[3-Dialkylamino-substituted 2H-1,4-benzoxazines]. / 2H-1,4-benzossazine 3-(dialchilammino)sostituite.

N,N,N',N'-Tetrasubstituted 2-(2-aminophenoxy)malonamides (IX) in the presence of phosphorus oxychloride led to the formation of N,N-dialkyl-3-(dialkylamino)-2H-1,4-benzoxazine-2-carboxamides (XII). In the same way 2-(2-amino-3-pyridyloxy)-N,N,N',N'-tetraethylmalonamide (X) yielded 3-(diethylamino)-N,N-diethyl-2H-pyrido[3,2-b] [1,4]oxazine-2-carboxamide (XIII). Also N,N-dialkyl-2-(2-aminophenoxy)acetamides (XIV) by the action of phosphorus oxychloride afforded 3-(dialkylamino)-2H-1,4-benzoxazines (XV). Some compounds when submitted to pharmacological screening showed a weak depressant activity in the Irwin test.

[Chemistry and pharmacology of pyran derivatives. XVII. Synthesis of 2-(dialkylamino)-5-hydroxychromones and their transformation to derivatives of 2H-pyran[4,3,2-de]-1-benzopyran]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota XVII. Sintesi dei 2-(dialchilammino)-5-idrossicromoni e loro trasformazione in derivati del 2H-pirano [4,3,2-de]-1-benzopirano.

Through the reaction of resorcin with N,N-dialkylethoxy-carbonylacetamides in suitable conditions 2-(dialkylamino)-5-hydroxychromones (II) were available. Transformation of these compounds into [5-acetoxy-2-(dialkylamino)-4H-chromen-4-ylidene] malononitriles (VII) by reaction with malononitrile in acetic anhydride and treatment of (VII) with hydrochloric acid gave rise to the formation of 5-(dialkylamino)-2-imino-2H-pyrano [4,3,2-de]-1-benzo-pyrans (VIII). Furthermore 5-hydroxychromones (II) when treated with methyl iodide gave the corresponding 5-methoxychromones (III) which in turn yielded 4H-chromen-4-ylidene derivatives (X) by reaction with malononitrile in acetic anhydride. The hydrolysis of the latter compounds with hydrochloric acid resulted in the formation of 2-(dialkylamino)-4-methyl-5-methoxychromenilium salts (XI). Among the compounds which were submitted to pharmacological screening for their antiallergic properties 5-methoxychromone (III a) and 2H-pyrano [4,3,2-de]-1-benzopyran (VIII b) showed a notable activity but also high toxicity.

[Chemistry and pharmacology of pyran derivatives. 16. Derivatives of 2-(dialkylamino)-7-methoxychromone with antiallergic activity]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota XVI. Derivati del 2-(dialchilammino)-7-metossicromone ad attività antiallergica.

Since 2-(diethylamino)-7-methoxychromone (III a) showed remarkable activity in the rat PCA test, some modifications to its structure were made. For instance new substituents such as chlorine or nitro group were introduced into the molecule and the diethylamino group modified. Thus, 2-(ethylamino)-7-methoxychromone (IX) was prepared by treating 3-methoxyphenol with N-ethylethoxycarbonylacetamide in the presence of phosphorus oxychloride. In this case a small amount of 4-chloro-7-methoxycoumarin was also isolated from the reaction mixture. Moreover compounds (XIV), (XV), (XVII) structurally related to sodium cromoglycate were prepared. The pharmacological screening of some compounds showed a useful antiallergic activity.

[1,5-benzodiazepines. V. Synthesis of pyrazolo (3,4-b)(1,5)benzodiazepines and 5H-pyrimido(4,5-b)(1,5)benzodiazepines]. / Ricerche su 1,5-benzodiazepine. Nota V - Sintesi di derivati della pirazolo[3,4-b][1,5]benzodiazepina e della 5H-pirimido[4,5-b][1,5]benzodiazepina.

