2814
VOL. 26
IYHITEHEAI), TRAVERSO, SCLLIV4Nl A N D MARSHALL [CONTRIBUTION FROM T H E
LILLYRESEARCH LABORATORIES]
Diuretics. V. 3,4-Dihydro-l,2,4-benzothiadiazine1,l-Dioxides CALVERT W. WHITEHEAD, JOHN J. TRAVERSO, HUGH R. SULLIVAN, AND FREDERICK J. MARSHALL
Received December I, 1860 The synthesis and properties of thirty new 3-cycloalkene and 3-cycloalkane-3,4dihydro-7-sultamoy1-1,2,Cbenzoth~diazine 1,l-dioxides are described. Correlations between their structure and biological activity confirm previously proposed analogies between similarly 3-substituted 3,4unsaturated and 3,4-dihydro derivatives of the benzothiadiazine 1,l-dioxide nucleus.
This paper describes the synthesis of new cycloalkene and cycloalkane acetaldehydes and the condensation of these aldehydes and cycloalkene carboxaldehydes with 4-amino-6-halo- and 4amino-6-trifluoromethylbeneene-1 ,Bdisulfonamides to yield 3-cycloalkene and 3-cycloalkane derivatives of 3,4-dihydro-l12,4-benzothiadiaaine1,ldioxide. The purpose of this investigation was to confirm the premise of the preceding paper wherein the saluretic and diuretic activities of these 3,4dihydro compounds could be anticipated. Cycloalkanones were allowed to react with cyanoacetic acid to yield 1-cycloalkenylacetonitriles. Catalytic hydrogenation of l-cycloalkenylacetonitriles gave cycloalkylacetonitriles. Acid hydrolysis of cycloheptylacetonitrile, 3-methylcyclopentylacetonitrile, 1-cyclohexenylacetonitrile, and l-cyclopentenylacetonitrile furnished the corresponding acetic acids. Distillation of 1-cyclopentene acetic acid caused a partial conversion of the acid to the lactone 2-ketohexahydrocyclopenta [b] furan. Acid hydrolysis of 1-cycloheptenylacetonitrile and 2methyl-1- or 5-cyclopentenyl-acetonitrile formed only the lactones, 2-ketooctahydrocyclohepta [b]furan and 2-keto-4- or 6a-methylhexahydrocyclopenta [blfuran. The Grignard reagent prepared from 5-norbornylenylmethylbromide was carbonated to yield 5-norbornylenylacetic acid. Acid chlorides were obtained by thionyl chloride treatment of 2-cyclopentene- ;2-cyclohexene, and 3-cyclohexeneacetic acids. The mixture of 1-cyclopentaneacetic acid and its lactone gave a 40% yield of l-cyclopentenylacetyl chloride. N-Methylanilides (I. R1 = COHO)of 2-cyclopentene-, cyclopentane-, 1cyclohexene-, 2-cyclohexene-, 3-cyclohexene-, cyclohexane-, 1-methylcyclohexane-, 3-methylcyclopentane-, cycloheptane-, and 5-norbornyleneacetic acids were reduced to the cycloalkene and cycloalkane acetaldehydes (11) with lithium aluminum hydride. N,N-Dimethylamides (I. R1 = CH3) of 2-cyclopentene- and 1-cyclohexeneacetic acids and lithium diethoxyaluminum hydride gave 2cyclopentene- and 1-cyclohexeneacetaldehydes. Yields from the N,N-dimethylamide were lower than those obtained from the N-methylanilides. The aldehydes were characterized as semicarbazones and 2,4dinitrophenylhydrazones. 5-Norbor(1) 0. Diels and K. Alder, Ann., 460,98 (1928).
