Anti-infective derivatives, method for the production thereof, pharmaceutical compositions containing same and uses of said derivatives in treatment
AssigneesCentre National de la Recherche Scientifique (CNRS), Universite Paul Sabatier Toulouse III
InventorsJean Bernadou, Vania Bernardes-Genisson, Tamara Delaine, Annaïck Quemard
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Abstract
The present invention relates to bi-substrate inhibitor molecules combining (i) a pyridine, pyridinium or dihydropyridine-type structure allied to active metabolites of isoniazide, or related structures, and (ii) a hydrophobic substituent. The invention also relates to the method for preparing said molecules, to the pharmaceutical compositions containing said molecules, and to the use thereof as inhibitors of enoyl reductase for the preparation of a drug, especially an anti-infective drug for the treatment of tuberculosis.
Claims15
Compounds of general formula (I):
- in which:
- the cycle
- represents a 6-membered aromatic optionally comprising one or more nitrogen atoms, said nitrogen atom(s) optionally being substituted by
- an optionally substituted tetrahydrofuran group, such as 2-hydroxymethyl-tetrahydrofuran-3,4-diol;
- or by
- a —CH2-E group, wherein E represents an electron-attracting group such as —CONRR′;
- —CO—SR;
- —CO—Oalkyl;
- —CO—Oalkyl-OH;
- —O-alkyl-OAc;
- phenyl substituted for example by a CN or NO2 group;
- wherein R and R′ are the same or different and independently represent a hydrogen atom or an alkyl group;
- and/or wherein said nitrogen atom(s) may be in the form of pyridinium salts, the counter ion being the anion of a halogen atom, such as bromide;
- represents a 5-to-10-membered mono- or bicyclic aryl group or heteroaryl group comprising one to three N atoms, substituted by one or more groups selected from the groups —OH;
- —(C5-C20)alkyl;
- —O(C2-C20)alkyl ;
- —S(O)palkyl wherein p=0, 1 or 2 ;
- alkenyl;
- alkynyl;
- —Oalkenyl;
- —C(=)O-alkyl;
- —C(═O)-alkenyl;
- phenyl substituted by an alkyl group;
- cycloalkyl
- optionally substituted by an alkyl group, wherein
- is substituted in the ortho or meta position;
- R1 represents a hydrogen atom or an alkyl group and R2 and R3 together form an ═O group;
- or alternatively
- R3 represents an —OH or —Oalkyl group and R2 forms, together with R1, a single bond;
- the groups —C(═O)NHR1 and C(R3)(R2)- being understood to be located in two adjacent
- positions on the ring
- in the form of a base or an acid addition salt, as well as in the form of a pharmaceutically acceptable hydrate or solvate.
Pharmaceutical composition comprising as an active ingredient a compound of general formula (I):
- in which:
- the cycle
- represents a 6-membered aromatic optionally comprising one or more nitrogen atoms, said nitrogen atom(s) optionally being substituted by an optionally substituted tetrahydrofuran group, such as 2-hydroxymethyl-tetrahydrofuran-3,4-diol;
- or by
- a —CH2-E group, wherein E represents an electron-attracting group such as —CONRR′;
- —CO—SR;
- —CO—Oalkyl;
- —CO—Oalkyl-OH;
- —O-alkyl-OAc;
- phenyl substituted for example by a CN or NO2 group;
- wherein R and R′ are the same or different and independently represent a hydrogen atom or an alkyl group;
- and/or wherein said nitrogen atom(s) may be in the form of pyridinium salts, the counter ion being the anion of a halogen atom, such as bromide;
- represents a 5-to-10-membered mono- or bicyclic aryl group or heteroaryl group comprising one to three N atoms, substituted by one or more groups selected from the groups —OH;
- —(C5-C20)alkyl;
- —O(C2-C20)alkyl;
- —S(O)palkyl wherein p=0, 1 or 2 ;
- alkenyl;
- alkynyl;
- -Oalkenyl;
- —C(═)O-alkyl;
- —C(═O)-alkenyl;
- phenyl optionally substituted by an alkyl group;
- cycloalkyl optionally substituted by an alkyl group;
- R1 represents a hydrogen atom or an alkyl group and R2 and R3 together form an ═O group;
- or alternatively R3 represents an —OH or —Oalkyl group and R2 forms, together with R1, a single bond;
- the groups —C(═O)NHR1 and C(R3)(R2)— being understood to be located in two adjacent positions on the ring
- in the form of a base or an acid addition salt, as well as in the form of a pharmaceutically acceptable hydrate or solvate;
- and at least one pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.