Joiirnul of LVItdicinal Chcrtiistry, 2970, Vol. lJ, S o . 6' 13 hr, after which the 1)MF \vas removed in
OUCLKJ.
The residue
xi?washed with ahs Et2(), dissolved iii H20, aiid the s o h wab
acidified with HC1. The product was removed by filtration, washed with HpO, and dried. Purification was effected bv recrystri. 3-Benzyloxyhydantoin (43).-A s o h of 36.9 g of beiizyloxyaniiiie and 3X.T g of et,hyl isocyariatoacetate iii 300 ml of ahs Et20 was refluxed for 1.25 hr. The Et& was removed in vucz~o,250 ml of 3.9 JI HC1 in abs EtOH was added to the residiie, aiid the solii \\-as reflrised for 2 hr. About 100 ml of EtOH was evaporated
1071
wider reduced pressure aiid the remainder of t,he soln was refrigerated, yielding 14.6 g of product which was sepd by filtratioii and purified by recrystii.
Acknowledgment.-The aut'hors aish to acknowledge the valuable assistance of Miss Kazimiera Tomeczek and Melvin Auerbach for their contributions in the preparation of some of the compounds described in this publication.
Aminobenzoic Acid Diuretics. 1. 4-Halogeno-5-sulfamylmetanilicAcid Derivatives I'ETEIZ
\v. I"ElT,
HERTL4 BRCUN, A N D CHItIhTIAN I1 g kg iv. >O..i g kg ip, and 2 2 g kg oral.
Experimental Section Chemistry.4 4-Chloro-5-chlorosulfonyl-3-nitrobenzoic Acid. To a mixture of concd H2S04 (450 g ) and HXOJ (225 g. tl = 1 41 it warm Yoln of 4-chloro-.i-c~hlorosulfonylbenzoic avid5 i l l 4 g I (4) .\naiyses ivere perftirrneci 1,s G . (~'tirnaliand \T-, Jigger tif these lahtirattiries. Melting points were coirected a n d taken in open glass capillaries iising a Hershberg apparatus. Anal?tical data are oil-en a s defined in ftiotnote c , Table I: analytical results were ivitiiin ~ t 0 . 2 3 ' 7of ~ calcd vairies. P I cept for *element* ( = t 0 . 4 L Z ) . Technical assistanre was given 11sH . I)aii. naciier. F,Eberwein, and \V. Ychlichtkruil.
METANILIC ACIDDIURETICS
Journal of J1dicinal Chemistry, 1.970, Vol. 13, S o . 6
1073
TABLE I1 PHYSICAL PKorr:Iwri;s OF YHR
R
NO.
Alp. OC
Recrystn solvent
Yieldb
Formula
.\nalysisc
B 1)
246 5 2 4 7 233 239-239 3 229-230 200-201 223-227 209 .i-211 199-200 24.5-24.5 3 228-229
aq EtOH aqEtOH aq EtOH aq LIeOH aq EtOH aq EtOH aqEtOH aq EtOH aq Et011 aq 11eOH
W 70J 2lJ lod
C, H, S C, H, C1, S , S C, H , C1, S C, H, Cl, S , S C, H, C1*, S,8 C, H, S , S C*, H, S , S C, H, C1, S , S
B
212-2 13
aq 11eOH
2Td
C, H, S
CH?CHrCH(CH?j.i iJ
11
184 .5-186
aq EtOH
3P
C, H, S , S*
CHzCHnCH(CH?),
I_,
196-197
aq EtOII
47d
C , H, S , 8
L,
218 3-220 223-224 21.5 .i-216 287-288 dec
aq MeOH
10 19d 3 40d
C, H, S , S C, H, C1, S C, H, S C, H, C1, S, S J
X!
Et n-Pr n-Bu n-Am n-C&13 i-BU i-Am CH2CHEtn CHzCMe3 CH(CHz);
33
CHZCH(CHz)j
43 44 4.5 46 47 48 49 50 .Ii
&lethod"
H I
L 1) 11
C C L,
23 61 6:Jd 34 24J 3.id
L-A
Ll
54
--
,>.)
