MXPA06006507A - N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprote in b - Google Patents

Abstract

N-aryl piperidine substituted biphenylcarboxamides compounds of formula (I), methods for preparing compounds, pharmaceutical compositions comprising said compounds as wee as the use of said compounds as a medicine for the treatment ofhyperlipidemia, obesity and type II diabetes.

Description

B1FENILCARBOXAMIDES SUBSTITUTED WITH N-AR1L PÍPERIDINA AS APOLIPOPROTEIN B INHIBITORS DESCRIPTIVE MEMORY The present invention relates to novel biphenylcarboxamide compounds substituted with N-aryl piperidine, which have apolipoprotein B inhibiting activity and lipid-lowering activity, concomitantly. The invention further relates to methods for preparing such compounds, to pharmaceutical compositions comprising such compounds, as well as the use of the 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 such as the onset in adults of diabetes and heart disease. In addition, weight loss is becoming an obsession between 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 to as LDL) and very low density lipoproteins (hereinafter referred to as VLDL), and premature atherosclerosis and / or Cardiovascular disease is now widely recognized. However, a limited number of Drugs are currently available for the treatment of hyperlipidemia. Drugs used mainly for the management of hyperlipidemia, include bile acid sequestering resins, such as cholestyramine and colestipol, fibric acid derivatives, such as bezafibrate, clofibrate, fenofibrate, ciprofibrate and gemfibrozil, and inhibitors of nicotinic acid synthesis and cholesterol, such as inhibitors of the HMG Co-enzyme-A reductase. There still remains a need for new agents that decrease lipids with improved efficacy and / or act via other mechanisms than the drugs mentioned above. Plasma lipoproteins are high molecular weight water soluble complexes formed of lipids (cholesterol, triglycerides, phospholipids) and apolipoproteins. Five main classes of lipoproteins have been defined that differ in the proportion of lipids and the type of apolipoprotein, all having their origin in the liver and / or the intestine, according to their density (measured by ultracentrifugation). They include LDL, VLDL, intermediate density lipoproteins (hereinafter referred to as IDL), high density lipoproteins (hereinafter referred to as HDL) and chylomicrons. Ten human apolipoproteins have been identified in major plasma. VLDL, which is secreted by the liver, and which contains apolipoprotein B (hereinafter referred to as Apo-B), undergoes degradation to LDL that transports 60 to 70% of total serum cholesterol. Apo-B is also the main protein component of LDL. LDL cholesterol increased in serum due to oversynthesis or decreased metabolism, is causally related to atherosclerosis. In contrast to high density lipoproteins (hereinafter referred to as HDL), which contain apolipoprotein A1, they have a protective effect and are inversely correlated with the risk of coronary heart disease. The HDL / LDL ratio is therefore a convenient method to assess the atherogenic potential of a lipid profile in an individual's plasma. The two isoforms of apolipoprotein (apo) B, apo B-48 and apo B-100, are important proteins in the metabolism of human lipoproteins. Apo B-48, so-called because it appears to be about 48% the size of apo B-100 in sodium dodecyl sulfate-polyacrylamide gels, is synthesized by the intestine in humans.

Apo B-48 is necessary for the assembly of chylomicrons and therefore has a mandatory role in the intestinal absorption of dietary fats. Apo B-100, which is produced in the liver in humans, is required for the synthesis and secretion of VLDL. LDL, which contains about 2/3 of the cholesterol in human plasma, are metabolic products of VLDL. Apo B-100 is virtually the only component of the LDL protein. Elevated levels of apo B-100 and plasma LDL cholesterol are recognized risk factors for developing atherosclerotic disease of the coronary artery.

