Fluorinated tricyclic neuroleptics with prolonged action: derivatives and analogues of 2-(4-(7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin-11-yl)-piperazine-1-yl)ethanol

1987 ◽  
Vol 52 (7) ◽  
pp. 1811-1833 ◽  
Author(s):  
Miroslav Protiva ◽  
Jiří Jílek ◽  
Miroslav Rajšner ◽  
Karel Šindelář ◽  
Václav Bártl ◽  
...  
Keyword(s):  
Acetyl Chloride ◽  
Decanoic Acid ◽  
Lithium Aluminium Hydride ◽  
Prolonged Action ◽  
Substitution Reactions ◽  
Lithium Aluminium ◽  
Neuroleptic Agent ◽  
Depot Neuroleptic ◽  
New Compounds ◽  
Pharmacological Testing

The preparation of 4-fluoro-2-nitrobenzonitrile (V), an intermediate in the synthesis of the title compound I, from 4-fluoro-2-nitroaniline via 5-fluoro-2-iodonitrobenzene (VII) was elaborated. Syntheses of 1,1,1,3,3,3-hexadeutero-2-propyl (XX) and 1,3,4-trideutero (XXVIII) analogues of compound I from hexadeuteroacetone, and pentadeuterobromobenzene, respectively, were carried out. Compound I was esterified with acetic anhydride, decanoic acid and 3,4,5-trimethoxybenzoyl chloride to give the esters II-IV. Acylation of compound XXX with acetyl chloride, 4-fluorophenoxyacetyl chloride and (4-fluorophenylthio)acetyl chloride and the following reduction of the amides with lithium aluminium hydride gave compounds XXXII, XXXIX and XL. Substitution reactions of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin with the corresponding N-monosubstituted piperazines resulted in compounds XXXIII-XXXV, XXXVII, XXXVIII, XLI and XLII. Alkylation of XXX with 2-(2-chloroethyl)-1,3-dioxolane afforded compound XXXVI. Pharmacological testing of the new compounds, derivatives and analogues of the neuroleptic agent isofloxythepin (I), for discoordinating and cataleptic activities, showed especially for compounds II, XXXIV and XXXVI very intensive and long-lasting effects. The decanoate III has properties of a depot neuroleptic agent.

N-substituted aminomethyl 4-cyclopentylphenyl ketones and 2-amino-1-(4-cyclopentylphenyl)ethanol: Synthesis and pharmacological screening

1983 ◽  
Vol 48 (2) ◽  
pp. 642-648 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Miroslav Protiva
Keyword(s):  
Secondary Amines ◽  
Lithium Aluminium Hydride ◽  
Substitution Reactions ◽  
Rotarod Test ◽  
Lithium Aluminium ◽  
Spontaneous Motility ◽  
Pharmacological Screening ◽  
Higher Doses ◽  
Hydroxyethyl Piperazine ◽  
Ethanol Synthesis

The non-characterized bromo derivative Ia, obtained by bromination of 4-cyclopentylacetophenone, afforded by substitution reactions with diethylamine, benzylmethylamine, benzylisopropylamine, piperidine, morpholine, 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine the amino ketones IIa-VIIIa which were reduced with lithium aluminium hydride to the aminoalcohols IIb-VIIIb. Compounds IIIb and IVb were debenzylated by catalytic hydrogenation on palladium to the secondary amines IXb and Xb. The compounds prepared have central stimulant effects in higher doses which appears also in the rotarod test and in the evaluation of spontaneous motility. They have mostly a mild spasmolytic effect of the anticholinergic type, some of them bring about local anesthetic and diuretic effects. The adrenolytic and hypotensive effects were found only with single compounds.

