piperidines and glutarimide

[reaction: see text] Using 5b as a common intermediate, the first asymmetric synthesis of (-)-epiquinamide (4) and a formal asymmetric synthesis of (-)-homopumiliotoxin 223G (2) is described. A key feature of our approach is the flexible introduction of a functionalized C(4) side chain to (S)-3-benzyloxyglutarimide 7 in a regio- and diastereoselective manner. Utilization of a tandem Swern oxidation-Grignard addition strategy efficiently prevented racemization. An unexpected NaN(3)-promoted methanesulfonic acid elimination yielded 17, a reaction which could be useful for the syntheses of 8-dehydrodesmethylpumiliotoxins such as alkaloid 235C (3).

Topics: Alkaloids; Catalysis; Indolizines; Molecular Structure; Piperidines; Piperidones; Quinolizines; Stereoisomerism

A series of 2-benzylglutarimides (4) and their N-methyl analogues (5) were prepared according to the Topliss scheme for the selection of benzyl substituents to maximize anticonvulsant activity. A total of 22 such compounds were subjected to initial (phase I) screening in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazol (scMet) and in the rotorod assay for neurotoxicity. From this series of test compounds, 10 were advanced to quantitative (phase II) testing. Of these, 2-(4-chlorobenzyl)glutarimide (4b) emerged as the most promising anticonvulsant drug candidate by demonstrating both good anti-scMet and anti-MES activity combined with low neurotoxicity after intraperitoneal administration in mice. In drug differentiation tests, 4b was also effective in nontoxic doses against seizures induced by bicuculline, picrotoxin, and strychnine. When compared with the clinically useful drugs phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide, 4b exhibited an overall pharmacological profile most closely resembling that of valproate.

Topics: Animals; Anticonvulsants; Benzyl Compounds; Mice; Piperidines; Piperidones; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Pharmacological activities of N-allyl, N-benzyl and N-o-xylyl derivatives of both 2,6-dioxopiperidine (DOP = glutarimide) and 4-ethyl-4-methyl-2,6-dioxopiperidine [bemegride(BG)] were studied in mice. Convulsant activity, hypnotic activity, anticonvulsant activity, acute toxicity and interactions with some hypnotics were used as pharmacological indexes. N-Benzyl-2,6-dioxopiperidine (ByDOP) and N-o-xylyl-2,6-dioxopiperidine (o-XyDOP) exhibited some hypnotic activity. N-Allyl-2,6-dioxopiperidine (ADOP), ByDOP and o-XyDOP prolonged the pentobarbital (PB)-induced sleep by 2.5-, 9- and 4-fold, respectively, as compared with the control at a dose of 80 mg/kg, i.p. On the other hand, N-allylbemegride (ABG) exhibited convulsant activity at a high dose. N-Benzylbemegride (ByBG) and N-o-xylylbemegride (o-XyBG) also showed some hypnotic and anticonvulsant activities. BG (20 mg/kg, i.p.) shortened the amobarbital (AB)- and thiopental (TP)-induced sleep, whereas ABG (80 mg/kg, i.p.) significantly shortened only the barbital (B)-induced sleep, in spite of showing with 20 and 80 mg/kg, i.p. the prolonging effect on the AB- and PB-induced sleep. At a dose of 80 mg/kg, i.p., ByBG significantly prolonged the phenobarbital (PheB)-, AB-, PB-, TP- and glutethimide (GI)-induced sleep, and o-XyBG also showed the prolonging effect on the PheB-, AB-, TP- and GI-induced sleep. These results indicate that ByDOP and o-XyDOP possess some central depressant effect, ABG has antagonistic effect on the B-induced sleep and that substitution of aromatic groups on the N position of BG reduces the convulsant activity but increases the depressant activity.

Topics: Animals; Anticonvulsants; Bemegride; Central Nervous System; Convulsants; Hypnotics and Sedatives; Male; Mice; Piperidines; Piperidones; Sleep; Structure-Activity Relationship

