Patent DE-19929031-A1 (DE)
Title: Synergistic drug combination, especially for treating cardiovascular diseases associated with metabolic disorders, comprising bi- or tricyclic aza-heterocyclic MTP inhibitor and lipid metabolism regulator or vitamin
Inventor: GRUETZMANN RUDI
IPC: A61K31/437
Filed: 1999-06-25
Abstract: A combination of MTP inhibitor(s) (A), selected from 5 classes of specific bi- or tricyclic aza-heterocyclic compounds, and lipid metabolism regulator(s) and/or vitamin(s) (B) is used in the treatment or prophylaxis of diseases. (B) are PPAR activators, nicotinic acid, nicotinic acid derivatives, anion exchangers or fat-soluble vitamins.  The use of a combination of at least one MTP (not further defined) inhibitor (A) and at least one other active agent (B) is claimed in the treatment or prophylaxis of diseases. (A) is selected from tricyclic pyrrole derivatives of formula (A1), heterocyclic-substituted phenylacetamide derivatives of formula (A2) or (A3), purine derivatives of formula (A4) and indolo-pyrimidine derivatives of formula (A5) (including isomers and salts). (B) is selected from PPAR activators (peroxisome proliferator-activated receptor activators). , nicotinic acid, nicotinic acid derivatives, anion exchangers and fat-soluble vitamins.  R1a + R2a  = group completing a phenyl or pyridyl ring or a dihydropyridone ring of formula (a) (all rings being optionally substituted by 1-3 of halo, CF3, COOH, OH, alkoxy, alkoxycarbonyl or alkyl (itself optionally substituted by OH or 1-4C alkoxy));  R3a + R4a  = group completing a pyridyl ring or a 4-8 membered cycloalkene or oxocycloalkene residue (all rings being optionally substituted as in R1a/R2a);  Da  = H, 4-12C cycloalkyl or 1-12C alkyl;  Ea  = CO or CS;  La  = O, S or N(R9a);  R9a  = H or alkyl (optionally substituted by OH or Ph);  R5a = Ph or 5-7 membered (un)saturated heterocycle (both optionally substituted by 1-3 of NO2, COOH, halo, CN, alkenyl, alkoxycarbonyl and alkyl (itself optionally substituted by OH, COOH, alkoxy or alkoxycarbonyl) and/or by OR10a or NR11aR12a);  R10a  = H, alkyl or alkenyl;  R11a, R12a  = Ph, H, alkyl or up to 8C acyl (optionally substituted by NR13aR14a);  R13a, R14a  = H or up to 8C acyl;  R6a  = H, COOH, (1-5C) alkoxycarbonyl or alkyl (optionally substituted by OH or OCOR15a);  R15a  = Ph (optionally substituted by 1-3 of halo, OH or 1-5C alkyl); or 1-22C alkyl or 2-22C alkenyl (both optionally substituted by OR16a);  R16a  = H, CH2Ph, CPh3 or alkyl;  R7a  = H; or R6a + R7a  = =O;  Ab  = bicyclic heterocyclic group of formula (b)-(g); Lb, Mb  = H, halo, CF3, COOH, 3-6C cycloalkyl, OH, Ph, alkyl, alkoxycarbonyl or alkoxy;  Qb  = N or CH;  Tb  = SO2, CO, O or S;  Vb  = O or S;  R5b-R6b  = H, alkyl, benzyl or phenyl (optionally substituted by by halo or alkyl);  Db, Eb  = H, halo, CF3, OH, COOH, alkoxy, alkoxy or alkoxycarbonyl;  Zb  = O or S;  R1b  = 3-10C cycloalkyl, 1-10C alkyl or phenyl (optionally substituted by 1 or 2 of halo, NO2, CN, OH, 1-4C alkyl and 1-4C alkoxy);  R2b  = H or 1-3C alkyl;  R3b  = H, 1-5C alkyl, 3-7C cycloalkyl, phenyl or 5-7 membered aromatic heterocyclyl (optionally substituted by 1-3 of halo, NO2, Ph, OH, alkyl and alkoxy);  R4b  = H, CH2OH or CH2OCOR11b;  R11b  = H, 1-8C alkyl or phenyl (optionally substituted by 1-3 of halo, OH, CN, 1-4C alkyl and 1-4C alkoxy);  Dc  = e.g. imidazolyl, aza-imidazolyl or a specified indolyl group; Ec, Lc  = H, halo, CF3, OH, COOH, alkyl, alkoxy or alkoxycarbonyl;  R1c-R4c  = as R1b-R4b respectively;  Ad  = a specified purinyl residue;  Dd, Ed  = H, halo, CF3, OH, COOH, alkyl, alkoxy or alkoxycarbonyl;  R1d  = e.g. H or cycloalkyl; 1-8C alkyl or 2-8C alkenyl (both optionally substituted by 3-6C cycloalkyl, Ph or 5- or 6-membered aromatic heterocyclyl); or Ph or 5- or 6-membered aromatic heterocyclyl (where the ring systems are optionally substituted);  Ld  = O or S;  R2d  = SH, OH, 1-8C alkoxy or -N(R13d)-CHR14dR15d;  R13d  = H or 1-4C alkyl;  R14d  = H, Ph or 5- or 6-membered aromatic heterocyclyl; R15d  = H or 1-8C alkyl (optionally substituted by OH); Ae, De, Ee, Ge, Le, Me  = H, halo, CF3, COOH, OH, alkoxy, alkoxycarbonyl or alkyl (optionally substituted by OH or 1-4C alkoxy);  R1e, R2e  = H, cycloalkyl, 1-10C alkyl (optionally substituted by 3-6C cycloalkyl) or Ph (optionally substituted by halo or CF3);  or CR1eR2e  = 4-8C cycloalkylidene; R3e  = phenyl (optionally substituted by 1-3 of NO2, COOH, halo, CN, alkenyl, alkoxycarbonyl or alkyl (optionally substituted by OH, COOH, 1-4C alkoxy or (1-4C) alkoxycarbonyl and/or by OR4e or NR5eR6e);  R4e = H, alkyl or alkenyl;  R5e, R6e  = Ph, H, alkyl or up to 8C acyl (optionally substituted by NR7eR8e);  R7e, R8e  = H or up to 8C acyl; unless specified otherwise alkyl moieties have 1-6C, alkenyl moieties 2-6C and cycloalkyl moieties 3-8C; heterocycles contain 1-3 of S, N and/or O as heteroatom(s).  For the full definitions, see DEFINITION (Full Definitions) field. Independent claims are included for:  (1) medicaments containing a combination of (A), (B) and optionally one or more further components; and  (2) production of the medicaments by converting (A), (B) and optionally further components into a suitable application form with auxiliaries and carriers.