CONFORMATIONALLY RESTRAINED BETA-BLOCKING OXIME ETHERS - SYNTHESIS AND BETA-ADRENERGIC PROPERTIES OF DIASTEREOISOMERIC ANTI AND SYN 2-(5'-ISOXAZOLIDINYL)-ETHANOLAMINES

被引:18
作者
BALSAMO, A
BRESCHI, MC
CHINI, M
DOMIANO, P
GIANNACCINI, G
LUCACCHINI, A
MACCHIA, B
MACCHIA, M
MANERA, C
MARTINELLI, A
MARTINI, C
MARTINOTTI, E
NIERI, P
ROSSELLO, A
机构
[1] UNIV PITTSBURGH,IST POLICATTEDRA DISCIPLINE BIOL,PITTSBURGH,PA 15260
[2] UNIV PISA,DIPARTIMENTO CHIM BIOORGAN,I-56126 PISA,ITALY
[3] UNIV PARMA,IST STRUTT CHIM,CNR,CTR STUDIO STRUTT DIFFRATTOMETR,I-43100 PARMA,ITALY
关键词
ADRENERGIC DRUGS; BETA-BLOCKING AGENTS; 2-(5'ISOXAZOLIDINYL)-ETHANOLAMINES;
D O I
10.1016/0223-5234(92)90110-M
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The diastereoisomeric N-isopropyl- and N-t-butyl-substituted 2-(5'-(3'-phenyl)- and 2-(5'-(3'-isopropyl)isoxazolidinyl)-ethanolamines (5-8), which can be viewed as conformationally restrained analogs of the corresponding beta-blocking oxime ethers 10 and 11, were synthesized. The relative configurations of 5-8 were assigned by H-1-NMR studies and by the determination of the solid state structure of one of the new compounds (6a). The new isoxazoline derivatives (5-8) were tested both by radioligand binding assays and by functional tests on isolated preparations. Compounds 5a-8a were found to retain, albeit to a lower extent, the beta-blocking properties of the corresponding oxime ethers 10a and 11a, thus indicating that these last compounds may prove to be still capable of interacting with the beta-receptors, even if their C = NOCH2 portion is constrained in a conformationally semi-rigid isoxazoline structure. Possible rationalizations of the results were sought by comparing the conformations and the molecular reactivity of model compounds of the isoxazolines 5-8 and of the oxime ethers 10 and 11.
引用
收藏
页码:751 / 764
页数:14
相关论文
共 38 条
[11]   CRYSTAL AND MOLECULAR STRUCTURE OF 3-PHENYLISOXAZOLIN-5-ONE [J].
CANNAS, M ;
BIAGINI, S ;
MARONGIU, G .
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL CRYSTALLOGRAPHY AND CRYSTAL CHEMISTRY, 1969, B 25 :1050-&
[12]   HYDROCHLORIDE OF 4-CHLORO-ACETOPHENONE-O-(3-TERT-BUTYLAMINO-2-HYDROXYPROPYL)OXIME [J].
CARPY, A ;
GADRET, M ;
LEGER, JM ;
WERMUTH, CG ;
LECLERC, G .
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1980, 36 (JUL) :1715-1718
[13]   CRYSTAL-STRUCTURE OF 9-(3-TERT-BUTYLAMINO-2-HYDROXYPROPOXYIMINO)FLUORENE (IPS 339) [J].
CARPY, A ;
GADRET, M ;
LEGER, JM ;
WERMUTH, CG ;
LECLERC, G .
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1979, 35 (MAY) :1144-1147
[14]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[15]  
CONNOLLY ML, 1985, MS MOL SURFACE PROGR
[16]   SILYL NITRONATES, NITRILE OXIDES, AND DERIVED 2-ISOXAZOLINES IN ORGANIC-SYNTHESIS - FUNCTIONALIZATION OF BUTADIENE, A NOVEL ROUTE TO FURANS AND 2-ISOXAZOLINES AS AN ALTERNATIVE TO ALDOL-TYPE CONDENSATIONS [J].
DAS, NB ;
TORSSELL, KBG .
TETRAHEDRON, 1983, 39 (13) :2247-2253
[17]   THE STRUCTURES OF 2 AUXIN-LIKE COMPOUNDS - 1,2-BENZISOTHIAZOL-3-YLACETIC ACID AND 1,2-BENZISOXAZOL-3-YLACETIC ACID [J].
DOMIANO, P ;
BRANCA, C .
ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS, 1990, 46 :510-512
[18]  
HIMBER J, 1989, METHOD FIND EXP CLIN, V11, P315
[19]  
JACKMAN LM, 1969, APPLICATIONS NUCLEAR, P180
[20]  
JOHNSON CK, 1976, ORNL5138 REP