A large number of genetic and acquired diseases can result in hyper-education. They can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperlipidemias are diabetes mellitus, alcohol abuse, drugs, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis and bulimia. Primary hyperlipidemias have also been classified into common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, residual hyperlipidemia, chylomicronemia syndrome, and familial hypertriglyceridemia. The microsomal triglyceride transfer protein (hereinafter referred to as MTP) is known to catalyze the transport of triglyceride and cholesterol ester in preference to phospholipids such as phosphatidylcholine. It was shown by D. Sharp et al., Nature (1993) 365: 65, that the defect that causes abetalipoproteinemia is in the MTP gene. This indicates that MTP is required for the synthesis of lipoproteins containing Apo B, such as VLDL, the precursors to LDL. Therefore, it turns out that an inhibitor of MTP, inhibit the synthesis of VLDL and LDL, thus decreasing the levels of VLDL, LDL, cholesterol and triglycerides in humans. One of the objects of the present invention is to provide an improved treatment for patients suffering from obesity or atherosclerosis, especially coronary atherosclerosis and more generally from disorders that are related to atherosclerosis, such as heart disease. ischemic, peripheral vascular disease and cerebral vascular disease. Another objective of the present invention is to cause the regression of atherosclerosis and inhibit its clinical consequences, particularly morbidity and mortality. The MTP inhibitors have been described in WO-00/32582, the WO-01/96327 and WO-02/20501. The present invention is based on the unexpected discovery that a class of novel biphenylcarboxamide compounds substituted with N-aryl piperidine is acting as selective inhibitors of MTP, that is, they are capable of selectively blocking the MTP at the wall level. of the intestine in mammals, and is therefore a promising candidate as a medicine, namely, for the treatment of hyperlipidemia. The present invention further provides various methods for preparing such biphenylcarboxamide compounds substituted with N-aryl piperidine, as well as pharmaceutical compositions including such compounds. In addition, the invention provides a number of novel compounds, which are useful intermediates for the preparation of the therapeutically active N-aryl piperidine-substituted biphenylcarboxamide compounds, as well as methods for preparing such intermediates. Finally, the invention provides a method for the treatment of a selected condition of atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, diabetes and type II diabetes, which comprises administering a therapeutically active amount of a compound of formula (I) to a mammal. The present invention relates to a family of novel compounds of formula (I) the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R 1 is hydrogen, C 1-4 alkyl, halo or C 1-4 polyhaloalkyl; R 2 is hydrogen, C 1 - alkyl, halo or polyhaloalkyl of C 1-4; R3 is hydrogen or C? -4 alkyl; R 4 is hydrogen, C 1-4 alkyl, or halo; n is an integer of 0 or 1; X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon; or X1 is carbon and X2 is nitrogen; X3 is carbon or nitrogen; Y represents O or NR6, wherein R6 is hydrogen or alkyl C? -4 R5 represents a radical of formula where m is an integer of 0, 1 or 2; Z is O or NH; R7 is hydrogen; C 1-6 alkyl; C? -6 alkyl substituted with hydroxy, amino, mono or di (C-? -) alkyl amino, C? -4 alkyloxycarbonyl, aminocarbonyl, aryl or heteroaryl; C 4 -4 O alkyl-C 1-4 alkyl; C? -4-S alkyl-C-? -4 alkyl; or aryl; R8 is hydrogen or C1-6alkyl; R 9 is hydrogen, C 1 - alkyl, aryl 1, or C 4 alkyl substituted with aryl 1; or when Y represents NR6, the radicals R5 and R6 can be taken together with the nitrogen to which they are attached to form a pyrrolidinyl substituted with C 1 -4 alkyloxycarbonyl, and optionally further substituted with hydroxy; or piperidinyl substituted with C 1-4 alkyloxycarbonyl; aryl is phenyl; phenyl substituted with one, two or three substituents, each independently selected from C - alkyl, C? -4 alkyloxy, halo, hydroxy, nitro, cyano, C -? - 4 alkyloxycarbonyl, trifluoromethyl or trifluoromethoxy; or benzo [1,3] dioxolyl; aryl1 is phenyl; phenyl substituted with one, two or three substituents, each independently selected from C 1-4 alkyl, C 1- alkyloxy, halo, hydroxy, nitro, cyano, C? - alkyloxycarbonyl, trifluoromethyl or trifluoromethoxy; and the heteroaryl is imidazolyl, thiazolyl, indolyl or pyridinyl. Unless otherwise indicated, as used in the above definitions and hereafter: halo is generically fluorine, chlorine, bromine and iodine; C -? - 4 alkyl 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; C 1-6 alkyl is defined to include C 1 -C 4 alkyl (as defined above), and larger homologs thereof having 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, n-pentyl, dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl and the like; polyhaloalkyl of C- is defined as C-alkyl substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl and the like; alkylamino C? - defines secondary amino radicals having from 1 to 4 carbon atoms such as, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino and the like; di (C? -) alkyl amino defines tertiary amino radicals having from 1 to 4 carbon atoms such as, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-methyl-N'-ethylamino, N-ethyl -N'-propylamino and the like. The pharmaceutically acceptable acid addition salts, as mentioned above, are defined to comprise the forms of therapeutically active non-toxic acid addition salts, compounds of formula (I) which are capable of being formed. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the basic form with the appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, for example, hydrochloric or hydrobromic, sulfuric, nitric, phosphoric acids and similar acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (ie, ethanedic), malonic, succinic (ie, butanedioic), maleic, fumaric, malic, tartaric, citric, methanesulfonic acids. , ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.

Conversely, salt forms can be converted, by treatment with an appropriate base in the free basic form. The term addition salt, as used hereinbefore, also comprises the solvates of the compounds of formula (I), as well as the salts thereof, which are capable of forming. Such solvates are, for example, hydrates, alcoholates and the like. The N-oxide forms of the compounds of formula (I), which can be prepared in the forms known in the art, are defined to comprise those compounds of formula (I), wherein a nitrogen atom is oxidized to the N- oxide. In particular, the N-oxide forms are compounds of formula (I), wherein the nitrogen of the piperidinyl group is oxidized. The term "stereochemically isomeric forms", as used hereinbefore, defines all possible isomeric forms that the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, the mixtures containing all the diastereomers and enantiomers of the basic molecular structure. More particularly, stereogénicos centers can have the configuration R or S; the substituents on the cyclic (partially) saturated radicals can have either the cis or the trans configuration. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereoisomeric forms, the mixtures containing all the diestereomers and the enantiomers of the basic molecular structure. The same applies to intermediaries as described herein, used to prepare the final products of formula (I). The terms cis and trans are used herein in accordance with the Chemical Abstracts nomenclature and refer to the position of the substituents in a portion of the ring. The absolute stereochemical configuration of the compounds of formula (I) and of the intermediates used in their preparation, can be readily determined by those skilled in the art, using well-known methods such as, for example, X-ray diffraction. compounds of formula (I) and some of the intermediates used in their preparation may exhibit polymorphism.