L-_l
36 57 -58 39
CH?CH(CH,)?C€I?OH CHnCH=CH? (CHn)GHa CHz-2-pyridyl
K B A
H*@
CHnCHz-2-pyridyl
s
1
223-224 dec
CH&H2-4-pyridyl
1-2
2.53-2.54 drc
CHz-2-quinolyl CHzC=CHCH=CHO
h
0
232-23.3 dec 197-198 dec
aq XeOH dil SaHCOIAcOH dil 16 SaHC03dil HC1 2i Y HC130 EtOH, I : 1 2 .Y HC128 EtOH, 1 : 1 DlIF-H!O 14d aq EtOH 40d
A
320-321 dec
DlIF-H?O
280-281 dec
60
61. HC1 62. HC1 63 64 6.i
CH,CC(CH,)C(OH)?;CiOH)Z:
L
C,*, H, X, S C, H, C1, S
J
18*
a - d See corresponding footnotes in Table I. e Dried in air the analytically pure 45 crystalliziiig with 0.5H20 was obtained. calcd 12.30; found 11.89. 0 Dried (10-14 mm) at room temp. h Dried (10-14) at 100" for 16 hr.
f
N:
4-Chloro-3-nitro-5-sulfamylbenzoic Acid.-To well-stirred and amount of boiliiig 2.4 N XaOH. After vooliiig the pptd salt was 4-chloro-5-chlorouulfonylice-cooled aq NHa6 (160 ml, 25Yc "3) collected arid dried (14 mm, 100"). 3-nitrobetizoic acid (90 g j was added during 1 hr. The react'ion 4-Bromo-5-sulfamylmetanilic Acid.-4-Bromo-3-nitro-5-sulniixt'ure was stirred for additional 4 hr and allowed to reach room famylbenzoic acid was reduced using the method described for the temp. The pptd XH3 salt of the reaction product was collected. corresponding chloro compd: yield 67y0; mp 260-262'. Anal. The crude salt was suspended in H?O (320 ml), acidified with (C,H7BrNz04S)C, H, N, S. concd HC1 to pH 1, and the mixture heated to boiling. After N3-Alkylated 4-Chloro-5-sulfamylmetanilicAcids. Method A filtration and cooling the ppt was collected and recrystd ~ H z O ) ; (Table I, Il).-A mixture of 1 (5 g, 0.02 mole), the appropriate 57 g, mp 233-236.5" dec. Anal. (C7H6Cll";zO&)C, H, K, S, aldehyde (0.02-0.022 mole), p-toluenesulfonic acid (0.05 g), and ~1.7 ilcOH (130 ml) was hydrogenated at room temp after addition of 4-Bromo-3-nitro-5-sulfamylbenzoic Acid.-4-Bromo-5-chloroPtO, catalyst. When the Hn uptake became negligible the ppt sulfonyl-3-nitrobeiizoic acid was treated with KH3 using the was filtered off and recrystd from the appropriate solvent and the method described for the corresponding chloro compd: yield catalyst was removed by filtration. Evaporation of the hcOH 65%; mp 242-243'. filtrate and recrystn of the residue gave additional material. -4nal. (CiH6BrNtOeS) C, H, Br*, N, S. 4-Chloro-5-sulfamylmetanilic Acid (1).-A solu of XaHS03 Method B (Table I, 11, III).-Xethod A% was followed except (104 g) in H20 (560 ml) \Tas added dropwise to a boiling suspenthat material was obtained from the AcOH filtrate. sion of 4-chloro-3-nitro-5-sulfamylbenzoic acid (56 g) inHuO (560 Method C (Table 11, III).-3lethod X was followed except that ml) during 1 hr. After stirring and additional refluxing for 1 hr 1070 Pd-C (0.3 g) \+as used as catalyst. 111 some cases additioiial the reaction mixt,ure was adjusted to pH 2 by addition of 4 N HC1 catalyst (0.3 g) was added during the hydrogeiiatioii. and the refluxing continued for 30 min. After cooline the DDt Method D (Table II).-Method C was followed except that was collected and recrystd (HzOj: 33 g ; mp 286-2665'. ilnal. the material was obtained from the AcOH filtrate. (C7H7ClN204Sj C, H, C1, N, S. Method E (Table I).-*% mixture of aiihyd S a salt of 1 (8.2 g, Na Salt of 1.-Compound 1 was dissolved in the theoretical 0.03 mole), the appropriate aldehyde (0.0315 mole), and 3IeOH (45 ml) was refluxed for 20 hr. After cooling the reaction mixture was filtered and to the filtrate S a B H 4 (1.5 g j was added in small ( 6 ) On larger scale preparation excess of liquid XHa was used. The NHs portions while stirring. Then HyO (70 nil) was added and the pH was removed totally in vacuo before addition of H20. (7) GI: calcd 12.63; found 13.26. of the reaction mixture adjusted to 7 by addition of 4 *\- HC1.
..