1-[2-(2-Hydroxymethylphenylthio)benzyl]-4-methylpiperzine and related compounds as potential antidepressants: Synthesis and pharmacological acreening

1984 ◽  
Vol 49 (4) ◽  
pp. 1009-1020 ◽  
Author(s):  
Irena Červená ◽  
Miroslav Protiva
Keyword(s):  
Potassium Carbonate ◽  
Secondary Alcohol ◽  
The Other ◽  
Lithium Aluminium Hydride ◽  
Keto Acid ◽  
Open Model ◽  
Lithium Aluminium ◽  
Neuroleptic Agent ◽  
The One ◽  
Related Compounds

Heating of 1-(2-iodobenzoyl)-4-methylpiperazine (II) with thiophenol and its 2-methyl, 4-methyl, 4-chloro and 2-hydroxymethyl derivatives in dimethylformamide in the presence of potassium carbonate, copper and cuprous iodide gave the piperazides IV-VIII; compound VIII was transformed by reduction with lithium aluminium hydride to the title compound I. The acid IX, obtained by a reaction of 5-chloro-2-iodobenzoic acid with 2-methylthiophenol, was reduced to the alcohol X, which was transformed via the chloride XI to 1-[5-chloro-2-(2-methylphenylthio)-benzyl]-4-methylpiperazine (XII), an open model of the neuroleptic agent clorothepin. Heating of 2,5-dichloroacetophenone with thiosalicylic acid afforded the keto acid XIII whose reaction with 1-methylpiperazine was carried out with the help of N,N"-carbonyldiimidazole. The piperazide XIV obtained was reduced on the one hand with sodium borohydride to the secondary alcohol XV, and with lithium aluminium hydride to 1-(2-[4-chloro-2-(1-hydroxyethyl)phenylthio]benzyl)-4-methylpiperazine (XVI) on the other. None of the dibasic piperazines (I, XII, XVI) did show antireserpine activity. In the general screening, some of the piperazides displayed a mild hypotensive (II, VIII, XIV, XV), adrenolytic (VIII), mild stimulating and antitussic (V), and spasmolytic, antiinflammatory and negatively ino- and chronotropic (XIV) activities.

Potential antidepressants: 2-(Phenylthio)aralkylamines

1989 ◽  
Vol 54 (7) ◽  
pp. 1995-2008 ◽  
Author(s):  
Jiří Jílek ◽  
Jiří Urban ◽  
Petr Taufmann ◽  
Jiří Holubek ◽  
Antonín Dlabač ◽  
...  
Keyword(s):  
Nmr Spectra ◽  
Benzyl Chloride ◽  
Lithium Aluminium Hydride ◽  
Pharmacological Profile ◽  
H Nmr ◽  
Lithium Aluminium ◽  
Alternative Approach ◽  
Phenyl Acetonitrile ◽  
Claisen Reaction ◽  
Pharmacological Testing

Reactions of 2-(phenylthio)benzyl chloride with dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine, and 1-methylpiperazine afforded the title compounds VI-XI. Reaction of 2-(phenylthio)benzaldehyde with nitromethane gave the nitrostyrene XIV which was reduced with lithium aluminium hydride to 2-(2-(phenylthio)phenyl)ethylamine (XVI). This was transformed to the N-methyl and N,N-dimethyl derivatives XVIII and XIX. The Claisen reaction of (2-(phenylthio)phenyl)acetonitrile with ethyl acetate afforded compound XXI which was cleaved by phosphoric acid to (2-(phenylthio)phenyl)acetone (XX). The Leuckart-Wallach reaction afforded the formamide XXIII which was used as starting material for preparing the amines XXIV-XXVI. The alternative approach to these compounds starting by reaction of the aldehyde XII with nitroethane was complicated by the fact that in addition to the nitropropene XV 2-(phenylthio)benzonitrile was also formed. The synthetic use of the inhomogeneous XV resulted then in mixtures of amines XXIV-XXVI with IV-VI which was followed by means of mass and 1H NMR spectra. The amines XXIV-XXVI were oxidized to the sulfoxides XXVII-XXIX. The oily bases were transformed to crystalline salts and spectra of all homogeneous bases were recorded. Pharmacological testing showed the amine VI (VÚFB-15 370) to be a promising potential antidepressant. The amines XI and XXV showed also pharmacological profile of potential antidepressants.