It should be understood that the present invention encompasses any polymorphic forms possessing properties useful in the treatment of the conditions denoted hereinabove. In one embodiment, the present invention relates to compounds of formula (I), the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R1 is hydrogen, C? 4, halo or polyhaloalkyl of C -? -; R 2 is hydrogen, C 4 alkyl, halo or polyhaloalkyl of C 1-4; R3 is hydrogen or C? - alkyl; R 4 is hydrogen, C 1-4 alkyl or halo; n is an integer of 0 or 1; X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon; or X1 is carbon and X2 is nitrogen; X3 is carbon or nitrogen; Y represents O or NR6, wherein R6 is hydrogen or alkyl '1-4. R5 represents a radical of formula where m is an integer of 0, 1 or 2; Z is O or NH; R7 is hydrogen; C? -6 alkyl; C-6 alkyl substituted with hydroxy, amino, mono or di (alkyl) C? -4) amino, C? -4 alkyloxycarbonyl, aminocarbonyl, aryl or heteroaryl; C? -4-O-alkyl of C? - alkyl; C 1-4 alkyl-S-C-? - alkyl; or aryl; R8 is hydrogen or C1-6alkyl; R9 is C? - alkyl, phenyl or benzyl; or when Y represents NR6, the radicals R5 and R6 can be taken together with the nitrogen to which they are attached to form a pyrrolidinyl substituted with C-? - alkyloxycarbonyl, and optionally further substituted with hydroxy; or piperidinyl substituted with C 1 - alkyloxycarbonyl.; aryl is phenyl; phenyl substituted with one, two or three substituents, each independently selected from C? _alkyl, C - ?4alkyloxy, halo, hydroxy, nitro, cyano, C? -4 alquiloalkyloxycarbonyl, trifluoromethyl or trifluoromethoxy; or benzo [1,3] dioxolyl; and heteroaryl is imidazolyl, thiazolyl, idolyl or pyridinyl. In another embodiment, the present invention relates to the compounds of formula (I) the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R1 is polyhaloalkyl of C? -; R 2 is hydrogen or C 4 alkyl; R3 is hydrogen or C1-4 alkyl; R4 is hydrogen; n is an integer of 0 or 1; X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon; or X1 is carbon and X2 is nitrogen; X3 is carbon or nitrogen; Y represents O or NR6, wherein R6 is hydrogen or alkyl C -? -; R 5 represents a radical of the formula R 8 O -C- (CH 2) SGC-Z-R 9 (a-2) 7 wherein m is an integer of 0 or 1; Z is O or NH; R7 is hydrogen; C? -6 alkyl; C? -6 alkyl substituted with amino, C? -4 alkyloxycarbonyl, aryl or heteroaryl; C.sub.1 -CS- alkyl- alkyl; or aryl; R8 is hydrogen or C-i-β alkyl; R 9 is C 4 alkyl; or when Y represents NR 6, the radicals R 5 and R 6 can be taken together with the nitrogen to which they are attached to form a pyrrolidinyl substituted with C 1 - 4 alkyloxycarbonyl, and optionally further substituted with hydroxy; or piperidinyl substituted with C? -4 alkyloxycarbonyl; aryl is phenyl; phenyl substituted with hydroxy; or benzo [1,3] dioxolyl; heteroaryl is imidazolyl.

A group of compounds of interest consists of those compounds of formula (I), wherein one or more of the following restrictions apply: a) R1 is tert-butyl or trifluoromethyl; b) R2 is hydrogen or C? -4 alkyl; c) R3 is hydrogen; d) R4 is hydrogen; e) Y represents NR6, wherein R6 is hydrogen or methyl; f) Z represents O; g) R8 represents hydrogen; h) R9 represents C? - alkyl. A first particular group of compounds are those compounds of formula (I), wherein X1, X2 and X3 are carbon. A second particular group of compounds are those compounds of formula (I), wherein X1 is carbon, X2 is nitrogen, and X3 is carbon. A third particular group of compounds are those compounds of formula (I), wherein X 1 is nitrogen, X 2 is carbon, and X 3 is carbon. A fourth particular group of compounds are those compounds of formula (I), wherein X1 is carbon, X2 is nitrogen, and X3 is nitrogen.

