Diuretic Agents - American Chemical Society

4 Sulfonamide Diuretics

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on March 9, 2016 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0083.ch004

L. H . WERNER, E . HABICHT, and J. ZERGENYI Research Department, Pharmaceuticals Division, CIBA-GEIGY Corp., Summit, NJ 07901 and Research Department, Pharmaceuticals Division, CIBA-GEIGY Ltd., Basle, Switzerland

More than twenty years have passed since the discovery of the thiazide diuretics. Since then many new developments in this f i e l d have occurred. The discovery of the thiazide diuretics i n 1957-58 was the beginning of a new era in the treatment of edema and hypertension. Prior to the introduction of the thiazide diuretics, one had to rely on the mercurial diuretics and later, on the carbonic anhydrase inhibitors with their well known drawbacks. The carbonic anhydrase inhibitors acted mainly i n the proximal tubule leading to increased urinary excretion of Na , Κ , and HCO and, as a consequence, to metabolic acidosis. At the time the carbonic anhydrase inhibitors were being developed, it was, however, the firm conviction of Drs. Beyer (1) and Baer of Merck Sharp and Dohme that a sulfonamide diuretic could be found that was saluretic, i.e., that increased urinary Na and Cl excretion i n equivalent quantities and therefore would not produce metabolic acidosis, if i t worked at the appropriate site along the nephron. This working hypothesis eventually led to chlorothiazide. It is now known that, depending on the site of action in the nephron, different diuretic profiles can be obtained, ranging from the carbonic anhydrase inhibitors to the thiazides and high-ceiling diuretics as is shown in Figure 1 (2, 3). Chemical structures, representing different types of diuretics have varied to a considerable extent. The structures of these various classes of diuretics are exemplified by the carbonic anhydrase inhibitors, acetazolamide (4) and dichlorphenamide (5), the thiazide saluretic, chloro thiazide (6), the high-ceiling diuretics, furosemide (7), ethacrynic acid (8) and bumetanide (9), the uricosuric diuretic, t i e n i l i c acid (10), and the more recent compounds, muzolimine (11) and MK-447 (12), the last two representing compounds without a sulfonamide or carboxy group (Figure 2). Some of the work that was carried out in our laboratories in the area of sulfonamide diuretics w i l l be presented. The sulfonamide diuretics currently in use are effective and safe; +

+

-

3

+

-

0-8412-0464-0/78/47-083-038$05.00/0 © American Chemical Society Cragoe; Diuretic Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1978.


WERNER ET AL.

Figure 1.

Sulfonamide Diuretics

Representation of sites of action of diuretics in the nephron

TABLE I D i u r e t i c Screen Reference Compounds

Unanesthetized Dog

Hydrochlorothiazide 5.0 mg/kg p.o.

1300 yEq Na/kg/210 min.

Furosemide 5./0 mg/kg p.o.


Bumetanide 0.3 mg/kg p.o.


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

DIURETIC AGENTS

40

Cl Cl

Cl

S0 NH

H N0 S 2

2

2

2


S ' 0

H N0 S

a

2

2

chlorothiazide

dichlorphenamide

^3 H N0 S 2

Cl

CH =Ç-C0—fi

>

2

C H

COOH

2

Cl

2

3

\ — 0CH C00H 2

\-=/

ethacrynic acid

furosemide

Cl

Οχ

Cl

J-4 0CH C00H 2

H N0 S ^ ^ s ^ ^ C O O H 2

2

tienilic

bumetanide

_ /

N

H

acid

2

CH NH 2

CH

Cl

a

Cl muzolimine Figure 2.

