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
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( 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 I1 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.
In 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).
Yi,
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I . -i-llethyl-1-piperazinearrtonitrile' 1 +l(Jt 111I-1-piperazine acetonitrilea 3 :
