Mediolanum Farmaceutici, S.r.l.

Mediolanum Farmaceutici

Patrizia Terni

Stefano Maiorana

Piergiuseppe Pagella

Arnaldo Fravolini

Pier G Pagella

Giuseppe Mascellani

Antonio Papagni

Mario Brufani

Pier L Rugarli

Donata Marchesini

Raffaello Fusco

Giacomina Mandelli

Lucia Mairani

Phenylcarbamate derivatives suitable to the use as anticholinesterase

A process for preparing pyrido-benzothiazine derivatives having the following general formula: ##STR1## in which R is H or a C.sub.1 -C.sub.6 alkyl or a C.sub.1 -C.sub.6 fluoroalkyl, and R.sub.1 is N-alkyl-3-pyrrolidinalkylamine with C.sub.1 to C.sub.6 alkyls or ##STR2## where R.sub.2 is a C.sub.1 -C.sub.6 alkyl or a C.sub.2 -C.sub.6 alkenyl or an arylalkyl group, possibly substituted by halogen, hydroxy or keto-groups, both in the racemic form and in the optically active form. The process for the preparation of derivatives of formula (I) starts with a first reaction cycle starting from 2,4-difluoro-3-chloronitrobenzene. Said derivatives possess a high antibacterial activity as well as a high bioavailability to tissues. The invention also refers to pharmaceutical compositions containing them as active components.

Process for preparing pyrido-benzothiazine derivatives having high

Pyrido-benzothiazine derivatives having the following general formula: ##STR1## in which R is H or a C.sub.1 -C.sub.6 alkyl or a C.sub.1 -C.sub.6 fluoroalkyl, and R.sub.1 is N-alkyl-3-pyrrolidinalkylamine with C.sub.1 to C.sub.6 alkyls or ##STR2## where R.sub.2 is a S.sub.1 -C.sub.6 alkyl or a C.sub.2 -C.sub.6 alkenyl or an arylalkyl group, possibly substituted by halogen, hydroxy or keto-groups, both in the racemic form and in the optically active form. The invention also comprises the process for the preparation of derivatives of formula (I) starting from 2.4-difluoro-3-chloronitrobenzene. Said derivatives possess a high antibacterial acitvity as well as a high bioavailability to tissues; the invention also refers to pharmaceutical compositions containing them as active components.

Pyrido-benzothiazine derivatives having high antibacterial activity and

New highly soluble antibacterially active salts of pyridobenzothiazines with organic acids are described. In particular, organic salts of 9-fluoro-10[N-(4'-methyl)piperazinyl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3][1 ,4]-benzothiazine-6-carboxylic acid are prepared with an acid chosen from the group consisting of methanesulphonic acid, ethanesulphonic acid, n-dodecanesulphonic acid, p-toluenesulphonic acid, 1-actadecanesulphonic acid, 2-chloro-ethanesulphonic acid, 2-bromo-ethanesulphonic acid, 3-hydroxy-propanesulphonic acid, citric acid, malonic acid, gluconic acid, malic acid, lactic acid and L-tartaric acid. A new process is also described for preparing said salts from 2,3,4-trichloronitrobenzene, by way of a 2-fluoro-3-chloro-4-mercapto derivative of the nitrobenzene and cyclizing the corresponding amino derivative.

Highly soluble antibacterially active organic salts of

The invention relates to antibacterially active pyrido-benzothiazine derivatives with long-term action, having the following general formula: ##STR1## in which R is ##STR2## Where R.sup.1 is H, C.sub.1 -C.sub.6 alkyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl or 2-pyridyl; or ##STR3## where R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 are lower alkyls. The invention also comprises the process for preparing compounds of general formula (I). Said process consists of a synthesis cycle using 2,4-difluoro-3-chloronitrobenzene and thiolactic acid as starting substances. The inventiona also comprises pharmaceutical compositions containing at least one of the compounds of general formula (I) as active principle.

Antibacterially active pyrido-benzothiazine derivatives with long-term

A new class of antimicrobial pyrido-benzothiazine compounds and processes for their preparation are described. The compounds have the general formula: ##STR1##

Anti-bacterial pyrido-benzothiazine derivative and pharmaceutical

Pyrido-benzothiazine compounds having anti-microbial activity are prepared by (a) reacting 3-chloro-4-fluoroaniline with potassium thiocyanate and bromine to produce 2-amino-6-fluoro-7-chlorobenzothiazole, (b) reacting 2-amino-6-fluoro-7-chlorobenzothiazole with sodium hydroxide to produce the disulfide of 2-amino-5-fluoro 6-chlorothiophenol, (c) reacting the disulfide with sodium monochloroacetate to produce 7-fluoro-8-chloro-2H-1,4-benzothiazin-3(4H)-one, (d) reducing 7-fluoro-8-chloro-2H-1,4-benzothiazin-3(4H)-one to produce 7-fluoro-8-chloro-3,4-dihydro-2H-1,4-benzothiazone, (e) reacting 7-fluoro-8-chloro-3,4-dihydro-2-H-1,4-benzothiazone with ethyl ethoxymethylenemalonate and cyclyzing the intermediate formed with polyphosphoric acid to produce ethyl 9-fluoro-10-chloro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3 de] [1,4]-benzothiazine-6-carboxylate and (f) hydrolyizing the ethyl carboxylate to produce the corresponding carboxylic acid.

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Milan, Italy

Patrizia Terni