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.

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.

3-(s-Hydrindacen-4-yl)propylamines and 4-(s-hydrindacen-4-yl)butylamines; Synthesis and pharmacological screening

1981 ◽  
Vol 46 (8) ◽  
pp. 1800-1807 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Marie Bartošová ◽  
Miroslav Protiva
Keyword(s):  
Malonic Acid ◽  
Local Anaesthetics ◽  
Lithium Aluminium Hydride ◽  
Spasmolytic Activity ◽  
Lithium Aluminium ◽  
Malonic Acid Derivatives ◽  
Pharmacological Screening ◽  
Hydroxyethyl Piperazine

4-Chloromethyl-s-hydrindacene (VIIa) was transformed via the malonic acid derivatives VIIIa and IXa to the acid Xb which afforded in four steps the homological acid Xc. Reactions of chlorides of both acids (XIbc ) with dimethylamine, 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine led to the amides XIIbc-XIVbc which were reduced with lithium aluminium hydride to the title compounds IVcd-VIcd. The amines obtained show central neuroleptic effects only in subtoxic doses; they are also potent local anaesthetics and have significant spasmolytic activity of the neurotropic as well as musculotropic type.

α-(4-Tolyl)dopamine, derivatives and analogues; Synthesis and pharmacological screening

1983 ◽  
Vol 48 (5) ◽  
pp. 1447-1464 ◽  
Author(s):  
Vladimír Valenta ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Antonín Dlabač ◽  
Marie Bartošová ◽  
...  
Keyword(s):  
Acetic Anhydride ◽  
Hydrobromic Acid ◽  
Benzoyl Chloride ◽  
Substitution Reactions ◽  
Low Degree ◽  
Anticataleptic Activity ◽  
Pharmacological Screening ◽  
Higher Doses ◽  
Hydroxyethyl Piperazine ◽  
Antiarrhythmic Effects

The ketone XIII, obtained by Friedel-Crafts reaction of toluene with homoveratroyl chloride, was converted by the Leuckart reaction to the formamido derivative IXb which was used as the starting product for the synthesis of amines IIIb-Vb. Reduction of the ketone XIII gave the alcohol XVI which was treated with hydrogen chloride and afforded the chloro compound XVII. Its substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)piperazine and 1-phenylpiperazine resulted in the piperazines VIb-VIIIb. Acylations of the amine IIIb with acetic anhydride and homoveratroyl chloride gave the amides Xb and XIb which, together with the formamide IXb, were subjected to the Bischler-Napieralski reaction. 3,4-Dihydroisoquinolines XXII-XXIV were obtained and reduced to the 1,2,3,4-tetrahydroisoquinolines XXVb-XXVIIb. Treatment of XXVIIb with formaldehyde afforded the berbine derivative XXVIII. Demethylation of the amine IIIb with hydrobromic acid resulted in the title compound IIIa. Similar demethylations of the dimethoxyamines IVb-VIIIb, XXVb and XXVIb led to the dihydroxyamines IVa-VIIIa, XXVa and XXVIa which are dopamine derivatives. Reaction of Va with benzoyl chloride gave the dibenzoate XXX. The CNS activities of the compounds prepared are of a low degree. Several of them (IIIa-VIa, IIIb-Vb, XXVb) show in higher doses signs of central stimulant action but only for compound IVa an antireserpine effect was proven. The expected anticataleptic activity was found only in a low degree with compound VIIIa; on the contrary, compounds IIIa and XXVa are procataleptogenic. Some compounds (IIIa, IXb, XXVIa, XXVIII) potentiated thiopental. In single cases local anaesthetic, spasmolytic, hypotensive, hypertensive, hypoglycaemic, diuretic and antiarrhythmic effects were observed.

Synthesis and pharmacological screening of 1-[2-tert-aminoethyl]-8-fluoro-5-[4-fluorophenyl]-2,3,4,5-tetrahydro-1H-1-benzazepines, their 1-[aminoacetyl] analogues and 1-substituted 9-fluoro-6-[4-fluorophenyl]-5,6-dihydro-4H-s-triazolo[4,3-a]-1-benzazepines

1981 ◽  
Vol 46 (1) ◽  
pp. 148-160 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Jan Metyš ◽  
Marie Bartošová ◽  
...  
Keyword(s):  
Secondary Amines ◽  
Lithium Aluminium Hydride ◽  
Phosphorus Pentasulfide ◽  
Lithium Aluminium ◽  
High Doses ◽  
Pharmacological Screening ◽  
Central Depressant