MK 447 Various classes of diuretics


2


4. WERNER ET AL.


41

there a r e , however, three u n d e s i r a b l e s i d e e f f e c t s a s s o c i a t e d with the chronic a d m i n i s t r a t i o n of these compounds: (1) potassium d e p l e t i o n , (2) e l e v a t i o n o f serum u r i c a c i d and (3) hyperglycemia. In p a t i e n t s with a normal f a s t i n g blood sugar, i t would appear that the r i s k o f p r e c i p i t a t i n g diabetes i s s m a l l . In p a t i e n t s who already have diabetes, the chance of d i s t u r b i n g the c o n t r o l o f blood sugar i s s u b s t a n t i a l . We hoped that our work would provide compounds e i t h e r with l e s s e f f e c t on potassium e x c r e t i o n o r on blood glucose l e v e l s . The compounds prepared were t e s t e d i n r a t s and dogs; however, only r e s u l t s i n dogs are reported as an i n d i c a t i o n o f the r e l a t i v e potency o f these compounds. Table I shows the values obtained with three standard sulfonamide d i u r e t i c s i n our d i u r e t i c screening using unanesthetized dogs. The values shown i n F i g u r e s 3 to 7 a l s o represent yEq Na/kg/210 min. In our f i r s t approach we decided to study b i - and t r i c y c l i c compounds derived from intermediates which had y i e l d e d h i g h l y active diuretics. I n i t i a l l y , we s t u d i e d compounds derived from the 2-hydrazino-5-sulfamoylbenzoic a c i d (Compound 1) p r e v i o u s l y described by Sturm and co-workers (7) (Figure 3). The hydrazone (Compound 2) derived from phenylacetaldehyde, was only s l i g h t l y a c t i v e . Hydrazines such as compound 3 obtained by c a t a l y t i c r e d u c t i o n o f the corresponding hydrazone were moderately a c t i v e at 5 mg/kg i n the dog. On r e f l u x i n g i n d i l u t e HC1, the hydrazine (Compound 3) c y c l i z e d to the indazolone (Compound 5 ) , which was almost i n a c t i v e . F i s c h e r i n d o l e r i n g c l o s u r e o f the hydrazone (Compound 2) i n a c e t i c a c i d y i e l d e d the i n d o l e (Compound 4) which e x h i b i t e d d i u r e t i c a c t i v i t y a t 50 mg/kg. A l l compounds were administered orally. Reaction o f the 2-hydrazino-5-sulfamoylbenzoic a c i d (Compound 1) with cyclohexanone (Figure 3) followed by c y c l i z a t i o n y i e l d e d the t e t r a h y d r o c a r b a z o l e (Compound 6) which was subsequently reduced c a t a l y t i c a l l y i n t r i f l u o r o a c e t i c a c i d with platinum to the hexahydrocarbazole (Compound 7 ) . Both compounds 6 and 7 had moderate d i u r e t i c a c t i v i t y a t 100 mg and 50 mg/kg i n the dog. Another approach s t a r t e d with 2 , 4 - d i c h l o r o - 3 - n i t r o - 5 sulfamoylbenzoic a c i d (Compound 8, F i g u r e 4 ) . Treatment o f compound 8 with sodium hydroxide y i e l d e d the s a l i c y l i c a c i d d e r i v a t i v e (Compound 9) (13). Reduction of the n i t r o group i n compound 9 followed by f u s i o n with b u t y r i c anhydride o r benzoic anhydride gave the benzoxazoles (Compounds 10a and 10b, respect i v e l y ) . Only the 2-phenyl d e r i v a t i v e (Compound 10b) showed a p p r e c i a b l e a c t i v i t y at' 20 mg/kg i n the dog. S i m i l a r l y , the benzimidazole (Compound 12, F i g u r e 4) was prepared. I t was i n a c t i v e . S t a r t i n g with the 3-amino-4a n i l i n o - 5 - s u l f a m o y l b e n z o i c a c i d (Compounds 13a (9) and 13b), two other benzimidazoles (Compounds 14a and 14b, F i g u r e 4) were prepared, but were a l s o i n a c t i v e as d i u r e t i c s .


