Polyarylcarboxamides useful as lipid lowering agents

#The present invention is concerned with novel polyarylcarboxamides having apolipoprotein B inhibiting activity and concomitant lipid lowering activity. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.

#Obesity is the cause of a myriad of serious health problems like the adult onset of diabetes and heart disease. In addition, the loss of weight is getting an obsession among an increasing proportion of the human population.

#The causal relationship between hypercholesterolemia, particularly that associated with increased plasma concentrations of low density lipoproteins (hereinafter referred as LDL) and very low density lipoproteins (hereinafter referred as VLDL), and premature atherosclerosis and/or cardiovascular disease is now widely recognized. However, a limited number of drugs are presently available for the treatment of hyperlipidemia. Drugs primarily used for the management of hyperlipidemia include bile acid sequestrant resins such as cholestyramine and colestipol, fibric acid derivatives such as bezafibrate, clofibrate, fenofibrate, ciprofibrate and gemfibrozil, nicotinic acid and cholesterol synthesis inhibitors such as HMG Co-enzyme-A reductase inhibitors. The inconvenience of administration (a granular form to be dispersed in water or orange juice) and the major side-effects (gastro-intestinal discomfort and constipation) of bile acid sequestrant resins constitute major drawbacks. Fibric acid derivatives induce a moderate decrease (by 5 to 25%) of LDL cholesterol (except in hypertriglyceridemic patients in whom initially low levels tend to increase) and, although usually well tolerated, suffer from side-effects including potentiation of warfarine, pruritus, fatigue, headache, insomnia, painful reversible myopathy and stiffness in large muscle groups, impotency and impaired renal function. Nicotinic acid is a potent lipid lowering agent resulting in a 15 to 40% decrease in LDL cholesterol (and even 45 to 60% when combined with a bile acid sequestrant resin) but with a high incidence of troublesome side-effects related to the drug's associated vasodilatory action, such as headache, flushing, palpitations, tachychardia and occasional syncopes, as well as other side-effects such as gastro-intestinal discomfort, hyperucemia and impairment of glucose tolerance. Among the family of HMG Co-enzyme-A reductase inhibitors, lovastatin and simvastatin are both inactive prodrugs containing a lactone ring which is hydrolyzed in the liver to form the corresponding active hydroxy-acid derivative. Inducing a reduction of LDL cholesterol by 35 to 45%, they are generally well tolerated with a low incidence of minor side effects. However there still remains a need for new lipid lowering agents with improved efficiency and/or acting via other mechanisms than the above mentioned drugs.

#The present invention relates to a family of novel polyarylcarboxamide compounds of formula (I)

