Non-steroidal antifertility agents.

PIP: About three decades ago a new era in the control of fertility began with the discovery of the steroidal hormonal contraceptive drugs, including estradiol and progesterone. The oral administration of progesterone inhibited ovulation in women, but heavy bleeding had to be controlled by estrogen. The development of a combination of pills dates back to Inhoffen in Germany, who synthesized ethisterone and ethinyl estradiol. Djerassi synthesized 19-norprogesterone and norethindrone, which were more potent than the naturally occurring progesterone. Subsequently, a large number of steroidal contraceptives were developed, of which, the fluorinated derivatives, 21-fluoroprogesterone (1a) and 21-fluoro-17alpha-acetoxyprogesterone (1b) were 2 to 4 times as active as progesterone; 21-fluoro-6alpha, 16alpha-dimethyl-17alpha-acetoxyprogesterone (1c) was 20 times as active as ethisterone. The effort to overcome heavy bleeding led to the synthesis of non-steroidal antifertility agents; aliphatic and allied derivatives; alicyclic compounds; aromatic and condensed systems; and heterocycles. All possible types of non-steroidal potential antifertility agents are reviewed, covering literature up to Chemical Abstracts (C.A.) volume 115 (1991), with occasional C.A. volume 116 (1992) references. A large number of prostaglandins and their derivatives were found to be useful as contraceptives even in mammals. Cloprosterol induced estrus in murrah and swamp buffalos. The prostaglandins El an PGF2alpha, when injected into rats, decreased sperm count and suppressed sperm motility and fertility. A number of prostaglandins were synthesized for evaluation of biological activity. Fluoroprostaglandins were evaluated for the interruption of pregnancy in hamsters (80-90 g body weight). Gossypol and gossypol acetate showed a high degree of antifertility activity in male and female animals up to mammals. Indomethacin administered up to 4 hours following mating decreased the number of implantations and increased premature resorption and mortality in rats; administered 8 hours after mating, it decreased pregnancies by 40%.^ieng

Spectral shift due to source correlation in conventional spectroradiometric measurements.

Keeping in view the recent findings of the spectral shift due to source correlation during propagation of light, a study has been undertaken to analyze the errors which may be introduced in spectroradiometric measurements.

Synthesis and antifertility activity of some new fluorine containing 2-([2-(fluoroaryl)-1H-indol-3- yl]methylene)hydrazinecarbothioamides and 2-(fluoroaryl)-([5-(substituted benzylidene)-4-oxo-2-thiazolidinylidene]hydrazone)- 1H-indole-3-carboxaldehydes.

New fluorine containing 2-(fluoroaryl)-1H-indole-3-carboxaldehydes have been synthesized and subjected to reaction with thiosemicarbazide to give corresponding 2-([2- (fluoroaryl)-1H-indol-3-yl]methylene)hydrazinecarbothiamides which were cyclized in the presence of chloroacetic acid, sodium acetate and substituted benzaldehydes to 2-(fluoroaryl)-([5- (substituted benzylidene)-4-oxo-2-thiazolidinylidene]hydrazone)- 1H-indole-3-carboxaldehydes as potential antifertility agents. In preliminary screening, 2-(4'-fluorophenyl)- ([5-(methylene-3,4-dioxyphenyl)-4-oxo-2- thiazolidinylidene]hydrazone)-1H-indole-3-carbocaldehyde exhibited pronounced antifertility activity. All these new compounds have been characterized by analytical and spectral (IR, PMR, MS) studies.

Studies in spiro heterocycles. Part 4(1): Investigation of the reactions of fluorinated 3-aroylmethylene-indol-2-ones with hydrazine and phenylhydrazine and synthesis of spiro [indole-3,3'-pyrazol]-2-ones.

Reactions of various 3-aroylmethylene-indol-2-ones with hydrazine and phenylhydrazine under exactly similar conditions have been carried out. The reaction with phenylhydrazine has not been investigated earlier. It was found that although the reaction with hydrazine hydrate afforded a spiro derivative viz., spiro[3H-indole-3,3'-(3H)pyrazol]-2(1H)-one, that with phenylhydrazine yielded simply a hydrazone derivative. Representative spiro compounds have been screened for antifertility activity but none was found active at a dose of 10 mg/kg in adult female rats.

Synthesis and central nervous system activities of certain fluorine-containing 3-substituted indol-2-ones.

Several fluorine-containing 3- aroylmethyl -3-hydroxyindol-2-ones (4a-g), 3- aroylmethyleneindol -2-ones (5a-g) and 3- aroylmethylindol -2-ones (6a-g) were synthesized from the corresponding fluorine-containing indole-2,3-diones and appropriate ketones. The compounds were characterized by spectral studies. Representative compounds of each series were tested on mice for CNS activities, viz. analgesic and anticonvulsant and the effects were also observed against amphetamine-induced stereotypy, on conditioned avoidance response and on potentiation of pentobarbitone sodium hypnosis. Of the compounds examined, the greatest degree of activity was observed in 3- aroyl - methyleneindol -2-ones with a pronounced unsaturation in the system.

