Hoffmann-la Roche Inc.

Other

Armin Walser

Rodney I Fryer

Eugene J Trybulski

Leo Henryk Sternbach

Louis Benjamin

Norman W Gilman

George F Field

Joseph Donald Surmatis

Erminio Costa

Hermann Bretschneider

Alessandro Guidotti

Joseph Hellerbach

Robert Ye-Fong Ning

Werner Rudolph

Rudolph Frank Lauer

The present invention is directed to imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide compounds of the formula: ##STR1## wherein R is hydrogen, C.sub.3 CH.sub.2 --, CH.sub.2 .dbd.CHCH.sub.2 --, (CH.sub.3).sub.2 CH--, CH.sub.3 CH.sub.2 CH.sub.2 --, or ##STR2## or a pharmaceutically acceptable salt thereof. These compounds and their pharmaceutically acceptable salts possess anti-anxiety and anti-epileptic activity.

Benzodiazepines and compositions for treating anxiety and panic

Racemic Compounds of the formula ##STR1## A is --C.tbd.C--R.sub.6, --CH.sub.2 --CH.sub.2 --R.sub.7 or ##STR2## and the remainder of the variables are as defined in the specification, and their enantiomers and salts thereof are described. The compounds of formula I exhibit activity as inhibitors of 5-lipoxygenase and inhibit lipid peroxidation. They are, therefore, useful in the treatment of diseases caused or aggravated by excess oxidative metabolism of arachidonic acid via the 5-lipoxygenase pathway and in the treatment of inflammation, arthritis, allergies, asthma and psoriasis. The compounds of formula I can also be used to prevent peroxidation of lipids and thus protect lipid membranes from oxidative stress.

Chromanes and their pharmaceutical compositions and methods

Racemic Compounds of the formula ##STR1## A is --C.tbd.C--R.sub.6, --CH.sub.2 --CH.sub.2 --R.sub.7 or ##STR2## R.sub.1 is hydrogen or lower alkanoyl, R.sub.2, R.sub.3, and R.sub.4 independently are hydrogen or lower alkyl,

Pharmacologically active chromanes

The invention relates to compounds of the formula ##STR1## wherein X is --CH.dbd.CH-- or S; R.sub.1 is lower alkyl, lower alkoxy or trifluoromethyl;

Triazolo(4,3-A)(1,4)benzodiazepines and thieno

There is presented 3H-2-benzazepines and 4,5-dihydro-3H-2-benzazepines of the formula ##STR1## wherein X is hydrogen, chloro or bromo, Y is hydrogen, fluoro or chloro with the proviso that X and Y cannot both be hydrogen and R.sub.1 is selected from the group consisting of hydrogen, bromo, chloro, iodo, a radical of the formula ##STR2## and a radical of the formula ##STR3## wherein R.sub.2 is hydrogen, phthalimido, lower alkyl, hydroxy, amino, monoalkylamino and dialkylamino and R.sub.3 is hydroxy, phthalimido or amino with the proviso that where R.sub.1 is other than hydrogen then the bonding at the 4,5-position is unsaturated, and the pharmaceutically acceptable salts thereof.

3H-2-Benzazepines

There is presented a compound of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, chloro, bromo, alkoxy, hydroxy, lower alkyl substituted thio and NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are hydrogen, lower alkyl and di-substituted lower alkylamino lower alkyl; R.sub.2 is selected from the group consisting of hydrogen, lower alkyl and amino; R.sub.3 is selected from the group consisting of hydrogen, acyloxy and hydroxy; X is halogen and Y is hydrogen or halogen and the N-oxides thereof when R.sub.3 is hydrogen and the pharmaceutically acceptable salts thereof. The pyrimido[4,5-d][2]benzazepines are useful as anxiolytic and sedative agents. Also presented are processes and intermediates in the production of the above pyrimido[4,5-d][2]benzazepines.

Pyrimido[4,5-d][2]benzazepines useful as sedatives and anxiolytic agents

There is presented compounds of the formula ##STR1## wherein A is selected from the group consisting of ##STR2## R.sub.1 is selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl, the group NR.sub.4 R.sub.5, the group --CH.sub.2 --CO--R.sub.7, the group --NH(CH.sub.2).sub.m NR.sub.8 R.sub.9, hydroxy, lower alkoxy, mercapto and lower alkyl mercapto; R.sub.2 is selected from the group consisting of hydrogen, amino and di-lower alkyl amino; R.sub.3 is selected from the group consisting of hydrogen, lower acyloxy and hydroxy; X is selected from the group consisting of hydrogen, halogen, trifluoromethyl, ethyl, .alpha.-hydroxy ethyl and acetyl; Y is hydrogen or halogen; R.sub.4 and R.sub.5 are hydrogen or lower alkyl or together with their co-bonded nitrogen atom form a five to seven membered heterocyclic group; R.sub.7 is selected from the group consisting of hydroxy lower alkoxy and NR.sub.8 R.sub.9 ; R.sub.8 and R.sub.9 are hydrogen or lower alkyl; n is 0 or 1 and m is 1 to 7 with the limitations that (1) at least one of R.sub.1 and R.sub.2 are hydrogen, (2) when R.sub.3 is lower acyloxy or hydroxy, A is the group (a), X is hydrogen, halogen, trifluoromethyl, ethyl or acetyl and R.sub.1 is the group --NH(CH.sub.2).sub.m NR.sub.8 R.sub.9, then R.sub.8 and R.sub.9 are lower alkyl, (3) when A is group (d) and R.sub.1 is the group --NH(CH.sub.2).sub.m NR.sub.8 R.sub.9 then R.sub.8 and R.sub.9 are lower alkyl and (4) when n is 1, R.sub.1 is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or the group --CH.sub.2 --CO--R.sub.7 with R.sub.7 as above then A is the group (a) or (b) and the pharmaceutically acceptable salts thereof. The compounds exhibit pharmacological activity as anxiolytics and sedatives. Also presented are various novel intermediates and processes to produce the above end products.

