Structure-Activity Relationships of 3- Substituted Dihydrobenzothiadiazine Diuretics' RICHARD 31. TAYLOR A N D ?JOHKG. T'OPLI~S Hzoloyical urd L'hetiiical IZeseai ch UzaiszotLs of the Scheritig C 'orporatzon, Blooitcfield, S e w J e m q
Receited September 21, 1961 The effect of change in the 3-substituent of 3lt-6-chloro-3,4-diliydro-7-sulfarn~ 11,2,4-benzothiadiazine 1,l-dioxides on natruretic activity in the rat and the dog \\as investigated. R represented diverse structural types. A wide range of activities \vas observed. Several compounds 4 ere found to be. considerably more potent than hydrochlorothiazide. In particular, alkyl, haloalkyl and aralkyl groups were associated u i t h a high level of activity. In general it was found that those substituents which had a favorable effect on activity were hydrophobic 111 character. When these were modified to groups of a more hydrophilic nature, natruretic activity was reduced. Substituents M hich lacked a hydrogen on the a-Carbon atom resulted in compounds of a low- order of activity, even in thow (*lasseswhere activity was otherwise good.
1;ollowing the observation 011 the marked diuretic potency of (ichloro-3,4-dihydro-7-~ulfamyl-l,2,4-benzothiadiazi1~e 1,l-dioxide (hydrochlorothiazide, 111), 2 sex-era1 reports h a w h e i i published 011 the synthesis of related compounds aiid their diuretic properti (1) Portions of this work a c r e presented at the l:j6tii iricctins of t h e :Inierican Clieuiical Society, -4tlantic City, N. J., 1959, and a t the Fall Meeting of the Ariierican Society for Pliariiiacology and Experimental Therapeutics, Rliami, Florida, September, 1969. 12) G. de Stevens, L. H. Werner, A. Halamandaris, and 9. Ricoa, Jr., Experienlia, 14, 4W
(1958).
13) 11. 12. Goldberg and K. Hnang. Fed. Proc., 18, 396 (1959). J . 11. XIclIanub, A . Scriabine, S. Y. Pan, 1%'. hl. hIcLaniore, and G . I). Laiibiicii, .I/,straels of Papers, 1Yfith M e e t i n g , Am. Chem. Soc., 1959, 13-0. ( 5 ) C. T. Holdrege, K. B. Babel, and L. C. Cheneg, J . .4nz. C h e m . S O C . , 81, 4807 (193'3). (6) W. J. Close, L. R . Snett. L. E. Brady, J. 1%. Short, and &I, Yernsten, zbid., 82, 1132 (1960). (7) J. H. Short arid 1:. Biermacher, ibid., 82, 1135 11960). (8) L. H. lt-erner. .A. Halamandaris, S. Ricca, Jr., L. Dorfman, and G . d r Stol-ens. ibid., 82, 1161 (1960). (9) H. L. Yale, K. Losee, and J. Bernstein, ibid., 82, 2042 (1960). (IO) F. C. Novello, 5. C. Bell, E. L. A. Abrams, C. Ziegler, and J. &I. Spragiie, .I. O w . Chem., 26, 965 (1960). (11) F. C. Novello, S. C. Bell, E. L. A. Abrams, C. Ziegler. and J. XI. Spragiie, ibid., 26, 970 (1980). ( 1 2 ) C. Pelayo, J. Iriarte, and H. J. Ringold, ibid., 26, 1067 (1960). ( 1 3 ) B. Issekutz Sen., N. Jobbhgyi, E. Osrald, and PI. SzBkely, Arch. I n t e r . P'iini.,n. YhBmp., 132, 281 (1961). (4)
March 1962
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Although a large body of information has been made available, little has been published in the realm of detailed studies of structureactivity relationships apart from the work of Lund and Kobinger.14 Their studies covered a broad range of compounds including a series of substituted 3,4-dihydro-1,2,4-benzothiadiazine 1,l-dioxides (hydrochlorothiazide and analogs). In this paper we have considered the effect of changes in the group R in 3R-G-chloro-3,4-dihydro-7sulfamyl-1,2,4-benzothiadiazine1,I-dioxides (I) on natruretic activity in rats and dogs. Synthesis.-3R-G-Chloro-3 ,A-dihydro -7 - sulfamyl- 1,2,4- benzothiadiazine 1,l-dioxides (I) were synthesized, with fern exceptions, by the condensation of 5-chloro-2,4-dieulfamylaniline (11) n-ith an aldehyde, RCHO, or the corresponding acetal in a suitable solvent, usually in the presence of an acid catalyst. Full details of this work have been reported. l5
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Pharmacological Methods A. Bioassay in the Dog (Intravenous Route).-Healthy mongrel dogs of either sex were anesthetized with 50 mg./kg. of vinbarbital administered intravenously. Mammalian Ringer's solution was infused into the cephalic vein a t a rate of 0.3 ml./min. to replace urine excreted and to facilitate administration of drugs. No additional fluid was given before or during the expcriment. Both ureters were exposed and cannulated with polyethylene tubing. Urine flow was recorded on smoked paper by means of a Thorp impulse counter and a drop recording unit. Total urine samples were collected every 20 min. for measurement of both volume and sodium concentration. When a uniform rate of urine excret'ion was achieved, solutions of the compounds were administered intravenously through the infusion tube. Compounds were first dissolved in 0.5 ml. of 1.0 N NaOH and the pH of the solution adjusted to 7.5 to 8.0 by back titration with 1.0 N HCl. The test for each dog was divided int.0 four 20 min. intervals with the standard (hydrochlorothiazide) and test drug administered alternately. Drug response was defined as the difference in urine output (m1./20 min.) between the control period preceding treatment and the drug period. Relative natruretic activity of (14) F. J. Lund and W. Kobinger, Acta Pharm. Tos.,Kbh., 16, 297 (1960). (15) J. G. Topliss, hl. H. Sherlock, F. H. Clarke, M. C. Daly, B. W. Pettersen, J. Lipski, a n d N. Spcrber, J . 070. Chem.. 26, 3842 (1961).
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the test drug iu terms of the standard was c.al(:ulat,ed hy a. “const,ant sta,ndard” method described by Finney.lfi The results of this assay n-ere used to provide estimat’esof dose levels used in the oral test,s:. B. Bioassay in the Dog (Oral Route).-Healthy male mongrel dogs weighing 8 to 15 kg. were maint.ained on :t diet of canned dog food and a bulk-forming agent. The dogs were offered thc food once daily except on the treat,ment day when food and water were \vit,hheld until the experiment was completed. On treatment’ days bladders m-ere emptied by catheterization and, aft,er oral administration of drug in capsule form, the animals w-ere placrd in individual metabolism mgrs. After 5 hr. the: dogs wero again catheterized and total urine voliime measured. Relative activity was det,ermined in crossover experiments as described by Finney.17 C. Bioassay in the Rat (Oral Route).-Male Charles River rats (175 to 225 g.) were used in it modified Lipschitz procedure.’* In the afternoon of the day preceding treatment (approximately 17 hr. prior to drug), 25 ml./kg. of water was administered by intubation to 60 rats which were then deprived of food and ttdditional water. On the treatment day the nnimals were subdivided int.o 6 groups of 10 eavh. Threr groiips rrcrivrd hydrochlorothiazide per os a t doses of 0.1, 0.1, :ind 1.(i mg./kg. i n 25 nil./kg. of 0.9 , alinc anti the rcniainirig groups received the test drug at. dose levels designed t,o produce similar natruretjic effect.