The reaction of 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (I a-c) with N,N-dimethylformamide in the presence of phosphorus pentachloride at room temperature gave rise to the formation of 4-(dialkylamino)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-1,5-benzodiazepin- 2-ones (IX a-c) which were useful starting materials to achieve the synthesis of tricyclic 1,5-benzodiazepine derivatives. Actually (IX a), selected for the smallest steric hindrance of the 4-dialkylamino substituent, by reaction with hydrazines afforded pyrazolo[3,4-b][1,5]benzodiazepine derivatives whereas reaction with guanidine or amidines gave 5H-pyrimido-[4,5-b][1,5]benzodiazepine derivatives. The structure of isomeric N-methyl-pyrazoles (X c) and (XI a) and of N-phenylpyrazole (X b) were elucidated by comparison with compounds prepared by unequivocal chemical methods. Pharmacological evaluation of some of the products showed only generic CNS depressant activity.

[Chemical and pharmacological research on pyran derivatives. XV. Phenyl-substituted 2-(dialkylamino)chromones]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota XV-2-(Dialchilammino)cromoni fenilsostituiti.

Some 2-(dialkylamino)chromones phenyl substituted in position 6 or 7 or 8 were synthesized by reaction of N,N-dialkylethoxycarbonylacetamides with 4- or 3- or 2-biphenylol, respectively, in the presence of phosphorus oxychloride. The pharmacological activity of these compounds was then evaluated and compared with that shown by naphthopyran derivatives of structures (I), (II), and (III). With this same purpose also 6- and 8-benzyl derivatives of 2-(dialkylamino)chromones were prepared by using in the reaction 4- or 2-benzylphenol. Pharmacological screening showed that 6-phenyl substituted 2-(dialkylamino)chromones maintained the antireserpine and antimetrazole acti-activities which were possessed by the 1H-naphtho[2,1-b]pyran derivatives (I) and the 4H-naphtho[2,3-b]pyran derivatives (II), whereas 7-phenyl substituted compounds were devoid of any activity. 8-Phenyl substituted 2-(dialkylamino)chromones maintained to some extent the antiamphetamine activity which was clearly shown by the 4H-naphtho[1,2-]pyran derivatives (III). Furthermore, the compounds bearing the benzyl substituent both in the 6 or 8 position showed only antimetrazole activity.

[Chemical and pharmacological research on pyran derivatives. XIV. 3-alkylaminoaphtho/2,1-b/pyran-1-ones and derivatives]. / Richerche chimiche e farmacologiche su derivati piranici. Nota XIV - 3-alchilamminonafto[2,1-b]piran-1-oni e derivati.

3-Alkyl(phenyl)aminoaphtho[2,1-b]pyran-1-ones (III) were prepared from N-alkyl or N-phenylethoxycarbonylacetamides and 2-naphthol in the presence of phosphorus oxychloride, in order to evaluate their pharmacological activity on the CNS in comparison with previously described 3-dialkylaminoaphtho[2,1-b]pyran-1-ones. Compounds (III) gave 2-morpholinomethyl derivatives as well as N-acetyl and N-ethtoxycarbonyl derivatives. The reaction of (III) in which R = alkyl and N,N-dimethylformamide-POCl3 afforded 2-formyl derivatives and in some cases also 8-alkyl-9,10-bisdimethylaminoaphtho[1',2':5,6]pyrano[2,3-b]pyrrol-11(8H)-ones; when R = phenyl, only naphtho[1',2':5,6]pyrano[2,3-b]quinolin-14-one was obtained from the same reaction. Pharmacological evaluation showed that compounds (III) had a weak CNS depressant activity. Some of them also exhibited antagonist effect on reserpine-induced blepharospasm and hypothermia and on metrazole-induced seizures in the mouse. Within the limits of these activities a special behavior was found for the compound 3-ethylaminoaphtho[2,1-b]pyran-1-one [(III b) - K 12479].

[Chemical and pharmacological research on pyran derivatives. XIII. Derivatives of 2H-pyrano/3,2-c/quinoline]. / Ricerche chimiche e farmacologiche su derivati piranici. XIII - Derivati della 2H-pirano[3,2-c]chinolina.

