Ciba-Geigy Corporation

Wilhelm Kump

Hans Bickel

Beat Muller

Keith Allan Menear

Oskar Wacker

Jen Chen

Peter Traxler

Benjamin B Mugrage

John E Francis

Siem J Veenstra

Peter William Taylor

Klaus Muller

Ian Timothy Matthews

Jane I Lowrie

Christian Borel

The invention relates to novel acyl derivatives of rifamycins of the formula ##STR1## and the salts thereof, in which the structural elements --A.sub.1 --A.sub.2 --, --A.sub.3 --A.sub.4 -- and --A.sub.5 --A.sub.6 -- each denote ethylene or vinylene or the elements --A.sub.1 --A.sub.2 -- and --A.sub.3 --A.sub.4 -- each denote ethylene and --A.sub.5 --A.sub.6 -- denotes vinylene; X represents &gt;C(R.sub.6)-- or &gt;N-- and R.sub.6 denotes hydrogen or alkyl; alk denotes an aliphatic hydrocarbon radical; R.sub.1 denotes hydrogen or acyl; R.sub.2 denotes acyl, or alkyl which is optionally substituted by an aromatic radical, and R.sub.3 and R.sub.3 ' represent a common bond, or R.sub.3 denotes hydrogen or acyl, and R.sub.3 ' is hydrogen; R.sub.4 denotes hydrogen, cycloalkyl or aryl; R.sub.5 denotes hydrogen or acetyl; R.sub.7 denotes hydrogen or alkyl, which can be used as active compounds in medicaments, the preparation and use thereof, and pharmaceutical products and the preparation thereof.

Acyl derivatives of oxazolorifamycins

The invention relates to the preparation of substituted azacyclohexyl derivatives of rifamycins of the formula ##STR1## and salts thereof in which R.sub.1 is hydrogen or trialkylacetyl, R.sub.2 is hydrogen or acetyl and R.sub.3 is alkyl, which exhibit valuable pharmacological properties.

Substituted azacyclohexyl derivatives

Compounds of the general formula: ##STR1## in which R is a lower alkyl group, and R.sub.1 is a tri-lower alkylmethylcarbonyl group, the structure elements --A.sub.1 --A.sub.2 --, A.sub.3 --A.sub.4 -- or A.sub.5 --A.sub.6 -- each represent ethylene or vinylene, or the elements --A.sub.1 --A.sub.2 -- and --A.sub.3 --A.sub.4 -- each represent ethylene and --A.sub.5 --A.sub.6 -- represents vinylene, their optical isomers and their salts exhibit valuable pharmaceutical properties.

Open chain rifamycin derivatives

The invention relates to a process for the preparation of a compound of formula ##STR1## or a salt thereof, wherein R.sub.1 is hydrogen or trialkylacetyl, R.sub.2 is hydrogen or acetyl and R.sub.3 is alkyl, which process comprises cyclising a compound of formula ##STR2## wherein R.sub.1 is trialkylacetyl and, if desired, converting a compound of formula I obtainable by said process or in another manner, or a salt thereof, into another compound of formula I or a salt thereof, or converting a resultant free compound of formula I into a salt and/or a resultant salt into the free compound of formula I or into another salt.

Process for the preparation of polycyclic compounds

The invention relates to novel substituted azacyclohexyl derivatives of formula ##STR1## and salts of thereof in which the structural elements --A.sub.1 -A.sub.2, --A.sub.3 -A.sub.4 -- and --A.sub.5 -A.sub.6 -- are each ethylene or vinylene or the elements --A.sub.1 -A.sub.2 -- and --A.sub.3 -A.sub.4 -- are each ethylene and --A.sub.5 -A.sub.6 -- is vinylene, X is &gt;CR.sub.6 -- or &gt;N-- and R.sub.6 is alkyl or hydrogen, alk is an aliphatic hydrocarbon radical or a bond, R.sub.1 is hydrogen or acyl, R.sub.2 is hydrogen or acetyl, R.sub.3 and R.sub.4 together are a bond or each is hydrogen, R.sub.5 is hydrogen, a cycloaliphatic hydrocarbon radical, aryl or heteroaryl and R.sub.7 is hydrogen or alkyl, with the proviso that when --A.sub.1 -A.sub.2 --, --A.sub.3 -A.sub.4 -- and --A.sub.5 -A.sub.6 -- are each vinylene, X is &gt;N--, R.sub.1 is hydrogen or trialkylacetyl, R.sub.2 is hydrogen or acetyl, R.sub.3 and R.sub.4 together are a bond and alk is methylene, R.sub.5 is other than 2,6-dimethyl-4-alkylphenyl, which can be used as active ingredients in medicaments, to their preparation and use and to pharmaceutical preparations.

Substituted azacyclohexyl derivatives of rifamycins

3-W-Rifamycin SV and S compound, wherein W is a piperazin-1-yl radical of the formula ##STR1## wherein R.sup.1 and R.sup.2 are C.sub.1 -C.sub.4 alkyl and R.sup.3, R.sup.4 and R.sup.5 are hydrogen or C.sub.1 -C.sub.4 alkyl, or R.sup.2 together with R.sup.3 or R.sup.3 together with R.sup.4 are buta-1,3-dien-1,4-ylene, trimethylene or tetramethylene, each of which is unsubstituted or substituted by C.sub.1 -C.sub.4 alkyl, and R.sup.1, R.sup.4 and R.sup.5 or R.sup.1, R.sup.2 and R.sup.5 are hydrogen or C.sub.1 -C.sub.4 alkyl, and salts thereof, have long-term antituberculotic and antimicrobial activity.

