Diuretic Agents - American Chemical Society

2 Structure-Activity Relationships of Aminobenzoic Acid Diuretics and Related Compounds (1)

Downloaded by UNIV OF NEW SOUTH WALES on August 11, 2015 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0083.ch002

O. B. TVAERMOSE NIELSEN and P. W. FEIT Leo Pharmaceutical Products, 2750 Ballerup, Denmark

In a series of papers (2-10) during the nineteen-seventies, we presented some of our results based on a more or less systematic structural alteration of the sulfamoylbenzoic acid diuretics in order to elucidate the structural requirements for high-ceiling diuretic a c t i v i t y . When we started this work, for reasons previously discussed (3), the only existing high-ceiling sulfonamide diuretics were the N-substituted 4-chloro-5-sulfamoylanthranilic acids represented by furosemide (Formula 1). Although the diuretic characteristics of furosemide were quite different from those of the thiazides or the thiazide-type diuretics, thereby reflecting a different site of action in the nephron, i t still shared structural features with the latter compounds. Thus, furosemide f i t the structural requirements for diuretic activity of the benzenesulfonamides and related bicyclic compounds originally proposed by Sprague (11). He predicted that an unsubstituted sulfamoyl group, an activating group represented mainly by chloro and trifluoromethyl and an electronegative substituent (which might be part of a condensed ring system) should be present in the molecule and have the mutual positions reflected in furosemide.

Our f i r s t approach was to move the substituted amino function (which is not part of Sprague's predictions) to the 3-position, with almost complete retention of diuretic activity (2). More surprisingly, replacement of the chlorine atom by various other groups in both the 2-substituted (4, 5) and the 3-substituted 0-8412-0464-0/78/47-083-012$05.00/0 © American Chemical Society In Diuretic Agents; Cragoe, E.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2.

NIELSEN

AND

13

Aminobenzoic Acid Diuretics

FEIT

(3, 6, 7, 8) sulfamoylbenzoic a c i d d i u r e t i c s , was found to enhance the d i u r e t i c potency. The most potent compounds (Formula 2) were those i n which an unsubstituted or s u b s t i t u t e d phenyl group was l i n k e d to the 4 - p o s i t i o n by a group X, which represents NH, 0, S, SO, S0 , CH or CO. These 4-substituents are not merely new a c t i v a t i n g groups" i n the sense t h a t Sprague described, s i n c e replacement of chloro by phenoxy or phenylthio i n some s e l e c t e d t h i a z i d e s and t h i a z i d e - t y p e d i u r e t i c s l e d to compounds which were not d i u r e t i c (12). The p r e d i c t i o n s of Sprague, although s t i l l of value as f a r as the t h i a z i d e - t y p e d i u r e t i c s were concerned, were found not to account f u l l y f o r the s t r u c t u r a l requirements of the high-ceiling diuretics. 2

2


11

X = NH,

0, S, SO, 1

R = NHR ,

1

OR ,

which R

1

S0 , 1

SR ,

CO

2

C^R

1

in

preferably i s

η-butyl, benzyl, methyl or

CH ,

2

furyl-

thienylmethyl

When placed i n the 3-position, many v a r i a t i o n s of the sub s t i t u e n t R i n formula 2 c o n t r i b u t e to high potency. However, when l o c a t e d i n the 2 - p o s i t i o n , the only a c t i v e compounds are those where R i s r e s t r i c t e d to a s u b s t i t u t e d amino f u n c t i o n , p r e f e r a b l y the 2-furylmethylamino group. Bumetanide (Formula 3) was s e l e c t e d f o r f u r t h e r i n v e s t i g a t i o n and shown (13) to be 40 to 60 times more potent than furosemide; t h i s was a l e v e l of potency e x h i b i t e d i n the dog assay by many compounds of formula 2. I t s u t i l i t y i n c l i n i c a l p r a c t i c e has since been e s t a b l i s h e d (14). NHCH CH CH CH 2

H N0 S ' 2

2

2

3

COOH

2

3 The compounds of formula 2, i n which X represents carbonyl and R a s u b s t i t u t e d amino f u n c t i o n , are not i s o l a b l e due to a pHdependent e q u i l i b r i u m i n aqueous s o l u t i o n . At p h y s i o l o g i c a l pH, the e q u i l i b r i u m favors the cyclodehydration products, i . e . , the b e n z i s o t h i a z o l e dioxides of formula 4. I t has been suggested (5>, 6), however, that the potent d i u r e t i c a c t i v i t y (one f o u r t h to one tenth of that of bumetanide) observed a f t e r a d m i n i s t r a t i o n of these b e n z i s o t h i a z o l e s to dogs i n v o l v e s the i n t e r a c t i o n of the corresponding 4-benzoylsulfamoylbenzoic a c i d s (Formula 5) with

In Diuretic Agents; Cragoe, E.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.


