Rhone-poulenc Sante

Rhone-poulenc Industries

Rhone-poulenc S.a.

Jean Bouchaudon

Daniel Farge

Claude James

Jean-Claude Aloup

Pierre Le Roy

Mayer Naoum Messer

Gilles Dutruc-Rosset

Rodolphe Margraff

Jean C Aloup

Guy Bourat

Tripeptides of the general formula: ##STR1## wherein the symbols R, which may be the same or different represent hydrogen or a fatty acid residue (at least one of them representing a fatty acid residue), R.sub.1 represents hydroxy, amino or alkoxy and R.sub.2 and R.sub.3, which may be the same or different, represent hydrogen, carboxy, carbamoyl or alkoxycarbonyl radical (with the proviso that R.sub.2 and R.sub.3 cannot simultaneously represent a hydrogen atom), the alanine moiety being in the L form, the glutamic acid moiety being in the D form, the lysine moiety (when R.sub.2 or R.sub.3 =a hydrogen atom) being in the L form and the 2,6-diaminopimelic acid moiety or its derivatives (when R.sub.2 and/or R.sub.3 =carboxy, carbamoyl or alkoxycarbonyl) being in the D,D, L,L, D,D/L,L (racemic) or D,L (meso) form, and salts thereof, possess immunological adjuvant and immunostimulant activity.

Peptides, their preparation and compositions containing them

N.sup.6 -Benzyloxycarbonyl-2,6-diaminopimelamic acid in L,L or D,D or racemic form is prepared by amidation of O.sup.1 -p-nitrobenzyl-N.sup.2 -benzyloxycarbonyl-2,6-diaminopimelic acid in L,L or D,D or racemic form.

Process for the preparation of N.sup.6

Thioformamide derivatives of the formula: ##STR1## wherein R is hydrogen or alkyl (1 to 4 C), Het is pyridin-3-yl[optionally substituted by alkyl (1 to 4 C) or a halogen], quinolin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, thiazol-5-yl, thieno[2,3-b]pyridin-5-yl or thieno[3,2-b]pyridin-6-yl, and Y is a valency bond or a methylene radical, are new compounds, which are particularly useful as antihypertensive agents.

Certain N-alkyl-2-[(quinolin-3-yl)-tetrahydro-pyran or

Tetrapeptides and pentapeptides of the formula: ##STR1## wherein R represents hydrogen or a fatty acid residue, R.sub.1 represents hydroxy, amino, alkoxy of 1 to 4 carbon atoms, optionally substituted by phenyl or nitrophenyl, one of R.sub.2 and R.sub.4 represents hydrogen, carboxy, carbamoyl, alkoxycarbonyl of 2 to 5 carbon atoms, optionally substituted by phenyl or nitrophenyl, or a N-carbonylglycine or N-carbonyl-D-alanine radical optionally esterified by alkyl of 1 to 4 carbon atoms (which is optionally substituted by phenyl or nitrophenyl) and the other symbol represents hydrogen, carboxy, carbamoyl, or alkoxycarbonyl fof 2 to 5 carbon atoms, optionally substituted by phenyl or nitrophenyl, and R.sub.3 represents hydrogen, a fatty acid residue or a glycyl or D-alanyl moiety in which the amine group is optionally substituted by a fatty acid residue, it being understood that R.sub.2 and R.sub.4 cannot simutaneously represent hydrogen, that at least one of R.sub.2, R.sub.3 and R.sub.4 represents a glycyl or D-alanyl moiety, that at least one of R and R.sub.3 represents or contains a fatty acid residue, and that the alanine moiety is in the L form, the glutamic acid moiety or its derivatives are in the D form, the lysine moiety or its derivatives, when one of the symbols R.sub.2 and R.sub.4 represents a hydrogen atom, are in the L form, and the 2,6-diaminopimelic acid moiety or fits derivatives, when R.sub.2 and R.sub.4 represent a carboxy, carbamoyl or alkoxycarbonyl radical, are in the D,D L,L,D,D/L,L (racemic) or D,L (meso) form, and salts thereof possess immunostimulant activity.

