Pyrrole derivatives, their preparation and pharmaceutical compositions containing them

A process for making a pyrrole compound having the following formula (I), its stereoisomer, salt, or a mixture thereof:

• in which
• R1 is chosen from carboxamide, cyano, carboxyl, alkyloxycarbonyl, acetyl and imidazolylcarbonyl radicals,
• R3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and hydroxyl radicals, and
• Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, and
• a) the bond - - - is a single bond,
• R2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl, alkyloxy and trihalomethyl radicals,
• R4 is a hydrogen atom, and
• R5 is chosen from hydroxyl, alkyloxy, amino and haloacylamino radicals,
• or alternatively
• b) the bond - - - is a double bond, and
• R2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl, alkyloxy, alkenyl and trihalomethyl radicals,
• R4 is chosen from a hydrogen atom, halogen atoms, alkyloxy radicals and alkylthio radicals which are unsubstituted or substituted with carboxyl, alkyloxycarbonyl, amino, alkylamino or dialkylamino in which the alkyl parts optionally form, with the nitrogen atom to which they are attached, phthalimido or a 4- to 6-membered heterocycle which optionally has another heteroatom chosen from nitrogen, oxygen and sulphur, and
• R5 is a hydrogen atom,
• wherein R2 is not chlorine when simultaneously R4 and R5 are hydrogen, and when R1 is cyano or carboxamido, and Het-R3 is 3-pyridyl optionally substituted with fluorine at the 2 position, or alternatively when simultaneously R4 is halogen, R5 is hydrogen, and when R1 is cyano or carboxamido and Het-R3 is 3-pyridyl substituted with methyl, chlorine or fluorine at the 2 position or when R1 is alkyloxycarbonyl or acetyl and when Het-R3 is 3-pyridyl,
• and wherein said alkyl radicals are straight or branched and contain from 1 to 4 carbon atoms and said acyl and alkenyl radicals are straight or branched and contain from 2 to 4 carbon atoms,
• said process comprising preparing a nitrile intermediate of the following formula (IV):
• in which Het, R2 and R3 are defined as above, by
• reacting an acrylic derivative of the following formula (II):
• in which R2 is chosen from a hydrogen atom and cyano, alkyl, alkyloxy and trihalomethyl radicals, R′1 is chosen from cyano and alkyloxycarbonyl radicals, and Hal is a halogen atom,
• with an acid of the following formula (III):
• in which Het and R3 are defined as above,
• introducing said double bond, said radicals R4 and R5, and/or said radical R2, and
• optionally converting said nitrile intermediate to an amide, an acid, an ester, an imidazole-containing radical or an acetyl radical,
• or optionally converting an ester radical to an acid, an imidazole-containing radical or an acetyl radical, and
• optionally separating the resulting compound into its stereoisomeric forms and/or converting the resulting compound to a salt.

A pharmaceutical composition comprising an effective amount of at least one pyrrole compound of the following formula (I):

• in which
• a) the bond - - - is a single bond,
• R1 is chosen from carboxamide, cyano, carboxyl, alkyloxycarbonyl, acetyl and imidazolylcarbonyl radicals,
• R3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and hydroxyl radicals, and
• Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, and
• R2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl, alkyloxy and trihalomethyl radicals,
• R4 is a hydrogen atom, and
• R5 is chosen from hydroxyl, alkyloxy, amino and haloacylamino radicals,
• or alternatively
• b) the bond - - - is a double bond, and
• R2 is chosen from a hydrogen atom, halogen atoms, cyano, alkyl, alkyloxy, alkenyl and trihalomethyl radicals,
• R4 is chosen from alkyloxy radicals and alkylthio radicals which are unsubstituted or substituted with carboxyl, alkyloxycarbonyl, amino, alkylamino or dialkylamino in which the alkyl parts optionally form, with the nitrogen atom to which they are attached, phthalimido or a 4- to 6-membered heterocyde which optionally has another heteroatom chosen from nitrogen, oxygen and sulphur,
• R5 is a hydrogen atom,
• R1 is chosen from carboxamido, cyano, carboxyl, alkyloxycarbonyl, acetyl and imidazolylcarbonyl radicals,
• R3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and hydroxyl radicals, and
• Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, or
• R2 is chosen form a hydrogen atom, a bromine atom, an iodine atom, a fluorine atom, cyano, alkyl, alkyloxy, alkenyl, and trihalomethyl radicals,
• R4 is chosen from a hydrogen atom and halogen atoms,
• R5 is a hydrogen atom,
• R1 is chosen from carboxamido, cyano, carboxyl, alkyloxycarbonyl, acetyl and imidazolylcarbonyl radicals,
• R3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and hydroxyl radicals, and
• Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, or
• R2 is a chlorine atom,
• R4 is chosen from a hydrogen atom and halogen atoms,
• R5 is a hydrogen atom,
• R1 is chosen from carboxyl and imidazolylcarbonyl radicals,
• R3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and hydroxyl radicals, and
• Het is chosen from pyridyl, pyridyl N-oxide and thiazolyl radicals, or
• R2 is a chlorine atom,
• R4 is chosen from a hydrogen atom and halogen atoms,
• R5 is a hydrogen atom,
• R1 is chosen from carboxamido, cyano, alkyloxycarbonyl and acetyl radicals, and
• R3 is chosen from a hydrogen atom, halogen atoms, alkyl radicals and hydroxyl radicals, and
• Het is chosen from pyridyl-2, pyridyl-4, pyridyl N-oxide and thiazolyl radicals, or
• R3 is chosen from a bromine atom, an iodine atom, and a hydroxyl radical, and
• Het is pyridyl-3,
• wherein said alkyl radicals are straight or branched and contain from 1 to 4 carbon atoms and said acyl and alkenyl radicals are straight or branched and contain from 2 to 4 carbon atoms,
• together with a pharmaceutically acceptable carrier.