.04 4.53 7.40 48.06 4.51 4.79 13.34 51.38 5 . 0 1 5 . 3 7 12.49 53.71 5.21 5.37 9.33 64.07 5 . 4 8 4.85 58.12 4.78 2 . 2 9 10.57 36.44 2.46 2 . 8 9 10.04 38.74 2.99 2 . 8 3 7.85 47.02 2 . 8 8 2.87 7.98 47.84 2.89 4.24 8 . 4 2 46.94 4.39 4.93 7.25 52.95 4 . 8 9 3.06 12.13 42.01 3.31 3.71 1 1 . 4 5 44.37 3 . 9 6 4.24 9 . 0 7 53.81 4 . 3 0 3.44 8 . 6 7 52.23 3.51 3.61 9.13 54.68 3.70 4.74 9.42 52.69 4 . 6 2 5.06 9 . 3 7 52.19 5.19 2.87 8 . 9 3 46.57 3 . 1 7 2.67 41.48 2.77 3 . 3 5 11.66 44.76 3 . 3 5 e Thiophene-2-methyl,
18.09 21.60 13.74= 12.45 11.21 10.65 7.01 7.02 12.02 11.15 11.37 10.33 10.04 9.39 6.97 6.87 7.27 10.42 10.05 7.14 13.09 12.34 9.12 10.46 9.83 7.60 7.97 8.22 7.00 11.90 11.44 8.67 8.57 9.07 9.23 9.23 9.00 11.45
A\ erage Yoblood pressure change
0 0 0 0 -8 0 -2 9 -2 3 0 0 +3 3 +12 +3 1 -3 9 -3 2 -14 9 -13 1 -7 6 -3 1 0 0 +I2 -13 7 -15 9 0 0 +3 1 -4 9 0 0 -5 8 -3 6 -2 0 0 0 -1 9 0 0 +2 4 -3 9 -4 6 -3 0 0 0 +2 1 -1 3 0 0
-3 8 4-1.9
274
R. '1'IHT.E
111
R 2
( 'I
H €1 H H H H I1
H II 11 11
H 14
I{ 11 li
H ('I ('I ('I
I'( ('I ('I ('I ('I ('I c 'I
benzene. The ensuing reaction iv:is exothermic, and the yellow product separated after 2 hr. The 1)rodiirt w:is collecnted and recrystallized from dilute alcohol or witer. The substituted phenyl benzyl sulfide, prepared above, n-as added to 1-2 1. of 30-50:G acetic arid and stirred rvhile chlorine gas was bubbled into the mixture. The reaction hecanie warm, and the solid disappeared after 4-8 hr. IYater was added, and the aqueous mixture was extracted x i t h ether. The ether solution was washed with water, dried over JIgHOI, filtered and evaporated. The resulting sulfonyl chloride \ v : ~ ndded to exc'ess liquid ammonia, and the ammonia \vas allowed to evaporate. 'The resulting sulfonamide was recrystallized from dilute alcohol. 2-Aminobenzenesulfonamides. Method A. Reduction of 2Nitrobenzenesulfonamides (Table I).---An alcoholic solution containing 25 g. of 4-chloro-5-methyl-2-nitrobenzenesulfonaniide or li-chloro-2-nitrobenzenesulfonamide was hydrogenated a t 2.8 kg./c*m.Z with Raney nickel. The catalyst was separated by filtration, and the filtrate was concentrated. The crystalline product,s were recrystallized from dilute alcohol while the aJJI'npyI and benzyl amides uf 2-amino-B-chlorobenzenesulfonic :icitl were intractable gums and were used in the subsequent reacticins without further purification. Method B. Amination of 2-Chloro-5-carboxybenzenesulfonamide (Table I).--& mixture of 2-c,hloro-5-(.arl)os.benze1iesiilfonaniide (100 g.), (SHd)LXI, (100 g . ) , CuSO4 ( 3 g.) and of concd. S H a O H (250 nil.) was sealed in a bomb and heated at 130" for 18 lir. It \vas concentrated on the steam liat'h, neutralized with :wetic. : i d and the residue extracted into alcohol. The alcohol sollition \vas clarified with carbon, conrmtrated and diluted with \vat,er. The product crystallized and \vas recrystallized several times frorn dilute alcohol. Method C.-These 2-aminobeneenesiiifon:tlnides \\-ere pre1):irwl by methods dewrihed in the li tt,iire: 2-amino-j-chlorc)-