Tetrapeptides and pentapeptides, their preparation and compositions

Thioformamide derivatives of formula: ##STR1## in which R is hydrogen or alkyl (1 to 4 C), R.sub.1 is alkyl (1 to 4 C), and X denotes sulphur or oxygen and Y is sulphur, oxygen, methylene radical, or, when X is oxygen, a valency bond, are inhibitors of gastric secretion and therefore useful in the treatment of gastric ulcers. They may be made by reaction of an amine R--NH.sub.2 with a corresponding thioester or, when R is alkyl, by reaction of an alkyl isothiocyanate with the product of reacting a base with a compound of formula: ##STR2##

Thioformamide derivatives and use in inhibiting gastric secretion

Thioformamide derivatives of the formula: ##STR1## wherein R is hydrogen or alkyl (1 to 4 C), Het is pyridin-3-yl [optionally substituted by alkyl (1 to 4 C) or a halogen], quinolin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, thiazol-5-yl, thieno[2,3-b]pyridin-5-yl or thieno[3,2-b]pyridin-6-yl, and Y is a valency bond or a methylene radical, are new compounds, which are particularly useful as antihypertensive agents.

Certain N-lower-alkyl-2-(pyridin-3yl)-tetrahydrothiophene or

New heterocyclic nitriles of the formula: ##STR1## wherein (i) Het represents a heterocyclic radical of aromatic character containing one or two nitrogen atoms selected from pyrid-3-yl, pyrid-4-yl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, imidazolyl, naphthyridinyl, quinoxalinyl and quinazolinyl, X represents an oxygen atom and Y represents a valency bond or a methylene radical, or altenatively X represents a sulphur atom and Y represents a sulphur atom, a valency bond or a methylene radical, or (ii) Het represents the pyrid-2-yl radical, X represents an oxygen atom and Y represents a valency bond or a methylene radical, or alternatively X represents a sulphur atom and Y represents a sulphur atom or a methylene radical, are useful, in particular, as intermediates for the preparation of therapeutically useful heterocyclic thioformamides by converting the depicted cyano radical into a grouping --CSNHR wherein R represents a hydrogen atom or an alkyl (C.sub.1-4) radical.

Heterocyclic nitriles

The invention provides tri-, tetra- or penta-peptides of the general formula: ##STR1## in which RCO is a fatty acid residue, R.sub.1 is hydroxyl, amino, alkoxy or benzyloxy, R.sub.2 and R.sub.4 (identical or different) represent hydrogen, carboxyl, alkoxycarbonyl or benzyloxycarbonyl or an optionally esterified N-carbonylglycyl or N-carbonyl-D-alanyl radical, it being impossible for R.sub.2 and R.sub.4 simultaneously to represent hydrogen, R.sub.3 is hydrogen, or represents a glycyl or D-alanyl residue (in which case, only one of the radicals R.sub.2 and R.sub.4 can represent an N-carbonylglycyl or N-carbonyl-D-alanyl radical), X is a sulphur atom or methylene, and m and n=1 or 2, it being understood that if X is methylene, m and n are different from 1, their salts, their preparation and compositions containing them: the compounds are useful as vaccine adjuvants or as non-specific stimulants of anti-infectious or anti-tumoral activity.

Tri-, tetra, and penta-peptides, their preparation and compositions

Thioformamide derivatives of the formula: ##STR1## wherein R represents hydrogen or alkyl of 1 through 4 carbon atoms, and (i) Het represents a heterocyclic radical selected from pyrid-3-yl, pyrid-4-yl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, imidazolyl, naphthyridinyl, quinoxalinyl and quinazolinyl, X represents sulphur or oxygen and Y represents sulphur or oxygen, a valency bond or methylene, or (ii) Het represents pyrid-2-yl, X represents sulphur or oxygen and Y represents sulphur or oxygen or methylene, or (iii) Het represents pyrid-2-yl, X represents oxygen and Y represents a valency bond, are new compounds possessing useful pharmacological properties. They are particularly useful in the treatment of gastrointestinal ulcers and in the treatment of hypertension, depending on the definition of the symbol Het.

