Hoffmann-la Roche Inc.

Emilio Kyburz

Walter Hunkeler

Max Gerecke

Jean-Pierre Kaplan

Rene Imhof

Werner Aschwanden

Willy Haefely

Petar Polc

Hanns Mohler

Lorenzo Pieri

Roland Jakob

Roland Jakob-Roetne

Quirico Branca

Rudolf Pfister

Walter Gassner

Rene Borer

Marc Meier

Hans Spiegelberg

Mose Da Prada

Pierre Charles Wyss

Philippe Dostert

Rene' Imhof

Renato Joos

Werner Aschwenden

The novel imidazodiazepine derivatives of the formula: ##STR1## wherein the substituents are as described in the specification, can be used for the control or prevention of epileptic seizures, anxiety, tension and excitation states, sleep disorders, schizophrenic symptoms, hepatic encephalopathy and senile dementia, as well as, in the partial or complete antagonization of undesired side-effects of substances acting on benzodiazepine receptors after over-dosage or after their use in intensive medicine and in anesthesia.

Imidazodiazepine derivatives

Benzamides of the formula ##STR1## wherein R.sup.1 and R.sup.2 each independently is hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono(lower alkyl)sulfamoyl or di(lower alkyl)sulfamoyl or R.sup.1 and R.sup.2 on adjacent carbon atoms together are a methylenedioxy group, with the proviso that R.sup.2 is different from hydrogen when R.sup.1 are bromine in the 3-position, and their pharmaceutically acceptable acid addition salts have monoamine oxidase inhibiting properties with low toxicity and can accordingly be used for the treatment of depressive states and Parkinsonism.

Benzamide derivatives

Pyrrolidine derivatives of the formula ##STR1## wherein R.sup.1 is hydrogen or lower alkanoyl, R.sup.2 is hydrogen or lower alkyl and R.sup.3 is hydrogen, lower alkyl or a group of the formula --(CH.sub.2).sub.n --NR.sup.4 R.sup.5, wherein n is a whole number of 2 to 4 and R.sup.4 and R.sup.5 each, independently, are hydrogen or lower alkyl, or R.sup.4 and R.sup.5 taken together with the nitrogen atom are a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted by one or two lower alkyl groups, enantiomers thereof, and acid addition salts of compounds of formula I and their enantiomers which are basic, are useful in the control or prevention of cerebral insufficiency or in the improvement of intellectual capacity. The compounds of formula I of the invention can be prepared starting from starting materials hereinafter described, and are useful as medicaments, for example, in the form of pharmaceutical preparations.

Methods and pharmaceutical compositions using pyrrolidine derivatives

Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted by .alpha. and .beta. represent one of the following groups ##STR2## R.sup.1 is a partially unsaturated lower hydrocarbon group which is optionally substituted with hydroxy, oxo, aryl or the group --OR, --SR or --OCOR or a lower alkyl group which is substituted with aryl or the group --OR', --SR' or --OCOR'. R and R' each represents aryl or a saturated or partially unsaturated C.sub.1-18 -hydrocarbon group which is optionally substituted with aryl or lower alkoxy, R.sup.2 is hydrogen and R.sup.3 is lower alkyl or R.sup.2 and R.sup.3 together represent dimethylene or trimethylene and R.sup.4 and R.sup.5 each is hydrogen, halogen, trifluoromethyl, cyano, nitro or lower alkyl, the group --OR' being different from lower alkoxy and the compounds of formula I having the (S)- or (R,S)-configuration with reference to the carbon atom denoted by .gamma. when R.sup.2 and R.sup.3 together represent dimethylene or trimethylene, can be used in the control or prevention of convulsions, anxiety states, stress conditions, excitation states and sleep disorders, or in the partial or complete selective antagonism of some or all activities which 1,4-benzodiazepines having tranquillizing activity or other substances exhibit via the central benzodiazepine receptors.