Pyrimido-2-benzazepines and intermediates in their preparation

Pyrimido-2-benzazepines

There is presented compounds of the formula ##STR1## wherein A is selected from the group consisting of ##STR2## R.sub.1 is selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl, the group NR.sub.4 R.sub.5, the group --CH.sub.2 --CO--R.sub.7, the group--NH(CH.sub.2).sub.m NR.sub.8 R.sub.9, hydroxy, lower alkoxy, mercapto and lower alkyl mercapto; R.sub.2 is selected from the group consisting of hydrogen, amino and dilower alkyl amino; R.sub.3 is selected from the group consisting of hydrogen, lower acyloxy and hydroxy; X is selected from the group consisting of hydrogen, halogen, trifluoromethyl, ethyl, .alpha.-hydroxy ethyl and acetyl; Y is hydrogen or halogen; R.sub.4 and R.sub.5 are hydrogen or lower alkyl or together with their co-bonded nitrogen atom form a five to seven membered heterocyclic group; R.sub.7 is selected from the group consisting of hydroxy lower alkoxy and NR.sub.8 R.sub.9 ; R.sub.8 and R.sub.9 are hydrogen or lower alkyl; n is 0 or 1 and m is 1 to 7 with the limitations that (1) at least one of R.sub.1 and R.sub.2 are hydrogen, (2) when R.sub.3 is lower acyloxy or hydroxy, A is the group (a), X is hydrogen, halogen, trifluoromethyl, ethyl or acetyl and R.sub.1 is the group --NH(CH.sub.2).sub.m NR.sub.8 R.sub.9, then R.sub.8 and R.sub.9 are lower alkyl, (3) when A is group (d) and R.sub.1 is the group --NH(CH.sub.2).sub.m NR.sub.8 R.sub.9 then R.sub.8 and R.sub.9 are lower alkyl and (4) when n is 1, R.sub.1 is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or the group --CH.sub.2 --CO-- R.sub.7 with R.sub.7 as above then A is the group (a) or (b) and the pharmaceutically acceptable salts thereof. The compounds exhibit pharmacological activity as anxiolytics and sedatives. Also presented Are various novel intermediates and processes to produce the above end products.

There are presented compounds of the formula ##STR1## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.6 is halo and R.sub.5 is hydrogen or halo; and compounds of the formulas ##STR2## wherein R.sub.2 and R.sub.3 are selected from the group consisting of hydrogen, lower alkyl, C.sub.2 to C.sub.7 carboxylic acids, hydroxy C.sub.2 to C.sub.7 alkyl, C.sub.2 to C.sub.7 carboxylic acid esters and amides and the group COR.sub.11 wherein R.sub.11 and is selected from the group consisting of alkoxy, amino or mono-lower alkyl amino; R.sub.35 is hydrogen or lower alkyl; R.sub.5 is hydrogen or halo; and R.sub.7 is methyl or chloromethyl, all of which are useful in the preparation of pyrazolobenzazepines.

4-(2-Benzoylphenyl-1-pyazole and 4-(2-benzoylphenyl)-1-pyrazoline

Novel Imidazobenzodiazepines and their analogs are useful as anticonvulsants, muscle relaxant, anxiolytic and sedative agents. Preferred compounds of this class belong to the imidazo[1,5-a] [1,4] diazepine series which may have a very wide variety of organic substituents. An especially preferred genus included with the purview of the invention encompasses a compound of the formula ##STR1## wherein R.sub.1 is hydrogen and lower alkyl, preferably methyl; R.sub.3 and R.sub.5 are hydrogen; R.sub.4 is hydrogen, nitro or halogen, most preferably, chlorine, and in a most preferred embodiment when positioned on the fused benzo portion of the imidazobenzodiazepine is in the 8-position thereof; R.sub.6 is phenyl or halo, nitro, or lower alkyl-substituted phenyl, preferably, halo, with fluorine being the preferred halogen, the substituted fluoro being positioned in the 2-position of the phenyl moiety; and R.sub.2 is hydrogen and lower alkyl.