nylenylcarboxldehyde' and 6-methyl-5-norbornylenylcarboxaldehyde2 were obtained by the methods described in the literature. The cycloalkene and cycloalkane acetaldehydes and carboxaldehydes were allowed to react with 4-amino-6-chlorobenzene-1,3-disulfonamide, 4amino-6-bromobenzene-l13-disulfonamide, and with 4-amino-6-trifluoromethylbenzene-l13disulfonamide in the presence of mineral acid to afford the 3,4-dihydro-3-substituted-6-sulfamoyl-1,2,4benzothiadiazine-1,l-dioxides (I11 and IV) listed in Tables I11and IV. Attempted catalytic reduction of 6-chloro-3-cyclohexyImethyl-7-sulfamoyl-l12,4benzothiadiazine 1,ldioxide failed to saturate the 3-4 double bond.3 In contrast to this sodium borohydride did reduce this compound as well as 6-chloro-3-cyclopentylmethyl - 7 - ( N - methylsulfamoyl) - 1,2,4benzothiadiazine 1,ldioxidea and 6-chloro-3cyclopentylmethyl 7 sulfamoyl - 1,2,4 - benzothiadiasine l,ldioxidea to yield 3,Pdihydro derivatives. The 3,4-dihydro-3-substituted 7sulfamoyl 1,2,4 - benzothiadiazine 1,l - dioxides are characterized by an intense absorption band in
- -
-
RCH,('ON(('H > ) R i
I
,
'\.
LiAI(OC:H,),H2 lit - C H I
R is shown in Table I1 02
I11 O.,
(2) 0. Diels and K. Alder, Ann., 470,62 (1929). (3) C. W. Whitehead, J. J. Traverso, F. J. Marshall, and D. Morrison J . 078. C h a . , 26, 2809 (1961).
AUGUST
1961
2s 15
DIURETICS. V
TABLE I RCH&ON(CHa)Ri
R
R1
ZCyclopentenyl 1-Cyclohexenyl Cyclopentyl 1-Cy clohexenyl ZCyclohexenyl 3-Cyclohexenyl Cyclohexyl SMethylcyclopentyl 5Norbornylenyl Cycloheptyl 1-Methylcyclohexyl
CHa CHs Car CaH,
Formula
Yield, %
C O H ~ ~ N O 79 CmHi7NO 75 80 CvHioNO Ci&LoNO 80 CeH5 ClsHloNO 82 CSH~ C 1 & N O 90 cas Ci6H&'O 95 CsH6 CI&NO 88 CS& CMHIBNO 95 CsH6 CiaHtaNO 95 C a s CleH23NO 98
B.P. 85 (0.25mm.) 95(0.4mm.) 130 (1 .O mm.) 130 (0.3 mm.) 130 (0,3 mm.) 132 (0.3mm.) 136 (0.4 mm.) 104 (0.08 mm.) 117 (0.08 mm.) 154 (1.Omm.) 151 (4.5 mm.)
C
Calcd. H
N
70.55 9.87 9 . 1 4 71.81 10.25 8.38 6.45 6.11 6.11 6.11 6.05 77 ,88 9.15 79.63 7 .94 i8.36 9.45 5.71 78.32 9.45 5.71
C
Found H
70.04 9.43 8.82 71.32 9.58 8.19 6.59 6.22 6.30 6.20 5.06 77.48 9.12 79.71 8.02 78.51' 9.56 B . 0 0 7 8 . 4 5 9.09 5 . 4 6 ~
the infrared a t approximately 6.2 p and by two pKa's in aqueous 66% N,N-dimethylformamide of 11.0-11.4 and13.0-13.3. These criteria were used to confirm their structures. Rzis shown in Table I11 and RB in Table IV. EXPERIMENTAL
1-Cycloalkenylacefonitr~le~. The folloming 1-cycloalkenylacetonitriles were prepared according to the method described by Cope and c o - ~ o r k e r s . ~ I-CyclohePtenYlaceton~tTile.Yield SI%, b.P. 104' at 11 n'," 1.4808 (reported5 b.p. 121-122' a t 23 mm., na. 1.4821). f-Cyclo~entenylacetonitm'le. Yield 64"1,, b.p. 72-73' a t 10 mm., n": 1.4672 (reported6 b.p. 172-1'75'). 3-Methyl-I- OT 5-cyclopentenylacetonit7ile. Yield SO%, b.p. n'," 1.4488 (reported' b.P. 82' a t 10 mm.7 78" at 10 "., nlz 1.45972). 2-Methyl-I- or 5-cyclopentenylacetoni~r~~e Yield 79% b.p. 83-84' at 11 mm., n'," 1.4672. Anal. Calcd. for C ~ H I I NC, : 79.29; H, 9.15; N, 11.56Found: C, 79.5'7; H, 9.15; N, 11.69. Cycloalklllacetonztriles. A solution of 0.8 mole of the I-cycloalkenylacetonitrile in 200 ml. of ethanol was hydrogenated over 2 g. of 5% palladium-on carbon with hydrogen a t 50 lbs. per sq. inch and at room temperature. The catalyst was separated by filtration and the cycloalkylacetonitrile was distilled. 