#the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z1 is selected from (CH2)n wherein n is 1 to 3, CH2CH2O and OCH2CH2; Z2 is (CH2)m wherein m is 1 or 2; X1 represents O, CH2, CO, NH, CH2O, OCH2, CH2S, SCH2 or a direct bond; X2 and X3 are each independently selected from CH, N and a sp2 carbon atom; R1 is hydrogen or C1-4alkyl; Ar1 is an aromatic ring selected from phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted with one or two R3 substituents; Ar2 is an aromatic ring selected from phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted with one, two or three R4 substituents; each R2 and R3 is independently selected from C1-4alkyl, C1-4alkyloxy, halo, trifluoromethyl; each R4 is independently selected from C1-4alkyl, C1-4alkyloxy, halo, hydroxy, mercapto, cyano, nitro, C1-4alkylthio or polyhaloC1-6alkyl, amino, C1-4alkylamino and di(C1-4alkyl)amino; p1 and p2 are each 0 to 2; p3 is 0 to 3; X1 and R4 taken together with the aromatic rings Ar1 and Ar2 to which they are attached may form a fluoren-1-yl or a fluoren-4-yl group; A represents a C1-6alkanediyl substituted with one or two groups selected from aryl, heteroaryl and C3-10cycloalkyl; or when X3 is CH, A may also represent a nitrogen atom substituted with hydrogen, C1-10alkyl, aryl, heteroaryl, arylC1-10alkyl, heteroarylC1-10alkyl or C3-10 cycloalkyl; B represents hydrogen; C1-10alkyl; aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, nitro, C1-4alkyloxy, amino, C1-10alkylamino, di(C1-10alkyl)amino, C1-10acyl, C1-10alkylthio, C1-10alkoxycarbonyl, C1-10alkylaminocarbonyl and di(C1-10alkyl)aminocarbonyl; arylC1-10alkyl; heteroaryl C1-10alkyl; C3-10cycloalkyl; polyhaloC1-6alkyl; C3-6 alkenyl; C3-6 alkynyl; NR6R7; or OR8; R6 and R7 each independently represent hydrogen, C1-10alkyl, aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, C1-4 alkyloxy, amino, C1-10alkylamino, di(C1-10alkyl)amino, C1-10acyl, C1-10alkylthio, C1-10alkylaminocarbonyl and di(C1-10alkyl)aminocarbonyl; arylC1-10alkyl, heteroarylC1-10alkyl, C3-10cycloalkyl, C7-10polycycloalkyl, polyhaloC1-6alkyl, C3-8alkenyl, C3-8 alkynyl, fused benzo-C5-8cycloalkyl, and awherein R6 and R7 taken together with the nitrogen atom to which they are attached may form a C4-8 saturated heterocyclic radical; and R8 represents C1-10alkyl, aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, nitro, C1-4alkyloxy, amino, C1-10alkylamino, di(C1-10alkyl)amino, C1-10acyl, C1-10alkylthio, C1-10alkylaminocarbonyl and di(C1-10alkyl)aminocarbonyl; arylC1-10alkyl; heteroarylC1-10alkyl; C3-10cycloalkyl; C7-10polycycloalkyl; polyhaloC1-6alkyl; C3-8 alkenyl; C3-8alkynyl; or fused benzo-C5-8cycloalkyl.

#Unless otherwise stated, as used in the foregoing definitions and hereinafter: halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, n-butyl, 1-methylethyl, 2-methylpropyl, 1,1-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl (as hereinabove defined) and the higher homologues thereof having 5 or 6 carbon atoms, such as for instance 2-methylbutyl, n-pentyl, dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl and the like; C1-10alkyl is meant to include C1-6alkyl (as hereinabove defined) and the higher homologues thereof having 7 to 10 carbon atoms, such as for instance heptyl, ethylhexyl, octyl, nonyl, decyl and the like; C3-10cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; polyhaloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl, in particular C1-6alkyl (as hereinabove defined) substituted with 2 to 13 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, octafluoropentyl and the like; aryl is defined as mono- and polyaromatic groups such as phenyl or naphthalenyl optionally substituted with one to three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C1-6 alkyl, C3-7cycloalkyl, C1-4alkyloxy, polyhaloC1-6alkyl, amino, mono- or di(C1-6alkyl)amino; heteroaryl is defined as mono- and polyheteroaromatic groups such as those including one or more heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, in particular pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl, thienyl and the like, including all possible isomeric forms thereof; C3-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl and the like; C3-6alkynyl defines straight and branched chain hydrocarbon radicals containing one triple bond and having from 3 to 6 carbon atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl and the like; C4-8cycloalkenyl defines cyclic hydrocarbon radicals containing one double bond and having from 4 to 8 carbon atoms such as, for example cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like; fused benzo-C5-8cycloalkyl defines radicals such as, for instance, indanyl, 1,2,3,4-tetrahydronaphthalenyl, fluorenyl and the like; C7-10 polycycloalkyl defines radicals having from 7 to 10 carbon atoms such as, for instance, norbornyl; C1-6alkylamino defines primary amino radicals having from 1 to 6 carbon atoms such as, for example, methylamino, ethylamino, propylamino, iso propylamino, butylamino, isobutylamino and the like; di(C1-6 alkyl)amino defines secondary amino radicals having from 1 to 6 carbon atoms such as, for example, dimethylamino, diethylamino, dipropylamino, di-isopropylamino, N-methyl-N′-ethylamino, N-ethyl-N′-propylamino and the like; C1-6alkylthio defines a C1-6alkyl group attached to a sulfur atom, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like; C1-6acyl defines a C1-6alkyl group attached to a carbonyl group such as, for instance acetyl, propionyl, butyryl, isobutyryl and the like.