Imidazodiazepines and processes therefor

The present invention relates to compounds of the formula ##STR1## wherein R.sub.1 and R.sub.3 are selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy and R.sub.2 and R.sub.4 are hydrogen or R.sub.1 and R.sub.2 and/or R.sub.3 and R.sub.4 taken together are oxo groups with the proviso that at least one oxo group is present; R is selected from the group consisting of hydrogen, lower alkyl, C.sub.2 to C.sub.7 carboxylic acids and the esters and amides thereof, hydroxy C.sub.2 to C.sub.7 alkyl and amino C.sub.2 to C.sub.7 alkyl or mono- or di-lower alkyl amino C.sub.2 to C.sub.7 alkyl; R.sub.5 is halogen or hydrogen; and R.sub.6 is halogen with the proviso that when R.sub.1 or R.sub.3 is hydroxy, lower alkoxy or acyloxy, then R is lower alkyl or hydrogen and the N-oxides and the pharmaceutically acceptable salts thereof.

Pyrrolo[3,4-d][2]benzazepinones

The present invention relates to compounds of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or alkynyl, hydroxymethyl, the ##STR2## wherein R.sub.11 is hydrogen, hydroxy, alkoxy, amino and mono- or di-lower alkylamino; and R.sub.3 is selected from the group consisting of hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or alkynyl, hydroxymethyl, the ##STR3## wherein R.sub.11 is hydrogen, hydroxy, trihalomethyl, alkoxy, amino and mono- or di-lower alkylamino; R.sub.2 is selected from the group consisting of hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or alkynyl, the ##STR4## C.sub.2 to C.sub.7 carboxylic acids and the esters and amides thereof, hydroxy C.sub.2 to C.sub.7 alkyl and amino or mono- or di-lower alkyl amino C.sub.2 to C.sub.7 alkyl; R.sub.4 is selected from the group consisting of hydrogen, acyloxy, straight chain lower alkoxy and hydroxy; R.sub.5 is halogen or hydrogen; R.sub.6 is halogen with the proviso that if one of R.sub.1 or R.sub.3 is hydroxymethyl or the ##STR5## wherein R.sub.11 is as above then the remaining substituent is selected from the group consisting of hydrogen, lower alkyl and C.sub.3 to C.sub.7 alkenyl or alkynyl, and R.sub.2 is hydrogen and the further proviso that (A) when R.sub.4 is acyloxy then R.sub.1 and R.sub.3 are hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or C.sub.3 C.sub.7 alkynyl, and R.sub.2 is the ##STR6## (B) when R.sub.4 is hydroxy then R.sub.1 and R.sub.3 are hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or C.sub.3 to C.sub.7 alkynyl, and R.sub.2 is hydrogen or (C) when R.sub.4 is alkoxy then R.sub.1 and R.sub.3 are hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or C.sub.3 to C.sub.7 alkynyl, and the pharmaceutically acceptable salts thereof. Also disclosed are certain 5,6 dihydro derivatives, N-oxides and quarternary iminium salts of the pyrrolobenzazepines.

1H-Pyrrole-3-carbonitrile-4(2-benzoyl)phenyl derivatives as

The present invention relates to compounds of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or alkynyl, hydroxymethyl, the group ##STR2## wherein R.sub.11 is hydrogen, hydroxy, alkoxy, amino and mono- or di-lower alkylamino; and R.sub.3 is selected from the group consisting of hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or alkynyl, hydroxymethyl, the group ##STR3## wherein R.sub.11 is hydrogen, hydroxy, trihalomethyl, alkoxy, amino and mono- or di-lower alkylamino; R.sub.2 is selected from the group consisting of hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or alkynyl, the group ##STR4## C.sub.2 to C.sub.7 carboxylic acids and the esters and amides thereof, hydroxy C.sub.2 to C.sub.7 alkyl and amino or mono- or di- lower alkyl amino C.sub.2 to C.sub.7 alkyl; R.sub.4 is selected from the group consisting of hydrogen , acyloxy, straight chain lower alkoxy and hydroxy; R.sub.5 is halogen or hydrogen; R.sub.6 is halogen with the proviso that if one of R.sub.1 or R.sub.3 is hydroxymethyl or the group ##STR5## wherein R.sub.11 is as above then the remaining substituent is selected from the group consisting of hydrogen, lower alkyl and C.sub.3 to C.sub.7 alkenyl or alkynyl, and R.sub.2 is hydrogen and the further proviso that (A) when R.sub.4 is acyloxy then R.sub.1 and R.sub.3 are hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or C.sub.3 to C.sub.7 alkynyl, and R.sub.2 is the group ##STR6## (B) when R.sub.4 is hydroxy then R.sub.1 and R.sub.3 are hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or C.sub.3 to C.sub.7 alkynyl, and R.sub.2 is hydrogen or (C) when R.sub.4 is alkoxy then R.sub.1 and R.sub.3 are hydrogen, lower alkyl, C.sub.3 to C.sub.7 alkenyl or C.sub.3 to C.sub.7 alkynyl, and the pharmaceutically acceptable salts thereof which exhibit activity as sedatives and anxiolytics. Also disclosed are certain 5,6 dihydro derivatives, N-oxides and quarternary iminium salts of the pyrrolobenzazepines.

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West Caldwell, NJ, United States of America

Armin Walser