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A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.

The syntheses of two novel pentacyclic ring systems, the thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepino-[4,5-a]benzimidazole and the indazolo[2,3-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine are described. Attachment of a propargyl linked quinolinone resulted in compounds 6 and 16 which showed PAF-antagonist activity by the intravenous route of administration in guinea pigs. The more potent compound 16 also exhibited good oral activity with an ID50 of 0.2 mg/kg in the bronchoconstriction assay.

The syntheses of two enantiomeric tetracyclic compounds, the thieno[3,2-f][pyrrolo[2,1-c][1,2,4]triazolo[4,3-a][1,4]diazepines 10a and 10b are described. Testing of these enantiomers as inhibitors of platelet activating factor (PAF) revealed good enantiospecificity, meaning that one enantiomer is responsible for the observed biological activity.

The syntheses of two enantiomeric tetracyclic compounds, the thieno[3,2-f][pyrrolo[2,1-c][1,2,4]triazolo[4,3-a][1,4]diazepines 10a and 10b are described. Testing of these enantiomers as inhibitors of platelet activating factor (PAF) revealed good enantiospecificity, meaning that one enantiomer is responsible for the observed biological activity.

The syntheses of two novel pentacyclic ring systems, the thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepino-[4,5-a]benzimidazole and the indazolo[2,3-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine are described. Attachment of a propargyl linked quinolinone resulted in compounds 6 and 16 which showed PAF-antagonist activity by the intravenous route of administration in guinea pigs. The more potent compound 16 also exhibited good oral activity with an ID50 of 0.2 mg/kg in the bronchoconstriction assay.

The quinazoline 3-oxides 2 were found to convert to the benzisoxazoloquinazolines 3 by heating in acetic anhydride. The dihydroquinazoline 3-oxides 1 underwent aromatization to 4 under the same conditions. Hydrolysis of 3 or 2 led to the 3-(2-aminophenyl)benzisoxazoles 8 which could be rearranged to the 3-(2-hydroxyphenyl)indazoles 11 by treatment with hydride. Possible mechanisms are discussed.

The preparation and oxidation of 2,3-dihydroindazoles to 1H, 2H or 3H-indazoles is described. A method for the synthesis of indazole 2-oxides has been found. Oxidation of 2-acetyl-2,3-dihydro-3,3-disubstituted indazoles 5a and 5c gave quinoid compounds 20a, 20b, 24a and 24b, which could be isomerized to 3H-indazoles upon removal of the acetyl group. A quinoid compound 21 was also obtained on treatment of 5a with tetracyanoethylene.

1,4-Benzodiazepine-2-acetic acid derivatives were prepared and converted to compounds with a heterocyclic ring fused to the a-face of the benzodiazepine system. Representatives of pyrido[1,2-a][1,4]benzodiaze-pines, pyrimido[1,6-a][1,4]benzodiazepines and [1,3]oxazino[3,4-a][1,4]benzodiazepines are described. Some of the compounds showed marked CNS-activity as measured by the antimetrazole test which is a well established primary screening method for assessment of benzodiazepine type activity.

The synthesis of the 1-phenylimidazobenzodiazepine 5 from 1 and the anion of the nitrone 2 is described. The 3-phenyl-derivative 14 was prepared via the ammo alcohol 11 which was obtained by condensation of the nitrosamine 9 with benzaldehyde followed by catalytic hydro-genolysis of the nitroso group.

1,4-Benzodiazepines bearing a carbon substituent at the 2-position were obtained by reaction of 2-chloromethylquinazoline 3-oxides with stabilized carbanions. The carbanions of alkyl acetates, N,N-disubstituted acetamides, acetonitrile, dimethylsulfone, N,N-dimethyl methanesulfonamide and 2-methylpyridine were successfully applied. The conversion of some of the 2-carbon substituted 1,4-benzodiazepines to imidazo[1,5-a][1,4]benzodiazepines and [1,2,5]oxadiazino[5,4-a][1,4]benzodiazepines is described.

Pyrano[3,2-d][2]benzazepines were synthesized by reaction of the beta-dimethylamino unsaturated ketone 1 with malonic ester or the anion of t-butyl acetate. Conversion of the pyrano derivative to the pyrido[3,2-d]-[2]benzazepine was achieved in low yield. A pyrrolo[3,2-d][2]benzazepine was prepared via an oxazepino-[6,7-d][2]benzazepine which was obtained by reaction of 1 with the anion of ethyl isocyanoacetate.

3-(2-Arninophenyl)indazoles 2 were prepared by the reaction of the o-fluorobenzophenones 1 with hydrazines. These indazoles were converted to the tetracyclic title compounds by conventional methods.

Variously substituted indolo[2,3-c]quinolines, benzofurano[2,3-c]quinolines and their positional isomers indolo[3,2-c]quinolines and benzofurano[3,2-c]quinolines respectively, were prepared from both indole and quinoline derivatives by intramolecular nucleophilic displacement of aromatic fluorine. The formation of an indolo[2,3-d]benzazepine was also observed.

A facile synthesis of the 4H-imidazo[5,1-c][1,4]benzothiazine ring system is described. The synthesis utilized the annulation of an imidazole ring onto a 2H-1,4-benzothiazin-3(4H)-one via the addition of the anion of ethyl isocyanoacetate. Methods for the functionalization of the 1-, 3-, 4-, and 5-positions of the ring system are presented.

