Substituted .alpha.-methylbenzyl and tricyclic arylalkyl lactamimides as inhibitors of blood platelet aggregation

Abstract

N-[1-(p-Phenoxyphenyl)ethyl]hexahydro-2H-azepin-2-imine hydrochloride (10) and N-[1-(2-dibenzothienyl)-ethyl]hexahydro-2H-azepin-2-imine hydrochloride (22) were found to inhibit in vitro aggregation of human blood platelets induced by ADP with minimal release of procoagulant platelet factor 3. The compounds were selected from a series of substituted alpha-methylbenzyl and tricyclic arylalkyl lactamimides that were free of hypoglycemic and diuretic effects. Compounds 10 and 22, as well as N-[1-(1-naphthyl)ethyl]hexahydro-2H-azepin-2-imine hydrochloride (I) and N-(2,2-diphenylpentyl)hexahydro-2H-azepin-2-imine hydrochloride (II), were evaluated for effects on ADP-induced platelet aggregation after repeated oral administration to guinea pigs. Compound II (RMI 12,366A) showed in vivo activity in this system 2 h after the last of four daily doses of 100 mg/kg po.

Enantioselective Living Coordinative Chain Transfer Polymerization: Production of Optically Active End-Group-Functionalized (+)- or (−)-Poly(methylene-1,3-cyclopentane) via a Homochiral C1-Symmetric Caproamidinate Hafnium Initiator

“…Recently, a significant breakthrough of the impasse to configurationally stable, homochiral C 1 -symmetric derivatives of I was made possible with our introduction of N-substituted iminocaprolactams as the basis for a structurally versatile new line of “caproamidinate” derivatives of I and II . As shown in Scheme , a large variety of N-substituted iminocaprolactams ( III ) can first be easily prepared on a large scale and in high yield from ε-caprolactam through a two-step process involving O -methylcaprolactim as an intermediate that is simply condensed with a range of primary amines. , For the present report, we chose to prepare and investigate the homochiral N -(1-phenylethyl) derivatives, ( R )-IIIa and ( S )-IIIa , with a specific optical rotation α D 26 = −73.7 and +75.9° ( c = 2, CH 3 Cl), respectively, as both of the required ( R )- and ( S )-1-phenylethylamines are relatively inexpensive and can be reliably obtained in enantiopure large quantities . Finally, the desired new homochiral caproamidinate hafnium derivatives ( S C , S Hf )-1 and ( R C , R Hf )-1 were obtained in high yield, with α D 26 = +31.8 and −31.2° ( c = 1, toluene), respectively, by condensing the respective ( S )- or ( R )- IIIa with Cp*HfMe 3 (Cp* = η 5 -C 5 Me 5 ) according to Scheme…”

“…13 As shown in Scheme 4, a large variety of N-substituted iminocaprolactams (III) can first be easily prepared on a large scale and in high yield from ε-caprolactam through a two-step process involving O-methylcaprolactim as an intermediate that is simply condensed with a range of primary amines. 14, 15 For the present report, we chose to prepare and investigate the homochiral N-(1-phenylethyl) derivatives, (R)-IIIa and (S)-IIIa, with a specific optical rotation α D 26 = −73.7 and +75.9°(c = 2, CH 3 Cl), respectively, as both of the required (R)-and (S)-1-phenylethylamines are relatively inexpensive and can be reliably obtained in enantiopure large quantities. 16 (Cp* = η 5 -C 5 Me 5 ) according to Scheme 4.…”