Potential antidepressants: Saturated side chain amines derived from 6,11-dihydrodibenzo[b,e]thiepin and 4,9-dihydrothieno[2,3-c]-2-benzothiepin

1989 ◽  
Vol 54 (1) ◽  
pp. 235-247 ◽  
Author(s):  
Zdeněk Polívka ◽  
Vladimír Valenta ◽  
Karel Šindelář ◽  
Jiří Holubek ◽  
Miloš Buděšínský ◽  
...  
Keyword(s):  
Alkaline Hydrolysis ◽  
Antidepressant Activity ◽  
Tertiary Alcohol ◽  
Side Chain ◽  
Ethyl Chloroformate ◽  
Hydroiodic Acid ◽  
Phenyl Derivative ◽  
Dihydro Derivative ◽  
Antidepressant Agent ◽  
Phenylmagnesium Bromide

Reduction of IV with hydroiodic acid afforded almost quantitatively the spirocyclic amino sulfide VII, evidently via V and VI. The carbamate II was chlorinated with N-chlorosuccinimide, the product (XII) was reacted with phenylmagnesium bromide and then reduced with LiAlH4 to give the 6-phenyl derivative X of the antidepressant agent hydrothiadene (I). Treatment of 11-methyl-6,11-dihydrodibenzo[b,e]thiepin (XIII) with butyllithium followed by alkylation with 3-dimethylaminopropyl chloride resulted in 6-(3-dimethylaminopropyl) derivative XIV. Reaction of XIV with ethyl chloroformate and the following alkaline hydrolysis gave the 6-(3-methylaminopropyl) derivative XV (mixture of stereoisomers). Reduction of the corresponding olefinic amine and the tertiary alcohol with hydroiodic acid gave the saturated side chain amines derived from 4,9-dihydrothieno[2,3-c]-2-benzothiepin XVIII and XIX. The dihydro derivative of dithiadene XVIII (VÚFB-17 031) proved very effective in a series of tests predictive of antidepressant activity.

Synthesis of Normuramic Acid Carba Analog and Its Glycopeptide Derivative Resistant to β-Elimination Splitting of the Side Chain

2000 ◽  
Vol 65 (11) ◽  
pp. 1726-1736 ◽  
Author(s):  
Miroslav Ledvina ◽  
Radka Pavelová ◽  
Anna Rohlenová ◽  
Jan Ježek ◽  
David Šaman
Keyword(s):  
Ethyl Ester ◽  
Alkaline Hydrolysis ◽  
Benzyl Ester ◽  
Side Chain ◽  
Propanoic Acid ◽  
Hydrolysis Of

Carba analogs of normuramic acid, i.e., 3-(benzyl 2-acetamido-2,3-dideoxy-4,6-O-isopropylidene-α-D-glucopyranosid-3-yl)propanoic acid derivatives (nitrile or esters) 3a-3c were prepared by addition of radicals generated from benzyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-3-O-[(methylsulfanyl)thiocarbonyl]- (2a) or -3-O-(phenoxythiocarbonyl)-α-D-glucopyranoside (2b) with Bu3SnH to acrylonitrile or acryl esters. Alkaline hydrolysis of ethyl ester 3c afforded 3-(benzyl 2-acetamido-2,3-dideoxy-4,6-O-isopropylidene-α-D-glucopyranosid-3-yl)propanoic acid (5). Coupling of acid 5 with L-2-aminobutanoyl-D-isoglutamine benzyl ester trifluoroacetate and subsequent deprotection of the intermediate 6 furnished N-[3-(2-acetamido-2,3-dideoxy-α-D-glucopyranosid-3-yl)propanoyl]-L-2-aminobutanoyl-D-isoglutamine (7).

Synthesis of 1-acyl- and 1-(thioacyl)-4-benzylpiperazines as potential antidepressants

1990 ◽  
Vol 55 (7) ◽  
pp. 1817-1827 ◽  
Author(s):  
Vojtěch Kmoníček ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Benzoic Acid ◽  
Thionyl Chloride ◽  
Antidepressant Activity ◽  
Acid Chlorides ◽  
Phosphorus Pentasulfide ◽  
Antidepressant Agent ◽  
Dimethylaminobenzoic Acid ◽  
Amino Amides