DIURETIC AGENTS


42

CI H N0 S 2

2

H NO a

COOH

3700 y e q N a 100 mg/kg

Figure 3.

COOH

+

2400 \ieq Na+ 50 mg/kg

Compounds derived from the 2-hydrazino-5-sulfamoylbenzoic acid


WERNER ET AL.



43

13

a) R=H b) R=NH

a

14 a) Ri=R =H b) Ri=NH Ra-C H (n) 2

a

e

Figure 4.

7

Benzoxazole and benzimidazole derivatives



DIURETIC AGENTS

Figure 5. Tricyclic derivatives



4. WERNER ET AL.


Figure 6. Phenoxazines and phenothiazines


45

DIURETIC AGENTS

46

CH 2CH 2R

(CH ) CH NH 2

2

2

CH =CHC0NH or CH =CH-CN 2

2


2

COOH

H N0 S 2

2

H N0 S

(COOH

27

a) R= C0NH b) R= CN

2

26

a) R=C1 b) R=OC H 6

s

2

2

2

28

2

34

35 ^ 6000 yeq Na 1.25 mg/kg

36

COOH

H N0 S

a) n=l< R-Cl, 0 C H b) n-2j

' V / 3500 yeq Na 1.25 mg/kg

^ 6000 yeq Na 1.25 mg/kg

Figure 7. Monocyclic aromatic sulfonamide derivatives


e

3


4. WERNER ET AL.


47

T r i c y c l i c d e r i v a t i v e s , as shown i n Figure 5, were a l s o investigated. The r e a c t i o n o f o-aminophenol with 4-chloro-5c h l o r o s u l f o n y l - 3 - n i t r o - b e n z o i c a c i d (Compound 15) (14) was o f i n t e r e s t . Depending on the solvent, ethanol o r THF, s u l f o n y l a t i o n occurred on oxygen o r n i t r o g e n . Ring c l o s u r e o f the sulfonamide intermediate i n aqueous NaHCO- y i e l d e d compound 16, whereas the s u l f o n y l o x y intermediate r i n g closed d i r e c t l y to y i e l d the isomeric t r i c y c l i c compound 17 (Figure 5 ) . The s t r u c t u r e o f compound 17 was confirmed by reduction o f the n i t r o group to the amine and r i n g closure to the imidazole d e r i v a t i v e (Compound 18) by r e f l u x i n g i n a c e t i c anhydride. S e v e r a l d e r i v a t i v e s o f these two t r i c y c l i c compounds were prepared, f o r example, compounds 19 and 20, both were i n a c t i v e as d i u r e t i c s (Figure 5 ) . Reaction o f o-acetaminophenol i n aqueous NaHCO- s o l u t i o n with the sulfamoylbenzoic a c i d (Compound 21) (14) gave the N-acetyldiphenylamine d e r i v a t i v e (Compound 22) i n low y i e l d (Figure 6 ) . Whether t h i s compound a r i s e s by d i r e c t r e a c t i o n o f the h i g h l y r e a c t i v e chlorosulfamoylbenzoic a c i d (Compound 21) with the acetamino group o f the phenol or i s formed v i a a Smiles rearrangement o f an intermediate diphenyl ether has not been explored. The main r e a c t i o n product was the phenoxazine (Com pound 23)· S i m i l a r r i n g c l o s u r e r e a c t i o n s v i a a Smiles r e a r rangement to phenoxazines and phenothiazines, e.g., compound 24 to compound 25, have been reviewed by Truce, e t a l (15). The phenoxazine (Compound 23) as well as the deacetylated d e r i v a t i v e had no d i u r e t i c a c t i v i t y . C e r t a i n monocyclic aromatic sulfonamide d e r i v a t i v e s were a l s o studied. S t a r t i n g with the 3-amino-5-sulfamoylbenzoic a c i d (Compound 26, F i g u r e 7) (9, 14), amino group was replaced by a propionamide o r p r o p i o n i t r i l e group under c o n d i t i o n s o f a Meerwein r e a c t i o n (Compound 16) using acrylamide or a c r y l o n i t r i l e , r e s p e c t i v e l y , to y i e l d compounds 27a and 27b. A Hoffmann degradation o f compound 27a gave the aminoethyl d e r i v a t i v e (Compound 28a). Reduction o f the n i t r i l e (Compound 27b) y i e l d e d the aminopropyl d e r i v a t i v e (Compound 28b, F i g u r e 7 ) . The N - a c e t y l d e r i v a t i v e (Compound 29) was i n a c t i v e . The e f f e c t of i n s e r t i n g a three carbon chain i n the 3 - p o s i t i o n o f the sulfamoylbenzoic a c i d moiety o f the bumetanide-type d i u r e t i c s was studied. Compound 30, which i s r e l a t e d to bumetanide, was only weakly a c t i v e , as was compound 31ι which d i f f e r s from furosemide only by a CHp group (Figure 7 ) . T h i s may be r e l a t e d to the increased b a s i c i t y o f the b e n z y l i c amine f u n c t i o n . F e i t and co-workers have shown that the aromatic amino group i n bumetanide can be replaced by an 0- o r S- ether linkage without a pronounced change i n d i u r e t i c potency; however, i n the a n t h r a n i l i c a c i d (furosemide) s e r i e s , the s t r u c t u r a l requirements are more s t r i n gent. I t i s g e n e r a l l y accepted that s u b s t i t u t i o n on the s u l fonamide n i t r o g e n o f sulfonamide d i u r e t i c s lowers the d i u r e t i c t

n

e

American Chemical Society Library 1155 16th St. N. W. Cragoe; Diuretic Washington, D. C.Agents 20031

ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

DIURETIC AGENTS

48 TABLE I I


32

a:

yEq/kg/4 hr Na K

Dose mg/kg p.o.

R NH

b:

NHCH

c:

NHCH C H

d:

NHC H

3

6

6

5

5

+

5000

6.25

2

2

+

Ref.

935

5

slight

5

1000

6.25

2200

400

370

340

Control

(Furosemide)

activity

(18)

TABLE I I I

N H C H

„ sV r - ^ ^

R

^ o

^COOH

2

\ f

33

Dose mg/kg p.o.

It a:

p-Cl

b:

P-NH

c:

p-NH-CH

d:

p-N(CH )

e:

o-NH

5 5

2

3

3

2

Control

2

2-0

5

UEq/kg/4 hr Na

+

very s l i g h t

slight

+

Ref.

activity

5000

800

(18)

activity

inactive

5 2.5

K

5500

900

370

340

(18)



4.

WERNER ET AL.


49

Figure 8. Comparative dose response curves—furosemide vs. compound 32d—Νa* excretion in dogs



Figure 9.

Comparative dose response curves—furosemide vs. compound 32d—K* excretion in dogs


Ω

α

WERNER ET AL.


4.


51

a c t i v i t y . S i n c e we were not p r i m a r i l y l o o k i n g f o r enhanced potency but were i n t e r e s t e d i n t r y i n g to modify some of the other p r o p e r t i e s such as potassium d e p l e t i o n and e f f e c t s on blood glucose l e v e l s , we i n v e s t i g a t e d t h i s area. Compound 32a (Table I I ) i s furosemide, methylation o f the sulfamoyl n i t r o g e n as i n compound 32b d r a s t i c a l l y reduced the d i u r e t i c a c t i v i t y , the N-benzyl d e r i v a t i v e (Compound 32c) r e tained a modest degree of a c t i v i t y . S u r p r i s i n g l y , the N-phenyl d e r i v a t i v e (Compound 32d) was q u i t e n a t r i u r e t i c and appeared to have very l i t t l e e f f e c t on potassium e x c r e t i o n as shown i n Table II. This observation was f u r t h e r explored by i n t r o d u c i n g a s u b s t i t u e n t on the phenyl r i n g attached to the sulfamoyl group of compound 32a. The p-chlorophenyl d e r i v a t i v e (Compound 33a, Table III) was only weakly a c t i v e ; however, the p-aminophenyl d e r i v a t i v e (Compound 33b) proved to be a very a c t i v e d i u r e t i c . Methyla t i o n of the amino group as i n compounds 33c and 33d g r e a t l y reduced the a c t i v i t y ; the 4-dimethylaminophenylsulfonamide (Compound 33d) was a c t u a l l y i n a c t i v e a t the 5 mg/kg dose (Table III). The o-aminophenylsulfonamide d e r i v a t i v e (Compound 33e) was more a c t i v e on a weight b a s i s than the p-aminophenyl d e r i v a t i v e (Compound 33b). Unfortunately, potassium e x c r e t i o n was a l s o elevated. The f i n d i n g that a para- or ortho-aminophenyl group can enhance a c t i v i t y was a l s o a p p l i e d to the 3-amino-5-sulfamoylbenzoic a c i d s e r i e s (Figure 7 ) . Compound 34 had moderate d i u r e t i c a c t i v i t y at 1.25 mg/kg p.o. i n the dog. Both compounds 35 and 36 were a c t i v e d i u r e t i c s (1£, 20). Compound 36 was of somewhat g r e a t e r i n t e r e s t and was a c t i v e i n a dose r e l a t e d sense over a range of 0.02 mg to 1 mg/kg. Thus, a number of compounds of p o t e n t i a l i n t e r e s t had been found and considered worthy of f u r t h e r study. Compound 32d (Table I I ) was of i n t e r e s t because i t appeared to have very l i t t l e e f f e c t on potassium e x c r e t i o n . I t was an a c t i v e d i u r e t i c i n dogs and reached a n a t r i u r e t i c c e i l i n g at a dose of approximately 6 mg/kg. Osmolar clearance increased two-to t h r e e - f o l d , while r e a b s o r p t i o n o f solute f r e e water remained p o s i t i v e i n the dog. F i g u r e 8 shows the dose response curve f o r sodium e x c r e t i o n i n dogs. At higher dosages, sodium e x c r e t i o n l e v e l e d o f f f o r compound 32d, whereas i t continued upward with furosemide. Figure 9 shows the e f f e c t on potassium e x c r e t i o n , which was p r a c t i c a l l y unaffected by higher doses. C l i n i c a l t r i a l s i n normal volunteers, however, f a i l e d to produce any d i u r e t i c e f f e c t s . Compound 33b was a l s o studied i n greater d e t a i l . The d i u r e t i c e f f e c t s i n the dog resembled those obtained with f u r o semide, except that at doses above 10 mg/kg, the e x c r e t i o n of Na , C l " , K and water decreased somewhat (Figure 10). During peak d i u r e s i s , the urine was almost i s o t o n i c . Renal plasma flow +

+


DIURETIC AGENTS


52

Figure 11. Diuretic effects of compound 33e and furosemide in dogs—excretion per dog per 6 hr