A fifth particular group of compounds are those compounds of formula (I), wherein n is the integer 1. A first preferred group of compounds are those compounds of formula (I), wherein R 1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6, wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1), wherein m is the integer 0. A second preferred group of compounds are those compounds of formula (I), wherein R is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6, wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1), wherein m is the integer 1. A third preferred group of compounds, are those compounds of formula (I), wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y. represents NR6, wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-2), wherein m is the integer 1. A fourth preferred group of compounds are those compounds of formula (I), wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 and R5 and R6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl substituted with C1-4alkyloxycarbonium and optionally further substituted as hydroxy, or piperidinyl substituted with C? -4 alkyloxycarbonyl. The groups of particular compounds are those groups of preferred compounds, wherein R8 represents hydrogen and R9 represents alkyl of d.4. A first method for preparing the compounds of formula (I) is a process wherein an intermediate of formula (II) wherein R3, R4, R5, Y, n, X1, X2 and X3, are as defined in formula (I), are reacted with a biphenylcarboxylic acid or a halide having the formula (III), wherein R1 and R2 are as defined in formula (I), and Q1 is selected from hydroxy and halo, in at least one reaction with an inert solvent and optionally, in the presence of a suitable base, the process optionally further comprises converting a compound of formula (I) into an addition salt thereof, and / or preparing the stereochemically isomeric forms thereof. In case Q1 is hydroxy, it may be convenient activating the biphenylcarboxylic acid of formula (III) by the addition of an effective amount of a reaction promoter. Non-limiting examples of such reaction promoters include carbonyldiimidazole, diimides; such as N, N, -dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide (EDCI), and the functional derivatives thereof. For this type of acylation process, it is preferred to use a polar aprotic solvent such as, for example, dichloromethane. Suitable bases for carrying out this first process include tertiary amines such as triethylamine, triisopropylamine and the like. Suitable temperatures for carrying out the first process of the invention typically range from about 20 ° C to about 140 ° C, depending on the particular solvent used, and more often will be the boiling temperature of the solvent. A second method for preparing a compound of the present invention is a process wherein an intermediate having the formula (IV) wherein R > 1, D R2, R O3, t R-) 4,, n_, X v2 and X are as defined in formula (I), and Q2 is selected from halo and hydroxy, reacted with an intermediate (V) of the formula H-NR5R6, wherein R5 and R6 are as defined for the compounds of formula (I), in at least one reaction with an inert solvent and, optionally, in the presence of at least one suitable coupling reagent and / or a suitable base, the process optionally further comprises converting a compound of formula (I) in an addition salt thereof, and / or preparing the stereochemically isomeric forms thereof. In the case that Q2 is hydroxy, it may be convenient to activate the carboxylic acid of formula (IV) by adding an effective amount of a reaction promoter. Non-limiting examples of such reaction promoters include carbonyl-diimidazole, diimides such as DCC, FOCI, hydroxybenzotriazole, benzotrlazol-1-yl-N-oxitris- (dimethylamino) phosphonium hexafluorophosphate (BOP), tetrapyrrolidino-phosphonium hexafluorophosphate , bromotripyrrolidinophosphonium hexafluorophosphate, or a functional derivative thereof, as described in "Solid-Phase Synthesis: A Practical Guide", edited by Steven A. Kates and Fernando Albericio, Marcel Dekker, Inc., 2000 (ISBN: 0 -8247-0359-6), at pages 306 to 319. A third method for preparing a compound according to the present invention, is a process wherein an intermediate having the formula (VI) wherein R1 R2 R3, R4, X1, X2 and X3 are as defined in formula (I), and Q3 is selected from halo, B (OH) 2, alkyl boronates and cyclic analogues thereof, is reacted with a reagent that has the formula (VII) wherein n, R5 and Y are as defined in formula (I), in at least one reaction with an inert solvent and optionally in the presence of at least one coupling reagent with a transition metal and / or at least one Suitable ligand, the process optionally further comprises converting a compound of formula (I) into an addition salt thereof, and / or preparing the stereochemically isomeric forms thereof. This type of reaction is known in the art as the Buchwald reaction, which refers to the applicable metal coupling reagents and / or suitable ligands, for example, palladium compounds such as tetra (triphenyl-phosphine) palladium, tris ( dibenzylidene-aceton) dipalladium, 2,2'-bis (diphenylfosphine) -1, 1'-bilafethyl (BINAP) and the like, can be found, for example, in Tetrahedron Letters, (1996), 37 (40), 7181- 7184 and J. Am. Chem. Soc, (1996), 118: 7216. If Q3 is B (OH) 2, an alkyl boronate or a cyclic analogue thereof, then the cupric acetate should be used as the coupling reagent, according to Tetrahedron Letters, (1998), 39: 2933-6. The compounds of formula (1-a), defined as compounds of formula (I), wherein Y represents NH and R3 represent hydrogen, can prepare conveniently using solid phase synthesis techniques as described in Reaction Scheme 1 below. In general, solid phase synthesis involves reacting an intermediate in a synthesis with a support polymer. This intermediary supported on the polymer can then be carried through several synthetic steps. After each step, the impurities are filtered through the resin and washed several times with several solvents. In each step, the resin can be separated to react with several intermediates in the next step, thus allowing the synthesis of a large number of compounds. After the final step in the process, the resin is treated with a reagent or a method to cleave the resin from the sample. The more detailed explanation of the techniques used in solid phase chemistry is described in, for example, "Handbook of Combinatorial Chemistry: Drugs, Catalysts, Materials", edited by KC Nicolaou, R. Hanko and W. Hartwig, volumes 1 and 2, Wiley (ISBN: 3-527-30509-2).

REACTION SCHEME 1 01-64-0261 room temperature (_,.] And \ 1 j a thesis a { I) -f H -C- (CH ^ j- (N ~~ PG *** J 2. elimination of the protective group PG Resin (llj reduca? n ream (illj) res-laugh. { TV! 1) DIPEUCH_C1_ 2) TFA / T-S / CHaCl_ s-a > The substituents R1, R2, R4, R4, R5, n, X1, X2 and X3 are as defined for the compounds of formula (I). PG represents a protecting group such as, for example, C 1-6 alkyloxycarbonyl, phenylmethyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and the like. The following abbreviations are used: "NMP" means N-methyl-2-pyrrolidone, "DIPEA" means diisopropylethylamine, "TFA" means trifluoroacetic acid; and "TIS" means triisopropylsilane. Compounds of formula (1-b), defined as compounds of formula (I), wherein R 3 represents hydrogen, can be prepared using a solid phase synthesis route as defined in Reaction Scheme 2.

REACTION SCHEME 2 ambient temperature NOVASIOCHEWI 01-64-0261 resin (V) resin (VI) resin (VII) The substituents R1, R2, R4, R4, R5, Y, n, X1, X2 and X3 are as defined for the compounds of formula (I). The following abbreviations are used: "NMP" means N-methyl-2-pyrrolidone, "DI PEA" means diisopropylethylamine, "TFA" means trifluoroacetic acid; and "TIS" means triisopropylsilane, "DMAP" means dimethylaminopyridine, and "BINAP" means 2,2'-bis (diphenylphosphino) -1, 1'-biphenyl. The compounds of formula (I) prepared in the processes described hereinabove can be synthesized in the form of racemic mixtures of enantiomers, which can be separated from one another following the resolution procedures known in the art. Those compounds of formula (I) which are obtained in racemic form can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The forms of the salts The diastereomers are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are liberated with an alkali. An alternate way to separate the enantiomeric forms of the compounds of formula (I), involves liquid chromatography, using a chiral stationary phase. The stereochemically pure isomeric forms can also be derived from the corresponding stereochemically pure isomeric forms of the appropriate raw materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparation methods. These methods will be employed advantageously, enantiomerically pure raw materials. The compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable salts and stereoisomeric forms thereof possess a favorable alloprotein B inhibitory activity, and lipid lowering activity, concomitantly. Therefore, the present compounds of formula (I) are useful as a medicine, especially in a method for treating patients suffering from hyperlipidemia, obesity, atherosclerosis or type II diabetes. In particular, the present compounds can be used for the manufacture of a medicine to treat disorders caused by an excess of very low density lipoproteins (VLDL) or low density lipoproteins (LDL), and especially disorders caused by cholesterol, associated with VLDL and LDL.

