Syntheses of (4,1-benzoxazepine-3-ylidene)acetic acid derivatives and their inhibition of squalene synthase

Chemical and Pharmaceutical Bulletin

Volumn 50, Issue 1, 2002, Pages 53-58

  Miki, Takashi ^a   Kori, Masakuni ^a   Tozawa, Ryu Ichi ^a   Nakamura, Masahira ^a   Sugiyama, Yasuo ^a   Yukimasa, Hidefumi ^a  

^a TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

Author keywords

(4,1 benzoxazepin 3 ylidene)acetic acid derivative; 4,1 benzoxazepine 3 acetic acid; Active conformation; Conformationally restricted analogue; Hypocholestemic agent; Squalene synthase

Indexed keywords

(4,1 BENZOXAZEPINE 3 YLIDENE)ACETIC ACID DERIVATIVE; 4,1 BENZOXAZEPINE 3 ACETIC ACID DERIVATIVE; ACETIC ACID DERIVATIVE; SQUALENE SYNTHASE; SQUALENE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG; (3,5) 7 CHLORO 5 (2 CHLOROPHENYL) 2 OXO 1,2,3,5 TETRAHYDRO 4,1 BENZOXAZEPINE 3 ACETIC ACID; (3,5)-7-CHLORO-5-(2-CHLOROPHENYL)-2-OXO-1,2,3,5-TETRAHYDRO-4,1-BENZOXAZEPINE-3-ACETIC ACID; AZEPINE DERIVATIVE; ENZYME INHIBITOR;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DRUG CONFORMATION; DRUG INHIBITION; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; ISOMER; NONHUMAN; RAT; ANIMAL; CELL CULTURE; CONFORMATION; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; LIVER; MALE; SPRAGUE DAWLEY RAT; STEREOISOMERISM; SYNTHESIS;

ANIMALS; AZEPINES; ENZYME INHIBITORS; FARNESYL-DIPHOSPHATE FARNESYLTRANSFERASE; HUMANS; LIVER; MALE; MOLECULAR CONFORMATION; RATS; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; TUMOR CELLS, CULTURED;

EID: 0036358769     PISSN: 00092363     EISSN: 13475223     Source Type: Journal    
DOI: 10.1248/cpb.50.53     Document Type: Article

References (12)

1. Part 3 in the scries of studies on 4,1-benzoxazepine derivatives as squalene synthase inhibitors; a) Part 1: Miki T., Kori M., Fujishima A., Mabuchi H., Tozawa R., Nakamura M., Sugiyama Y., Yukimasa H., Bioorg. Med. Chem., 10, 385-400 (2002);
2. b) Part 2: Miki T., Kori M., Mabuchi H., Banno H., Tozawa R., Nakamura M., Itokawa S., Sugiyama Y., Yukimasa H., Bioorg. Med. Chem., ibid., 10, 401-414 (2002).
3. Yukimasa H., Kori M., Tozawa R., Sigiyama Y. (Takeda), Eur. Patent, 645377 (1995) [Chem. Abstr., 123, 256777w (1995)].
4. Tamai M., Yokoo C., Murata M., Oguma K., Sota K., Sato E., Kanaoka Y., Chem. Pharm. Bull., 35, 1098-1104 (1987).
5. 3) of DL-trans-epoxysuccinic acid monoethyl ester did not proceed.
6. Yamamoto M., Yoshitake M., Kishikawa K., Kohmoto S., Yuki Gosei Kagaku Kyokai Shi., 50, 638-651 (1992).
7. Only one spot was detected by TLC analysis of the mixture of 7a and 7b. Separation of the mixture by column chromatography was unsucessful, even when this mixture was converted to acetate or benzoate.
8. We initially tried to synthesize the epimer [(3RS,5SR,αRS)- derivative] of 7a using cesium propionate, which is a reagent for inversion of the configuration of secondary alcohol. Kruizinga W. H., Strijtveen B., Kellogg R. M., J. Org. Chem., 46, 4321-4323 (1981).
9. The mechanism of this elimination is considered to be ElcB.
10. Cohen L. H., Griffioen A. M., Wanders R. J. A., Van Roermund C. W. T., Huysmans C. M. G., Princen H. M. G., Biochem. Biophys. Res. Commun., 138, 335-341 (1986).
11. The active conformation of 5-naphtyl-4,1-benzoxazepine derivative in the crystal of protein-inhibitor complex supports our results. Pandit J., Danley D. E., Schulte G. K., Mazzalupo S., Pauly T. A., Hayward C. M., Hamanaka E. S., Thompson J. F., Harwood U. J., Jr., J. Biol. Chem., 275, 30610-30617 (2000).
12. Davisson V. J., Woodside A. B., Poulter C. D., Methods Enzymol., 110, 130-144 (1985).