Substituted 4-benzylpiperazinyl compounds

Diacyl derivatives of 4-(trialkylbenzyl)-piperazinyl compounds

3-Hydroxyrifamycin S and its new analogues with an etherified or esterified 3-hydroxyl group of the formula ##STR1## in which each of R and R' represents a hydrogen atom, or R' represents acetyl and R represents hydrogen, an optionally substituted hydrocarbyl or the acyl radical of a carboxylic acid, and also the corresponding compounds of the SV series, are obtained by a novel process in which 3-bromorifamycin S is treated with a reagent ROH, in which R has the meanings mentioned above, or with a salt thereof, in a neutral to weakly basic medium. The final products are primarily suitable as antibiotics for combating microbial infections and/or as intermediates for the manufacture of the same.

Process for introducing an oxygen-containing functional group into

Antibiotically active compounds derived from rifamycin S or from the corresponding hydroquinone, rifamycin SV, or from derivatives at least partially hydrogenated in positions 16, 17; 18, 19; 28, 29, such as the 16, 17; 18, 19--tetrahydro- or the 16, 17; 18, 19; 28, 29--hexahydro derivatives, which contain in position 3 a free or an aliphatically substituted amino group. The hydrocarbon radicals of the aliphatically substituted amino group can also be interrupted in their carbon chain by heteroatoms and/or be substituted by functional groups. A special group of these new compounds is represented by 3-amino derivatives as defined above, in which the amino group is a particular type of N-aza-cyclo-aliphatic radical unsubstituted by functional groups, and which has, in addition to the antibiotic action against sensitive microorganisms also an antibacterial activity against certain types of resistant microorganisms. Another special group is represented by 3-amino derivatives as defined above, in which the amino group is a particular type of a 4R-1-piperazinyl radical, in which R is a hydrocarbon radical; they have a special high antituberculosis action, while having very low toxicity.

Substituted rifamycins

Derivatives of 5-norbicyclomycin of the formula ##STR1## wherein R represents an unsubstituted or substituted monovalent hydrocarbon radical in which one, two or more carbon atoms can be replaced by heteroatoms, and X represents a bivalent group of the formula --O-- or --N(R')--, wherein R' has one of the meanings assigned to R, whilst R and R', if both have a meaning which is different from hydrogen, can also be linked to each other through a C--C bond or an oxygen, sulphur or nitrogen atom, and corresponding compounds, in which at least one hydroxyl group is protected, and salts of said compounds, provided they contain salt-forming groups, are useful as antibiotics, especially against Enterobacteriaceae, or as intermediates for the production of such antibiotics. They are obtained by condensing a corresponding 5-norbicyclomycin-5-one with a compound of the formula R--X--NH.sub.2 in which X and R have the above meaning.

Bicyclomycin derivatives, compositions thereof and process of use thereof

Antibiotically active compounds derived from rifamycin S or from the corresponding hydroquinone, rifamycin SV, or from derivatives at least partially hydrogenated in positions 16, 17; 18, 19; 28, 29, such as the 16, 17; 18, 19-tetrahydro-or the 16, 17; 18, 19; 28, 29-hexahydro derivatives, which contain in position 3 a free or an aliphatically substituted amino group. The hydrocarbon radicals of the aliphatically substituted amino group can also be interrupted in their carbon chain by heteroatoms and/or be substituted by functional groups. A special group of these new compounds is represented by 3-amino derivatives as defined above, in which the amino group is a particular type of N-aza-cyclo-aliphatic radical unsubstituted by functional groups, and which has, in addition to the antibiotic action against sensitive microorganisms also an antibacterial activity against certain types of resistant microorganisms. Another special group is represented by 3-amino derivatives as defined above, in which the amino group is a particular type of a 4R-1-piperazinyl radical, in which R is a hydrocarbon radical; they have a special high antituberculosis action, while having very low toxicity.

Antibiotically active rifamycin derivatives

Bicyclomycin derivatives (i.e. compounds with the skeleton of the 5-methylene-2-oxa-7,9-diazabicyclo�4,2,2!decane) of the formula ##STR1## wherein R.sup.a to R.sub.d represent hydrogen atoms or hydroxyl protective groups, X represents a free or functionally modified carboxyl group, a substituted or unsubstituted hydrocarbon radical or a halogen atom, and n is 0 or 1, possess valuable antibiotic properties which are of importance in particular for combating infections caused by Enterobacteriaceae and Proteus species.

Bicyclomycin derivatives

Antibiotically active compounds derived from rifamycin S or from the corresponding hydroquinone, rifamycin SV, or from derivatives at least partially hydrogenated in positions 16, 17; 18, 19; 28, 29, such as the 16, 17; 18, 19 - tetrahydro- or the 16, 17; 18, 19; 28, 29 - hexahydro derivatives, which contain in position 3 a free or an aliphatically substituted amino group. The hydrocarbon radicals of the aliphatically substituted amino group can also be interrupted in their carbon chain by heteroatoms and/or be substituted by functional groups. A special group of these new compounds is represented by 3-amino derivatives as defined above, in which the amino group is a particular type of N- aza - cyclo - aliphatic radical unsubstituted by functional groups, and which has, in addition to the antibiotic action against sensitive microorganisms also an antibacterial activity against certain types of resistant microorganisms. Another special group is represented by 3- amino derivatives as defined above, in which the amino group is a particular type of a 4R - 1 - piperazinyl radical, in which R is a hydrocarbon radical ; they have a special high antituberculosis action, while having very low toxicity.

Growing community of inventors

Biel-Benken, Switzerland

Wilhelm Kump