Some new triazolylbenzophenones 3 were prepared by reaction of the corresponding quinazolines 2 with formic acid. Conversions of compounds 3 to known triazolobenzodiazepines are described. One of the processes proceeds via the double bond isomer 13. The reaction of the aldehyde 9 with hydrazine interestingly yielded the triazoloquinolines 11 and 12. The cyclization of the benzophenones 3 to the triazoloindoles 15 and the alkylation of the latter to derivatives with basic and acidic side chains are also reported. Quaternization of compound 16 with ethyl bromoacetate followed by treatment with hydroxide resulted in the formation of the triazinoindole 12.

The thieno[3,2-e][1,4]diazepin-2-one (1a), the thieno[2,3-e] [ 1,4] diazepin-2-one (1b), the pyrazolo[3,4-e][1,4]diazepin-2-one (1c) and a chloro analog of 1b, compound 1d, were each converted to derivatives of the novel tricyclic ring systems 4H-imidazo[1,5-a]thieno[2,3-f] [1,4]-diazepine, 4Himidazo[1,5a]thieno[2,3f][1,4]diazepine and 4H-imidazo[ 1,5-a]pyrazolo[4,3-f]-[1,4]diazepine. Depending on the substituents desired on the imidazo ring, two different synthetic pathways were employed.

The preparation of the title compounds 3 and 4 using two different methods of synthesis is described. These compounds are readily reduced to 2,3-dihydro-1H-derivatives 5. Oxidation of 2-alkylthio-1H-1,4-benzodiazepines leads to the corresponding sulfoxides and sulfones. The oxidative rearrangement of sulfones 9 to a 2H-1,4-benzodiazepin-2-one derivative 10 is also given. The “normal” addition of azodicarboxylate together with an unusual addition of two moles of acetylenedicarboxylate to the enamine double bond of 1H compounds is discussed.

The 2-hydrazinobenzodiazepines 1 were reacted with acelylacelone to form the hydroxy-pyrazolines 2 which were converted to the triazolobenzodiazcpines 6 and the 2-pyrazolyl-benzodiazepine 4. Ring cleavage of the hydrazone 8 obtained from cyclohexane-1,3-dione and 1a led similarly to the 1-(4-oxopentyl)triazolol)enzodiazepine 12.

The addition of diethyl azodicarboxylate to an electron rich double bond was employed as the key step for the preparation of the title compounds. Novel tetracyclic [1,2,4]triazino[1′,6′:3,4]imidazo[1,5-a][1,4]benzodiazepines were accessible from these 2-aminoimidazo[1,5-a][1,4]benzodiazepin-1-ones.

A series of pyrazino[1,2-a][1,4]benzodiazepines were prepared by acylating the primary amino group of an α-amino-1,4-benzodiazepine-2-ylideneacetic acid ester (1) with α-chloroacyl chlorides followed by cyclo-dehydrohalogenation with triethylamine in dimethylformamide. Some pharmacological data for CNS-activity are discussed.

The displacement of the nitro group in nitrooximes by other nucleophiles was used to prepare various 2-(hydroxyimino)methyl- and 2-(methoxyimino)methyl-1,4-benzodiazepines. These compounds were converted to imidazo[1,5-a][1,4]benzodiazepines bearing a tertiary amine, methoxy or thiomethyl group in the 3-position.

s-Triazolo[4,3-a][1,4]benzodiazepines bearing various substituents in the 1 position were prepared by oxidative cyclization of the appropriate aldehyde hydrazones of 2-hydrazinobenzodiazepines. Diethyl azodicarboxylate and activated manganese dioxide were used as oxidizing agents. The new triazolo compounds were active in the CNS tests but none of them reached the potency of the known triazolobenzodiazepines.

The 2-benzazepine 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (1) has been selected for development as an anxiolytic agent. In support of this program, we have confirmed by chemical synthesis the structures of three in vitro (rat liver homogenate) metabolites of 1 and confirmed the structure of the major in vivo (dog and man) metabolite of 1, compound 2. Two of the metabolites, arising from hydroxylation of the pyrimidobenzazepine ring at the 5-position (2) and N-oxide formation at the 3-position of the pyrimidobenzazepine ring (3), were found to be as active as 1 in a series of pharmacological tests. The third metabolite, formed by hydroxylation of the 7-phenyl group in the 4-position (4), was found to be inactive in the same pharmacological screens.

Aus dem Aminomethyl- benzodiazepin (II) erhalt man mit Zink/Essigsaure das Reduktionsprodukt (I), wahrend mit Orthoessigsaureester (III) das Cyclisierungsprodukt (IV) gebildet wird.

The reaction of the 2-methylquinoline-3-carboxylic acid 1b with thionyl chloride gave the dichlorothiolactone 2, the structure of which was confirmed by chemical transformations.

Base catalyzed cyclization of the 2-methylazoxybenzophenone (4B) obtained by condensation of the 2-nitrosobenzophenone (2a) with methylhydroxylamine led to the cinnoline 2-oxide (7) which is the major product of the peracid oxidation of the corresponding cinnoline (5).