The main mechanism of action of the compounds of formula (I), seems to involve the inhibition of the activity of MTP (protein transfer of microsomal triglycerides), in hepatocytes and intestinal epithelial cells, resulting in VLDL and production of decreased chylomicrons, respectively. This is a novel and innovative procedure for hyperlipidemia, and it is expected to lower LDL cholesterol and triglycerides through reduced hepatic production of VLDL and intestinal production of chylomicrons. A large number of genetic and acquired diseases can result in hyperlipidemia. They can be classified into primary and secondary hyperlipidemic states. The most common causes of secondary hyperllpidemia are diabetes mellitus, alcohol abuse, drugs, hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis and bulimia. Primary hyperlipidemias are common hypercholesterolemia, familial combined hyperlipidemia, familial hypercholesterolemia, residual hyperlipidemia, chylomicronemia syndrome, familial hypertriglyceridemia. The present compounds can also be used to prevent or treat patients suffering from obesity or atherosclerosis, especially coronary atherosclerosis, and more generally, disorders that are related to atherosclerosis, eg, ischemic heart disease, peripheral vascular disease and cerebral vascular disease. . The present compounds can cause regression of atherosclerosis and inhibit the clinical consequences of atherosclerosis, particularly morbidity and mortality.

In view of the usefulness of the compounds of formula (I), it appears that the present invention also provides a method for treating warm-blooded animals, including humans (generally referred to as patients herein), suffering from disorders caused by an excess of very low density lipoproteins (VLDL) or low density lipoproteins (LDL), and especially disorders caused by cholesterol associated with VLDL and LDL. Accordingly, a method of treatment is provided to relieve patients suffering from the conditions, such as, for example, hyperlipidemia, obesity, atherosclerosis or type II diabetes. Apo B-48, synthesized by the intestine, is necessary for the assembly of chylomicrons and therefore, has a mandatory role in the intestinal absorption of dietary fats. The present invention provides biphenylcarboxamide compounds that act as selective inhibitors of MTP at the level of the bowel wall. In addition, the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). In order to prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of base or addition salt, as the active ingredient, is intimately combined with at least one pharmaceutically acceptable carrier, carrier which It can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a unit dosage form, suitable, preferably, for oral administration, rectal administration, percutaneous administration or parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations, may be employed. as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like, in the case of powders, pills, capsules and tablets. Due to their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve the solubility of the active ingredient. Injectable solutions can be prepared, for example, by using a pharmaceutical carrier comprising a physiological saline solution, a glucose solution or a mixture of both. Injectable suspensions can also be prepared using appropriate liquid carriers, suspending agents and the like. -In the appropriate compositions for percutaneous administration, the The pharmaceutical carrier can optionally comprise an agent that improves penetration and / or a suitable wetting agent, optionally combined with minor proportions of suitable additives, which do not cause a significant damaging effect to the skin. Such additives may be selected in order to facilitate administration of the active ingredient to the skin and / or be useful for preparing the desired compositions. These topical compositions can be administered in various ways, for example, as a transdermal patch, as localized placement or an ointment. The addition salts of the compounds of formula (I), due to their increased solubility in water with respect to the corresponding basic form, are obviously more suitable in the preparation of the aqueous compositions. It is especially advantageous to formulate the pharmaceutical compositions of the invention in a dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form", as used herein, refers to physically discrete units suitable as unit dosages, each unit containing a predetermined amount of active ingredient, calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, spoons and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions of the present invention can take the form of solid dosage forms, for example, tablets (both swallowable and chewable forms), gelatin capsules or capsules, prepared by conventional means by pharmaceutically acceptable carriers and excipients. , such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g., lactose, microcrystalline cellulose, calcium phosphate and similar io), lubricants (e.g., magnesium stearate, talc , silica and the like), disintegrating agents (e.g., potato starch, sodium gylcolate starch and the like), wetting agents (e.g., sodium lauryl sulfate) and the like. Such tablets can also be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be formulated as a dry product for mixing with water and / or other suitable liquid carrier before use. Such liquid preparations can be prepared by conventional means, optionally with other pharmaceutically acceptable additives, such as suspending agents (for example, sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (for example, lecithin or acacia), carriers. non-aqueous (for example, almond oil, oily esters or ethyl alcohol), sweeteners, flavorings, masking agents and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention preferably comprise at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a sweetener of dihydrochalcone, monelin, stevioside sucralose (4,1 ' , 6'-trichloro-4,1 ', 6'-tridesoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin and optionally, at least one bulk sweetener such as sorbitol. Mannitol, fructose, sucrose, maltose, isomait, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used at low concentrations. For example, in the case of sodium saccharin, the concentration may vary from about 0.04% to 0.1% (weight / volume) of the final formulation. The bulk sweetener can be used effectively in higher concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight / volume). The pharmaceutically acceptable flavors that can mask the bitter taste ingredients in the low dosage formulations are preferably fruit flavors such as cherry, raspberry, blackcurrant or strawberry flavors. A combination of two flavors can provide very good results. In the high dosage formulations, pharmaceutically flavorants may be required acceptable more 'strong, such as Chocolate Candy, Fresh Mint, Fantasy and the like. Each flavor may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight / volume). Strong flavor combinations are advantageously used. Preferably, a flavor is used that does not undergo any change or loss of flavor and / or color under the circumstances of the formulation. The compounds of formula (I) can be formulated for parenteral administration by injection, intramuscular intramuscular or convenient subcutaneous injection, for example, by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in a unit dosage form, for example, in ampoules or multi-dose containers, including an added conservator. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be present in powder form to be mixed with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds of formula (I) can also be formulated in rectal compositions such as suppositories or retention enemas for example, which contain conventional suppository bases, such as cocoa butter and / or other glycerides.

