Hoffmann-la Roche Inc.

Andre Szente

Albert E Fischli

Quirico Branca

Anna Krasso

Henri Stalder

Hans P Marki

Romano Derungs

Henri Ramuz

Jean-Marie Cassal

Joseph Hellerbach

Rene Borer

Max Gerecke-Jecklin

Bernd B{umlaut Over (u)}ttelmann

The invention is concerned with hydroxymethyl-imidazodiazepines and their esters of general formula I. These compounds can be used as anxiolytic and/or anticonvulsant and/or muscle relaxant and/or sedative-hypnotic active substances.

Hydroxymethylimidazodiazepines and their esters

Novel compounds of the formula ##STR1## wherein Q, R.sup.1 and R.sup.2 are described herein, are disclosed along with pharmaceutical compositions, methods of use, and process for producing compounds of formula I which starts from the corresponding .beta.-hydroxycarboxylic acids.

Oxetanones

Oxetanone compounds containing proline and pharmaceutical compositions

Oxetanone compounds and pharmaceutical compositions containing them

Tricyclic imidazole derivatives of formula I ##STR1## wherein one of R.sup.1 and R.sup.3 is lower alkyl and the other is hydrogen or lower alkyl, R.sup.2 is lower alkyl, n is the number 0 or 1, A is ##STR2## R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each is lower alkyl land R.sup.8 is hydrogen nor lower alkyl, and their acid addition salts are described. These compounds are useful as agents for control or prevention of ulcers and of increaased gastric acid secretion.

Tricyclic imidazole derivatives

A compound of the formula ##STR1## wherein R.sup.1 -R.sup.19 are as described in the specification. The present invention is concerned with benzimidazole derivatives, particularly benzimidazole-2-yl pyridinium compounds of formula I which are pharmaceutically useful in treating or preventing gastric and duodenal ulcers. The invention includes the compounds I, pharmaceutical compositions containing such compounds and the use of such compounds in therapeutic treatment or prevention of gastric and duodenal ulcers.

Benzimidazole derivative compounds and method of making

(Benzimidazol-2-yl)-pyridinium compounds of the formula ##STR1## wherein A is --SR.sup.9, --SO.sub.3.sup.- or --S--SO.sub.3.sup.- ; R.sup.1 and R.sup.3 each is hydrogen or (C.sub.1 -C.sub.7)-alkyl; R.sup.2 is hydrogen, (C.sub.1 -C.sub.7)-alkyl, (C.sub.1 -C.sub.7)-alkoxy or a negatively charged oxygen atom; R.sup.4 is hydrogen or a negative charge; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each is hydrogen, (C.sub.1 -C.sub.7)-alkyl, aryl, halogen, cyano, nitro, formyl, (C.sub.2 -C.sub.7)-alkanoyl, arylcarbonyl, carboxy, carboxy-(C.sub.1 -C.sub.7)-alkyl, (C.sub.1 -C.sub.7)-alkoxycarbonyl, aryloxycarbonyl, aryl-(C.sub.1 -C.sub.7)-alkoxycarbonyl, (C.sub.1 -C.sub.7)-alkoxycarbonyl-(C.sub.1 -C.sub.7)-alkyl, carbamoyl, mono- or di-(C.sub.1 -C.sub.7)-alkylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, carbamoyl-(C.sub.1 -C.sub.7)-alkyl, mono- or di-(C.sub.1 -C.sub.7)-alkylcarbamoyl-(C.sub.1 -C.sub.7)-alkyl, pyrrolidinocarbonyl-(C.sub.1 -C.sub.7)-alkyl, piperdinocarbonyl-(C.sub.1 -C.sub.7)-alkyl, hydroxy, (C.sub.1 -C.sub.7)-alkoxy, (C.sub.2 -C.sub.7)-alkanoloxy, aryloxy, arylcarbonyloxy, (C.sub.1 -C.sub.7)-alkoxycarbonyloxy, aryl-(C.sub.1 -C.sub.7)-alkoxycarbonyloxy, aryloxycarbonyloxy, carbamoyloxy, mono- or di-(C.sub.1 -C.sub.7)-alkylcarbamoyloxy, pyrrolidinocarbonyloxy, piperidinocarbonyloxy, hydroxy-(C.sub.1 -C.sub.7)-alkyl, trifluoromethyl, di-(C.sub.1 -C.sub.7)-alkoxymethyl or (C.sub.2 -C.sub.3)-alkylenedioxymethyl or two of these substituents which are adjacent jointly and together with the carbon atoms to which they are attached are a 5-, 6- or 7-membered ring; and R.sup.9 is (C.sub.1 -C.sub.20)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, (C.sub.3 -C.sub.7)-alkenylalkyl, (C.sub.3 -C.sub.7)-alkynylalkyl, substituted (C.sub.3 -C.sub.7)- alkenyl-alkyl, aryl, aryl-(C.sub.1 -C.sub.7)-alkyl, hydroxy- (C.sub.2 -C.sub.7)-alkyl, (C.sub.1 -C.sub.7)-alkoxy- (C.sub.2 -C.sub.7)-alkyl, (C.sub.1 -C.sub.7)-alkoxycarbonyl- (C.sub.1 -C.sub.7)-alkyl, carboxy-(C.sub.1 -C.sub.7)-alkyl, di-(C.sub.1 -C.sub.7)-alkoxycarbonyl-(C.sub.2 -C.sub.7)-alkyl, dicarboxy-(C.sub.2 -C.sub.7)-alkyl, carboxy-(C.sub.1 -C.sub.7)-alkylcarbamoyl-(C.sub.1 -C.sub.7)-alkyl, optionally N-substituted amino-(C.sub.2 -C.sub.7)-alkyl, optionally N-substituted amino-carboxy-(C.sub.2 -C.sub.7)-alkyl, optionally N-substituted amino-(C.sub.1 -C.sub.7)-alkoxycarbonyl-(C.sub.2 -C.sub.7)-alkyl, heteroaryl, heteroaryl-(C.sub.1 -C.sub.7)-alkyl or a residue derived from a cysteine-containing oligopeptide by elimination of the SH group; provided that when there is a net single positive charge there is an external anion, or a pharmaceutically acceptable acid addition salt thereof.

