Roussel Uclaf

Other

Vesperto Torelli

Lucien Nedelec

Daniel Philibert

Roger Deraedt

Jean-Georges Teutsch

Robert Fournex

Germain Costerousse

Andre Poittevin

Josette Benzoni

Genevieve Rousseau

Claude Dumont

Jean G Teutsch

Andre Pierdet

Anne-Marie Moura

Pierre Henri Derible

Michel Hardy

Colette Tournemine

Jean Vacher

Martine Moguilewski

Novel 19-nor-steroids of the formula ##STR1## wherein R.sub.1 is an organic group of 1 to 18 carbon atoms optionally containing at least one heteroatom with the atom immediately adjacent the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated--bond, the A and B rings are selected from the group consisting of ##STR2## R' and R' are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms, R.sub.x is selected from the group consisting of hydrogen and OR.sub.e, R.sub.e is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R.sub.a may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR3## and acyloxy, R'.sub.a and R'.sub.a are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom--with the proviso that when A and B are ##STR4## wherein R' and R' are both hydrogen, R.sub.1 contains at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR5## R.sub.1 is not a linear alkyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antiglucocorticoid activity, their preparation and novel intermediates.

Novel 11.beta.-substituted -19-nor-steriods

Novel 19-nor-steroids of the formula ##STR1## wherein R.sub.1 is an organic group of 1 to 18 carbon atoms optionally containing at leat one heteroatom with the atom immediately adjacent the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated bond, the A and B rings are selected from the group consisting of ##STR2## R' and R' are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms, R.sub.x is selected from the group consisting of hydrogen and OR.sub.e, R.sub.e is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R.sub.a may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR3## and acyloxy, R.sub.a ' and R.sub.a ' are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom with the proviso that when A and B are ##STR4## wherein R' and R' are both hydrogen, R.sub.1 contain at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR5## R.sub.1 is not a linear alkyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antiglucocorticoid activity, their preparation and novel intermediates.

Novel 11.beta.-substituted-19-nor-steroids

A novel steroid of the formula ##STR1## wherein X is methylene and R is an optionally substituted carbocyclic aryl or heterocyclic aryl or optionally substituted vinyl or ethynyl or X is a simple bond or --S-- and R is optionally substituted carbocyclic aryl or heterocyclic aryl, R.sub.2 is methyl or ethyl, R.sub.3 is selected from the group consisting of optionally substituted alkyl of 1 to 8 carbon atoms and optionally substituted alkenyl and alkynyl of 2 to 8 carbon atoms, R.sub.4 is selected from the group consisting of hydrogen and acyl, ##STR2## is selected from the group consisting of ##STR3## R.sub.6 is selected from the group consisting of hydrogen and methyl, the wavy line indicates .alpha. or .beta.- and the dotted line in 1(2) indicates the optional presence of a second carbon-carbon bond and novel process and intermediates therefore having anti-glucocorticoid activity.

Novel 10-substituted steroids

Novel 10-substituted steroids of the formula ##STR1## wherein R is selected from the group consisting of hydrogen, alkyl and substituted alkyl of 1 to 8 carbon atoms, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl of 2 to 8 carbon atoms, aryl and substituted aryl, aralkyl and substituted aralkyl, protected hydroxy, optionally esterified carboxy, --NH.sub.2, protected amino, mono and di-alkyl amino of 1 to 4 alkyl carbon atoms, halogen and trialkylsilyl, R.sub.2 is methyl or ethyl, R.sub.6 and R.sub.7 together with the carbon atoms to which they are attached form cyclopropyl or R.sub.6 is hydrogen and R.sub.7 is R.sub.1, R.sub.1 is selected from the group consisting of hydrogen, alkyl and substituted alkyl of 1 to 6 carbon atoms, acetylthio and alkenyl, substituted alkenyl, alkynyl and substituted alkynyl of 2 to 6 carbon atoms, X is optionally acylated or etherified hydroxyl and Y is selected from the group consisting of hydrogen, R.sub.4, --CH.sub.2 --CH.sub.2 COOM and --CH.sub.2 --CH.sub.2 --CH.sub.2 OH, M is hydrogen, alkali metal or --NH.sub.4 or X and Y together form a member of the group consisting of ##STR2## or X is --OH and Y is ##STR3## R.sub.4 is selected from the group consisting of alkyl of 1 to 6 carbon atoms and alkenyl and alkynyl of 2 to 6 carbon atoms, Alk is alkyl of 1 to 8 carbon atoms, the dotted lines in the 1(2) and 6(7) indicate the optional presence of a second carbon-carbon bond with the proviso that when R.sub.6 and R.sub.7 form cyclopropyl, there is no 6(7) second bond, the dotted line in 10-substituent indicates the optional presence of a third carbon-carbon bond, the wavy lines at R.sub.6 and R.sub.7 indicate the possible .alpha.- or .beta.-position with the proviso that R is not hydrogen when R.sub.6 and R.sub.7 are hydrogen R.sub.2 is methyl, X is hydroxy or acetoxy and Y is hydrogen, the dotted lines at 1(2) and 6(7) do not represent a second bond and the dotted line in the 10-substituent is a third carbon-carbon bond useful as aldosterone antagonists and for increasing hydrosodium diuresis while preserving organic potassium with reduced hormonal side effects.

