Anti-implantation agents: Part I. 1-Arylthiosemicarbazides

Several 1-arylthiosemicarbazides, 2-arylhydrazinothiazolines and 2-arylhydrazinodihydrothiazines have been examined for their antiimplantation activity in rats. Among the active compounds, 4-methyl-1-(3,5-bistrifluorornethylphenyl)thioserni-carbazide (3, C 2696-Go) and the corresponding 4,4-dimethyl (47), ethyl (4), n-butyl (5) and allyl (6) derivatives completely inhibit implantation at doses of 10, 3, 20, 20 and 30mg/kg respectively. The 3,4-dichlorophenyl analogue (32) is effective at a dose of 30mg/kg. 2-(3,5-Bistrifluoromethylphenyl)hydrazinothiazoline (51) and the corresponding dlhydrothiazine (63) show a weaker activity. The biological profile of C 2696-Go has been investigated in detail. It appears to prevent implantation by its antiuterotropic activity and ability to inhibit desiduoma formation

1-Substituted-2,6,6-trimethyl-3-(1-oxo-3-hydroxy-5,5-dimethyl-2-cyclohexen-2-yl)-4-oxo-4,5,6,7-tetrahydroindoles: a novel class of potent hypoglycemic agents

1-Phenyl-2,6,6-trimethyl-3-(1-oxo-3-hydroxy-5,5-dimethyl-2-cyclohexen-2-yl)-4-oxo-4,5,6,7-tetrahydroindole (II) (CGI 14600) is a novel substance with marked hypoglycemic activity in the rat. While structurally very different from sulphonylureas, II has a similar biological profile, including stimulation of insulin release

Antiimplantation agents: Part IV. 4-Benzhydrylidenepiperidines & tetrahydropyran analogues of F 6066

Several α-(4-pyridyl)benzhydrols (8) have been synthesised by Grignard reaction on 4-aroylpyridines (6) or ethyl isonicotinate (7). The quaternary salts,9 of 8 are reduced catalytically to α-(4-piperidyi)benzhydrols (10) which undergo dehydration to benzhydrylidenepiperidines (11). Demethylation of 11c with HBr affords 11d which is further acelylated to provide 11e, an azaisoster of F 6066. Reduction of 9 with sodium borohydride furnishes the tetrahydropyridyl derivatives (12) which undergo acid-catalysed rearrangement to the benzhydrylidenepiperidin-3-ols 13 (14). Treatment of ethyl tetrahydropyran-4-earboxylate with p-anisylmagnesium bromide affords the benzhydrol (19), which is dehydrated to 20. Among the compounds tested, 8b-8d show moderate antiimplantation activity in rats

Synthesis and oral hypoglycemic properties of two 4-oxo-4,5,6,7-tetrahydroindole-3-acetic acids

Condensation of β -acetyl-2-hydroxy-4,4-dimethyl-6-oxo-1-cyclohexene-1-propionic acid(3) with n-butyl and isobutylamines affords the title acids 4 and 5, respectively, which show good oral hypoglycemic activity in normal rats. Acids 4 and 5, are also active in streptozocin-induced diabetic rats. Results of extensive pharmacological and acute toxicity tests are reported

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

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

Antiimplantation agents: Part II. 1,2-Diaryl-1,2,3,4-tetrahydroisoquinolines

1,2-Diaryl-3,4-dihydroisoquinolinium derivatives (5) have been synthesised from N-aryl-N-aroyl-α-phenethylamines (4) and found to exhibit no antiimplantation activity in the rat whereas many of the corresponding tetrahydroisoquinolines (6) are active. Structure-activity relationships have also been studied. 1-(p-Fluorophenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (6u) and its nor derivative (6v) are very potent, while the onho (6g)and lhemeta(6n) fluoro analogues as well as the des-fluoro derivative (6d) are quite active. Extensive biological tests have been carried out on 6g. The enantiomers(+)-6p.HCl and(-)-6g.HCl of 6n have similar activity profiles as that of 6n showing no separation of antiimplantation and estrogenic properties. Diastereoisomeric 2-(2-methyl-2-phenethyl)-1-phenyl-r,2,3,4-tetrahydrpisqquinolines (13a and 13b) show similar properties, while the tetracyclic derivative 19 is inactive. 2-Phenoxyethyl-l-phenyl-1.2,3,4-tetrahydroisoquinpline (26) shows moderate activity, but (α-phenethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline 29 is inactive