Hoffmann-la Roche Inc.

Werner Hofheinz

Andre Furlenmeier

Harro Stohler

Christian N Hubschwerlen

Hans P Isenring

Paul Hebeisen

Gerard Schmid

Helmut Link

Raffaello Masciadri

Emil A Broger

Peter Angehrn

Erwin Gotschi

Solange Adam-Molina

Werner Leupin

Arthur Meili

Syn Ese Jolidon

Catherine Jaquet

The invention relates to novel quinoline derivatives and their therapeutic use against malaria.

Quinoline derivatives for treating malaria

N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation and their

Novel aminoquinoline derivatives of the general formula ##STR1## are described. Also described are methods for the treatment of malaria pathogens, particularly chloroquine-resistance malaria pathogens with compounds of formula I or the pharmaceutically acceptable salts and hydrolyzable esters thereof.

Method of treating chloroquine-resistant malaria with aminoquinoline

A novel process for the asymmetric hydrogenation of compounds of the formula: ##STR1## wherein R represent aryl or heteroaryl, to compounds of the formula: ##STR2## wherein R has the above significance, is carried out using rhodium-diphosphine complexes.

Assymetric synthesis process

Cephalosporin derivatives have the formula ##STR1## wherein Z.sup.1, Z.sup.2, X, Y, P, Q, m, n and p are as defined in the following text. Also described are the readily hydrolyzable esters and pharmaceutically compatible salts of these compounds, and hydrates of compounds of formula I, their esters and salts. Processes are provided for manufacture and pharmaceutical preparations which contain these compounds. Intermediates from the manufacture of these compounds are described, as is the use of the compounds in the control of illnesses and for the manufacture of the aforementioned preparations.

Cephalosporin derivatives

Novel 4-substituted-4,8-dimethyl-2,3-dioxabicyclo[3.3.1] nonan-7-ones which have a pronounced activity against the causative organism of malaria and can be used for the prevention and control of malaria.

Bicyclic peroxides

Acyl derivatives of the formula ##STR1## in which R is an acyl group, excluding those acyl groups of the formula ##STR2## in which A is a group of the formulae --NHCO--, --NHCONHCO--, --NHCOCH.dbd.CH--, ##STR3## wherein R.sup.6 is hydrogen or lower alkyl; R.sup.1 and R.sup.2 are hydrogen or a protecting group, X is hydrogen, halogen, lower alkoxy, nitro or --OR.sup.2, n is 1 or 2, R.sup.4 and R.sup.5 are hydrogen or together represent an additional bond and Z is a direct bond or carbonyl (where R.sup.4 and R.sup.5 both represent hydrogen) or a group of the formula --O--B-- (where R.sup.4 and R.sup.5 together represent an additional bond) in which B is a straight-chain, branched or cyclic lower alkylene;

Bicyclic peroxides compositions for and treatment of malaria therewith

The manufacture of 1-sulpho-2-oxazetidine derivatives of the formula ##STR1## in which Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom, R.sup.1 is hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, phenyl-lower-alkoxycarbonyl-lower alkyl, nitrophenyl-lower-alkoxycarbonyl-lower alkyl or carboxy-lower alkyl and R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxycarbonyl, lower alkanoyloxy-lower alkyl, lower alkoxycarbonyl-lower alkenyl, hydroxyiminomethyl, lower alkoxyiminomethyl, carbamoyl, carbamoyl-lower alkenyl or carbamoyloxy-lower alkyl, the group .dbd.NOR.sup.1 being present at least partially in the syn-form, in racemic form or in the form of the 3S-enantiomer, and of readily hydrolyzable esters and pharmaceutically compatible salts of these compounds, by acylating a compound of the formula ##STR2## in which R.sup.20 equals R.sup.2 or can also represent a 2,2-dimethyl-1,3-dioxolan-4-yl group and R.sup.3 is hydrogen or sulpho, or a salt thereof with a thioester of the formula ##STR3## in which Het is as above and R.sup.10 has any of the values of R.sup.1 except carboxy-lower alkyl, and can also represent a tri-lower alkyl-silyl-lower-alkoxycarbonyl-lower alkyl group or a carboxy-lower alkyl group converted into a readily hydrolyzable ester group, and the group .dbd.NOR.sup.10 is present at least partially in the syn-form, and carrying out subsequent steps (N-sulphonation, conversion of R.sup.20 into R.sup.2, R.sup.10 into R.sup.1), some of which are optional. The invention also provides certain novel products of formula I and benzthiazolyl thioesters of formula III per se and the preparation of the benzthiazolyl thioesters by esterifying corresponding carboxylic acids. Finally, the invention provides a process for the preparation of carboxylic acids in which R.sup.1 is t-alkoxycarbonylmethyl. The compounds of formula I have antimicrobial activity.

Process for the manufacture of 1-sulpho-2-oxoazetidine derivatives

Antimicrobial 2-oxo-1-azetidinesulphonic acids of the formula ##STR1## in which H.sub.2 N ##STR2## represents an amino-substituted thiazolyl group, R.sup.1 is lower alkyl which is substituted by carbamoyl, lower alkylsuphonyl, azido, piperidine-carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl or lower alkynyl, and R.sup.2 is hydrogen or a lower organic group, typically, carbamoyloxymethyl.

Antimicrobial 2-oxo-1-azetidinesulphonic acids

Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid

2-Nitroimidazoles having protozoocidal activity of the formula ##STR1## wherein R.sup.1 is 1-methyl-2-pyrrolidinyl or a group --CH.sub.2 -- NR.sup.2 R.sup.3 in which R.sup.2 and R.sup.3 each represent C.sub.1-4 -alkyl or --NR.sup.2 R.sup.3 is the residue of a five-membered or six-membered saturated heterocyclic ring system which optionally contains an additional nitrogen or oxygen atom in the ring, physiologically acceptable acid addition salts thereof, processes for their preparation, and pharmaceutical compositions containing these compounds are described.

Antiprotozoal 2-nitroimidazole compounds

There are presented .beta.-lactams of the formula ##STR1## wherein R.sup.1 is cyano or a group of the formula R.sup.4 --CO-- or R.sup.5 --A--CO--, R.sup.2 is hydrogen, lower alkyl or halogen, R.sup.3 is hydrogen or a group readily cleavable by hydrolysis, n is the number 0, 1 or 2, R.sup.4 is hydrogen, hydroxy, lower alkoxy, lower alkyl, aryl or a group of the formula ##STR2## R.sup.5 is halogen, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphinyl, arylsulphonyl or di-(loweralkoxy)phoshinyl, R.sup.6 and R.sup.7 are lower alkyl and A is lower alkylene, and pharmaceutically acceptable salts of carboxylic acids of formula I with bases. The compounds exhibit pronounced .beta.-lactamase-inhibiting properties.

Method of inhibiting .beta.-lactamase forming pathogens

2-Nitroimidazoles having filaricidal activity of the formula ##STR1## wherein A is one of the groups ##STR2## --C(R.sup.3).dbd.C(R.sup.1)(R.sup.2),--CHBr--CH.sub.2 Br or --CH.sub.2 --CCl.dbd.CH.sub.2 ;

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Bottmingen, Switzerland

Werner Hofheinz