Potential antidepressants: 1-(2-(Methoxy- and hydroxyphenylthio)phenyl)-2-propylamines

1990 ◽  
Vol 55 (4) ◽  
pp. 1077-1098 ◽  
Author(s):  
Jiří Urban ◽  
Zdeněk Šedivý ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Ethyl Formate ◽  
Secondary Amines ◽  
Primary Amines ◽  
Alternative Route ◽  
Lithium Aluminium Hydride ◽  
Tertiary Amines ◽  
Lithium Aluminium ◽  
Boron Tribromide ◽  
Pharmacological Testing ◽  
By Products

2-(Methoxyphenylthio)benzaldehydes Xa-Xd were reacted with nitroethane in boiling acetic acid to give the corresponding 1-aryl-2-nitropropenes XIIa-XIId; benzonitriles XIIIa and XIIIc and benzaldoximes XXIc and XXId were isolated as by-products. Chromatographed compounds XIIa-XIId were reduced with lithium aluminium hydride to the primary amines VIIa-VIId, and formylated by heating with ethyl formate to the formamides XIVa, XIVc, and XIVd. Reduction of the formamides with lithium aluminium hydride afforded the secondary amines VIIIa, VIIIc, and VIIId, and methylation of the primary amines with formic acid and formaldehyde gave the tertiary amines IXa, IXc, and IXd. Compound VIIIa was prepared also by an alternative route starting from the nitrile XIIIa and proceeding via XIXa and XIVa. Some of the methoxylated amines were demethylated either by heating with pyridine hydrochloride or by treatment with boron tribromide to the title compounds IVa, IVc, Vc, Vd, VIa, and VIc. The amines prepared were transformed to salts for characterization and for pharmacological testing. Compound VIIIa (hydrogen oxalate V⁄FB-15 475) showed clearly the character of a potential antidepressant.

Tricyclic neuroleptics: Synthesis of metabolites of isofloxythepin and some related compounds

1990 ◽  
Vol 55 (9) ◽  
pp. 2282-2303 ◽  
Author(s):  
Karel Šindelář ◽  
Jiří Jílek ◽  
Josef Pomykáček ◽  
Vladimír Valenta ◽  
Marta Hrubantová ◽  
...  
Keyword(s):  
Formic Acid ◽  
Substitution Reaction ◽  
Lithium Aluminium Hydride ◽  
Enol Ether ◽  
Basic Product ◽  
Lithium Aluminium ◽  
Toluenesulfonic Acid ◽  
Neuroleptic Agent ◽  
Related Compounds ◽  
By Products

The isofloxythepin (I) metabolite IV was synthesized via the acids IX and XI and the esters X and XII. The enamine VIII was prepared from 3-fluoro-8-(2-propyl)dibenzo[b,f]thiepin-10(11H)-one by two methods and was reduced to I. Cloflumide (II) was obtained by reaction of 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin with 3-(1-piperazinyl)propionamide and was oxidized to the sulfoxide XVI. The unsaturated analogue XVII of clopithepin (III) was prepared from 2-chlorodibenzo[b,f]thiepin-10(11H)-one by reaction with 2-bromoethanol in the presence of 4-toluenesulfonic acid in boiling benzene and by the following substitution reaction with 2-(1-piperazinyl)ethanol. An improved synthesis of 6-methyldibenzo[b,f]thiepin-10(11H)-one (XIX) was elaborated. The acid XXVII was synthesized and cyclized with polyphosphate ester. A mixture of compounds was formed from which the ketone XXXVI was isolated and processed by reaction with formamide and formic acid at 200 °C. One of the products was characterized as the formamide XXXIII and was reduced with lithium aluminium hydride to a basic product supposed to be XXXIV. A series of by-products was isolated and characterized. The enamine VIII (V⁄FB-17 156) was found to be a strong neuroleptic agent, similar to isofloxythepin (I). The enol ether XVII (V⁄FB-17 733) was characterized as a mild, practically noncataleptic neuroleptic agent.