2-Nitro, 3-nitro- and 4-nitrobenzoyl chloride were reacted with 1-benzylpiperazine in benzene in the presence of triethylamine and gave the amides IV-VI, the first of which is considered a bioisostere of the antidepressant agent piberaline (I). 2-Dimethylamino-, 3-dimethylamino- and 4-dimethylaminobenzoic acid were treated with thionyl chloride in benzene in the presence of triethylamine or pyridine, and the acid chlorides formed were reacted in situ with 1-benzylpiperazine affording the amides VII-IX. The amides I and IV-VI were transformed by treatment with phosphorus pentasulfide in pyridine to the thioamides X-XIII. 4-(Dimethylaminomethyl)benzoic acid was reacted with 1-benzylpiperazine in dimethylformamide in the presence of N,N'-carbonyldiimidazole and afforded the amide XIV. Heating of ethyl 5-methylimidazole-4-carboxylate with 1-benzylpiperazine to 200-210 °C gave the amide XV together with the unexpected 1-benzyl-4-ethylpiperazine (XVI). The oily or crystalline bases of the amino amides or thioamides were mostly transformed to crystalline salts and characterized by spectra. Out of the compounds prepared only X (V⁄FB-17 070) and XIV (V⁄FB-17 114) showed indications of efficacy in tests which are considered indicative of antidepressant activity. Compounds VII, VIII, and X appeared to be mildly antidopaminergic - similarly like piberaline (I), and compounds IV, V, XI, XIV, and XV on the contrary showed signs of dopaminominetic activity.

The isolation of 11-oxotetrahydrorhombifoline from Ormosia coutinhoi and a study of its mass spectrum

1967 ◽  
Vol 45 (7) ◽  
pp. 751-757 ◽  
Author(s):  
Stewart McLean ◽  
A. G. Harrison ◽  
D. G. Murray
Keyword(s):  
Mass Spectrum ◽  
Electron Impact ◽  
Mass Spectra ◽  
Equilibrium Theory ◽  
Side Chain ◽  
Fragmentation Reaction ◽  
Quasi Equilibrium ◽  
Molecular Ion ◽  
Dihydro Derivative ◽  
A Minor

11-Oxotetrahydrorhombifoline (I) has been isolated from the alkaloidal extract of the bark of Ormosia coutinhoi, and its dihydro derivative II has been prepared. An examination of the mass spectra of these compounds and of their 3,3-d2 derivatives has led to the elucidation of the course of the major electron impact induced fragmentations undergone by the molecules. The main fragmentation of I leads to loss of C3H5 from the side chain to form an ion of m/e 221, with a minor path involving a central fission of the molecular ion to form an ion of m/e 150. The mass spectrum of II shows that the loss of C3H7 to form the ion of m/e 221 is a minor process, the main fragmentation reaction involving a central fission to form an ion of m/e 152 analogous to the ion of m/e 150 from I. This change in the spectrum is shown to be consistent with predictions based on the quasi-equilibrium theory of mass spectra.

scholarly journals Anxiolytic and Antidepressant Effects of the Hydroethanolic Extract from the Leaves of Aloysia polystachya (Griseb.) Moldenke: A Study on Zebrafish (Danio rerio)

2019 ◽  
Vol 12 (3) ◽  
pp. 106 ◽  
Author(s):  
Nayara Costa de Melo ◽  
Brenda Lorena Sánchez-Ortiz ◽  
Tafnis Ingret dos Santos Sampaio ◽  
Arlindo César Matias Pereira ◽  
Fernando Luiz Pinheiro da Silva Neto ◽  
...  
Keyword(s):  
Folk Medicine ◽  
Anxiolytic Effect ◽  
Antidepressant Activity ◽  
Ultra Performance Liquid Chromatography ◽  
Positive Control ◽  
Antidepressant Effect ◽  
Main Compound ◽  
Anxiogenic Effect ◽  
Antidepressant Agent ◽  
Hydroethanolic Extract

Medicinal plants such as Aloysia polystachya are often used in the treatment of psychiatric diseases, including anxiety- and depression-related humor disturbances. In folk medicine, A. polystachya is used to treat digestive and respiratory tract disturbances, as a sedative and antidepressant agent, and as a tonic for the nerves. This study aimed to evaluate the antidepressant and anxiolytic effect from the hydroethanolic extract from the leaves of Aloysia polystachya (HELAp) in zebrafish. The extract was analyzed through ultra-performance liquid chromatography-mass spectroscopy (UPLC-MS) and the main compound detected was acteoside. HELAp was administered orally (10 mg/kg) and through immersion (mg/L). The anxiolytic activity was evaluated through the scototaxis (light–dark) test using caffeine as an anxiogenic agent and buspirone as a positive control. The parameters assessed were: period spent in the white compartment (s), latency (s), alternations (n), erratic swims (n), period of freezing (s), thigmotaxis (s), and risk evaluation (n). The antidepressant effect was evaluated through the novel tank diving test using 1% ethanol, unpredictable chronic stress, and social isolation as depressors; fluoxetine was used as a positive control. The parameters assessed were: period spent at the top of the tank, latency, quadrants crossed, erratic swim, period of freezing, and distance of swam. The main chemical compound of HELAp was acteoside. The administration of the extract on zebrafish managed to revert the anxiogenic effect of caffeine without impairing their locomotion. Additionally, the treatment exerted antidepressant activity similarly to fluoxetine. Overall, the results suggest a significant anxiolytic and antidepressant activity to the extract, which is probably due to the presence of the major compound, acteoside.

