C I a N H J
1 lR’CO1,O
,
C I a h ’ H C O R
2 KMnO4
COOH
CK
I
I1
1. ( R C O , , O
Iloute a 2 . CIS0
I
1 CISO,H
H
Route b
3. Y Z S H
2. YZNH
Iv
111
NaBH,-diglgme
+
AICI, o r h”iBH4-EtOH-H20
0
V
\
soc1,
R I
R“’-\H c--
CO( I. cHOAc
CONHR“‘
VI1
Route a in Scheme I gave the desired amido acid IV in reasonable yield when Y and Z = H, but when Y = CH3, dealkylation occurred on oxidation of 111. The N-methylsulfamy1 compound could be obtained by route b, but the chlorosulfonation step proceeded in very poor yield (ea. 10%). The last two steps of Scheme I proved to be quite time consuming and gave only fair yields. Consequently other more satisfactory procedures were worked out. These are outlined in Scheme 11. The intermediate alkylamino acids VI1 in Scheme 11 were preparcd most coriveniently by ch1orosulfori:Ltioii of 2,4-dichlorobenzoic acid, treatment of the resulting sulfonyl chloride with cold ay amine to give the dichlo-
XI
X
rosulfamyl acid, arid finally by heating this acid with the appropriate alkylamine, according to Sturm’s pr0cedure.j Two methods were used in the preparation of the amino amides IX. The appropriate isatoic anhydride VI11 was treated with the desired amine, either neat or in pyridine solution, or the dichloroamide XI was treated with an excess of the amine a t 60-100”. The latter reaction gave some replacement of the 1-:ts well as of the 2-C1, but the impurity could usually t e separated by recrystallization. The isatoic anhydrides VI11 were prepared in almost quantitative yield by the (5) K. Sturin, \V. Siedel, R . TVeyer, and H. R u s c h i a Chem. Ber., 99, 328 (1966).
888 Journal of Xcrlzcinal Chemistry, 1970, 1-d. 13, 'Yo. ,i
0
IL
H
It"
II H H €I H I3 I1 H I1
H H r-I €I H €I H H I1 €I I€
11
H
11
II 11
H
I1 C
II
I1
H
H 11
I1
I1 II H I% C6H4CII2 11
11 11 L'
H 11 I1
EI I1
Ii H ( 'H 3 II I1 ir II Ei
I1 I1
F(!J7
)
Journal of Medicinal Chewtistry, 1.970, Val. 13, Xo. 5 889
QUINAZOLINESULFONAMIDES
Recrystallization solvent
Vol
Analysis
MP, "C
H, N, C1, S H, N, C1, S H, C1, N, S H, C1, N, S c, H, N C, H, C1, N, S C, H, C1, N, S C, H, C1, N, S C, H, C1, N, S C, H, C1, N, S C, H, N, C1, S
252-254 250-253.5 238-240 241-243 163-165 3 16-3 18 264-267 234-235 221-224 145-153 199-20 1
C, C, C, C,
147-150
C, H, C1, F, N, S
135-137 223-227
C, H, N, C1, S C, H, N, C1, 8
MeOH Dissolve in EtOAc, pptn with 2 vol of EtzO EtOH
256-258 193-195
C, H, N, C1, S C, H, C1, N, S
247-251
EtOAc digestion
163-166
C, H, C1, N, S C, H, C1, N, S
EtOH EtOH DlIF-HpO 2: 1
238-240 216-218 291-293 26 1-263 163-165 204-205
