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.

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.

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.

Selective O-Methyloxime Formation From 6-Methoxy-2-[(1'-methyl-2',5'-dioxocyclopentyl)-methyl]-3,4-dihydronaphthalen-1(2H)-one

1994 ◽  
Vol 47 (4) ◽  
pp. 649 ◽  
Author(s):  
DJ Collins ◽  
GD Fallon ◽  
CE Skene
Keyword(s):  
Lithium Aluminium Hydride ◽  
X Ray ◽  
X Ray Crystallography ◽  
Lithium Aluminium ◽  
Major Isomer ◽  
Toluenesulfonic Acid ◽  
Ester Formation ◽  
Diastereomeric Mixture ◽  
A Minor

Reaction of 6-methoxy-2-[(1′-methyl-2′,5′-dioxocyclopentyl)methyl]-3,4-dihydronaphthalen-1(2H)-one (4a) with 1 or 2 moles of O- methylhydroxylamine hydrochloride in pyridine gave (1′SR,2RS)-6-methoxy-2-[(1′-methyl-2′,5′-dioxocyclopentyl)methyl]-3,4-dihydronaphthalen-1(2H)-one (E)-2′-O-methyloxime (5a), or the corresponding 2′,5′-bis(O-methyloxime ) (6), respectively. A minor product from the formation of the bis (O- methyloxime ) (6) was the (Z) isomer (5b) of the mono(O- methyloxime ) (5a); the structure and stereochemistry of (5a) and (5b) were established by X-ray crystallography. Reduction of the keto bis (O-methyloxime ) (6) with 0.25 mole of lithium aluminium hydride gave a diastereomeric mixture of the corresponding alcohols (7a), of which the major isomer was characterized by ester formation. The bis (O-methyloxime ) (6) could be hydrolysed to the parent triketone (4a), but it resisted deprotection with cetyltrimethylammonium permanganate. Reaction of the triketone (4a) with 1 mole of 4-anisidine in the presence of 4-toluenesulfonic acid resulted in retro Michael cleavage with formation of 3-(4′-methoxyphenyl)amino-2-methylcyclopent-2-en-1-one (1).

(6,11-Dihydrodibenzo[b,e]thiepin-11-yl)methylamine, (4-methoxy-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-methylamine and derivatives; Synthesis and pharmacological screening

1982 ◽  
Vol 47 (3) ◽  
pp. 984-993 ◽  
Author(s):  
Vladimír Valenta ◽  
Jan Metyš ◽  
Miroslav Protiva
Keyword(s):  
Formic Acid ◽  
Alkaline Hydrolysis ◽  
Antiinflammatory Activity ◽  
Primary Amines ◽  
Lithium Aluminium Hydride ◽  
Lithium Aluminium ◽  
Methyl Derivatives ◽  
Curtius Reaction ◽  
Pharmacological Screening

Using the Curtius reaction, the acids VIa and VIv were transformed to the carbamates IVa and IVb which afforded by alkaline hydrolysis the primary amines Ia and Ib. The N-methyl derivatives IIab were obtained by reduction of the carbamates IVa with lithium aluminium hydride. The N,N-dimethyl derivatives IIIab resulted by methylation of the primary amines Iab with formaldehyde and formic acid. The synthesis of the acid VIb was carried out from phthalide and 2-methoxythiophenol in seven steps. The amines Iab-IIIab showed clear thymoleptic properties in the test of reserpine ptosis in mice and by inhibition of the perphenazine catalepsy in rats. The acid VIb has antiinflammatory activity.

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.

Synthesis of N-(1-phenyl-2-propyl)-2,5-diphenylpentylamine and some related compounds as potential neurotropic and cardiovascular drugs

1986 ◽  
Vol 51 (7) ◽  
pp. 1487-1493 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Jiří Němec ◽  
Miroslav Protiva
Keyword(s):  
Butyric Acid ◽  
Cardiovascular Drugs ◽  
Lithium Aluminium Hydride ◽  
Dibutyl Ether ◽  
Lithium Aluminium ◽  
Related Compounds ◽  
Antiarrhythmic Effects

Heating of 2,5-diphenylvaleric acid with 2-phenylethylamine, 1-phenyl-2-propylamine, 1-phenyl-2-butylamine (IX), 1-(4-methoxyphenyl)-2-propylamine, 1-(4-methoxyphenyl)-2-butylamine (X) and 1-(4-dimethylaminophenyl)-2-propylamine to 200-210 °C resulted in the amides IIb-VIIb which were reduced with lithium aluminium hydride in boiling dibutyl ether to give the amines IIa, IIIa, and Va - VIIa. A similar two-step sequence starting from 4-phenyl-4-(phenylthio)-butyric acid and the amine IX gave compound VIIIa. The salts of the title amines revealed some central stimulating, antireserpine, thiopental potentiating, anticonvulsant, and antiarrhythmic effects. 1-(4-Dimethylaminophenyl)-2-butylamine (XI), prepared in this connection, proved anoretic activity.