Treatment of N-alkylanilines or diphenylamine with N,N-dialkylethoxycarbonylacetamides in the presence of phosphorus oxychloride afforded 6-alkyl(phenyl)-4-dialkylaminopyrano [3,2-c] quinoline-2,5-(6H)-diones, two molecules of amide being involved in the reaction. In some instances 6-alkyl(phenyl)-4-alkylaminopyrano [3,2-c] quinoline-2,5(6H)-diones were obtained through a partial dealkylation of the amino group. Pharmacological evaluation of some compounds showed no activity on the CNS.

Psychopharmacological study with K 8409, a 1H-naphtho[2,1-b]pyran 3-dialkylamino substituted derivative.

A 1H-naphtho[2,1-b]pyran derivative (K 8409) has undergone pharmacological investigation for psychotropic activity. The results show potential antidepressant action quantitatively similar to that of imipramine and amitriptyline, but due rather to MAO inhibition than to imipramine-like activity; interestingly enough, anti-MAO activity was particularly selective for the serotonin-converting enzyme, both centrally and peripherally. The outcome of the other tests suggests that the incidence of untoward effects is likely to be limited.

[Chemical and pharmacological research on pyran derivatives. XII. Bis-(beta-chloroethyl)amino-substituted chromones and benzochromones]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota XII. Cromoni e benzocromoni bis-(beta-cloroetil)amminosostituiti.

By the reaction of phenols or naphthols with N,N-bis-(beta-methoxyethyl)ethoxycarbonylacetamide in the presence of phosphorus oxychloride the preparation of bis-(beta-methoxyethyl)amino substituted chromones or benzochromones was achieved. Treatment of these compounds with hydriodic acid at 95 degrees and then with thionyl chloride gave rise to the formation of the corresponding bis-(beta-chloroethyl)amino derivatives. When beta-naphthols reacted with N-ethoxycarbonylacetylmorpholine 1-oxo-3-morpholino-1H-naphtho[2,1-b]pyrans were obtained. These compounds as well as the corresponding 3-bis-(beta-methoxyethyl)amino derivatives afforded 1-oxo-3-bis-(beta-iodoethyl)amino-1H-naphtho[2,1-b]pyrans by treatment with hydriodic acid at reflux. The latter compounds were also easily transformed into 3-bis-(beta-chloroethyl)amino derivatives by reaction with phosphorus oxychloride in N,N-dimethylformamide. Pharmacological screening of some of the compounds described indicated no tumor-inhibiting activity.

[1,5-Benzodiazepines. III. Synthesis of 2,4-bisdialkylamino-3H-1,5-benzodiazepines]. / Ricerche su 1,5-benzodiazepine. Nota III. Sintesi di 2,4-bisdialchilammino-3H-1,5-benzodiazepine.

Treatment of 2,3-dihydro-2-oxo-4-dialkylamino-1H-1,5-benzodiazepines with phosphorus pentasulfide afforded 2-thio derivatives which in turn gave the corresponding methylmercapto derivatives by reaction with sodium hydride and methyl iodide. By treating these compounds with dialkylamines the formation of 2,4-bisdialkylamino-3H-1,5-benzodiazepines was achieved. Pharmacological screening of some of the products indicated that the introduction of a second dialkylamino substituent into the 1,5-benzodiazepine molecule gave the compounds CNS excitant properties, while the initial monodialkylamino derivatives containing sulfur showed a CNS depressant activity.

[Chemical and pharmaceutical research on pyran derivatives. XI. Synthesis of 2-dialkylamino-4-oxo-10-methyl-4H-naphtho[2,3b]pyrans]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota XI-Sintesi di 2-dialchilammino-4-oxo-10-metil-4H-nafto[2,3-b]pirani.

Reaction of N,N-dialkylethoxycarbonylacetamides with 1-methyl-2-naphthol, in the presence of phosphorus oxychloride, gave rise to the formation of 2-dialkylamino-4-oxo-10-methyl-4H-naphtho[2,3-b] pyrans through the preliminary attack of the amide-phosphorus oxychloride reactant at the phenolic hydroxyl and cyclization at position 3 of the naphthalene moiety. However when (N-alkyl,N-phenyl)ethoxycarbonylacetamides were used in the reaction an ortho position of the N-phenyl group was involved in the cyclization and 1-alkyl-2(1'-methyl-2'-naphthoxy)-4-quinolones were achieved. Pharmacological investigation showed that some naphtho[2,3-b]pyran derivatives have neurotropic activity of the sedative, anticonvulsant and antidepressant type very similar to that shown by previously studied 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans (5).