Fluorinated tricyclic neuroleptics: Synthesis and pharmacology of 2-chloro-8-fluoro-4-(4-methylpiperazino)-4,5-dihydrothieno[2,3-b]-1-benzothiepin

1981 ◽  
Vol 46 (9) ◽  
pp. 2222-2233 ◽  
Author(s):  
Zdeněk Polívka ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Acetic Acid ◽  
Title Compound ◽  
Substitution Reaction ◽  
Phosphorus Pentoxide ◽  
Lithium Aluminium Hydride ◽  
Lithium Aluminium ◽  
Chloro Derivative ◽  
Neuroleptic Agent ◽  
Long Acting ◽  
Animal Tests

Diazotization of 4-fluoroanthranilic acid (V) and the following reaction with sodium disulfide gave the dithio diacid VII which was reduced with lithium aluminium hydride to 4-fluoro-2-mercaprobenzyl alcohol (XI). Its reaction with 2-chloro-5-iodothiophene afforded the alcohol XIII which was transformed via the chloride XIV and the nitrile XV to [2-(5-chloro-2-thienylthio)-4-fluorophenyl]acetic acid (XVI). Cyclization with phosphorus pentoxide in toluene resulted in 2-chloro-8-fluorothieno[2,3-b]-1-benzothiepin-4(5H)-one (XVIII) which was converted via the alcohol XIX to the chloro derivative XX. The substitution reaction with 1-methylpiperazine led to the title compound IV which is a long-acting and very potent tranquillizer but did not reveal, in the animal tests performed, the properties of a neuroleptic agent.

scholarly journals A Stereospecific Synthesis of (±)-Abscisic Acid

1992 ◽  
Vol 45 (1) ◽  
pp. 179 ◽  
Author(s):  
J Cornforth ◽  
JE Hawes ◽  
R Mallaby
Keyword(s):  
Abscisic Acid ◽  
Thionyl Chloride ◽  
Acetyl Chloride ◽  
Selenium Dioxide ◽  
Stereospecific Synthesis ◽  
Lithium Aluminium Hydride ◽  
Cyclic Anhydride ◽  
Lithium Aluminium

A convenient separation of (E)- and (Z)-3-methylpent-2-enedioic acids was devised, and it was shown that with acetyl chloride or thionyl chloride the (Z)-acid yields the cyclic anhydride while the (E)-acid forms 6-chloro-4-methylpyran-2-one. The chloropyranone by conventional chemistry gave 4-methyl-6-(2′-oxopropyl)pyran-2-one which condensed with 4-methylpent-3-en-2-one in the presence of pyrrolidine, yielding 4-methyl-6-(2′,6′,6′-trimethyl-4′-oxocyclohex-2′-enyl)pyran-2-one. Oxidation with selenium dioxide or t-butyl chromate then gave 6-(1′-hydroxy-2′,6′,6′-trimethyl-4′-oxotyclohex-2′-enyl)-4-methylpyran-2-one, which on reduction by lithium aluminium hydride and reoxidation afforded (±)-abscisic acid stereospecifically.