Hydrocinnamic acid derivatives of the formula ##STR1## wherein one or two of the symbols R.sup.1 to R.sup.4 are halogen or methoxy and the others are hydrogen;

Hydrocinnamic acid derivatives

Ethylenediamine monoamides of the formula

Compounds for treating and preventing cognitive diseases and depression

Benzazecinediones of the formula ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen or chlorine, R.sup.3 is hydrogen, fluorine, chlorine, bromine or methoxy, R.sup.4 is hydrogen, chlorine or methoxy and R.sup.5 is hydrogen, acetyl, propionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl, with the proviso that 2 or 3 of the groups R.sup.1 to R.sup.4 are hydrogen, as well as many of the corresponding benzo[f]quinolines from which these benzazecinediones can be prepared by oxidation are suitable for the control or prevention of cerebral insufficiency or for the improvement of cognitive functions in mammals. They can be produced according to various processes and can be prepared into pharmaceutical compositions.

Benzazecine derivatives for cognitive and memory functions

Benzazecinediones of the formula ##STR1## where R.sup.1 and R.sup.2 are independently hydrogen or chlorine, R.sup.3 is hydrogen, fluorine, chlorine, bromine or methoxy, R.sup.4 is hydrogen, chlorine or methoxy and R.sup.5 is hydrogen, acetyl, propionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl, with the proviso that 2 or 3 of the groups R.sup.1 to R.sup.4 are hydrogen, as well as many of the corresponding benzo[f]quinolines from which these benzazecinediones can be prepared by oxidation are suitable for the control or prevention of cerebral insufficiency or for the improvement of cognitive functions in mammals. They can be produced according to various processes and can be prepared into pharmaceutical compositions.

A compound for treating disorders of the central nervous system, which is of the formula wherein A taken together with the two carbon atoms denoted by .alpha. and .beta. is one of the following groups: ##STR1## R.sup.1 is one of the following groups:

Imidazodiazepine derivatives for treatment of disorders of the central

There is presented compounds of the formula ##STR1## wherein A together with the two carbon atoms denoted by .alpha. and .beta. signifies one of the groups ##STR2## and the dotted line signifies the double bond present in cases (1), (2) and (4) and wherein R.sup.1 signifies a 5- or 6-membered aromatic heterocyclic group or the group --C(R.sup.6).dbd.NOR.sup.7 (B), R.sup.2 signifies hydrogen and R.sup.3 signifies hydrogen or lower alkyl or R.sup.2 and R.sup.3 together signify dimethylene, trimethylene or propenylene, R.sup.4 and R.sup.5 each signify hydrogen, halogen, trifluoromethyl, cyano, nitro, amino or lower alkyl, R.sup.6 signifies hydrogen or lower alkyl and R.sup.7 signifies lower alkyl, the compound of formula I having the (S) or (R,S) configuration with reference to the carbon atom denoted by .gamma. when R.sup.2 and R.sup.3 together signify dimethylene, trimethylene or propenylene, and pharmaceutically acceptable acid addition salts thereof have a pronounced affinity to the central benzodiazepine receptors and have anxiolytic, anticonvulsant, muscle relaxant and sedative-hypnotic properties.

Imidazodiazepines

Compounds of the formula ##STR1## wherein R is an aromatic, 5- or 6-membered heterocyclic residue, as described herein, and their pharmaceutically usable acid addition salts are described. These compounds have interesting monoamine oxidase inhibiting properties with low toxicity and can accordingly be used for the treatment of depressive states and parkinsonism.

Ethylenediamine monoamides

Benzo[f]quinoline intermediates

Benzazecinediones of the formula ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen or chlorine, R.sup.3 is hydrogen, fluorine, chlorine, bromine or methoxy, R.sup.4 is hydrogen, chlorine or methoxy and R.sup.5 is hydrogen, acetyl, propionyl, benzoyl, chlorobenzoyl, methoxybenzoyl or phenylacetyl, with the proviso that 2 or 3 of the groups R.sup.1 to R.sup.4 are hydrogen. as well as many of the corresponding benzo[f]quinolines from which these benzazecinediones can be prepared by oxidation are suitable for the control or prevention of cerebral insufficiency or for the improvement of cognitive functions in mammals. They can be produced according to various processes and can be prepared into pharmaceutical compositions.

1-[2-(4,5,10,11-Tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidin e of the formula ##STR1## and its pharmaceutically acceptable acid addition salts, prepared through various intermediates, are described. The compounds have valuable histamine-H.sub.1 antagonistic properties and are suitable for the control or prevention of allergic reactions,such as, urticaria, hay fever, anaphylaxis and over-sensitivity to medicaments.

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Reinach, Switzerland

Emilio Kyburz