[Chemical and pharmaceutical research on pyran derivatives. X. Synthesis of 1-oxo-2-alkyl-3-dialkylamino-1H-naphtho[2,1b]pyrans]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota X. Sintesi di 1-oxo-2-alchil-3-dialchilammino-1H-nafto[2,1-b]pirani.

When reaction of N,N-dialkyl-alpha-ethoxycarbonyl-alpha-alkylacetamides with beta-naphthol in the presence of phosphorus oxychloride was carried out in chlorobenzene at reflux, formation of 1-oxo-2-alkyl-3-dialkyl-amino-1H-naphtho[2,1-b]pyrans was achieved together with some other products whose structure was defined. Moreover, substitution of the 2 position of 1-oxo-3-dialkylamino-1H"naphtho[2,1-b]pyrans with chlorine or cyano group as well as the preparation of 1-thio-3-dialkylamino-1H-naphtho[2,1-b]pyrans was obtained by suitable chemical methods. Pharmacological screening of these compounds showed the lack of psychotropic activity of the corresponding 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans.

[Chemical and pharmacologic study on pyran derivatives. IX. Synthesis of 2-dialkylaminochromones]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota IX. Sintesi di 2-dialchilamminocromoni.

Under suitable conditions the reaction of phenol and N,N-dialkylethoxycarbonylacetamides, in the presence of phosphorus oxychloride, resulted in the formation of 2-dialkylaminochromones. In a similar manner, variously substituted phenols afforded 2-dialkylaminochromones with substituents in different positions of the benzene ring. Pharmacological screening of all these compounds showed that they markedly affect the CNS, activity being mainly excitatory. Decreased activity was shown by compounds with particular substituents in the positions 6,7,8 among which two products [(V e) - K 12440, (V s) - K 12420] have weak but clear anticonvulsant effect.

[Study of 1,5-benzodiazepines. II. Synthesis of 2,4-di-(N-alkyl,N-phenyl)amino-3H-1,5-benzodiazepine]. / Ricerche su 1,5-benzodiazepine. Nota II - Sintesi di 2,5-di-(N-alchil,N-fenil)amino-3H-1,5-benzodiazepine.

Following the procedure we described for synthesizing analogous compounds in Note I (7), reaction of N,N-dialkyl or (N-alkyl,N-phenyl)ethoxycarbonylacetamides with 4-chloro-1,2-phenylendiamine, in the presence of phosphorus oxychloride, afforded 2,3-dihydro-2-oxo-4-dialkyl (N-alkyl,N-phenyl)amino-chloro-1H-1,5-benzodiazepines. When a large amount of phosphorus oxychloride was employed in the reaction, the formation of 2,4-di-(N-alkyl,N-phenyl)amino-3H-1,5-benzodiazepines was achieved, starting from suitable o-phenylendiamines and (N-alkyl,N-phenyl)ethoxycarbonylacetamides. Pharmacological tests were carried out on some compounds described in the present paper and on others reported in the preceding Note (7); in this connection 4-amino-1,5-benzodiazepine derivatives showed weak CNS depressing activity in addition, in some cases, to clear, although moderate, anticonvulsant activity, whereas 2,4-diamino-1,5-benzodiazepine derivatives were practically without effect.

[Chemical and pharmacological research on pyran derivatives. VIII. Synthesis of 2-dialkylamino-7-methoxychromones and derivatives]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota VIII - Sintesi di 2-dialchilammino-7-metossicromoni e derivati

2-Dialkylamino-7-methoxychromones were prepared by reaction of a m-methoxyphenol with N,N-dialkylethoxycarbonylacetamides in the presence of phosphorus oxychloride. Treatment of such compounds with 57% hydriodic acid resulted in the formation of the corresponding 7-hydroxy derivatives. These latter, treated with dialkylamines and formaldehyde, were transformed into the 8-dialkylaminomethyl derivatives. On the other hand the reaction of 2-dialkylamino-7-methoxychromones with morpholine and formaldehyde, in the presence of acetic acid, led to the formation of the corresponding 3-morpholinomethyl derivatives. Pharmacological investigation showed that 2-dialkylamino-7-hydroxy-chromones were without effect, whereas all other compounds tested had a clear, but generally weak, CNS stimulant activity.