Selective Reduction of Peptidic Ergot Alkaloids

2000 ◽  
Vol 65 (11) ◽  
pp. 1762-1776 ◽  
Author(s):  
Ladislav Cvak ◽  
Josef Stuchlík ◽  
Magdalena Schreiberová ◽  
Petr Sedmera ◽  
Vladimír Havlíček ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Mass Spectrometry ◽  
Nmr Spectroscopy ◽  
Ergot Alkaloids ◽  
Selective Reduction ◽  
Lithium Aluminium Hydride ◽  
Lithium Aluminium ◽  
New Compounds ◽  
Representative Member

Five 6'-deoxoergopeptines were prepared in 51-68% yield by selective reduction of parent alkaloids with lithium aluminium hydride in tetrahydrofuran at low temperature. New compounds were characterized by mass spectrometry and NMR spectroscopy. The conformation of the peptide part in starting compounds and reduced derivatives is discussed on the basis of crystal structure determination of 6'-deoxo-9,10-dihydroergotamine dihydrate butan-2-one solvate as a representative member of the series.

N-(Aminoacyl) and N-(aminoalkyl) derivatives of 4-cyclopentylaniline and N-ethyl-4-cyclopentylaniline; Synthesis and pharmacological screening

1983 ◽  
Vol 48 (1) ◽  
pp. 156-162 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Marie Bartošová ◽  
Miroslav Protiva
Keyword(s):  
Lithium Aluminium Hydride ◽  
Substitution Reactions ◽  
Rotarod Test ◽  
Lithium Aluminium ◽  
Local Anaesthetic Effect ◽  
Anorectic Effect ◽  
Pharmacological Screening ◽  
Derivatives Of ◽  
Higher Doses ◽  
Anaesthetic Effect

Acylation of 4-cyclopentylaniline (I) with chloracetyl chloride, 3-chloropropionyl chloride, 4-chlorobutyryl chloride and 2-bromo-4-methylvaleryl bromide gave the halogenoacyl derivatives IV - VII out of which the first two were subjected to substitution reactions with diethylamine and piperidine. The N-(aminoacyl) derivatives VIII - XI obtained were reduced with lithium aluminium hydride to the N-(aminoalkyl) derivatives XII and XV. N-Ethyl-4-cyclopentylaniline (XVI), prepared by reduction of N-(4-cyclopentylphenyl)acetamide (II), was similarly transformed via the chloroacetyl derivative XVII to the amide XVIII and the diamine XIX. Salts of the compounds prepared (amino amides and diamines) bring about in higher doses central excitation which is apparently in close connection with the found discoordinating effect of a part of products (VIII - XI, XIII) in the rotarod test, further with the antireserpine effects in the tests of antagonization of reserpine ptosis and hypothermia (VIII, X, XII, XIII) and finally with the anorectic effect of compound X. All substances showed a mild spasmolytic effect of the anticholinergic type. On the other hand, the expected local anaesthetic effect was found only with compounds VIII, XVIII, XIX.

scholarly journals 1,1-Disilylethan, CH3CH(SiH3)2 / 1,1-Disilylethane, CH3CH(SiH3)2

1988 ◽  
Vol 43 (5) ◽  
pp. 571-573 ◽  
Author(s):  
Hubert Schmidbaur ◽  
Rudolf Hager
Keyword(s):  
Silicon Carbide ◽  
Acetyl Chloride ◽  
Vapour Deposition ◽  
Chemical Vapour ◽  
Lithium Aluminium Hydride ◽  
Stable Isomer ◽  
Lithium Aluminium ◽  
Silicon Carbon ◽  
Volatile Liquid ◽  
Catalytic Hydrosilylation

Abstract 1,1-Bis(trichlorosilyl)ethane, CH3CH(SiCl3)2 (1) is readily available through catalytic hydrosilylation of vinyltrichlorosilane and silicochloroform (90% yield), or through the base-induced reduction of acetyl chloride using again silicochloroform (60%). 1 can be converted into the title compound 2 in 80% yield by lithium aluminium hydride in di-n-butylether. Compound 2 is a highly volatile liquid (bp. 40-42 °C), not spontaneously inflamable in air. which is of interest as a precursor for chemical vapour deposition of hydrogen-containing silicon/carbon alloys (a-Si, C:H) and silicon carbide. Based on thermodynamical data, it is the least stable isomer of the composition C2Si2H10.

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