The compounds of formula (I) may be used in conjunction with other pharmaceutical agents, in particular the pharmaceutical compositions of the present invention may further comprise, at least one additional lipid-lowering agent, thus leading to a so-called combination therapy that decreases the lipids. The additional lipid lowering agent may be, for example, a known drug conventionally used for the management of hyperlipidemia, such as, for example, a bile acid sequestrant resin, a fibric acid derivative or nicotinic acid as mentioned. previously in the background of the invention. Additional, suitable, lipid-lowering agents also include other inhibitors of cholesterol biosynthesis and cholesterol absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors, gene expression inhibitors. of HMG-CoA reductase, CETP inhibitors, ACAT inhibitors, squalene synthetase inhibitors and the like. Any inhibitor of HMG-CoA reductase can be used as the second compound in the aspect of the combination therapy of this invention. The term "HMG-CoA reductase inhibitor", as used herein, unless otherwise indicated, refers to a compound that inhibits the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such "HMG-CoA reductase inhibitors" are, for example, lovastatin, simvastatin, fluvastatin, pravastatin, rivastatin and atorvastatin.

Any inhibitor of HMG-CoA synthase can be used as the second compound in the aspect of the combination therapy of this invention. The term "HMG-CoA synthase inhibitor" as used herein, unless otherwise indicated, refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A of acetyl-coenzyme A and acetoacetyl -coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Any inhibitor of the expression of the HMG-CoA reductase gene can be used as the second compound in the aspect of the combination therapy of this invention. These agents can be transcription inhibitors of HMG-CoA reductase that block transcription of DNA or translational inhibitors that prevent translation of the mRNA encoding the HMG-CoA reductase into the protein. Such inhibitors can directly affect transcription or translation or can be biotransformed into compounds having the above-mentioned attributes, by one or more enzymes in the cholesterol biosynthetic cascade or can lead to the accumulation of a metabolite having the aforementioned activities. Any CETP inhibitor can be used as the second compound in the aspect of the combination therapy of this invention. The term "CETP inhibitor" as used herein, unless otherwise indicated, refers to a compound that inhibits transport mediated by the cholesteryl ester transfer protein (CETP) of several cholesteryl esters and triglycerides of HDL to LDL and VLDL. Any ACAT inhibitor can be used as the second compound in the aspect of the combination therapy of this invention. The term "ACAT inhibitor" as used herein, unless otherwise indicated, refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Any squalene synthetase inhibitor can be used as the second compound in the aspect of the combination therapy of this invention. The term "squalene synthetase inhibitor" as used herein, unless otherwise indicated, refers to a compound that inhibits the condensation of two molecules of farnesyl pyrophosphate to form squalene., catalyzed by the enzyme squalene synthetase. Those with experience in the treatment of hyperlipidemia will readily determine the therapeutically effective amount of a compound of formula (I) from the test results presented hereinafter. In general, it is contemplated that a therapeutically effective dose will be from about 0.001 mg / kg to about 5 mg / kg of body weight, more preferably from about 0.01 mg / kg to about 0.5 mg / kg of body weight of the patient to be treaty. It may be appropriate to administer the therapeutically effective dose in the form of two or more sub-doses at appropriate intervals throughout the day. The Subdoses may be formulated as unit dosage forms, e.g., each containing from about 0.1 mg to about 350 mg, more particularly from about 1 to about 200 mg of the active ingredient per unit dosage form. The exact dosage and frequency of administration depends on the particular compound of formula (I), the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, as well as other medication. (including the lipid lowering agents, additional, mentioned above), that the patient may be taking, as is well known to those skilled in the art. In addition, the effective daily amount may be decreased or increased depending on the response of the treated patient and / or depending on the evaluation of the prescribing physician of the biphenylcarboxamide compounds of the present invention. The intervals of the effective daily amount mentioned above are, therefore, only guides.

Experimental part In the procedures described hereinafter, the following abbreviations were used: "PS-DIEA" means N, N- (diisopropyl) aminomethylpolystyrene resin, obtained from Argonaut (New Road, Hengoed, Mid Glamorgan CF82 8AU, United Kingdom) with the product code 800279. "PS-DCC" is the N-cyclohexylcarbodiimide N'-methyl polystyrene resin, which was obtained from Calbiochem-Novabiochem AG, (Weidenmattweg 4, CH-4448 Laulelfingen, Switzerland), with the Novabiochem product code 01-64-0211 . "THF" means tetrahydrofuran.