New glutarimide compounds were synthesized by incorporating piperidine (compounds 1 to 7), diethylamine (8 and 9), morpholine moities (10 to 13), and alkyl derivatives of 3,5 dicyanoglutarimide (14 to 20) at position -1 of the nitrogen atom. Only compounds 1 to 7 at a dose of 8 mg/kg i.p. caused hypermotility, ataxia, tachypnoea and mild tremors in mice. At higher doses (32 mg/kg i.p.), all compounds induced tonic and clonic convulsions, respiratory paralysis and death. The LD50 values of compounds 1 to 20 in mice range from 152 to 488 mg/kg i.p. and for compounds 21 to 23, the p.o. values are 484, 500 and 525 mg/kg. The relative toxicity of compounds 1 to 7 and 14 to 20 showed inverse ratio in their numbers. Basic compounds 21 to 23 at high dose levels (64 mg/kg i.p.) induced only hypnotic depression. No change was observed in organ-wise histopathological study except patchy necrosis at the site of injection of basic compounds. The CNS pharmacological studies were negative with reference to anti-convulsion, analgesic, antipyretic tests by conventional methods except at higher doses (32 or 64 mg/kg i.p.), which exhibited synergistic effects in mice and rats.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Behavior, Animal; Diethylamines; Drug Evaluation, Preclinical; Female; Male; Mice; Morpholines; Piperidines; Piperidones; Structure-Activity Relationship

The effect of depressant/convulsant pair of glutarimides on the isolated spinal cord of the immature rat was examined using extracellular recording. At concentrations of 300 microM the depressant beta-butyl-beta-methyl glutarimide enhanced the response of motoneurones and dorsal root fibres to gamma-aminobutyric acid (GABA) while the convulsant bemegride (beta-ethyl-beta-methyl glutarimide) decreased both responses to GABA. At this concentration both the convulsant and depressant reduced mono- and polysynaptic reflex activity. Neither the convulsant or depressant had prominent direct actions, with only a small hyperpolarization being produced by both glutarimides on dorsal root fibres. The overall depressant or convulsant properties of these glutarimides may be due in part therefore to a differential effect on the postsynaptic action of the inhibitory transmitter GABA. Furthermore, the depressant glutarimide reduced the excitatory effects of L-glutamate and the convulsant reduced the inhibitory effects of glycine on spinal neurones; thus, actions on these transmitters may also contribute to the overall effects of these glutarimides.

Topics: Amino Acids; Animals; Bemegride; Central Nervous System Depressants; Convulsants; Female; gamma-Aminobutyric Acid; In Vitro Techniques; Male; Neurons; Piperidines; Piperidones; Rats; Rats, Inbred Strains; Reflex, Monosynaptic; Spinal Cord

Topics: Animals; Anura; Cats; In Vitro Techniques; Muscle Contraction; Muscles; Neuromuscular Junction; Piperidines; Piperidones; Rats

For purposes of carrying out structure-activity studies on a series of pure R and S enantiomorphs of various para-substituted N-acetyl-alpha-amino-N-phenylglutarimides, we synthesized the p-acetyl, iodo, cyano, ethyl, and n-butyl analogues. These compounds complimented previous R and S isomers (unsubstituted and the p-chloro, methyl, nitro, and methoxyl analogues) synthesized in our laboratories from amino acids of known absolute configuration. The neurotoxic doses (TD50's), anticonvulsant potencies [maximal electroshock seizures (MES) and subcutaneous metrazole (sc Met) ED50's], protective indices (PI = TD50/ED50), and effects on minimal seizure threshold (iv Met) were compared with similar values concomitantly determined for clinically employed anticonvulsants. A parallel relationship was shown between neutotoxicity (TD50) and potency (ED50) for the R and S analogues. In most cases R isomers had a more rapid onset of action and possessed greater neurotoxicity and greater anticonvulsant potency.

Topics: Animals; Anticonvulsants; Ethosuximide; Male; Mice; Phenytoin; Piperidines; Piperidones; Seizures; Stereoisomerism; Structure-Activity Relationship; Trimethadione

Topics: Bemegride; Chromatography; Glutethimide; Imides; Piperidines; Piperidones; Research

Topics: Abnormalities, Drug-Induced; Animals; Female; Humans; Mice; Piperidines; Piperidones; Pregnancy; Pregnancy, Animal; Rabbits; Research; Thalidomide; Toxicology

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Chemistry, Pharmaceutical; Ketones; Leukemia L1210; Neoplasms, Experimental; Pharmacology; Piperidines; Piperidones; Research; Sarcoma 180

Topics: Glucuronates; Glutethimide; Piperidines; Piperidones

Topics: Piperidines; Piperidones

Topics: Cholinergic Antagonists; Hypnotics and Sedatives; Parasympatholytics; Piperidines; Piperidones

Topics: Glutethimide; Piperidines; Piperidones

Topics: Glutethimide; Humans; Imides; Piperidines; Piperidones

Topics: Amobarbital; Animals; Barbiturates; Cell Respiration; Liver; Mitochondria; Piperidines; Piperidones; Rats

Topics: Anticonvulsants; Piperidines; Piperidones; Sleep Wake Disorders

Topics: Piperidines; Piperidones

Topics: Imides; Piperidines; Piperidones