I,enzenesulfonsmitle,' ~ - ~ ~ n i i n o - ~ , ( i - t l i c . l i i l ~ r ~ ~ l ~ e r ~ z e r ~ e s i ~ l f o n a r i i i d e ~-aniino-4-c~h~orot)en~enesu~fc~naiiii~e,~ 2'-:tinixio-3,T,-di(~~i~(~ri)l)~iizenesulfonaniide,3 '-'-nniino-5-nitri,benzeiiesuIforinniidc,' and P-amirlo-4-trifluori,rnethylhenzenesulf~~n:~~iii~le.~ N-Methyl-N-phenyl.adamantane-l-carboxami~e.--~~~~1)rc'piirt. :id:iniant:rnr-l-c~:~rl~trr~~l c.hl(iride :i mistiire of 30 g. o f :idaiiinnt:tne-l-carI,c,s!.lic' widfi:tiid 12 g. of 1 T l 5was heated iindcr reflux for 3 hr. The solution tlieii ivns distilled under rrducwl pressure to reriiove ('T )('I3. The rtisiducl, \\-hic*hsolidified upon riooling, \vas dissolved in dry ether. The ether Yolution was filtered, and the ether \\':is removed hy distillation under reducwl pressure. The product \\:is purified l)y sulilimation. The yield c.f : i d (ahloride \vas 21.3 8 . \ 0 4 . 5 * , ) ,a n d 0.6 g . of t h e starting acid x a s recovered. The :wit1 c*liloride hydrolyzes r:tpi rooni temperature and \v;is placed in :tn evacuated des until it was used. .\solution of 20.3 g. of adaniantane-1-(:a chloride in TO nil. of dry benzene was added dropxvise to :t stirred mixture of 13..5 g. of ?r'-methylaniline, 9.J g. of triethylamine :mtl 7 0 nil. of dry benzene which was cooled in ire. The stirring \vas cwntinued for 15 min. after the :tddition of the acid chloride solution. The benzene was remcved under reduced pressure, and the residue was dissolved in petroleum ether. The solution w:ts dried overnight with RIgSO,. The petroleum et,her \$-as removed under reduced pressure, :inti wrntcr \vas added to the resitluc,. The product then I\-: ci from a n acaetonr-water niisture, 11i.1).9no, yield,
May, 1963
SYMPATHOLYTIC GUASIDISES
Anal. Calcd. for C16H23SO: C, 80.25; H, 8.60. Found: C, 80.04; H, 8.58. Adamantane-1 -carboxaldeh yde.-X-Methvl-N-phenyladamant,ane-1-carboxamide (32 g., 0.082 mole) ~ : t sdissolved in 100 nil. of dry, rediqtilled tetrahydrofuran. The stirred solution was maintained a t 0-5' with an ice bath. A slurry of 1.03 g. (0.02i mole) of LihlHa in 50 ml. of dry redistilled tetrahydrofuran LYas added portionwise to the cooled, stirred solution through a cottonstoppered dropping funnel with a large bore. The mixture was allowed to come to room temperature overnight with stirring. It was cooled in ice and decomposed by the dropwise addition of cold 6 N HCI. The strongly acidic aqueous mixture was extracted with three 300 ml. portions of ether. The combined ether extract u-as washed with water to remove acid and then dried over MgSO1. .4n oil was obtained when the ether was removed under reduced pressure. Unreduced anilide (4 g.) was recovered from the oil when it \vas cooled in ice. The remaining oil was shown to be approximately a 50% mixture of anilide and aldehyde by comparing the relative infrared absorption intensities of the aldehyde and of the amide bands cbserved in t'he oil. Further attempts to separate the aldehyde from the anilide, including distillation, were fruitless. The oily mixture u-as used as such, yield 7 g. (presumably 3.5 g. of aldehyde, 26y0). The aldehyde portion was characterized by converting i t to 34 adamantane-I) - 6 , i - dichloro - 1,2,4 - benzothiadiazine 1,l - dioxide (Table 11). 1,2,4-Benzothiadiazine-l,l-dioxides(Table 11'1. Method A. R = H, CH3, CBHr.-The 2-aminobenzenesulfonamide ( 5 g.) was heated on the steam bath with excess formic acid according to the procedure of Pnrk and Williams,? or with excess triethyl crthoformate, orthoacetate or orthopropionate according to Freeman and Wagner.8 The reaction misture nas added to water or the excess reagent was distilled, and the resulting solid was recrystallized from dilute alcohol. Method B. R is Other than H, CH,, CzHi.-The 2-aminobenzenesulfonamide ( 5 9.) was treated Tvith an equal molar amount of the mixed anhydride of the appropriate carboxylic
-
( 7 ) D. V. Park and R.T . Williams, J . Chem. Soc.. 1760, (1950). (8) J. H. Freeman and E. C. JVagner, J . Org. Chem., 16, 815 (1951).
