Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof

Substituted nitrogen heterocyclic derivatives of the formula I

• wherein
• A is a divalent group selected from the ensemble consisting of
• Z is N;
• R2 and R6 are independent of one another, and represent H, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl alkyl or R6′—X, wherein
• X is an —NH—, —N(C,—C6-alkyl)—, —O— or —S— moiety;
• R6′ is H, alkyl, substituted alkyl, acyl, amido, sulpho, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, arylalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroarylalkyl, heteroalkyl, cycloalkyl alkyl and heterocycloalkyl alkyl;
• and
• R8 is hydroxyl, carboxyl, cyano, nitro, amido, sulpho, sulphamino, carbamino, cycloalkyl, substituted cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, cycloalkyl alkyl, heterocycloalkyl alkyl or R8′—X, wherein X is —N(alkyl)- or —S— moiety and R8′ is according to any one of the substituents defined above for R2 or R6′;
• and
• R9 is alkyl, substituted alkyl, acyl, carboxyl, amido, sulphamino, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, heteroalkylcycloalkyl alkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, arylalkyl, substituted aryl, heterocycle, heteroaryl, heteroarylalkyl, substituted heteroaryl, or —B—R9′ wherein B is —CH2—, —(CH2)2—, —CH(CH3)CH2—, —CH(CH2F)CH2—, —CH(CH2OH)CH2—, or the groups of the following structure,
• and
• wherein the left hand bond is linked
• to nitrogen of 5-membered ring of compounds of the formula I;
• and
• wherein R4 and R5, that are independent of one another, represent hydrogen, hydroxyl, halogen, amino, acyloxy substituents having 1-5 carbon atoms, alkoxy substituents having 1-5 carbon atoms, alkylmercapto substituents having 1-5 carbon atoms, alkylamino substituents having 1-5 carbon atoms and dialkylamino in which each alkyl substituent has 1-5 carbon atoms;
• R7 and R10, that are independent of one another, represent H or alkyl substituent having 1-10 carbon atoms;
• or R9 is —(CH2)n—R9′, wherein n=1-2 and the R9′ is —X(CH2)mY wherein
• X is —O—, —S—, —NH— or —N (alkyl)-substituent having 1-6 carbon atoms;
• m=1-2;
• Y is carboxyl, amido, sulpho, sulphamino, carboxyl, mercapto, carbylmercapto, amino, alkylamino, carbamino —PO(OH)2, —PO(O—C1-C6-alkyl)2, —PO(NH—C1-C6-alkyl)2, PO(O—C,—C1-C6-alkyl)(NH—C1-6-alkyl), —PO(OH)(O—C1-C6-alkyl);
• —PO(OH)(NH—C1-C6-alkyl);
• wherein:
• “halogen” is fluorine, bromine, chlorine, and iodine atoms;
• “alkyl” is:
• a) a branched or unbranched alkyl group having 1-6 carbon atoms,
• b) a branched or unbranched alkenyl group having 2-6 carbon atoms, and
• c) a branched or unbranched alkinyl group having 2-6 carbon atoms;
• “substituted alkyl” is a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and having substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl;
• “carbyloxy” is the group —ORa, where Ra is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “carbylmercapto” is the group —SRb where Rb is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl whereas these general groups have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “sulpho” is the group —SO3Rc where Rc is:
• a) hydrogen,
• b) a branched or unbranched alkyl group having 1-6 carbon atoms,
• c) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• d) a branched or unbranched alkinyl group having 2-6 carbon atoms, and
• e) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl, whereas these generic groups have meanings being identical with the definitions of the corresponding groups as defined in this legend;
• “sulphamino” is the group —NHSO3Rd wherein Rd is:
• a) hydrogen,
• b) a branched or unbranched alkyl group having 1-6 carbon atoms,
• c) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• d) a branched or unbranched alkinyl group having 2-6 carbon atoms, and
• e) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl, whereas these generic substituents have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “acyl” is, the group —C(O)Re where Re is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “aryloxy” is the group —OAr, where Ar is an aryl, substituted aryl, heteroaryl or substituted heteroaryl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “alkylamino” is the group —NRfRg where Rf and Rg, that are independent of one another, represent hydrogen, alkyl, substituted alkyl, provided that Rf and Rg are not both hydrogens;
• “amido” is the group —C(O)NRhRi′, where Rh and Ri′ may independently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “carboxyl” is the group —C(O)ORj where Rj is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• “carbamino” is the group —NHCORk where Rk may be hydrogen, alkyl, substituted alkyl, heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;
• “aryl” is an aromatic carbocyclic group having from 6 to 18 carbon atoms and being composed of at least one aromatic or multiple condensed rings in which at least one of which being aromatic;
• “substituted aryl” is an aromatic carbocyclic group having from 6 to 18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic;
• The ring(s) are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulpho;
• “heterocycle” is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S;
• “heteroaryl” is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic;
• “substituted heteroaryl” is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic and this group being substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulpho;
• “arylalkyl” is the group —Rj—Ar wherein Rj is:
• a) a branched or unbranched alkyl group having 1-6 carbon atoms,
• b) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• c) a branched or unbranched alkinyl group having 2-6 carbon atoms;
• “Ar” is an aromatic carbocyclic group having from 6-18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic and the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulpho;
• “heteroalkyl” is the group —Rm—L wherein Rm is:
• a) a branched or unbranched alkyl group having 1-6 carbon atoms,
• b) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• c) a branched or unbranched alkinyl group having 2-6 carbon atoms,
• d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl;
• and
• L is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S and the group being unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, alkylmercapto, alkylamino, amido, carboxyl, hydroxy, nitro, mercapto or sulpho;
• “heteroarylalkyl” is the group —Rn—G wherein Rn is
• a) a branched or unbranched alkyl group having 1-6 carbon atoms,
• b) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• c) a branched or unbranched alkinyl group having 2-6 carbon atoms,
• d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl;
• and
• G is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of which being aromatic and the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulpho;
• “cycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms;
• “substituted cycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms and being substituted by one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho;
• “heterocycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P;
• “substituted heterocycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho;
• “cycloalkyl alkyl” is the group —Ro—J where Ro is:
• a) a branched or unbranched alkyl group having 1-6 carbon atoms,
• b) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• c) a branched or unbranched alkinyl group having 2-6 carbon atoms,
• d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl, whereas these generic substituent group have meanings being identical with definitions of the corresponding groups as defined in this legend;
• and
• J is:
• a) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms;
• and
• b) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho;
• “heterocycloalkylalkyl” is the group —RpV where Rp is:
• a) a branched or unbranched alkyl group having 1-6 carbon atoms,
• b) a branched or unbranched alkenyl group having 2-6 carbon atoms,
• c) a branched or unbranched alkinyl group having 2-6 carbon atoms, and
• d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl;
• and
• V is:
• a) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms with at least one being replaced with a heteroatom selected from the group consisting of N, O, S or P;
• and
• b) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms with at least one being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho.