J. Med. Chem. 1991,34, 2702-2708
2702
Studies on Uricosuric Diuretics. 4. Three-Dimensional Structure-Activity Relationships and Receptor Mapping of (Ary1oxy)acetic Acid Diuretics' Hiroshi Koga,* Haruhiko Sato, Takashi Dan, and Bunya Aoki Fuji-gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., 135, 1-Chome Komakado, Gotemba-shi, Shizuoka, 412, Japan. Received February 12,1991 Attempts to develop new (ary1oxy)acetic acids with a better profile of diuretic and uricosuric activities as well as with fewer side effects have produced a series of compounds in which the ring system has been varied. Diuretic screening of these analogues in rats indicated that the great difference in the activity between these compounds might be ascribed to a difference in the ring system rather than that in the substituent effect and that the annulation hypothesis described before is not necessarily applicable to all of these compounds. This prompted us to study the relationship between the structure and the diuretic activity of the (ary1oxy)acetic acids. An active model (receptor model) was created with the indanone moiety of R-(-)-3 and the dihydrobenzofuran-2-carboxylicacid moiety of S-(+)-4. The three-dimensional structure-activity study of known compounds 2-4, and 5a using the active model showed that the degree of fitting to the model is related to the diuretic activity of these compounds. This was also confirmed for compounds 6a, 6b, 9a, loa, lla, 12a, 13a, 14a, 15a, and 16a, and the relation between the structure and the diuretic activity was rationalized qualitatively. With these insights in mind, a modified receptor model was constructed. We believe that this model is useful for a prediction of the activity of compounds not yet synthesized as well as for designing new (ary1oxy)acetic acid diuretics.
Since the discovery of ethacrynic acid (l), many (aryloxy)acetic acid derivatives have been synthesized and evaluated for their diuretic properties.2 Further advance in this class of compounds has been made by the development of tienilic acid (2),2a diuretic with uricosuric activity. Unfortunately, however, this drug has been withdrawn from the market in most countries because of its liver toxicity.
Cl c I,&OCH~COOH R
4
Cl
1: R = COC(= CH2)C2H5
2: R = c0-0
A w 4
5: X = Br Sa: X = CI
c2YH2c*H
0
'6 5
X
CI
M e Y Ph
3
S
Attempts to develop this type of uricosuric diuretics led to the discovery of indacrinone (3),23a tienilic acid analogue 4,2t4and HP-522 (5).275 From these discoveries, it has been suggested that annulation of phenoxyacetic acids (as represented by 1 and 2) leads to a high-ceiling uricosuric.2 Also interesting is that the salidiuretic and uricosuric activities of compound 4 have been found to reside separately in the (+)- and (-)-enantiomers, respe~tively.~ We have studied how to obtain new (ary1oxy)aceticacids with a better profile of diuretic and uricosuric activities as well as with fewer side effects. We have selected tienilic acid (2)as a lead. It is highly conceivable that the liver This work was presented at the 15th Symposium on Structure-Activity Relationships; Nov 6-8, 1987, Tokyo, Japan; Abstract of papers; pp 334-337. Cragoe, E. J., Jr. The (Ary1oxy)aceticAcid Family of Diuretics. In Diuretics. Chemistry, Pharmocology, and Medicine: Cragoe, E . J., Jr., Ed.; Wiley-Interscience: New York, 1983; pp 201-266. deSolms, S. J.; Woltersdorf, 0. W., Jr.; Cragoe, E. J., Jr.; Watson, L. S.; Fanelli, C. M., Jr. (Acylary1oxy)acetic Acid Diuretics. 2. (2-Alkyl-2-aryl-l-oxo-5-indanyloxy)acetic Acids. J. Med. Chem. 1978, 21,437-443. Hoffman, W. F.; Woltersdorf, 0. W., Jr.; Novello, F. C.; Cragoe, E. J., Jr.; Springer, J. P.; Watson, L. S.; Fanelli, G. M., Jr. (Acylary1oxy)acetic Acid Diuretics. 3. 2,3-Dihydro-5-acyl-2benzofurancarboxylic Acids, a New Class of Uricosuric Diuretics. J. Med. Chem. 1981, 24, 865-873. Shutske, G. M.; Setescak, L. L.; Allen, R. C.; Davis, L.; Effland, R. C.; Ranbom, K.; Kitzen, J. M.; Wilker, J. C.; Novick, W. J., Acids. A New Jr. [(3-AryI-l,2-benzisoxazol-6-yl)oxy]acetic Diuretic Series. J. Med. Chem. 1982, 25, 36-44.