Triterpene quinone-methides from Gymnosporia montana.

Iguesterin, pristimerin, tingenone, beta-amyrin, beta-sitosterol and maytenonic acid have been isolated from the light petroleum extract of the stem bark and iguesterin, pristimerin, tingenone, beta-amyrin and beta-sitosterol from the root bark of Gymnosporia montana.

Studies in potential organo-fluorine antibacterial agents. Part 6: Synthesis and antibacterial activity of some new fluorine containing 1,3,4,5,7-pentasubstituted dipyrazolo[3,4-b,; 4,3-3]pyridines.

Ten new fluorine containing dipyrazolo [3,4-b;4,3-3]pyridines have been synthesized as possible antibacterial agents. The synthesis involves the condensation of 5-amino-1,3-disubstituted pyrazoles with an appropriate arylaldehyde at 220-240 degrees C. The synthesized compounds have been characterized by their m. p.'s elemental analysis, TLC, IR, 1H-NMR and 19F-NMR. A representative number of compounds have also been screened for their antibacterial activity and most of them were found to inhibit the growth of different bacteria.

Studies of potential organo-fluorine antibacterial agents. Part 5: Synthesis and antibacterial activity of some new fluorine-containing indole-2,3-dione derivatives.

A series of new 1-dialkylaminoacetyl-5/6-fluoroindole-2,3-diones and 3-arylhydrazino-5/6-fluoro-1-morpholinomethylindol-2-ones have been synthesized; the former by the reaction of different secondary amines with N-chloro-acetyl-5/6-fluoroindole-2,3-diones and the latter, by the condensation of substituted phenylhydrazines with 5/6-fluoro-1-morpholinomethylindole-2,3-diones. All synthesized compounds have been characterized by their IR, 1H-NMR and elemental analysis. These compounds have been screened for their antibacterial activity against the Gram positive bacterium Staphylococcus albus and the Gram negative bacterium Escherichia coli.

Effect of phenelzine, a monoamine oxidase inhibitor, on isoproterenol-induced myocardial damage.

The effect of phenelzine on isoproterenol-induced myocardial necrosis was studied in rats. Male albino rats were pretreated with 20 mg/kg body wt of phenelzine, intraperitoneally, on 4 consecutive days. The same animals were given 80 mg/kg of isoproterenol subcutaneously on the third and fourth days of the study. After 48 hr of isoproterenol, ECG was recorded, the animals were killed, and blood, heart, and adrenal glands were removed for biochemical and histopathological studies. Phenelzine returned toward normal the isoproterenol-induced decreased in cardiac glycogen but decreased serum lactic acid only slightly toward normal. The serum enzymes, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT), showed the protective effect of phenelzine. The increase in isoproterenol-induced free fatty acid (FFA) was significantly reduced in the group pretreated with phenelzine. Our studies on adrenal ascorbic acid suggest that the animals pretreated with phenelzine suffered less stress compared to the group treated with isoproterenol alone. Histopathological changes including focal areas of necrosis and characteristic cellular exudation were less marked in the hearts of rats pretreated with phenelzine. S-T segment elevation was more marked in the group treated with isoproterenol only.

Possible psychopharmacological agents. Part 9: Synthesis and CNS activity of some new fluorine-containing 1,2,4-triazolo[4,3-b]pyridazines.

A number of new fluorine-containing 1,2,4-triazolo[4,3-b]pyridazines have been synthesized by the condensation of 4-amino-(4H)-1,2,4-triazole with appropriate fluorinated beta-diketones in glacial acetic acid. All synthesized compounds were characterized by their m.p.'s, nitrogen analysis, IR, 1H NMR and 19F NMR. A representative number of compounds was screened for their CNS activity and found to be mild stimulants.

Possible psychopharmacological agents. Part 7: Synthesis and CNS activity of some fluorinated 2,4,7/8-trisubstituted-3H-1,5-benzodiazepinium monoperchlorates.

A series of new fluorinated 2,4'7/8-trisubstituted-3H-1,5-benzodiazepinium monoperchlorates have been synthesized and characterized by IR and NMR spectral studies. Representative compounds have been screened for their CNS activity viz., behavioural, analgesic, anticonvulsant and antireserpine. 8-Chloro-2-(4'-fluorophenyl)-4-phenyl-3H-1,5-benzodiazepinium monoperchlorate has shown pronounced antireserpine activity.

Possible psychopharmacological agents. Part 3: Synthesis and CNS activity of some new fluorine-containing pyrazolo[3,4-e][1,4]thiazepines.

A series of new fluorine-containing pyrazolo [3,4-e][1,4]thiazepines has been synthesized by the condensation of 5-amino-3/1, 3-substituted pyrazole with appropriate arylaldehydes or ketones and mercaptoacetic acid in dry toluene. All synthesized compounds have been characterized by their m.p.'s elemental analysis, IR, H-NMR and F-NMR. A representative number of compounds has also been screened for their CNS activity and found to act as mild stimulants.