7-Fluoro-4-(4-flurophenyl)-1-naphthylamine (III) was identified as a by-product in the transformation of 7-fluoro-4-(4-fluorophenyl)-1-tetralone oxime to the lactam I. Reaction of 8-fluoro-5-(4-flurophenyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (V) with chloracetyl chloride gave the chloramide VI which was treated with secondary amines to give the aminoacetamides VII, VIII, XI and XII. reduction with lithium aluminium hydride afforded the amines IX, X, XIV and XV. Acylation of the piperazinoethanols XII and XV led to the esters XIII, XVI and XVII. Reaction of the lactam I with phosphorus pentasulfide gave the thiolactam II which was treated with a series of acid hydrazides and gave the title compounds XVIII-XXIV. Some of the compounds exhibited only in relatively high doses anticonvulsant and central depressant effects in various tests.

Potential antidepressants: 10-Amino-2-chloro-10,11-dihydrodibenzo[b,f]thiepins

1989 ◽  
Vol 54 (7) ◽  
pp. 1979-1994 ◽  
Author(s):  
Vladimír Valenta ◽  
Marie Vlková ◽  
Jiří Holubek ◽  
Jiřina Metyšová ◽  
Miroslav Protiva
Keyword(s):  
Formic Acid ◽  
Secondary Amines ◽  
Lithium Aluminium Hydride ◽  
Pharmacological Profile ◽  
Substitution Reactions ◽  
Lithium Aluminium ◽  
Primary And Secondary Amines ◽  
Aqueous Formaldehyde

Reduction of N-(2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)formamide with lithium aluminium hydride resulted in the methylamino compound IV. The dimethylamino compound V was obtained by methylation of 10-amino-2-chloro-10,11-dihydrodibenzo[b,f]thiepin with formic acid and aqueous formaldehyde. Substitution reactions of 2,10-dichloro-10,11-dihydrodibenzo[b,f]thiepin with a series of primary and secondary amines afforded the title compounds VI to XXVIII. The bases were transformed to salts and pharmacologically tested. Only the pyrrolidino compound IX (hydrogen succinate VÚFB-15 551) showed a clear pharmacological profile of a potential antidepressant.

Cyclic amidines derived from benz[c,d]indole and 4,5-dihydro-3H-1-benzazepine including some related compounds: Synthesis and pharmacological screening

1985 ◽  
Vol 50 (8) ◽  
pp. 1888-1898 ◽  
Author(s):  
Miroslav Protiva ◽  
Zdeněk Šedivý ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Jiří Němec
Keyword(s):  
Titanium Tetrachloride ◽  
Aqueous Sodium Hydroxide ◽  
Secondary Amines ◽  
Primary Amines ◽  
Open Chain ◽  
Lithium Aluminium ◽  
Pharmacological Screening ◽  
Antiinflammatory Effects ◽  
Related Compounds ◽  
Sodium Amide

Reactions of naphthostyril (I) with primary and secondary amines and titanium tetrachloride afforded cyclic amidines III-IX. Hydrogenation of I on Pd-C resulted in the 6,7,8,8a-tetrahydro derivative X which gave by treatment with sodium amide and 3-dimethylaminopropyl chloride the N-(aminoalkyl) compound XI. Reduction of I and its N-methyl derivative II with sodium amalgam in aqueous sodium hydroxide gave the 2a,3,4,5-tetrahydro derivatives XII and XIII. Reaction of XIII with sodium amide and 3-dimethylaminopropyl chloride afforded the 2a-(aminoalkyl) compound XIV. 1,3,4,5-Tetrahydro-1-benzazepin-2-one (XV) treated with primary amines and titanium tetrachloride gave the amidines XVI-XVIII. 3-Methyl-7,8,9,9a-tetrahydro-1H-benz[d,e]isoquinoline (XIX) was reduced with sodium borohydride to compound XX which was alkylated with propargyl bromide to 1-methyl-2-propargyl-2,3,3a,4,5,6-hexahydro-1H-benz[d,e]isoquinoline (XXI). An attempt to prepare the 2-(2-phenylethyl) analogue by treatment of compound XX with phenylacetyl chloride and by the following reduction with lithium aluminium hydride resulted in the open-chain amine XXII. The lactams I, II, X, and XIII showed some discoordinating, hypothermic, peripheral vasodilating, hyperglycaemic, diuretic and antiinflammatory effects. The amidines III-IX and XVI-XVIII had local anaesthetic, slight hypotensive, antiarrhythmic, peripheral myorelaxant, papaverine-like spasmolytic and thiopental potentiating effects.

(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.

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