14

DIURETIC

AGENTS

the r e c e p t o r which i s p o s s i b l e because of the dynamic e q u i l i b r a t i o n i n plasma. Thus, the potency of the b e n z i s o t h i a z o l e dioxides (Formula H) appears to be due to t h i s remarkable prope r t y . For the corresponding 3-alkoxyr- or 3-alkylthio-4-benzoyl5-sulfamoylbenzoic a c i d s , the e q u i l i b r i u m i s t o t a l l y to the s i d e of the benzoyl compound (8); t h i s might e x p l a i n why compound 6 (Table I) i s one of the most potent, h i g h - c e i l i n g d i u r e t i c s that we synthesized. Since t h i s compound shows s i g n i f i c a n t d i u r e t i c a c t i v i t y i n the dog assay a f t e r an o r a l dose of only 1 yg/kg, i t i s 5 to 10 times more potent than bumetanide ( 8_).

TABLE I u r i n a r y E x c r e t i o n i n a 3 hr. P e r i o d f o l l o w i n g I.V. A d m i n i s t r a t i o n of Compound 6 to Dogs, Expressed f o r V o l . i n ml/kg and f o r E l e c t r o l y t e s i n mEq/kg.

Treatment mg/kg

control

0.001 0.01 0.1

Vol.

1 k

25 38

Na

+

0.10 0.7 2.5 h.k

K

+

o.i6 0.28 0.53 0.97


Cl"

o.o8 0.7 3-5 *.9

2.

NIELSEN

f^*yS>£

X = NH, 0, S, CO Il


15


A N D FETT

1

1

R = NHR , OR , SR

1

i n which R

H a C O s S ^ ^ ^ COOH

preferably i s n-butyl,

Y

benzyl or furylmethyl

1

Another d i s c o v e r y was that a c t i v e d i u r e t i c s of the type represented by formula 7 could be obtained when the sulfamoyl group was replaced by the s t e r i c a l l y s i m i l a r mesyl group (°J · Various 3-substituents c o n t r i b u t e to the comparatively high potency o f these compounds; whereas, v i r t u a l l y the only 2-subs t i t u e n t allowed i s the 2-furylmethylamino group. These observa t i o n s encouraged the i n v e s t i g a t i o n o f the i n f l u e n c e o f other s u b s t i t u e n t s i n the 5 - p o s i t i o n . A s u i t a b l y s u b s t i t u t e d amino f u n c t i o n , p r e f e r a b l y a formamido group i n place o f the sulfamoyl group (Formula 8), l e d to a c t i v e d i u r e t i c s (10). 0, S, CH , CO 2

1

1

1

1

NHR , OR , SR , CHsR i n which R p r e f e r a b l y i s η-butyl, b e n z y l , f u r y l methyl o r t h i e n y l m e t h y l . 1

H, lower a l k y l , NEfe, NH-lower a l k y l ,

lower

alkoxy

Table I I shows the data obtained with one o f the most potent compounds with t h i s p a r t i c u l a r s t r u c t u r a l a l t e r a t i o n . Compound 9 was found to be approximately one tenth as potent as bumetanide. D i s a p p o i n t i n g l y , the e l e c t r o l y t e e x c r e t i o n p a t t e r n was s t i l l s i m i l a r to that o f bumetanide. The corresponding 2,4disubstituted-5-acylaminobenzoic a c i d s were, however, i n a c t i v e . X = NH, 0, S, CO 1

1

R = NHR , OR , SR

1

i n which

p r e f e r a b l y i s η-butyl o r benzyl R2 = OH, NHg, NH-lower a l k y l


R

1

DIURETIC

16

AGENTS


TABLE I I U r i n a r y E x c r e t i o n (Average o f 3 Values) i n a 3 n r . Period f o l l o w i n g I.V. A d m i n i s t r a t i o n o f Compound 9 to Dogs, Expressed f o r V o l . i n ml/kg and f o r E l e c t r o l y t e s i n mEq/kg.

HJjHN^^/^COOH 0

9 Treatment mg/kg

control

0.1 0.25 1.0 5.0

Vol.