Thiocarboxamide derivatives and their use as pharmaceuticals

Dipeptides of the formula: ##STR1## in which R-CO represents a fatty acid residue and the symbols R.sub.1, which are identical or different, represent hydroxyl, amino or alkoxy containing 1 to 4 carbon atoms, which is optionally substituted by phenyl or nitrophenyl, it being understood that the alanine is in the L form and the glutamic acid or derivative thereof is in the D form, and their salts are immunological adjuvants and immunostimulants. They may be made using methods known per se in peptide chemistry and may be incorporated in pharmaceutical compositions.

Dipeptides, their preparation and compositions containing them

Compounds of the formula: ##STR1## wherein R represents hydrogen or alkyl of 1 through 4 carbon atoms, and R.sub.1 and R.sub.2 represent hydrogen or alkyl of 1 through 15 carbon atoms, or alkyl of 1 through 15 carbon atoms substituted by one substituent selected from (i) hydroxy, (ii) alkylamino in which the alkyl radical is of 1 through 4 carbon atoms, (iii) dialkylamino in which the alkyl radicals are of 1 through 4 carbon atoms, (iv) phenyl, (v) carboxy, and (vi) alkoxycarbonyl in which the alkoxy radical is of 1 through 4 carbon atoms, or R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached represent a five- or six-membered heterocyclic radical, are new compounds. They possess pharmacological properties and are particularly useful in the treatment of gastro-intestinal ulcers.

2-(Pyrid-2-yl)tetrahydrothiophene derivatives

Polyoxetanes are provided which consist essentially of a plurality of units of the formula: ##EQU1## AND OPTIONALLY, OF UNITS OF AT LEAST ONE OF THE FORMULAE: ##EQU2## in which: EACH OF X.sub.1 and X.sub.2, which may be identical or different, represents a chlorine or bromine atom,

Polyoxetanes which can be used in peptide synthesis

Ampicillin is prepared by reacting an inorganic or organic base with a new penicillin G derivative of the formula: ##EQU1## (wherein R.sub.1 represents a group protecting the carboxy radical and R.sub.2 represents a strong electron-attracting group, e.g. a halogenoethyl group) to open the imidazolidine ring and give an intermediate product of the formula: ##EQU2## and removing by methods known per se the groups --R.sub.1 and R.sub.2 O--CS-- which protect the carboxy radical and amine functions respectively.

Process for the preparation of ampicillin

The invention provides 7-trichloroacetamido-3-desacetoxy-cephalosporanic acid derivatives of the formula: ##SPC1## Wherein R is a group which protects the carboxylic acid radical, which can be converted into 7-amino-3-desacetoxycephalosporanic acid by replacing the R-- and Cl.sub.3 C--CO-- radicals by hydrogen atoms.

7-Trichloroacetamido-3-desacetoxy-cephalosporanic acid esters

Derivatives of penicillanic acid of formula: ##SPC1## In which R represents hydrogen or a radical of formula: ##EQU1## which is easily removable enzymatically, and in which R.sub.1 is hydrogen or straight or branched chain C.sub.1-4 alkyl, phenyl, or phenyl C.sub.1-2 alkyl and R.sub.2 is straight or branched chain C.sub.1-4 alkyl or alkoxy, cyclohexyl, phenyl or phenyl C.sub.1-2 alkyl, together with their pharmaceutically acceptable non-toxic metal salts or addition salts with nitrogen-containing bases, have particularly valuable anti-bacterial properties, especially against Gram-positive and Gram-negative bacteria.

Growing community of inventors

Morsang-sur-Orge, France

Jean Bouchaudon