After ,several est raction. with Et20 the reaction pridrirt \viis pptd from the aq layer by addition of 4 * HC1 I' until pH 3. Method F (Table I).--A holu of anhyd Na salt of 1 12.7 g, 0.01 mole) arid of the appropriate aldehyde (0.01 mole) iii 1IeOH 120 mlj \vas left at room temp for several days u r j alterriativelg-, i'efiiixed for some hr. After cooling pptd S a salt of the Schiff Base \vas cdlected by filtration aiid air-dried. This compd was added i i i miall portion* to a stirred ice-cooled mln of NaBH4 (0.5 g ) iii 2 S S a O H (20 ml). 111 some cases the temp of the reaction mixtiire \vas raised t o approx 30". Then dil HC1 \vas added slo~vly i i i i t i l p H :I-1. The criide pptd material \vas c*ollected aiid iviihhed Tvith H2(). Method G . .V-Benzy1-4-chloro-5-sulfamylmetanilic Acid ( 2J (Table I).- X mixtiire of 1 (5 g) a i d 1 S NaOH (10 nil) vias ad,ji~stetlt t r pIT 7 . 1 by additioii uf 2.4 S SaOH i i s i i i y aii automatic. w i d - p o i i i t titrator. 'To i,he rehiilted sohi BzCl (2.52g) \vas added aiid l.lie lemp (30") atid pH n w e kept constant for 12 hr while Stirriiig. After cooliiig the pptd S a salt of 2 was collected (5.3 yj. The ,-:ik W I S dissolved i i i boiliiig H n O (50 ml) and crude 2 (4.2 g ) pptd by additioii of XcOH (2 ml). Method H. 4-Chloro-~~-ethyl-5-sulfamylmetanilic Acid (43) (Table I).---,\ mixtiire of 1 (2.5 g), Et1 (6.4 g ) : and aiihyd Et014 \vas i,efliixed for 7%hi,. .kfter cooliiig the pptd ethyl 4-chloro-.Vethyl-5-sulfamylmetanilate caollected, washed with EtOH 11 nil), aiitl i,ecryald (EtOH): 1.:35 g; mp 158-161". .inui. (C'~lIll;(~lN?04S) C, H, C1, N . The E t ester (0.9 g ) was saponjficd by heating i i i 2 A' N a O H (8 nil) at 100" for 30 mill. The roolctl soli1 wa, adjusted t,o pII 4 and the ppt collected. The w i d
solid \v:i- redi-4ved i n 1 A' ?iaHCOa ( 5 ml) and crude 43 pptd by adjusting the pH to 4. Method 1. 4-Chloro-.\;-rr-propyl-5-sulfamylmetanilicAcid (44)(Table 11):- .Imixtiire of 1 (20 gi, allyl bromide (12 g), aiiti aiihyd EtOH ivak refliixed for 18 hr. Xfter staiidiiig iii a refrigerator the pptd ethyl 4-chloro-S-allyl-5-sulfamylmetanilate war td (EtOII): 12.1 g; mp 154-155". ..3nul. H, S . Hydrogenation of this ester 11.6 g ) in EtOH (10 ml) wing PtOz catalyst (20 mg) in the usual wity gave after removing of the catalyst and dilution with H.20 ( I O 4c.h~orc~-n'n-propyl-ri-sulfamylmetarii~ale ( 1 .0.i II i;iq 1X)II) yield 0.53 g ; mp 145146". . l r d . C:, El, X . This ester (0.5 g ) was hapoiiifieti l)y heatiiip i i i 1 .V S a O H 17 nil). ilfter rooliiig AcOH was added until pH 4 and t'he pptd crude 44 collected. Method K. ~~'-Allyl-4-chloro-5.sulfamylmetanilicAcid (57J (Table 11).---To :t h o l n of 1 (5 g) in 1 N NaOH ('20 ml) allyl bromide (2.1" g) \va- added aud the reaction mixture stirred at room temp while the p H \vas kept) at 7.4 by additioii of 2.4 S XaOII iisitig an aiitomatic. eiidpoiiit titrator. After the XaOH corisumptioii had beconic iiegligible. crude 57 (1.i g ) was ppt'd by addii of AcOH (2 ml). Method L. .V-~~-Butyl-4-chloro-5-sulfamylmetanilic Acid (45) (Table 11).-- A mixl,iire of 1 (40 g ) , n-BuOH (500 ml), and concd H n S 0 4 (4 nil) \vas refliixed for several days usiiig a water trap. The react ioii w a s controlled b y iimr spectroscopy of taken samples dild with n-BuOH. dignals of the aromatic prot,ons were recorded only. 'rhc W a d ( J I 1 was stopped when the proportioil uf t h c ~