1 9 18 22 32

Na

Cl"

+

0.10 1.0 2.1 2.5 3.7

0.16 0.2k

οΛι 0.49 0.83

0.08 1-3 2.6 3.1



2.

NIELSEN AND

FEiT


17

In a d d i t i o n , i s o p h t h a l i c a c i d d e r i v a t i v e s o f formula 10 were prepared (15). Some o f them exerted moderate d i u r e t i c a c t i v i t y ; however, again, the c h a r a c t e r i s t i c e l e c t r o l y t e e x c r e t i o n p r o f i l e of bumetanide was observed. The above b r i e f survey o f p r e v i o u s l y reported r e s u l t s o f s t r u c t u r a l m o d i f i c a t i o n s i n benzoic a c i d d i u r e t i c s r e v e a l s that our e f f o r t s had been d i r e c t e d toward compounds i n which the c a r b o x y l i c a c i d f u n c t i o n remained i n t a c t . I f such a f u n c t i o n i s present i n b i o l o g i c a l l y a c t i v e molecules, i t s a c i d i c character u s u a l l y has, f o r known reasons, an e f f e c t on a c t i v i t y and/or potency. Therefore, i t was considered to be o f i n t e r e s t to i n v e s t i g a t e whether a carboxyl f u n c t i o n i s a p r e r e q u i s i t e f o r high-ceiling diuretic activity. Consequently, d e r i v a t i v e s i n which t h i s group was replaced by other f u n c t i o n s were synthesized. 3,4-Disubstituted-5-sulfamoylbenzenesulfinic a c i d s and s u l f o n i c a c i d s o f formula 11 (Table I I I ) were prepared from the corresponding c a r b o x y l i c a c i d s . Conversion o f t h e i r azides by means o f a C u r t i u s degradation f u r n i s h e d the corresponding a n i lines. The l a t t e r d e r i v a t i v e s were converted to the s u l f o n y l c h l o r i d e s v i a d i a z o t i z a t i o n and the Meerwein-reaction. These were subsequently hydrolyzed to s u l f o n i c a c i d s or reduced to s u l f i n i c a c i d s . I t can be seen from Table I I I that these rather strong acids possess potent d i u r e t i c a c t i v i t y . Their d i u r e t i c p r o f i l e i s q u i t e s i m i l a r to that o f bumetanide; however, they have a s h o r t e r duration o f a c t i o n . The corresponding" 2 , 4 , 5 - t r i s u b s t i t u t e d a c i d s were not i n v e s t i g a t e d s i n c e , 15 years p r e v i o u s l y , the s u l f i n i c a c i d analogue o f furosemide had been found by us to be devoid o f a c t i v i t y a t a dose o f 10 mg/kg i n the dog assay. In c o n t r a s t , 3-butylamino-4-chloro-5-sulfamoylbenzenesulfinic a c i d was found to be d i u r e t i c a t a dose o f 1 mg/kg. A s e r i e s o f 3,4-disubstituted-5-sulfamoylbenzylamines was synthesized (16). In the dog assay, many of these compounds e x h i b i t e d h i g h - c e i l i n g d i u r e t i c a c t i v i t y i n the range o f potency from that o f furosemide to that o f bumetanide. Therefore, an extended s e r i e s o f benzylamines o f formula 12 (see Table IV) having the 3-, 4-»·, and 5-substituents o f bumetanide was preparecj i n order to e l u c i d a t e the i n f l u e n c e o f the N-substituent(s) i n the benzylamine moiety on d i u r e t i c a c t i v i t y . S e l e c t e d members, o f t h i s s e r i e s are tabulated i n Table IV. I t appears that many R and R s u b s t i t u e n t s , such as hydrogen, lower s t r a i g h t chain a l k y l , a l l y l , benzyl, f u r y l m e t h y l , pyridylmethyl and unsubstituted as w e l l as s u i t a b l y s u b s t i t u t e d phenyl, c o n t r i b u t e to high potency. Disubs t i t u t i o n , as exemplified by N,N-dimethyl, Ν,Ν-diethyl and some N - a l k y l , N-hydroxyethyl d e r i v a t i v e s , a l s o i s an allowed s t r u c t u r a l m o d i f i c a t i o n . I n c o n t r a s t , i n c o r p o r a t i o n o f a n i t r o g e n atom i n a r i n g system to provide d e r i v a t i v e s o f p i p e r i d i n e , morpholine and Ν'-substituted piperazine r e s u l t s i n compounds which are i n a c t i v e at the doses t e s t e d . Likewise, s u b s t i t u t i o n with branched a l k y l , a c y l , carbamoyl or N-substituted carbamoyl groups g e n e r a l l y decreases or abolishes d i u r e t i c a c t i v i t y .