A. Synthesis of intermediaries EXAMPLE A.1 a) Preparation of the intermediary (1) 4 '- (trifiuoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (0.0069 mol), was dissolved in dichloromethane (400 ml), together with oxalyl chloride (0.069 mol) and dimethylformamide (one drop) at 0 ° C. Additional 4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (0.0621 mol) was added in portions under a stream of nitrogen. Oxalyl chloride (0.069 mol) and dimethylformamide (one drop) were added, and the reaction mixture was stirred for 2 hours at 0 ° C. The reaction mixture was filtered, the residue was dissolved in dichloromethane (100 ml), and the resulting mixture was added dropwise at 0 ° C to a mixture of the ethyl ester of 1- (4-aminophenyl) -4- piperidinacetic (0.069 moles) in triethylamine (17.5 ml) and dichloromethane (300 ml). The reaction mixture was allowed to reach room temperature in 90 minutes. The resulting reaction mixture was washed with water, dried and the solvent was evaporated. The residue was stirred in a hot mixture of hexane and ethyl acetate, and the resulting precipitate was filtered hot on celite. The filtrate was cooled and the resulting precipitate was filtered, washed with ether and dried to provide 31 g of intermediate (1) (mp 160-162 ° C). b) Preparation of the intermediary (2) A mixture of intermediate (1) (0.015 mol) in a concentrated HCl solution (50 ml) was stirred and refluxed for 90 minutes. The resulting precipitate was filtered, washed with water and dried. The precipitate (0.008 mol) was dissolved in a mixture of a solution of NaOH (1 N, 50 ml) and 2-propanol (100 ml), and stirred for 1 hour at 50 ° C. The reaction mixture was cooled to room temperature and HCl (1 N, 70 mL) was added, and the mixture was extracted twice with dichloromethane. The. The extracts were combined, evaporated and the resulting residue was triturated under dichloromethane, providing 4.1 g of the intermediate (2).

EXAMPLE A.2 a) Preparation of the intermediary (3) 6-Methyl-4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (0.0025 mol) was dissolved in dry dichloromethane (140 ml) together with ethanedioyl dichloride (2.4 ml) and a few drops of dimethylformamide at 0 ° C. Then, all the 6-methyl-4 '- (trifluoromethyl) - [1] acid was added, 1 '-biphenyl] -2-carboxylic (0.0225 moles) remaining in portions, under a stream of nitrogen. The reaction mixture was heated gently at 40 ° C until a homogeneous solution resulted and the gas evolution stopped. The mixture was allowed to cool to room temperature, then filtered on a Buchner filter. The filtered residue was dissolved in dichloromethane, then added dropwise at 0 ° C to a solution of 1- (4-aminophenyl) -4-piperidineacetic acid ethyl ester (1 equivalent, 0.025 mol) and triethylamine (3 g) ) in dry dichloromethane (140 ml). The reaction mixture was allowed to warm to room temperature for 90 minutes. The precipitate was filtered and dried to provide 13.65 g of intermediate (3) (p.p. 150-151 ° C). b) Preparation of the intermediary (4) Sodium hydroxide (1 N, 100 ml) was added to a solution of intermediate (3) (0.0334 mol) in methanol (300 ml), then the reaction mixture was stirred for 2 hours at 50 ° C and for 20 hours at room temperature. Water (300 ml) was added, and the mixture was acidified with 1N HCl. Dichloromethane (200 ml) was added, and the reaction mixture was stirred for 2 hours, then the resulting precipitate was filtered, washed with water and with dichloromethane and finally dried, giving 17.1 g of the intermediate (4), was isolated as a 1: 1 hydrochloric acid salt.

EXAMPLE A.3 a) Preparation of the intermediary (5) A mixture of 4-piperidinecarboxylic acid ethyl ester (0.03 mol), 1-fluoro-4-nitrobenzene (0.03 mol) and potassium carbonate (4.5 g) in dimethylformamide (50 ml) was reacted for 4 hours at 60 ° C. C, a Then the solvent was evaporated under reduced pressure, and the obtained residue was stirred in water. The yellow solid obtained was filtered and taken up in dichloromethane (100 ml). The organic layer was dried and the solvent was evaporated. The resulting oil was crystallized from hexane, and the desired product was collected, yielding 7 g of the intermediate (5) (mp 70-71 ° C). b) Preparation of the intermediary (6) A mixture of intermediate (5) (0. 025 moles) in ethanol (150 ml) was subjected to hydrogenation under pressure (30 bars = 3,106 Pa)) overnight at 25 ° C with 10% Pd / C (0.5 g) as a catalyst. After uptake of hydrogen (3 equivalents), the reaction mixture was filtered and the solvent was evaporated under reduced pressure, yielding 6 g of the intermediate (6). c) Preparation of the intermediary (7) Reaction under nitrogen: 0.2 g of 4 '- (trifluoromethyl) - [1,1' -biphenyl-2-carboxylic acid in dichloromethane (50 ml) were reacted with ethanediyl dichloride (0.01 mol) at 0 ° C, and then the reaction was started with dimethylformamide (1 drop). The residue of 4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (1.8 g) was added in portions, and an additional amount of ethanediyl dichloride was added. The reaction mixture was stirred for 2 hours at 0 ° C (without the presence of acid when the sample of the reaction mixture was taken in methanol for TLC analysis) and dichloromethane, and the excess of ethanedioyl dichloride was evaporated under reduced pressure. The residue obtained was taken up in dichloromethane (50 ml) and added dropwise to a mixture of intermediate (6) (0.0075 mol) and triethyl amine (0.0075 mol) in dichloromethane (50 ml) at 0 ° C. The resulting mixture was stirred for 1 hour at room temperature, then the organic layer was washed with water, dried and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol and the desired product was collected, yielding 2.9 g of the intermediate (7) (p.p. 190-192 ° C). d) Preparation of the intermediary (8) Intermediate (7) (0.006 mole) was added to a solution of NaOH (0.018 mole) in ethanol (20 ml) and water (20 ml), and then the reaction mixture was heated to 60 ° C. The resulting solution was kept at 60 ° C for 1 hour and cooled. The mixture was acidified with 4N HCl and stirred for 1 hour, then the resulting precipitate was filtered and washed with water to provide 2.7 g of intermediate (8) (mp 260-262 ° C).