WERNER ET AL. Sulfonamide Diuretics


54

DIURETIC AGENTS

and glomerular f i l t r a t i o n rate were only slightly affected. In normal volunteers, doses of 40 to 120 mg produced a rapid onset of diuresis which persisted for 5 to 6 hours, similar to that of furosemide. The natriuretic effect reached a ceiling at the 80 to 120 mg dose and was about equal to 40 mg of furosemide. Compound 33e was a somewhat more potent diuretic in dogs than furosemide. The onset of action was prompt, reaching a peak after 90 minutes and subsiding aft^r 5 to 6 hours. The dose re sponse curves for urine volume, Na , Κ and Cl"" are shown in Figure 11. In normal volunteers, contrary to the results obtained in animal experiments, compound 33e was not a high-ceiling diuretic. An activity plateau was reached at 80-120 mg, two to three times the threshold dosage (Figure 12). Its natriuretic effect at this level was less than that induced by 100 mg of hydrochlorothiazide. Interestingly, this compound did not produce a peak level of excretion, but rather a more constant effect persisting over five hours. This type of diuretic response may be desirable in the treatment of hypertension. Unfortunately, none of the compounds described were potassium-sparing nor did they have appreciably less effect on glucose tolerance; however, no uricosuric effect was observed. This brief overview of some of our work on sulfonamide diuretics illustrates one of the problems we encounter in medicinal chem i s t r y ; namely, that encouraging biological data in animals do not always translate into equally favorable c l i n i c a l results. Acknowledgments - We wish to thank Dr. O. Bîîch, Dr. P. R. Hedwall and Dr. J. Kraetz, Basle, and Dr. M. J. Antonaccio, Dr. W. E. Barrett and Mr. R. Rutledge, Summit, for the pharma cological data and Dr. P. R. Imhof, Basle, for the c l i n i c a l data. Literature Cited 1. Beyer, Κ. Η., Jr., Perspectives in Biology and Med. (1976), 19, 500. 2. Jacobson, H. R. and Kokko, J. P., Ann. Rev. Pharmacol. Toxicol. (1976), 16, 201. 3. Anderton, J. L . and Kincaid-Smith, P., Drugs (1971), 1, 54. 4. Roblin, R. O., Jr., and Clapp, J. W., J. Am. Chem. Soc. (1950), 72, 4890. 5. Beyer, Κ. H. and Baer, J. Ε . , Pharmacol. Rev. (1961), 13, 517. 6. Novello, F. C . , B e l l , S. C . , Abrams, E. L . Α . , Ziegler, C. and Sprague, J. M . , J. Org. Chem. (1960), 25, 965. 7. Sturm, K . , Siedel, W., Weyer, R. and Ruschig, Η . , Chem. Ber. (1966), 99, 329. 8. Schultz, E. M . , Cragoe, E. J., Jr., Bicking, J. Β . , Bolhofer, W. A. and Sprague, J. M . , J. Med. Chem. (1962), 5, 660. 9. F e i t , P. W., J. Med. Chem. (1971), 14, 432. 10. T h u i l l i e r , G . , Laforest, J., Cariou, B. Bessin, P., Bonnet, J. and T h u i l l i e r , J., Eur. J. Med. Chem. (1974), 9, 625. 11. M ö l l e r , Ε . , Horstmann, Η . , Meng, K. and Loew, D . , Experientia


+



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(1977), 33, 382. 12. Affrime, Μ. Β., Lowenthal, D. T., Onesti, G. Busby, P . , Swartz, C. and L e i , Β., C l i n . Pharmacol. Ther. (1977), 21, 97. 13. Liebenow, W., Canadian Patent 952,536 (1974), Chem. Abstr. (1975), 82, P170,430. 14. Feit, P. W., Bruun, H. and Nielsen, C. K . , J. Med Chem. (1970), 13, 1071. 15. Truce, W. E., Kreider, E . M. and Brand, W. W., "Organic Reactions", V o l . 18, p. 99, E d . , W. G. Dauben, John Wiley & Sons, Inc., New York, 1970. 16. Müller, Ε . , Angew. Chem. (1949), 61, 179. 17. Feit, P. W., Tvaermose-Nielsen, O. B. and Bruun, H., J. Med. Chem. (1974), 17, 572. 18. Werner, L . H., U.S. Patent 3,812,104 (1974); Chem. Abstr. (1969), 70, P67908r. 19. Werner, L . H., U.S. Patent 3,927,218 (1975); Chem. Abstr. (1976), 84, P105217p. 20. Werner, L . H., U.S. Patent 3,939,267 (1976); Ger. Offen. 2,349,900 (1974). RECEIVED August 21, 1978.


Diuretic Agents - American Chemical Society

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