Novel 10-substituted steroids and their use in the induction of

Novel 19-nor-steroids of the formula ##STR1## wherein R.sub.1 is an organic group of 1 to 18 carbon atoms optionally containing at least one heteroatom with the atom immediately adjacent the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated--bond, the A and B rings are selected from the group consisting of ##STR2## R' and R' are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms with at least one being other than hydrogen, R.sub.x is selected from the group consisting of hydrogen and OR.sub.e, R.sub.e is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R.sub.a may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR3## and acyloxy, R.sub.a ' and R.sub.a ' are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom with the proviso that when A and B are ##STR4## R.sub.1 contains at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR5## R.sub.1 is not a linear alkyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antigluococorticoid activity, their preparation and novel intermediates.

Novel 11 beta-substituted-19-nor-steroids

Novel 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR1## wherein R.sub.1 is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the C.dbd.A group at position 3 is selected from the group consisting of C.dbd.O, ketal, which may be open or closed ##STR2## are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anti-glucocorticoid activity and a process for their preparation.

Steroid derivatives

A novel process for the preparation of 17.beta.-hydroxyacetyl-17.alpha.-ol-steroids of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms optionally substituted with halogen or an oxygen or nitrogen function and alkenyl and alkynyl of 2 to 4 carbon atoms, R.sub.2 is alkyl of 1 to 4 carbon atoms and the A,B,C and D rings may contain one or more double bonds and are optionally substituted with at least one member of the group consisting of hydroxy, keto, halogen, alkyl and alkoxy of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms which compounds are generally known of the cortisonic type with known properties.

Preparation of 17.beta.-hydroxyacetyl-17.alpha.-ol-steroids

Novel 19-nor-steroids of the formula ##STR1## wherein R.sub.1 is an organic group of 1 to 18 carbon atoms optionally containing at least one heteroatom with the atom immediately adjacent the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated bond, the A and B rings are selected from the group consisting of ##STR2## R' and R' are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms with at least one being other than hydrogen, R.sub.x is selected from the group consisting of hydrogen and OR.sub.e R.sub.e is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R.sub.a may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR3## and acyloxy, R.sub.a ' and R.sub.a ' are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom with the proviso that when A and B are ##STR4## R.sub.1 contains at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR5## R.sub.1 is not a linear alkyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antigluococorticoid activity, their preparation and novel intermediates.

Novel 17-[(hydroxymethyl)formamido methylene]-steroids of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms optionally substituted with halogen or an oxygen or nitrogen function and alkenyl and alkynyl of 2 to 4 carbon atoms, R.sub.2 is alkyl of 1 to 4 carbon atoms and the A,B,C and D rings may contain one or more double bonds and are optionally substituted with at least one member of the group consisting of hydroxy, keto, halogen, alkyl and alkoxy of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms and a process for their preparation which are intermediates for the preparation of the corresponding 17-hydroxyacetyl steroids.

17-[(Hydroxymethyl)formamido-methylene]-steroids

A compound selected from the group consisting of: 3-amino-.DELTA..sup.5 -pregnenes of the formula I: ##STR1## wherein X is selected from the group of ##STR2## the wavy lines indicate that the group may be in the .alpha.-or .beta.-position, R.sub.1 is selected from the group consisting of hydrogen and hydroxyalkyl or 2 to 5 carbon atoms, R.sub.2 is selected from the group consisting of hydrogen, hydroxyalkyl of 2 to 5 carbon atoms, acyl of an aliphatic carboxylic acid of 3 to 8 carbon atoms, alkoxycarbonyl of 2 to 8 carbon atoms, acyl of an .alpha.-amino-carboxylic acid or from a peptide of 2 to 3 amino acids of which amines may be either unsubstituted or mono-or disubstituted with alkyl of 1 to 5 carbon atoms with the proviso that R.sub.1 and R.sub.2 are not both hydrogen and that if the 3-amino group is in the .beta.-position, (i) when X is ##STR3## R.sub.1 and R.sub.2 are not both hydroxyethyl or (ii) when X is ##STR4## and R.sub.1 is hydrogen, R.sub.2 is not ethoxycarbonyl, the compound of the formula I wherein X is ##STR5## R.sub.1 is hydrogen and R.sub.2 is methyl, the 3-amino group is in the .alpha.-position and their non-toxic, pharmaceutically acceptable acid addition salts which are useful as stimulants of the mammalian immune system.