3-Melhylcyclopentyhcefonitrile. Yield 97% b.p. 79' a t 10 mm., n'," 1.4411. Anal. Calcd. for CSHKN:C, 77.99; H, 10.63; NI 11.37. Found: C, 78.34; H, 10.86; X I 11.36. CycloheptyIacetonitrile. Yield 88%, b.p. 102" a t 10 nlm-, no: 1.4654. Anal. Calcd. for CsH,,N: N, 10.24. Found: N, 10.14. Acid hydrolysis of the c?lcloalk?llacetonilriles and C?/cl* alkenylacetonitriles. A solution of 0.8 mole of the cycloalkyl acetonitrile or cycloalkeiiylacetoIlitrile in 200 ml. of diosane and 400 ml. of conrd. hydrochloric acid was boiled under reflux for 24-48 hr. The dioxane was distilled under reduced pressure and the organic layer was extracted into ether. The ether solution was extracted with 2% sodium hydroside solution. Acidification of the basic aqueous layer yielded the carboxylic acid which was dried and distilled. The ether layer was evaporated and the residue was distilled to yidd the lactones of the 1-cycloalkenylacetic acids. (4) A. c. cope, A. A. pAddieco, D, E. \nyte, and s, A. Glickman, Org. Syntheses, 31, 25 (1951). (5) W. C. McCarthy and T. H. Brown, J. Am. Pharm. Assoc., 43,661 (1954). (6) E. Rohrmann, U.S.Patent 2,520,015 (Chem. Abstr., 45,647h (1951). (7) R. D. Dessi, J. C h a . Soc., 1931, 1216.
N
-~~~~- ..
Cycloheptylacetic acid. Yield 57%, b.p. 146-147" at 10 (reporteds b.p. lG5'at 19 "*)* I-Cyclohezenylacetic acid. l-ield tXir;, n g 1.4852, b.1). 150-1550 at 13 mni. b.p, 1 4 6 at ~ nlm.). I-Cyclopentenylacetic acid nnd 2-ketoherah~~droc~clo~rnln[b]-furan. Yield 41yp, n'," 1.4ii1. The distillate \vas considered to be a misture of almost q u a l parts of l-ryrlopentenylacrtic arid 2nd the lactone 2-krtohc'x:ihydroc!.clopenta [blfuran herniisc of the prearnrc of two rqually intrnsc carbonyl bands. Thr lartone cnrhonyl h i i d n x s :it 5.65 p and the rarbosylic otrhonyl b w d n'ns at 5.84 p . Thp w r 1)osglic grollp was : I ~ s o ill cnvidrllcsc tllr cnrbosylic nrid OH dimer bands in the 3.0-3.2 p rcbgion. An intense C=(: band is present at 6.05 p and a lactone ester hand nt 8.1 p . i l n d . Calrd. for C7Hlo02:C, ti6.56; H, 7.98. Found: C, 66.10. H, 7.94. Sixty-four grams of the misture of rarbosylic arid and lactone was allowed to stand with an csr('ss of thionyl chloride. The mixture was distilled. Aftrr the esrws thionyl chloride was collected, thr carboxylic. acid chloride tx4icvcd to be l-cyc~lo~)entenglarrt~l chloridcb boi1c.d at, 88-1 00' at 10 mm.; yield 25.6 g. or 407'. l'he l:ic-tonc hoilcd at 118-120' at IO nim.; yic,Id 35 g. or 55Cx. Thc lnrtorir w:is insoluble in cold sodium hydroside solution. Y-dlethylcyrlopenfylacetic arid. Yield 58r;, b . p 120-124O
*"
at 10 ".,
1.4472,
Anal. Calcd. for CsH&: C, ( i i . 5 i ; IT, 9.92; 0, 22.51. Found: c, 67.17; H, '3.38; 0. "2.58. b-Ketoocfah?/droellclnh~~ta [blfrtmn. Yicl(i io$;, b.p. 146150" at 10 mni. 2-Keto-&- or 6 ~ - ~ ~ ~ e t h ~ l h e x a h y d r o c . ? / c IblJztran. l n p o l l n ~'it4ti i4