Synthesis of racemic and optically active erythro- and threo-9-(2,3,4-trihydroxybutyl)adenines and related compounds

1979 ◽  
Vol 44 (2) ◽  
pp. 593-612 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Sodium Borohydride ◽  
Sodium Salt ◽  
Sodium Periodate ◽  
Optically Active ◽  
Protecting Groups ◽  
Lithium Aluminium Hydride ◽  
Acidic Hydrolysis ◽  
Lithium Aluminium ◽  
Hydrolysis Of ◽  
Related Compounds

Reduction of diethyl 2,3-O-isopropylidene-DL-tartrate (II) with lithium aluminium hydride afforded 2,2-dimethyl-1,3-dioxolane-threo-4,5-dimethanol (III) which was transformed to the monotosyl derivative VI. Reaction of this compound with sodium salt of adenine, followed by acidic deblocking, gave 9-(DL)-threo-(2,3,4-trihydroxybutyl)adenine (IX). Analogously, 9-(DL)-erythro-(2,3,4-trihydroxybutyl)adenine (XVII) was prepared from diethyl meso-tartrate (XI) via the diol XIII and the tosyl derivative XV. 1,3-O-Benzylidene-D-threitol (D-XVIII) was converted successively into the 4-O-tosyl derivative XIX and the 2-O-benzoyl-4-O-tosyl derivative XX. Reaction of the compound XX with sodium salt of adenine, followed by removal of the protecting groups in the intermediate XXI, afforded 9-(D)-threo-(2,3,4-trihydroxybutyl)adenine (D-XXII); analogously, 1,3-O-benzylidene-L-threitol (L-XVIII) was transformed into the 9-(L)-threo-derivative L-XXII. The D-threo-derivative D-XXII was prepared also from 5-O-tosyl-3-O-benzoyl-1,2-O-isopropylidene-α-D-xylofuranoside (XXIII) or from 3-O-benzyl derivative XXIX by condensation with sodium salt of adenine, followed by acidic hydrolysis, degradation of the 1,2-diol grouping by sodium periodate and sodium borohydride, and methanolysis or hydrogenolysis. An analogous procedure was used for preparation of 1-(D)-threo-(2,3,4-trihydroxybutyl)uracil (D-XXVII). Methyl 2,3-O-isopropylidene-5-benzoyl-6-tosyl-D-mannofuranoside (XXXVI) was transformed to the 5-(adenin-9-yl) derivative XXXVII which after hydrolysis of the dioxolane ring, followed by cleavage of the cis-diol with sodium periodate, reduction with sodium borohydride and methanolysis, afforded 9-(D)-erythro-(2,3,4-trihydroxybutyl)adenine (D-XL). The L-enantiomer (L-XL) was obtained from 5-O-(adenin-9-yl)-3-O-benzoyl-1,2-O-isopropylidene-β-L-arabinofuranoside (XXXIIIb) by acidic cleavage, degradation of the intermediate XXXIV with periodate and methanolysis.

SYNTHESIS OF 8-AZA-D-HOMO-18-NORESTRONE METHYL ETHER

1965 ◽  
Vol 43 (5) ◽  
pp. 1323-1328 ◽  
Author(s):  
Norman A. Nelson ◽  
Yasumitsu Tamura
Keyword(s):  
Acid Hydrolysis ◽  
Methyl Ether ◽  
Potassium Salt ◽  
Lithium Aluminium Hydride ◽  
Enol Ether ◽  
Hydride Reduction ◽  
Lithium Aluminium ◽  
Similar Series

Alkylation of the potassium salt of 1,4-dihydro-2,6-dimethoxybenzene with 2-(2-bromoethyl)piperidine yielded the bis-enol ether I, which, on acid hydrolysis, afforded the crystalline vinylogous amide II. Lithium aluminium hydride reduction of II gave two isomers of 1,2,3,4,4a,5,6,6a,8,9,10,10a-dodecahydro-7H-benzo[c]quinolizin-7-one (III). A similar series of reactions starting with 1-(2-chloroethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (V) gave two isomers of 2,3,4,4a, 6,7,11b,12,13,13a-decahydro-9-methoxy-1H-di-benzo[a,f]quinolizin-1-one (8-aza-D-homo-18-norestrone methyl ether) (IX).