Derivatives of 3-amino-pregn-5-ene

A 3-amino-steroid of the formula ##STR1## wherein W is selected from the group consisting of hydrogen and --OH and taken together with X is ethylidene, X is selected from the group consisting of ethyl, ##STR2## the wavy line indicates the substituent has the .alpha.- and .beta.-position, R.sub.1 is selected from the group consisting of hydrogen and --CH.sub.3, R.sub.2 is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and hydroxyalkyl of 2 to 5 carbon atoms, R.sub.3 is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, acyl of organic acid of 2 to 8 carbon atoms, alkoxycarbonyl of 2 to 8 carbon atoms, acyl of an .alpha.-amino-carboxylic acid and a peptide of 2 to 3 .alpha.-amino-carboxylic acids and their non-toxic, pharmaceutically acceptable acid addition acids with the proviso that R.sub.2 and R.sub.3 are not both hydrogen and (i) when R.sub.1 is methyl, W and R.sub.2 are hydrogen and X is ##STR3## in the case R.sub.3 is not methyl, acetyl or derived from an anminocarboxylic acid, (ii) when R.sub.1 is --CH.sub.3, W is hydrogen, R.sub.2 is --CH.sub.3 and X is ##STR4## in the case R.sub.3 is not methyl or acetyl, (iii) when R.sub.1 is methyl, R.sub.2 and W are hydrogen, X is ##STR5## with the --OH having the (S) configuration and the amino group is in the .alpha.-position in the case R.sub.3 is not methyl (iiii) R.sub.2 and W are hydrogen, X is ##STR6## and the 3-amino is in the .alpha.-position in the case at least one of R.sub.1, R.sub.2 and R.sub.3 is not methyl and (iiiii) R.sub.2 and W are hydrogen, R.sub.1 is methyl, X is ##STR7## with the --OH having the (R) configuration and the 3-amino is in the .alpha.-position in the case R.sub.3 is not ethoxycarbonyl capable of stimulating the defenses of an organism, especially by potentializing the production of IgE (immunoglobulins E) and their preparation.

Novel 3 .alpha.-amino steroids

Novel steroids of the formula ##STR1## wherein R is selected from the group consisting of R.sub.1 and R.sub.2, R.sub.1 is selected from the group consisting of alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms R.sub.2 is --(CH.sub.2).sub.n --R.sub.3, n is an integer from 1 to 8 and R.sub.3 is selected from the group consisting of free or protected --OH, free or protected --NH.sub.2, monoalkyl and dialkylamino with 1 to 6 carbon atoms, a free, esterified or salified --COOH and halogen X and Y together form ##STR2## or X is OH and Y is --CH.sub.2 --CH.sub.2 --COOM, M is selected from the group consisting of hydrogen, an alkali metal and --NH.sub.4, Ra is selected from the group consisting of hydrogen and methyl, the dotted line in the I(2)-position indicates the optional presence of a double bond and the wavy line indicates that R may be in the .alpha.- or .beta.-position, with the proviso that R is not R.sub.1 or R.sub.2 when n is 1 and R.sub.3 is halogen, when the 1(2) bond is a simple bond and when Ra is --CH.sub.3, R.sub.3 is not a free carboxyl when Y is --CH.sub.2 --CH.sub.2 --COOM in which M is an alkali metal or --NH.sub.4 and R.sub.3 is not a salified carboxyl when Y is --CH.sub.2 --CH.sub.2 --COOH having aldosterone antagonistic properties and increases aqueous sodium diuresis while conserving organic potassium without secondary hormonal effects and their preparation.

Novel steroids

Novel 3-amino-steroids of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen and methyl, W is selected from the group consisting of hydrogen and --OH and taken together with x forms ethylidene, X is selected from the group consisting of ethyl, ##STR2## and taken together with W forms ethylidene and the wavy lines signify that the substituents are in the .alpha. or .beta.-position with the proviso that when R.sub.1 is methyl and X is ethyl, ##STR3## W is --OH and their non-toxic, pharmaceutically acceptable acid addition salts and their preparation and intermediates therefore capable of stimulating immunitary activity.

Steroids

A novel process for the preparation of 3-amino-steroids of the formula ##STR1## wherein X is selected from the group consisting of ##STR2## and the wavy lines indicate that the substituents may be in the .alpha.- or .beta.-position and their non-toxic, pharmaceutically acceptable acid addition salts in good yields and novel intermediates.

Process for 3-amino-steroid preparation

Novel 19-nor-steroids of the formula ##STR1## wherein R.sub.1 and R.sub.2 taken together form a cycloalkyl of 3 to 8 carbon atoms or are individually selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 6 carbon atoms with the proviso that both cannot be hydrogen, R.sub.3 is alkyl of 2 to 4 carbon atoms, R.sub.4 ' is selected from the group consisting of hydrogen, hydroxyl, acyloxy of an organic carboxylic acid of 1 to 18 carbon atoms and ##STR2## and M is selected from the group consisting of hydrogen and alkali metal, having antagonistic properties to aldosterone and increasing sodium-water diuresis with conservation of organic potassium and a novel process and novel intermediates for their preparation.

Growing community of inventors

Maisons-Alfort, France

Vesperto Torelli