DIURETIC AGENTS

18

TABLE I I I


U r i n a r y E x c r e t i o n i n a 6 n r . Period f o l l o w i n g I.V. A d m i n i s t r a t i o n to Dogs o f 1 mg/kg Expressed f o r V o l . i n ml/kg and f o r E l e c t r o l y t e s i n mEq/kg.

H

e

N O

a

S ^ ^ SO H(Na) n

11 η

Control (extreme values from 108 exp.)

Vol.

1

Cl

k.2

0.05 0Λ5

O.3O

0.06 0.28

37

4.1

1.02

5-3

4.7

1.05

4.5

0.3-

2

Na"

0.06

0

NHC Ife

0

NHCH C H5

2

0

SC H9 4

2

29

4.0

1.15

1.7

0C4lfe

2

34

3.0

1.31

5-2

0

NHC He

3

22

2.6

0.62

3.1

0

NHCH C H5

3

48

4.3

0.91

6.6

0

•a

3

35

3.3

0.91

4.1

CH

4

2

2

e

4

2

e



2.

NIELSEN AND

FEiT


19

Various 3- and 4-substituents, found i n the s e r i e s of benzoic a c i d s of formula 2 to c o n t r i b u t e to h i g h - c e i l i n g potency, were incorporated i n a s e r i e s of compounds i n which the v a r i a t i o n of the benzylamine moiety was r e s t r i c t e d to s e l e c t e d N - s u b s t i t u e n t s . Since the i n f l u e n c e of these N-substituents d i d not deviate from that observed i n the s e r i e s of bumetanide analogues, only the r e s u l t s obtained with compounds of formula 13 having the benzylamino n i t r o g e n atom s u b s t i t u t e d by phenyl are given i n Table V. As p r e v i o u s l y observed with the.benzoic a c i d d i u r e t i c s of formula 2, groups such as R 0, R S or R NH (where R i s η-butyl, benzyl, f u r y l m e t h y l or thienylmethyl) placed i n the 3-position enhanced the d i u r e t i c a c t i v i t y . Likewise, phenyl attached to the 4p o s i t i o n through the well-known l i n k s , NH, 0, S or CHp, a l s o was found to c o n t r i b u t e to the potent h i g h - c e i l i n g d i u r e t i c a c t i v i t y of the benzylamine s e r i e s . A number of 2,4-disubstituted-5-sulfamoylbenzylamines having as the 2-substituent the outstanding 2-furylmethylamino group of furosemide and r e l a t e d a n t h r a n i l i c a c i d s were found to be i n a c t i v e . T h i s l a c k of a c t i v i t y might w e l l be due to an i n a d m i s s i b l e s t r u c t u r a l m o d i f i c a t i o n . However, a f t e r a d m i n i s t r a t i o n of se l e c t e d 3-substituted benzylamines to dogs, the presence of the corresponding benzoic a c i d s i n the urine has been demonstrated qualitatively. Consequently, the question a r i s e s as to whether the d i u r e t i c response f o l l o w i n g treatment with 3-substituted benzylamines should be explained s o l e l y on the b a s i s of metabolic transformation to the corresponding benzoic a c i d d i u r e t i c s of formula 2. The marked d i f f e r e n c e i n d i u r e t i c a c t i v i t y between the 2- s u b s t i t u t e d and the 3-substituted benzylamines could be due only to the repressed metabolism of the 2 - d e r i v a t i v e s due to the s t e r i c e f f e c t of the o r t h o - s u b s t i t u e n t . On the other hand, the above mentioned e f f e c t s on d i u r e t i c a c t i v i t y may be accounted f o r by the s i m i l a r d i f f e r e n c e s between the 2- and the 3-substituted d e r i v a t i v e s i n the 5-acylaminobenzoic s e r i e s and between the 2- and 3- substituted-4-chloro-5-sulfamoylbenzenesulfinic a c i d s e r i e s . Furthermore, the i n c o n s i s t e n c y between the observed d i u r e t i c a c t i v i t i e s and the r a t e at which the subject benzylamines (Table IV) would be expected to be metabolized, might support the view that the 3-substituted benzylamines possess i n t r i n s i c d i u r e t i c activity. The only conclusions we dare to draw from the r e s u l t s of our research during more than a decade i n the e x c i t i n g f i e l d of d i u r e t i c s are that numerous s t r u c t u r a l a l t e r a t i o n s of d i s u b s t i tuted sulfamoylbenzoic a c i d d i u r e t i c s l e d to compounds with h i g h l y potent h i g h - c e i l i n g d i u r e t i c a c t i v i t y , and that the 3>4-disubstituted members of t h i s s e r i e s are l e s s s e n s i t i v e to such a l t e r a t i o n s than are the 2,4-disubstituted members. F u r t h e r e x p l o r a t i o n i n t h i s area might s t i l l , i n our o p i n i o n , uncover benzene r i n g s u b s t i t u e n t s or s u b s t i t u t i o n patterns l e a d i n g to compounds with high-ceiling diuretic activity. Acknowledgment - The authors are g r e a t l y indebted to the