H, H, H, H, C, H, C, H,
140-156 amorphous 281-283 271.5-274, 258-260
e
EtOH or n-BuOH
EtOH EtOH EtOAC-CsHlh 4: 1 EtOH EtOH EtOH EtOH EtOH THF-CsH6 1 :4 EtOAc, then lIeOCH2CHzOH CHCh, then pptn from i-PrOH with EtzO EtOH EtOH-H20 5: 1
CHxOCHzCHzOH-HtO
C, C, C, C,
C1, N, S C1, N, S N, C1, S N, C1, S C1, N, S
Nd
Diuretic activityu Na
K
++++ ++++ ++++ ++++ ++++ ++++ ++ ++ ++ ++ +++ +++ ++ ++ ++ + + + ++ ++ ++ +++ ++ ++ ++++ + ++ +++ ++ ++++ ++++ ++++ + ++ ++ +++ ++ ++ ++ ++ +.+ ++
+++ + +++ + +
++ + +++ + +
+ + +++ +++ +
+ + +++ + ++++ ++++ + +
+ + + +++
2: 1
HOCHJ3fTiOII EtOH EtOH
C , H, N, C1, S C, H,N, C1, S C, H, N, C1, S
CHiOH
241-243
C, H, N, C1, S
EtOH Digested with THF, then with C6H5 EtOH EtOH EtOH EtOAc EtOH HOAc Digested with hot CHBOH H20 EtOH
305-307 269-273
C, H, N, C1, F, S C, H, C1, N, F, S
134-135 302-303.5 257-26W.Q 232-234 222-236 345-3471 294-295
C, H, C1, N, C, H, C1, N, C, H, C1, N, C, H, N, C1, C, H, N, C1, C, H, N, C1, C, H, N, C1,
257 dec 148-151 261-263 273-276 257-259 dec
C, C, C, C, C,
279-287 205-210 305-306
C, H, C1, N, S C, H, C1, N, S C, H, N, C1, S
EtOH CH~OCHZCH~OHCHCb 3: 1 CHiOH EtOH HOCHzCHnOH
-
S S S S S S S
++++ ++++ + + ++++ ++++ + +
H, N, C1, S H, C1, N, S H, N, C1, S H, N, C1, S H, N, C1, S
+++ +++ ++++ ++++ +++ +++ + +
-
-
++ ++++
-
-
++ +++
++
+++ +++ +++ ++ + -
+++ +++ +++ + -
+++ ++++
3-
II
I1 li
of COCl, on the arylamino acid YII glacial HOAc. The dichloroamideh XI were prepared in good yield by reaction of the acid chloride X with an excess of the desired amine at ambient teniperature; usually little or no rrplacemerit of nuclear ('1 occurs under these conditions. The resulting aminoamidrs IX could be cyclized, 111 mimy cahe'i, by both acid- and biw-catalyzed addition of the appropriate carbonyl compound. However, tht, br1-t rrsults were consistently obtained with btrong acid H,SOJ) catalysis in glacial HOAc. either a t room temperature or a t reflux, depending on the individual carbonyl compound or acetal. Acetals generally gave better results than aldehydes, while ketones worked better than ketals. Alost of the aldehydes, ketones. and acetals reacted rapidly with the amino amidea. The only exception was cyclopentanone, which required a much longer reaction time than did most of the other carbonyl compounds, including cyclohexanone. An indirect method was generally used to make compounds with an unsaturated substituent in the 2 position (such as vinyl, allyl, propargyl, etc). Th(. 2-:111yI rompoilrid, for w a m p l r , W:L\ rwdily prcp:trcd b) in
(c2.y.