(Bezimidazol-2-yl)-pyridinium compounds

Tricyclic imidazole derivatives of formula I ##STR1## wherein one of R.sup.1 and R.sup.3 is lower alkyl and the other is hydrogen or lower alkyl, R.sup.2 is lower alkyl, n is the number 0 or 1, A is ##STR2## R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each is lower alkyl and R.sup.8 is hydrogen or lower alkyl, and their acid addition salts are described. These compounds are useful as agents for control or prevention of ulcers and of increased gastric acid secretion.

There are presented novel pharmaceutically active substances which inhibit the intestinal resorption of cholesterol and which accordingly can be used in the control or prevention of atherosclerosis. These active substances are benzodiazepines of the formula ##STR1## wherein R.sup.1 is (C.sub.1 -C.sub.4)-alkyl, R.sup.2 is hydrogen or methyl, R.sup.3 and R.sup.4 each are halogen and R.sup.5 is (C.sub.3 -C.sub.9)-alkylamino substituted by at least two hydroxy groups, (C.sub.3 -C.sub.6)-cycloalkylamino substituted by at least one hydroxy group, glucosamino, galactosamino, mannosamino, monohydroxy-1-azetidinyl, mono- or dihydroxy-1-pyrrolidinyl or mono-, di- or trihydroxy-1-piperidinyl, and the readily hydrolyzable esters and ethers thereof, as well as pharmaceutically acceptable salts of these compounds.

Benzodiazepine derivatives and their pharmaceutical use

There is presented novel benzophenone derivatives of the formula ##STR1## wherein R.sup.1 is hydrogen or lower alkyl, R.sup.2 is hydrogen or aminoacetyl, R.sup.3 is hydrogen or lower alkyl, R.sup.4 is hydrogen or halogen, R.sup.5 is hydrogen, amino, nitro or a group of the formula R.sup.3 --ON.dbd.C(R.sup.6)--and R.sup.6 is lower alkyl, with the proviso that R.sup.5 is a group of the formula H--ON.dbd.C(R.sup.6)--when R.sup.2 and R.sup.3 are both hydrogen, and their pharmaceutically acceptable acid addition salts. The compounds exhibit aldosterone-antagonistic properties and are accordingly suitable for the control or prevention of heart failure, hepatic ascites, primary aldosteronism and idiopathic hypertension.

Benzophenone derivatives useful in treating heart failure

There are presented novel benzodiazepine derivatives of the formula ##STR1## wherein R.sup.1 is lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl, R.sup.2 and R.sup.3 each are lower alkyl, R.sup.4 is halogen, R.sup.5, R.sup.7 and R.sup.8 each are hydrogen or halogen and R.sup.6 is nitro, amino, lower alkylamino, lower dialkylamino or a group of the formula H.sub.2 N--C(CH.sub.3).sub.2 --CO--NH--, R.sup.9 R.sup.10 N--CO--NH-- or ##STR2## and either R.sup.9 is hydrogen or lower alkyl and R.sup.10 is lower alkyl or lower hydroxyalkyl or R.sup.9 and R.sup.10 together with the nitrogen atom are a 3- to 7-membered heterocycle which, provided it is at least 5-membered, can contain as a ring member an oxygen or sulfur atom or a group of the formula &gt;N--R in which R is hydrogen or lower alkyl, and their pharmaceutically acceptable acid addition salts. The compounds possess aldosterone-antagonistic properties and are accordingly suitable for the control or prevention of heart failure, hepatic ascites, primary aldosteronism and idiopathic hypertension.