Enolic Ortho Esters. VII Involvement of Magnesium Halides as Lewis Acids in the Reaction of Grignard Reagents with 1,6-Dideoxy- 1,1-ethylenedioxy-2,3,4-tri-O-methyl-D-xylo-hex-5- enopyranose and its 6-Phenyl Derivative: a Correction

1998 ◽  
Vol 51 (8) ◽  
pp. 681 ◽  
Author(s):  
David J. Collins ◽  
Angus I. Hibberd ◽  
Brian W. Skelton ◽  
Allan H. White
Keyword(s):  
Single Crystal ◽  
Lewis Acids ◽  
Titanium Tetrachloride ◽  
Grignard Reagents ◽  
Ortho Ester ◽  
X Ray ◽  
Phenyl Derivative ◽  
Methylmagnesium Iodide ◽  
Ortho Esters ◽  
Phenylmagnesium Bromide

The known aldehyde methyl 2,3,4-tri-O-methyl-α-D-gluco-hexodialdo-1,5-pyranoside (9) was converted in eight steps into the 6-phenyl glucose-derived enolic ortho ester (Z)-1,6-dideoxy-1,1-ethylenedioxy- 2,3,4-tri-O-methyl-6-phenyl-D-xylo-hex-5-enopyranose (22), the geometry of which was established by a single-crystal X-ray study. Treatment of the 6-phenyl enolic ortho ester (22) with titanium tetrachloride at –78° effected clean rearrangement into (2R/S,4R,5R,6S)-3,3-ethylenedioxy-4,5,6-trimethoxy-2-phenylcyclohexanone (26). Reaction of (22) with methylmagnesium iodide gave (1R,2S,4R,5S,6S)-3,3-ethylenedioxy-4,5,6-trimethoxy-1-methyl-2-phenylcyclohexanol (24), the structure and stereochemistry of which were established by an X-ray study. Reaction of (22) with phenylmagnesium bromide gave (25), the 1-phenyl analogue of (24). The firmly established structure of (24) led to proof both chemically and by X-ray means that the product from reaction of 1,6-dideoxy-1,1-ethylenedioxy-2,3,4-tri-O-methyl-D-xylo-hex-5-enopyranose (5) with methylmagnesium iodide has the hydroxy acetal structure (7) rather than the originally assigned hemiacetal structure (3).

Some 4-Substituted 1-(3-Pyridylmethyl)piperazines with Antihistamine Activity

1994 ◽  
Vol 59 (10) ◽  
pp. 2343-2350 ◽  
Author(s):  
Vojtěch Kmoníček ◽  
Martin Valchář ◽  
Zdeněk Polívka
Keyword(s):  
Acetic Acid ◽  
Nicotinic Acid ◽  
Addition Reaction ◽  
Antidepressant Activity ◽  
Structural Resemblance ◽  
Antihistamine Activity ◽  
Antidepressant Agent ◽  
Pharmacological Testing ◽  
Substituted 1