275
acid and trifluoroacetic acid, and the resulting 2-Y-acylaminobenzenesulfonamides were cyclized in SHaOH according to the previously reported p r o ~ e d u r e . ~ 2,4-Dihydro-1,2,4-benzothiadiazine-l,l-dioxides(Table III).The 2-aminobenzenesulfonamide ( 5 g.) was treated with an equal molar amount of the appropriate aldehyde in alcoholic-aqueous HCl according to previously reported procedures.10 The products were recryrtallized from dilute alcohol. Pharmacology.-The compounds were tested in renal hypertensive rats prepared by the procedure described by Kempf and Page." Systolic blood pressure was determined by the microphonic manometric method of Friedman and Freed.'? Following the control blood pressure determination the compounds were administered by mouth to groups of three rats. Blood pressure readings were recorded howl! for 7 hr. The results are reported in Tables I1 and I11 as the average percentage change in blood pressure from control over the 7 hr. observation period. Each figure represents the mean change in blood pressure for three animals resulting from an o r d dose of 20 mg./kg. From past experience in this laboratory with known hypotensive agents a 5(2 blood pressurr lowering is considered to be signihcant. Eight representative compounds from Tables I 1 and I11 produced electrolyte retention in saline-loaded female rats. There did not seem to be a relationship between the intensitj of electrol\ te retention and this hypotensive activitj .
Acknowledgments.-The biological activities of these compounds were determined by Drs. P. W. Willard and F'. G. Henderson. The microanalyses were done by hlessrs. William L. Brown, Howard Hunter, George blaciak, A41fredBrown, and David Cline. (9) C. W.Whitehead, J. J. Trayerso, F. J. llarsliall, and D. E. llorrison, ibid., 26, 2809 (19til). (10) C. W.Whitehead, J. J . Traverso. H. R. Sullivan. and F. J. Alarshall, ibid., 26, 2814 (1961). (11) G . F. Kenipf and I . H. Page, J. Lab. C l i n . .Wed., 27, 1192 (1942). (12) %I. Friedman and 9. C. Freed, Proc. SOC.b ' z p . B i d . M e d . , 70, 670 (1949).
Sympathetic Nervous System Blocking Agents. Derivatives of Guanidine and Related Compounds1 JAMES H. SHORT,URSULABIERMACHER, DANIELA. DUSSIGAS,AND THO MA^ D. LETH Organic Chentistry Departniewt, Research Dii'ision, Ahbott Laboratories, Sorth Chtcago, Illinois
Received .YovenLber 15, 1962 A serics of 81 derivatives of guaiiidinc, including 2-aniino-2-imidltzolines, 'L-ariiino-l,1,5,(i-tc.tr~li~~r(~p~.riiiiidines. nitroguanidincs, and aminoguanidines, has been prepared by standard methods. These conipounds have been investigated for their ability to block the sympathetic nervous system, but without blocking the parasympathetic nervous system. Pharmacology and structure-activity relationships are discussed.
I n our Laboratories for a number of years we have been interested in derivatives of guanidine both as chemotherapeutic agents and for their effects on the cardiovascular system. In this paper we wish to report our efforts to find an effective antihypertensive agent in this series of compounds. With the discovery of the potent antihypertensive agent, g ~ a n e t h i d i n e [2-(octahydro-l-azocinyl)-ethyl]~,~ guanidine sulfate, we were prompted to reinvestigate our series of compounds in comparison with guaneth(1) Portions of this work were presented before the Division of Medicinal Chemistry at t h P 1 4 1 e t Xational Meeting of the .inierican Chemical Society, Washington, D.C.. M a r c h . 1962. (2) R. A . Maxwell. R . P. Mull, and A . .J. Plutiinier, Ezpei,ientin, 16, 267 (19.59). (3) R.P. l l u l l , 31.E. E g b r r t , and 31. R. Dapero, J. O r g . Chem., 25, 1953 (1960).
idine, and to synthesize others which might show this type of activity. Guanethidine differs from older antihypertensive agents in that it blocks the effects of stiniulation of the sympathetic nervous system, as do the ganglionic blocking agents, but does not a t the same time block the parasympathetic nervous system. Since parasympathetic blockade causes undesirable side effects such as constipation, dry mouth, urinary retention, and impaired visual accommodation, guanethidine maintains the advantages of the ganglionic blocking agents without many of their disadvantages. Chemistry.-The guanidines described in Tahles 111-VI1 were prepared by standard methods. Method X is that of Rathke4 and involves the reaction of a (4) B. Ratlihe, Ber.. 14, 1774 (1881).