Benzodiazepine derivatives

There are presented compounds of the formula ##STR1## wherein R.sup.1 is a hydrogen atom or a lower alkyl group, R.sup.2 and R.sup.3 each are a hydrogen atom or a lower alkyl group, R.sup.4 is a halogen atom and either R.sup.5 is a hydrogen atom or a lower alkyl group and R.sup.6 is a lower alkyl or lower hydroxyalkyl group or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached are a 3-membered to 7-membered heterocycle, and pharmaceutically acceptable acid addition salts thereof. The compounds and their salts are novel and possess valuable pharmacodynamic properties.

Triazolo-benzodiazepine derivatives

There are presented compounds of the formula ##STR1## wherein R.sup.1 is a lower alkyl group, R.sup.2 is a hydrogen atom or a lower alkyl group, R.sup.3 is a hydrogen or halogen atom, R.sup.4 is a hydrogen atom or a group of the formula R.sup.5 --CO--,R.sup.6 R.sup.7 N--O--, ##STR2## A is a lower alkylene group, X is an oxygen or sulphur atom or a group of the formula &gt;N--.sup.8 , R.sup.5 is a lower alkyl or lower haloalkyl group, R.sup.6 is a hydrogen atom or a lower alkyl group, R.sup.7 is a lower alkyl group and R.sup.8 is a hydrogen atom or a lower alkyl or lower hydroxyalkyl group, and their pharmaceutically acceptable acid addition salts. The compounds have aldosterone-antagonistic properties and are accordingly suitable for the control or prevention of heart failure, hepatic ascites, primary aldosteronism and idiopathic hypertension.

This invention provides benzodiazepine derivatives of the general formula ##STR1## wherein R.sup.1 represents a lower alkyl group, R.sup.2 represents a hydrogen atom or a lower alkyl group, R.sup.3 represents a halogen atom and R.sup.4 represents a hydrogen or halogen atom and either R.sup.5 represents a hydrogen atom or a lower alkyl group and R.sup.6 represents a lower alkyl, lower hydroxyalkyl or lower acyloxyalkyl group or R.sup.5 represents a hydrogen atom and R.sup.6 represents an aryl or lower aralkyl group or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached represent a 3-membered to 7-membered heterocycle which, when it is at least 5-membered, can contain as a ring member an oxygen or sulphur atom or a group of the formula ##STR2## in which R.sup.7 represents a hydrogen atom or a lower alkyl group, and pharmaceutically acceptable acid addition salts thereof, which possess aldosterone-antagonistic properties and are accordingly suitable for the control or prevention of heart failure, of hepatic ascites, of primary aldosteronism and of idiopathic hypertension. Some of these compounds and salts also inhibit the intestinal resorption of cholesterol and are according suitable for the prevention or control of atherosclerosis. Also provided are a process for the manufacture of the above end products and novel intermediates therefor.

This invention provides benzodiazepine derivatives of the general formula ##STR1## wherein R.sup.1 represents a lower alkyl group, R.sup.2 represents a hydrogen atom or a lower alkyl group, R.sup.3 represents a halogen atom and R.sup.4 represents a hydrogen or halogen atom and either R.sup.5 represents a hydrogen atom or a lower alkyl group and R.sup.6 represents a lower alkyl, lower hydroxyalkyl or lower acyloxyalkyl group or R.sup.5 represents a hydrogen atom and R.sup.6 represents an aryl or lower aralkyl group or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached represent a 3-membered to 7-membered heterocycle which, when it is at least 5-membered, can contain as a ring member an oxygen or sulphur atom or a group of the formula &gt;N--R.sup.7 in which R.sup.7 represents a hydrogen atom or a lower alkyl group, and pharmaceutically acceptable acid addition salts thereof, which possess aldosterone-antagonistic properties and are accordingly suitable for the control or prevention of heart failure, of hepatic ascites, of primary aldosteronism and of idiopathic hypertension. Some of these compounds and salts also inhibit the intestinal resorption of cholesterol and are according suitable for the prevention or control of atherosclerosis. Also provided are a process for the manufacture of the above end products and novel intermediates therefor.

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Riehen, Switzerland

Andre Szente