20

DIURETIC

AGENTS

TABLE IV


Urinary E x c r e t i o n (Mean o f 2 Values) i n a 6 n r . Period f o l l o w i n g I.V. (when marked with an a s t e r i s k p.o.) A d m i n i s t r a t i o n to Dogs of 1 mg/kg, Expressed f o r V o l . i n ml/kg and f o r E l e c t r o l y t e s i n mEq/kg.

R

R

2

3

Control (extreme values from 108 exp.) H methyl ethyl n-propyl isopropyl allyl CH C(CH )=CH n- b u t y l isobutyl sec-butyl tert-butyl isopentyl n-hexyl CH CH 0H CH CH0HCH CH CH NEt methyl ethyl n-propyl methyl ethyl isopropyl CH CQH5 CH C H -4-Me CH C H -3-Cl 2

3

2

2

2

3

2

2

2

2

2

e

4

2

e

4

2

H H H H H H H H H H H H H H H H methyl ethyl η-propyl CHgCI^OH CH CEfeOH CH CH 0H H H H 2

2

2

K+

Cl"

0.05 0.45

0.06 0.30

0.06 0.28

t.5

0.81 0.35

2.6 2.4 2.4 2.6 0.7 3.7 2.1 1.6 0.2 0.4 1.2 0.2 0.6 0.3 1.1 0.1 2.6 1.2 0.6 0.4 1.9 2.0

Vol.

Na

0.3 4.2 23 19 17 *17 12 29 20 8 3 5 *7 3 9 3 9 1 21 10 *4 3 13 15 33 3 *11

+

1.5 2.0 1.9 0.8 3-5 1.4 1.4

O.k o.k

1.1 0.3 1.1 0.3 1.0 0.1 2.1 1.0 0.5 0.5 1.3 1.5 3-1 0.4 1.1

0.48

0.67 0.32 1.3 0.35 0.42 0.30 0.09 0.27 0.13 0.75 0.18 0.39 0.05 0.48

0.37 0.21 0.18 0.32 0Λ7 1.02 0.16 0.24

k.5

0.5 1.4


2.

NIELSEN

Table IV

AND

(Continued)

CH c H -3-0H (H C H -4-0Me CH CgH5 2

4

e

2

4

e


2

CoH -2-Me C H -4-Me CQH -2-CF C H -3-F C H -3-Cl C H -4-Br C H -2-0H CeH -4-0H C H -2-0CH C H -3-0C H 4

e

4

4

e

3

4

e

4

e

4

e

4

e

4

e

4

4

3

2

5

Vol.

Na

Η Η methyl

7

6

0.8 0.8 0.8

0.22

11

0.4-0

0.6 1.3 1.0

Η

19

2.8

0.86

1.9

Η

16

1.0

0.31

1.1

Η

25

2.6

0.67

2.9

Η

16

1.7

0.46

2.1

Η

2

0.3

0.11

0.2

methyl

7

0.6

0.38

0.7

methyl

7

0.9

0.26

0.9

*.5

1.15 0.45 0.23 0.09 0.15

33

Η Η Η Η Η Η Η Η Η Η Η

21

9 5 2

Ό Ν •CH

Ο" 3

2

3

3

T

2

Η Η Η Η

2

0.11

5Λ

3.7 0.7 0.2 0.3 0.2

1.9

0.2

0.12

0.2

5

0.7

0.48

1.1

3

0.2

ο.3ΐ

0.2

3

0.4

0.22

0.3

2 1

0.3 0.1 0.7 1.0

0.14

0.1 0.1 0.7 1.0

3

•CH CH OH

0.25

0.2 0.2

2

3

2.0 0.8 0.2 0.5 0.2 1.1 0.5 1.2 0.2 0.2

+

0.37 0.14 0.39 0.32 0.18

13 6 14

c °

+

Κ

Cl"