The Structure and Function of Oestrogens. II. The Synthesis and Oestrogenic Activity of 4b-Methyl 4b,5,6,12-tetrahydrochrysene-2,8-diol and 4b-Methyl-cis-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol and Related Compounds

1979 ◽  
Vol 32 (5) ◽  
pp. 1107 ◽  
Author(s):  
DJ Collins ◽  
WA Matthews ◽  
GM Stone
Keyword(s):  
Hydrogen Peroxide ◽  
Structure And Function ◽  
Lithium Aluminium Hydride ◽  
Alkaline Hydrogen Peroxide ◽  
Lithium Aluminium ◽  
Methylmagnesium Iodide ◽  
And Function ◽  
Dihydroxy Compound ◽  
Related Compounds

Hydroboration of an inseparable mixture of 2,8-dimethoxy-5,6-dihydrochrysene (5a) and 2,8-dimethoxy-4b-methyl-4b,5,6,12-tetrahydrochrysene (6a) followed by oxidation with alkaline hydrogen peroxide gave a mixture of (4bα,10bβ,11β)-2,8-dimethoxy-4b-methyl-4b,5,6,10a,11,12-hexahydrochrysen-11-ol (10a) and its (4bβ,10bβ,11β) isomer(11a). Reduction of the methanesulfonate ester of (10a) with lithium aluminium hydride in ether gave 2,8-dimethoxy-4b-methyl-trans-4b,5,6,10b,11,12- hexahydrochrysene (2b), identical with material prepared by another route. Reduction of the methanesulfonate of (4bβ,10bβ,l1β)-2,8-dimethoxy-4b-methyl-4b,5,6,10a,11,12-hexahydrochrysen- 11-ol afforded 2,8-dimethoxy-4b-methyl-cis-4b,5,6,10b,11,12-hexahydrochrysene (12), demethylation of which afforded 4b-methyl-cis-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol (14b). Dehydration of the mixture of the 11-epimeric alcohols (10a) and (lla) with phosphorus oxytrichloride in pyridine yielded pure 2,8-dimethoxy-4b-methyl-4b,5,6,12-tetrahydrochrysene (6a) which was demethylated with methylmagnesium iodide to give the corresponding dihydroxy compound (9). Other compounds prepared in the course of examining possible routes to (9) and (14b) include 13,13-dichloro-2,8-dimethoxy-4b,5,6,10b,11,12-hexahydro-4b,10b-methanoch rysene (3a), 1-bromo- 2,8-dimethoxy-5,6-dihydrochrysene (5b), and 11-bromo-2,8-dimethoxy-4b-methy1-4b,5,6,12-tetra- hydrochrysene (7). The oestrogenic activities of some of the new angularly methylated hydrochrysenes and of 9α- methyloestradiol (15) are reported.

N-(piperazinoacyl) and N-(piperazinoalkyl) derivatives of 4-cyclopentylaniline and related compounds: Synthesis and pharmacological screening

1986 ◽  
Vol 51 (7) ◽  
pp. 1494-1502
Author(s):  
Zdeněk Vejdělek ◽  
Miroslav Protiva
Keyword(s):  
Similar Reaction ◽  
Lithium Aluminium Hydride ◽  
Antispasmodic Activity ◽  
Analgesic Effects ◽  
Basic Amides ◽  
Lithium Aluminium ◽  
Propionyl Chloride ◽  
Pharmacological Screening ◽  
Derivatives Of ◽  
Related Compounds

Five N-(4-cyclopentylphenyl)haloalkanecarboxamides were reacted with 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine to give the corresponding N-(4-cyclopentylphenyl)piperazinoalkanecarboxamides Iab -Vab. Their reduction with lithium aluminium hydride afforded the triamines VIIab - XIab. Acylation of the N-(4-methylpiperazino)alkyl-4-cyclopentylanilines Xa and XIa with propionyl chloride resulted in the propionanilides XIVa and XVa, whereas a similar reaction of the N-(4-(2-hydroxyethyl)piperazino)alkyl-4-cyclopentylanilines VIIb and IXb - XIb produced the propionoxypropionanilides XIIc - XVc. Ethanolysis of these compounds afforded corresponding hydroxypropionanilides XIIb - XVb. Many of the basic amides showed local anaesthetic and papaverine-like antispasmodic activity. The propionanilides XIIb, XIVc, and XVa proved interesting analgesic effects in the peritoneal test in mice.

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