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.

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.

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.

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.

(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.

4,5-Seco-4,6-cyclosteroids. III. Observations on the course of reductive rearrangement of 6β-Bromo-4β,5-epoxy-5β-cholestan-3β-ol

1969 ◽  
Vol 22 (4) ◽  
pp. 807 ◽  
Author(s):  
DJ Collins ◽  
JJ Hobbs ◽  
RJ Rawson
Keyword(s):  
Hydrogen Bromide ◽  
High Yield ◽  
Lithium Aluminium Hydride ◽  
Experimental Conditions ◽  
Lithium Aluminium ◽  
Reaction Proceeds ◽  
Derivatives Of

It has been shown that reductive rearrangement of 6β-bromo-4β,5-epoxy- 5β-cholestan-3β-ol (I) to 4,5-seco-4,6-cycle-6β-cholestane-3β,5α-diol (IXa) with lithium aluminium hydride in tetrahydrofuran proceeds via 6β-bromo-5β-cholestane-3β,5-diol (IIa). Relevant reactions of the latter and the corresponding 3-ketone are discussed. ��� Similar conversion of the 3-epimer of (I) into 4,5-seco-4,6-cyclo- 6β-cholestane-3α,5α-diol (XIIIa) in high yield indicates that reductive rearrangement of the 6β-bromo-5β-hydroxy moiety proceeds without participation of the 3-aluminate complex. Some derivatives of (XIIIa) are described. ��� Experimental conditions required for the conversion of (I) into (IXa) are defined. ��� Combined evidence indicates that the reaction proceeds in a concerted manner by essentially base-catalysed, 1,3-elimination of hydrogen bromide from diol (IIa) with 4,5-bond migration to give the formal intermediate 3β-hydroxy-4,5-seco-4,6-cyclo-6β-cholestan-5-one (VI), further reduced to (IXa).

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.

Synthesis of piperidine derivatives as potential analgetic agents

1990 ◽  
Vol 55 (7) ◽  
pp. 1828-1853 ◽  
Author(s):  
Jiří Jílek ◽  
Miroslav Rajšner ◽  
Vladimír Valenta ◽  
Miloš Borovička ◽  
Jiří Holubek ◽  
...  
Keyword(s):  
Model Compound ◽  
Lithium Aluminium Hydride ◽  
Sodium Cyanoborohydride ◽  
Sulfurous Acid ◽  
Phosphorus Pentasulfide ◽  
Tertiary Alcohols ◽  
Lithium Aluminium ◽  
Propionyl Chloride ◽  
Fentanyl Analogues ◽  
Neurotropic Agents

Reaction of N-(1-(2-phenylethyl)-4-piperidinyl)propionanilide (I) with phosphorus pentasulfide gave the thioamide VI. Acylation of N-(1-(2-phenylethyl)-4-piperidinyl)aniline with 2-(methoxy)acetic and 2-(methylthio)acetic anhydrides afforded the amides II and III. Treatment of 4-anilino-1-benzylpiperidine-4-methanol with thionyl chloride gave the spirocyclic sulfurous acid ester amide XIV. Reduction of the hydrochloride of ethyl 3-(1-ethoxycarbonyl-4-phenylimino-3-piperidinyl)propionate (XXII) with sodium cyanoborohydride gave the perhydro-1,6-naphthyridine derivative XIX, a model compound in the synthesis of the cyclic analogue of fentanyl (I). Ethyl 4-anilino-1-(2-phenylethyl)-1,2,3,6-tetrahydropyridine-3-carboxylate (XXIX) hydrochloride, obtained by reaction of ethyl 4-oxo-1-(2-phenylethyl)piperidine-3-carboxylate hydrochloride with aniline, was reduced with lithium aluminium hydride to 4-anilino-1-(2-phenylethyl)piperidine-3-methanol (XXXI). 1-Methyl- and 1-benzyl-4-piperidone were reacted with 4-cyclopropylphenylmagnesium bromide and the tertiary alcohols XXXVII and XXXVIII obtained were acylated with propionyl chloride to give the esters XXXIX and XL. The piperidine derivatives XLI, XLVI and XLVIII were prepared as potential neurotropic agents. Alkylation of 8-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (XLIX) with 2-(2-chloroethyl)-1,3-dioxane and -1,3-dioxolane resulted in the 6,7-benzomorphan derivatives L and LI. Out of the compounds prepared, only the closest fentanyl analogues II, III, and VI showed very strong analgetic activity.

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