[Studies on 1,5-benzodiazepine. I. Derivatives of 4-amino-1,5-benzodiazepine]. / Ricerche su 1,5-benzodiazepine. Nota I-Derivati della 4-ammino-1,5-benzodiazepina

Condensation of o-phenylendiamine and N,N-dialkyl-ethoxycarbonylacetamides in the presence of phosphorus oxychloride afforded 2,3-dihydro-2-oxo-4-dialkylamino-1H-1,5-benzodiazepines. These same compounds with a substituent in the 3 position were obtained when N,N-dialkylamino-alpha-ethoxycarbonyl-alpha-alkylacetamides were employed in the reaction. In a similar manner from N-phenyl-o-phenylendiamine the synthesis of 1-phenyl-2,3-dihydro-2-oxo-4-dialkylamino-1H-1,5-benzodiazepines was achieved. The formation of benzimidazole-2-acetic acid derivatives was observed in these reactions.

[Chemical and pharmacological research on pyran derivatives. VII. Derivatives of naphto/1',2':5,6/pyran/2,3-c/pyrazole and of 12H-naphto/1',2':5,6/pyran/2,3-d/pyrimidine]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota VII--derivati del nafto[1',2':5,6]pirano[2,3-c]pirazolo e della 12H-nafto[1',2':5,6]pirano[2,3-d]pirimidina

Reaction of substituted 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans with N,N-dimethylformamide in the presence of phosphorus oxychloride afforded the corresponding substituted 1-oxo-2-formyl-3-dialkyl-amino-1H-naphtho[2,1-b]pyrans. Condensation of substituted 1-oxo-2-formyl-3-dimethylamino-1H-naphtho[2,1-b]pyrans with hydrazine or monosubstituted hydrazines led to the formation of 11-oxo-8H,11H-naphtho[1',2':5,6]pyrano[2,3-c]pyrazole derivatives through the intermediate hydrazones and subsequent cyclization. Similarly, condensation with acetamidine or guanidine gave rise to the formation of 12-oxo-12H-naphtho[1',2':5,6]pyrano[2,3-d]pyrimidine derivatives. Some of these compounds were tested for their pharmacological properties, but no noteworthy activity was observed.

[Chemical and pharmacological research on pyran derivatives. VI. 2-Dialkylamino-4-oxo-4H-naphto/1,2-b/pyrans and derivatives]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota VI-2-dialchilammino-4-oxo-4H-nafto [1,2-b] pirani e derivati

The 2-dialkylamino-4-oxo-4H-naphtho [1,2-b]pyrans are obtained by the reaction of N,N-dialkylethoxycarbonylacetamides with alpha-naphthol and with substituted alpha-naphthols. The products on treatment with formaldehyde and morpholine or piperidine or N-methylpiperazine are transformed into the 2-dialkylamino-3-dialkylaminomethyl-4-oxo-4H-naphtho [1,2-b]pyrans. Pharmacological investigation has shown that 2-dimethylamino (K 12164), 2-(N-ethyl, N-methyl)amino- (K 12087) and 2-diethylamino-4-oxox-4H-naphtho [1,2-b]pyran (K 12165) show clear neurotropic activity of the neuroleptic type whereas compounds of the isomeric series, 1H-naphtho-[2,1-b]pyrans, studied previously (1), show anticonvulsive and sedative activity. This difference in pharmacological activity has prompted a more complete comparative examination of the activity of the two series of compounds. Study of antagonism to the effects of reserpine by both 4H-naphtho [1,2-b]pyrans and 1H-naphtho [2,1-b]pyrans has shown that in the latter series the 1-oxo-3-dimethylamino- (K 8291), the 1-oxo-3-(N-ethyl, N-methyl)amino- (K 8409) and the 1-oxo-3-diethylamino-1H-naphtho [2,1-b]-pyran (K 8292) have marked neurotropic activity of the antidepressive type.