toxicity of 2 might be due to the metabolic change of the thienyl moiety in the livere and that the formation of metabolites might be reduced by changing the thienyl group to a phenyl group and constructing more hydrophilic ring systems. With these in mind, we designed and synthesized (ary1oxy)aceticacids with a variety of ring systems (Scheme I),7but the substituents were generally limited to a halogen atom or methyl group from the reported results of structure-activity relationships studies of the (ary1oxy)acetic acid diureticsa2 Annulation to position 3 or 5 of 2 affords (xanthonyloxy)acetic acids 6, which are subsequently annulated to give dihydrofuroxanthone-2-carboxylicacids 9 and Dihydrofuro-1,2-benzisoxazoles11 and 12 are derived by annulation to each ortho position of the oxyacetic acid group of HP-522derivative 7.7b Annulation of phenoxyacetic acids 8 leads to the dihydrobenzofurans 13. The displacement of the methylene group of 11 and 12 by an oxygen atom affords the more hydrophilic compounds 14 and 15,re~pectively.~~ Dihydrofurobenzoxazoles 167bare the isomer of 12 and formally derived by Beckmann rearrangement and annulation of the oxime of 2. The preparation of compounds 11 and 13 has been reported by Plattner et ala,@immediately after we completed the synthetic study. (6) Nelson, S. D. Metabolic Activation and Drug Toxicity. J. Med. Chem. 1982,25, 753-765. (7) (a) Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Koga, H. Studiee on Uricosuric Diuretics. I. Syntheses and Activities of Xanthonyloxyacetic Acids and Dihydrofuroxanthone-2-carboxylic Acids. Chem. Pharm. Bull. 1990,38,1266-1277. (b) Sato. H.; Dan,T.; Onuma, E.; Tanaka, H.; Aoki, B.; Koga, H. Studies on Uircosuric Diuretics. 11. Substituted 7,8-Dihydrofuro[2,3g]-1,2-benzisoxazole-7-carboxylic Acids and 7,8-Dihydrofuro[2,3-g]benzoxazole-7-carboxylicAcids. Chem. Pharm. Bull., in press. (c) Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Aoki, B.; Koga, H. Studies on Uricosuric Diuretics. 111. Substituted 1,3-Dioxolo[4,5-fl-1,2-benzisoxazole-6-carboxylic Acids and 1,3-Dioxolo[4,5-g]-1,2-benzisoxazole-7-carboxylic Acids. Chem. Pharm. Bull., in press.
0022-2623/91/1834-2102$02.50/0 0 1991 American Chemical Society
Studies on Uricosuric Diuretics
Table I. Rat Diuretic Activity for (Ary1oxy)acetic Acids7 no.
structure
6a
wo
Journal of Medicinal Chemistry, 1991, Vol. 34, No. 9 2703 activity scoreb
no.
2
12a
0
&&o
activity scoreb
structure
f
N-0
OH
OH
7
4
9a
15a
1
OH
0 HO
1Oa
P
WH 2
16a
7
CI
OH
lla
4
4
13a
OH
OH
OTest compounds were administered at 100 mg/kg PO to Wistar-Imamichi rata and the relative activity (%) to the control (100%) wm calculated. See Experimental Section for details of test protocol. *To simplify the data, the diuretic resulta were scored according to the following criteria. The scores 0, f, 1, 2, 3, 4, 5, 6, and 7 represent the relative activity of