R3

Ο

COCH CONH CONHCH CONHC H

21


FEiT

8 8

0.10

0.59 0.39

0.5

1.5


22

DIURETIC

AGENTS

TABLE V


u r i n a r y E x c r e t i o n (Mean o f 2 Values) i n a 6 h r . P e r i o d f o l l o w i n g I.V. A d m i n i s t r a t i o n to Dogs o f 1 mg/kg, Expressed f o r V o l . i n ml/kg and f o r E l e c t r o l y t e s i n mEq/kg.

X

R

Control (extreme values from 108 exp.)

0 0 0 0 0 0

NHCH CH=CH NHCH C=CH NHCH CH=CHCH NHCH CH CH CH NHiCHg^CHs 2

2

2

2

3

2

2

2

3

NHCHSCQHS

0

JQ^

NHCHs

0 S

NHCHSCQHS

NH CHg CH CH CH

NHCIfeC H5 NHd^CEfeCH CHQ NHCHgCeHs OCH CH CH CH OCHgCglL^

2

2

2

e

2

2

2

2

3

+

K

+

Cl"

Vol.

Na

0.5 4.2

0.05 0.45

0.06 0.50

0.06 0.28

5 5 7 55 4 25

0.5 0.5 0.9 4.5 0.5 5-0

0.51 0.15 0.45 1.15 0.20 1.5

0.5 0.4 0.9 5.4 0.4 5-8

12

1.4

0.52

0.9

28

5-2

Ο.85

2.2

20 11 7 19 14 16

2.4 1.5 1.0 2.8 1.9 2.1

0.68

2.4 1.0 0.7 2.0 1.4 2.0

0.46

0.55 0.64

0.61 0.4o



2.

NIELSEN

AND

FEIT


23

staff of the Department of Pharmacology and to the Huntingdon Research Centre, Huntingdon, England, for the diuretic screening. Literature Cited 1. Presented i n part at the 174th National Meeting of the American Chemical Society, Division of Medicinal Chemistry, Chicago, I l l i n o i s , August-September, 1977. 2. F e i t , P. W., Bruun, H. and Nielsen, C. Κ., J. Med. Chem. (1970), 13, 1071. 3. F e i t , P. W., J. Med. Chem. (1971), 14, 432. 4. F e i t , P. W. and Nielsen, O. B. T., J. Med. Chem. (1972), 15, 79. 5. F e i t , P. W., Nielsen, O. Β. T. and Rastrup-Andersen, N., J. Med. Chem. (1973), 16, 127. 6. Nielsen, O. B. T., Nielsen, C. K. and F e i t , P. W., J. Med. Chem. (1973), 16, 1170. 7. F e i t , P. W., Nielsen, O. Β. T. and Bruun, H . , J. Med. Chem. (1974), 17, 572. 8. Nielsen, O. B. T., Bruun, H . , Bretting, C. and F e i t , P. W., J. Med. Chem. (1975), 18, 41. 9. F e i t , P. W. and Nielsen, O. B. T., J. Med. Chem. (1976), 19, 402. 10. F e i t , P. W. and Nielsen, O. B. T., J. Med. Chem. (1977), 20, 1687. 11. Sprague, J. M. i n "Topics in Medicinal Chemistry," V o l . II, pp. 22-24, Rabinowitz, J. L . and Myerson, R. M . , E d . , Wiley, New York, Ν. Υ . , 1968. 12. F e i t , P. W., Nielsen, O. Β. T. and Bruun, H . , J. Med. Chem. (1972), 15, 437. 13. Østergaard, E . H . , Magnussen, M. P . , Nielsen, C. K . , Eilertsen, E . and Frey, H . - H . , Arzneim. Forsch. (1972), 22, 66. 14. Postgrad. Med. J. (1975), 51, Suppl. 6, "Bumetanide," Hoffbrand, Β. I . and Jones, G . , Ed. 15. F e i t , P. W. and Bruun, H . , U.S. Patent 3,864,385 (1973). 16. F e i t , P. W., Nielsen, O. B. T., Bretting, C. and Bruun, H . , U.S. Patent 4,082,851 (1978). RECEIVED

August 21, 1978.


Diuretic Agents - American Chemical Society

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