Several compounds derived from nicotinic acid were prepared within a more extensive programme aiming at the synthesis of new substances with expected antihistamine and antidepressant activity. Some of these compounds display certain structural resemblance with the antidepressant agent piberaline (EGYT 475, Trelibet®, I) and its analogues. The products were used as intermediates for the synthesis of further compounds and most of them were subjected to pharmacological testing. Substituted nicotinic acid piperazides IIa - IId and IVa - IVe were obtained by reactions of nicotinoyl chloride (prepared in situ) with the correspondingly substituted piperazines. Reduction of the piperazides IIa - IId and IVa - IVd with diborane in situ in tetrahydrofuran afforded corresponding 1-substituted 4-(3-pyridylmethyl)piperazines IIIa - IIId and Va - Vd. Whereas the alkylation of 1-(2-pyrimidinyl)piperazine with 2-(chloromethyl)pyridine in ethanol in the presence of triethylamine resulted in compounds Ve, compound Vf was obtained by the addition reaction of 1-(3-pyridylmethyl)piperazine to acrylamide. The piperazides VIe and VIf were prepared by reactions of 2-(3-pyridyl)acetic acid with 1-(2-pyrimidinyl)piperazine or 3-(1-piperazinyl)propionamide in N,N-dimethylformamide in the presence 1,1'-carbonyldiimidazole. A similar procedure starting from nicotinic acid afforded the piperazide IVf. Compounds Vc and Vd showed significant affinity for the histamine H1-receptors (inhibition of binding of 2 nmol/l [3H]mepyramine in membranes from the rat brain: Vc, IC50 = 28 nmol/l; Vd, IC50 = 148 nmol/l). They also proved active in test of histamine aerosol in guinea pigs (PD50 = 4.1 mg/kg p.o. for compound Vc and 2.4 for compound Vd). Results of a more detailed pharmacological testing of these compounds will be published elsewhere.

On the synthesis of 4- and 5-pyrimidinyl-diphenyl-(1-imidazolyl)methanes and their antifungal activity

1980 ◽  
Vol 45 (2) ◽  
pp. 539-547 ◽  
Author(s):  
Zdeněk Buděšínský ◽  
Josef Vavřina ◽  
Leon Langšádl ◽  
Jiří Holubek
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Dimethyl Sulfoxide ◽  
Ethyl Ester ◽  
Ethylmagnesium Bromide ◽  
Dihydro Derivative ◽  
Phenylmagnesium Bromide

On reaction of phenylmagnesium bromide with ethyl ester of 5-chloro-2-methyl-, 5-chloro-2-methylthio-, 5-bromo-2-methylthio-4-pyrimidinecarboxylic acid and 2,4-dimethyl-5-pyrimidinecarboxylic acid (IIa, IIb, IIc, V) corresponding 4-pyrimidinyl- or 5-pyrimidinyl-diphenylmethanols (IIIa, IIIb, IIIc, VI) were obtained. On reaction of thionyl-bis-imidazole with these methanols (4- or 5-pyrimidinyl)-diphenyl-(1-imidazolyl)-methanes IVa, IVb, IVc and VII were prepared. Phenylmagnesium bromide reacted with ethyl 4-methyl-2-methylthio-5-pyrimidinecarboxylate (VIII) under formation of dihydro derivative IX. We were unable to prepare Grignard's reagent from 5-bromo-2-methylthiopyrimidine and magnesium; it reacted with ethylmagnesium bromide under formation of dihydro derivative I. 5-Chloro-2-methylthio-4-pyrimidinecarboxylic acid when heated with NaOH in dimethyl sulfoxide gave 5-hydroxy-2-methylsulfinyl-4-pyrimidinecarboxylic acid. Compounds IVb and IVc prevented the growth of Candida albicans in vitro at almost the same concentrations as clotrimazole.

Potential antidepressants: 3-Aryl-3-(arylthio)propylamines as selective inhibitors of 5-hydroxytryptamine re-uptake in the brain

1991 ◽  
Vol 56 (7) ◽  
pp. 1525-1533 ◽  
Author(s):  
Vladimír Valenta ◽  
Marie Vlková ◽  
Martin Valchář ◽  
Karel Dobrovský ◽  
Zdeněk Polívka
Keyword(s):  
Rat Brain ◽  
Antidepressant Activity ◽  
Secondary Amines ◽  
Ethyl Chloroformate ◽  
Selective Inhibitors ◽  
Rat Brain Synaptosomes ◽  
Brain Synaptosomes ◽  
The Brain

4-(Trifluoromethyl)thiophenol, 2-methylthiophenol, 2-methoxythiophenol, and 1-naphthalenethiol were transformed by reactions with N,N-dimethyl-3-chloro-3-phenylpropylamine to N,N-dimethyl-3-aryl-3-(arylthio)propylamines IVa-VIIa. These afforded the secondary amines IVb-VIIb by treatment with ethyl chloroformate and by the following hydrolysis and decarboxylation of the primarily formed N-(methyl)-N-(ethoxycarbonyl) analogues. Reaction of 1-naphthalenethiol with the 4-toluenesulfonic ester X in situ gave the thiophene analogue VIIIa which was similarly demethylated to VIIIb. Some of the prepared compounds (IVa, IVb, Va, VIIIa)were found to be selective inhibitors of 5-hydroxytryptamine re-uptake in the rat brain synaptosomes which indicates their potential antidepressant activity.

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