Antiimplantation agents: Part III. 1,2-Diaryl-4,5-polymethylenepyrroles & 1,2-diaryl-4-oxo- & 1,2-diaryl-4-hydraxy-4,5,6,7-tetrahydroindoles

Abstract

2-Phenacylcycloalkanones(3) and anilines give rise to polymcthylcricpyrroles(4). Pyrrolopipcridinc(10) is likewise obtained from 2-phenacylpiperidotie (9). 2-phenacylcycli]hcxanc-1,3-dioncs undergo condensation with anilines to form 1,2-dinryl-4-oxo-4,5,6,7-tetrahydroindoles (15) and with a variety of other amines to give 28, while 2-acetonyldimedone and p-fluoroaniline afford 32. Some members of 15, and 28a and 32 are reduced to alcohols 20, 29 and 33 respectively. Attempted dehydration of 20d and acylation of 33 lead to the formation of dimers 21 and 34, while hydrogenolysis of the former transforms it to 22. 15c and 15n are converted into azepinones 24c and 24a via oximes 16c and 16a. 24a is aminoalkylated to 24b and reduced to 27.4c and 15c undergo Mannich reaction at β-position of the pyrrole ring to form 5 and 18a, while I5n is attacked at a position a to the C = 0 group giving a mixture of 18b and 19b. Perhydroindoline 36 is obtained from 2-allyldimedone. l,2-Diary)-4-acetyl-5-methylpyrroles 38a and 38b made available from triketone 37 are reduced to alcohols 39a and 39b. Several compounds of the study exhibit antiimplantation activity in the rat, among which the ethers 4m, 4n and 4p of l-(p-hydroxyphenyl)-2-phenyl-4,5-polymethylenepyrroles, l,2-diaryl-4-oxo-4,5,6,7-tetrahydroindoles (l5e, 15n. 15w and 15z), l,2-diaryl-4-hydroxy-4,5,6,7-tetrahydroindoles [20a, 20d (C 6924-Go) arid 20c] and the desoxy derivative 22 of 224 are effective at a dose of 10 mg/kg p.o. x 6 days or less. Compounds 4p (MED₁₀₀ 1 mg), 20d (MED₁₀₀ 2mg) and 22(MED₁₀₀ 1 mg) show no dissociation between antiimplantation and estrogenic activities. Detailed studies on C-6924 reveal that it owes its activity to weak estrogenic-antiestrogenic properties.