integrals of the 2 doublets of the formed Bu ester of 1 to the integrals of the corresponding signals of the Bu ester of 45 situated a t higher field was about 0.1. NaOH (2 N , 300 ml) was then added and saponificat,ion performed by refluxing for 30 min. After cooling t,he p H was adjusted to 7.5 by addition of concd HC1. After standing the pptd Na salt of 45 was collected and washed with satd NaCl s o h . This salt could be recrystd (HZO). B n a l . ( C 1 1 H l a C l S ~ S a 0 4 S . 3 HC, ~ 0H, ) N, H20. The crude Na salt was dissolved in hot HzO (350ml) and after filtration crude 45 ( X 3 gi was pptd by addn of AcOH (1.3 ml). Method M. 4-Chloro-S-n-hexyl-5-sulfamylmetanilicAcid (47) (Table lI).-A suspensioii of 1 (5 g) in n-CeH130H (35 ml) containing MeS03H (0.05 ml) was refluxed using a water trap. After 2 hr additional n-C6HI3OH (10 ml) and I, (0.2 g ) were added and the refluxing continued for 4 days. ilfter cooling the pptd n-hexyI-4-chloro-N-~r-hexy1-5-sulfamylmetanilate (3.35 g) was collected and washed with n-C6H130H and pet ether. A sample was recrystd (n-C6Hl,0H); mp 108-110'. Anal. (C,9H31ClN,O&) C, H, S . The hexyl ester (2.1 g) was saponified by heating in 2 1V NaOH (10 ml) on a steam bath for 4.5 min. After cooling and extraction with EteO the aq layer was adjusted to pH 7.5 by addit,ion of 4 S HC1. The ppt,d Ya salt of 47 (1.7 g) was redissolved in hot HnO (25 ml), 47 was pptd by addit,ion of AcOH and collected. Method N1. 4-Chloro-S-(2-pyridylethyl)-5-sulfamylmetanilic Acid Hydrochloride (61 .HCI) (Table Il).--A mixt'ure of 1 (5 g), 2vinylpgridine (2.4 g), AcOH (1.2 g), and anhyd MeOH (20 ml) became a clear soln by refluxing. CuC1 (0.05 g) was added and the refluxing continued for additional 2.5 days to ppt 62. The crude 62 was collected, washed with aq EtOH, and, after drying, dissolved in 4 Ar HCl(10 ml). After standiiig in a refrigerator the sepd 61. HCl was collected and washed with MeOH. Method N2. 4-Chloro-S-(4-pyridylethyl)-5-sulfamylmetanilic Acid Hydrochloride (62.HCI) (Table II).-1 (5 g), 4-vinylpyridine (2.1 g), AcOH (1.2 g), and anhyd MeOH (20 ml) were joined to form a cake (exothermic reaction). The mixture was heated on a steam bath for 3.5 hr resiiltiiig in a solution followed by spontaneous pptn of 62. After cooling 62 was collected, washed with lIeOH, and dried. The compd was dissolved in 4 LV HCl (50 ml). After standing in a refrigerator the sepd 62.HC1 was collected. Method 0. 4-Chloro-~V-(2-furylmethyl)-5-sulfamylmetanilic Acid (64) (Table II).-A soln of 1 (55 g) and furfural (22 g) in MeOH (370 ml) was refluxed for 24 hr. After standing for 16 hr XaBHI (13 g) was added in small portions while stirring and cooling in an ice bath. The stirring was cont,iriued for 3 hr while the reaction mixture was allowed to reach room t'emp. Bfter evaporation ill vac the residue was redissolved in HZO (200 nil). Slow adjustment of the sohi to pH 4 by addition of AcOH pptd 64. After atanding in a refrigerator the ppt was collected and washed with HnO t,o give 14.1 g of crude 64. LV-n-Butyl-4-chloro-5-sulfamylanthranilic Acid.-2,4-Dichloro5-sulfamglbenzoic arid (5 g) was treated with n-B~iT\"a (16.5 ml) according to the general method described,' mp 220.5-221' (aq EtOH). Anal. (CiiHi&lXzOjS, HZO) C,H,S. Diuretic Experiments* (Table IV, Figures 1 and 2).-Female ( 8 ) Technical assistance was supplied by Karen X I . Jepsen
r n l / k g rnequlv/kg
50..5
0t--
.
H,O Na*
40.4
,
,,,'
O--K'
,,"
cI-
___._
0,5
1
2
8
L
/+
16 rng/kg i v
Figure l.-Urinary volume and excretion of elect,rolytes duriiig a 3-hr period after intraveuous injection (soln in NaOH) of 45. Each dose level is represented by a single dog.
,'
7,'
0,5
1
2
4
8
16 mg 1 kg PO
Figure P.--Urinary volume and excretion of electrolytes during a 5-hr period after oral administration (gelantine capsules) of 45. Each dose level is represented by a single dog. mongrel dogs weighing fiom 9 to 30 kg vere used. About 16 hr before the expt the dogs were starved, but had H?O available always. The urine was taken by catheter hourly. The S a + , K+, and C1- were determined by flame photometry and potentiometric titration, respectively. The excretion of H,O and the electrolytes during 2 hr before dosage of the test compd served as control of the conditions.