f ! : j 4 I'
tie1iydrohalogCIi:itiiiK the "-(:2-bronioproI,!-i) dt1riv:it 11 \\ ith 1.3-diazabicj clo [?.:~.O]-.i-norir~~r..~~ S m r studieh of home 2-alkyl-3-o-tolyl derivat1vc.c indiciited that thew is considerable hteric intertictioil betnecw thr. two sribhtituents. i-Chloro-l,",:~.-t-tc.ti.:ihydro-2-me thyl-3-oxo-3-o-tolyl- (i -yuiriazolineiuli'ori:~niidc has two doublets for the ?-)re group and ti\ o quwrttlts for the 2-H group nhen the *pectritm i h r u i i a t room trnipentturr. At 70" the doubling & r c t di-:ippears imd t h o ixxprcted doublet arid (1u:uft.t :ir(' observed Thih temperature effect7 io tJvidrwx, to1 hindered rotation about the S aryl bond :it tiit, :i position due t o tho \t,eric intereactiori of the o-lIe and the 2-11e. Normal peaks are obtained for 'i-chloro-lI2,3,4-tetrahydro-2-methyl-4-oxo-3phenyl - 6- quinazolinesulfonamide where the absence of the 0-11 t' permits free rotation of the P h ring. 7-Chloro-l,2,3,4tetrahydro-2,2-dimethyl-4-0~0-3-0tolyl - 6 -quinazolinrJsulfonamide has two peaks for the geminal Me g r o u p (s
Recrystallization solvent
Analysis
Mp, "C
Vol
HOAc EtOH .\Ie?CO-H~O2 . 5 : 1 EtOH or CHC13 EtOH EtOH i-PrOH EtOH EtoFr
232-239 243-246 178-180 2 07 -2 09 241 -243 183-184 293-296 2778-282
C, H , C1, N,S C, H, C1, N, 8 C, H, N , C1, S H, s,CI, s C, H, N, Cl, S C, H, N, C1, S C, H, N, C1, S C1, s C, H, N, C1 C, H, N, 8 P C, H, N, S
EtOH
26X-270.5
C, H, N, C1,
r-PrOH
216-218
C, H, X, C1, S
9 5 q EtOH PPtn from TBF with EtOAc 9,5% EtOH 957, EtOH 957, EtOH 95% EtOH 9.57, EtOH 95co EtOH 9t5c(, EtOH
21 6-218
C, H, S , C1, S C, H, X, C1, 8
270-278 dec 283-290 dec 250-253 dec 248-249 dec 238-240 289-291 2 16-2 19
C, H, N, C1, S C, H, N, C1, S C, H, C1, N , S C, H, K,C1, S C, H, CI, N , d C, H, Cl, N, S C, H, N , S
DMF-H?O
262-267
C, H, C1, N, S
i-PrOH
241 -248
C, H, C1,
229-230 283-287 202-204 193-19.5
c,
PI;,
-----+++ ++++ ++++ ++ +++ +++ ++ ++ ++
S
S
Diuretic activitya-----Na
I(
+++ ++++ ++++ +++ +++ +++ ++ ++ ++
+++ ++++ ++++ t++ +++ +++ ++ ++ ++
-
-
-
+ ++ ++ + ++ + ++ +-
+ ++ ++ + ++ + ++ +-
-
+ +++ + ++ + ++ +-
++ ++
++ ++
++ ++
957, EtOH 163-165 C, H, C1, N , S CiaHzaCIN304S orat,ed and the thick oil was chromatographed on Si02 using 25% D l I F in CHCL as eluent. Crude reaction product chromatographed on silica using 20Yc I>MF in EtzO. Made by acylation of sulfamyl compound with AcxO in pyridine at, room temperat,ure for 6 hr. Catalytic debenxylation of 2-benzyloxymethyl derivative with 5% Pd-C in T H F at 4.2 kgIcm2. Chromatographed o n SiOz using King closure in D l I F instead of AcOH. 15Yc D M F in EtsO as eliient. 6-C1 replaced by PhCH?. P Not analyzed; ir in accord with structure.
'
which must be nonequivalent. The nonequivalence is due t o the restricted rotation of the o-tolyl group.s The activities of the compounds synthesized in this study, as well as their methods of preparation, are indicated in Tables 1-111. Pharmacology.-The diuretic and saluretic effects of each of the compounds listed in Table I were assayed by the method of Lipschitz, et U Z . ~ Male Sprague-Dawley rats, weighing 125-250 g were used. The animals were allowed to equilibrate for a t least a week in their new environment before they were used in an assay. During this time they were maintained on Purina Laboratory Chow Checkers. Food, but not HzO, was withdrawn 18 hr prior to testing. The animals were placed in HNOs-washed, distilled-H20-rinsed, stainless steel metabolism cages for urine collection following compound and/or vehicle administration. I n these experiments 4 or 5 animals per dose and control, housed individually in small stainless steel metabolism cages, were used. Urine was collected under light mineral oil ( 8 ) Lawrence Colebrook, Chemistrl Department, Unir ersity of Rochester, Rocliester, N P , personal communication ( 0 ) \\ I. I i p ~ c h i t 7 ,Z Hadidian, and A , Kerpcsar, J Phiirmacol Exp. Yhti
. 79, 07 (1943)
for 3 hr. Urine volume was measured, S a + and I