EXAMPLE A.4 a) Preparation of the intermediary (9) A mixture of the sodium salt hydrate of nitromalonaldehyde (CAS 53821-72-0) (0.06 moles), carbamimidothioic acid methyl ester sulfate (2: 1) (0.03 moles) and 4-piperidine-carboxylic acid ethyl ester ( 0.047 mole) in water (200 ml), stirred for 2 hours at 80 ° C or until the evolution of the metantiol gas was stopped, then the resulting precipitate was filtered and washed with water. The solids were stirred in a minimum amount of methanol, then filtered again and washed with ether to give 4.8 g of intermediate (9) (mp 114-116 ° C). b) Preparation of the intermediary (10) A mixture of intermediate (9) (0.017 mol) in ethanol (100 ml) was hydrogenated for 4 hours at 60 ° C with 10% palladium on carbon (0.5 g) as a catalyst. After uptake of hydrogen (3 equivalents), the reaction mixture was filtered and the solvent was evaporated. The obtained residue was purified by column chromatography (eluent: ethyl acetate / hexane 1/2). The fractions of the product were collected and the solvent was evaporated, providing 3 g of the intermediate (10). c) Preparation of the intermediary (11) Reaction under nitrogen: 0.3 g of 4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid in dichloromethane (50 ml), were reacted with ethanedioyl dichloride (0.01 mol) at 0 ° C, and then the reaction was started with dimethylformamide (1 drop). The remaining 4'- (trifluoromethyl) - [1, 1'-biphenyl] -2-carboxylic acid (2.7 g) was added in portions (without acid present when the reaction mixture was taken in methanol for TLC analyzes), and the solvent was evaporated under reduced pressure. The residue thus obtained was taken up in dichloromethane (50 ml) and added dropwise to a mixture of intermediate (10) (0.011 mol) and triethylamine (0.011 mol) in dichloromethane (50 ml) at 0 ° C. The resulting mixture was stirred for 30 minutes and further purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 1/4, 1/2). The product fractions were collected and the solvent was evaporated, providing 2.9 g of the intermediate (11) (pp. 171-173 ° C). d) Preparation of the intermediary (12) The intermediate (11) (0.006 moles) was added to a solution of NaOH (0.018 mol) in ethanol (20 ml) and water (20 ml), then the reaction mixture was heated for 1 hour at 60 ° C, cooled and acidified with 4N HCl. The resulting precipitate was filtered, washed with water and dried to give 2.6 g of the intermediate (12) (mp 231-233 ° C).

EXAMPLE A.5 a) Preparation of the intermediary (13) A mixture of 2-chloro-5-nitro-pyridine (0.0227 moles), 4-piperidineacetic acid ethyl ester (0.0227 moles) and sodium carbonate (0.091 moles) in dimethyl sulfoxide (40 ml), was heated to 60 ° C and was stirred for 2 hours, then the reaction mixture was cooled to room temperature and poured into ice-water. The resulting precipitate was filtered and washed with water. The crude solid was purified by crystallization from ethyl acetate / hexane and the resulting precipitate was collected to provide 3.2 g of intermediate (13) (pp. 99-101 ° C). b) Preparation of the intermediary (4) A mixture of intermediate (13) (0.0102 mol) in THF (50 ml) was subjected to hydrogenation for 30 minutes at 50 ° C with 10% palladium on carbon (0.3 g) as a catalyst. After uptake of hydrogen (3 equivalents), the reaction mixture was cooled and the catalyst filtered, then the filtrate was evaporated, providing 2.6 g of the intermediate (14). c) Preparation of the intermediary (15) A solution of 6-methyl-4 '- (trifluoromethyl) - [1,1' -biphenyl] -2-carboxylic acid (0.005 mol) in 1,4-dioxane (5 ml) was added to a solution of the intermediate ( 14) (0.005 moles) and triethylamine (0.005 moles) in 1,4-dioxane (15 ml) at 10 ° C, then the reaction mixture was stirred at room temperature for 60 hours. The mixture was diluted with water and extracted with ethyl acetate (100 ml). The product was washed with brine, dried and the solvent was evaporated. The residue was purified by column chromatography (eluent: ethyl acetate / hexane 1/4). The product fractions were collected and the solvent was evaporated, yielding 1.7 g of the intermediate (15) (pp. 134-137 ° C). d) Preparation of the intermediary (16) A solution of NaOH (0.0114 mol) in water (20 ml) was added to a mixture of intermediate (15) (0.0038 mol) in ethanol (20 ml), and then the reaction mixture was stirred for 2 hours at 60 °. C. After cooling to room temperature, the mixture was acidified with concentrated HCl, and the solvent was evaporated. The obtained residue was stirred in diethyl ether and the desired product was collected, providing 2.2 g of the intermediate (16).

EXAMPLE A.6 a) Preparation of the intermediary (17) An aqueous solution of 37% formaldehyde (0.0072 mole) and palladium on carbon (10%, 0.15 g) was added to a solution of 1- (4-amniphenyl) -4-piperidineacetic acid ethyl ester (0.0057 mole). ) in ethyl acetate (40 ml), and then the reaction mixture was subjected to hydrogenation for 5 hours. After uptake of hydrogen (1 equivalent), the catalyst was filtered over celite, and the celite was washed with ethyl acetate (40 ml). The filtrate was evaporated and the obtained residue was combined with the residue obtained analogously. The resulting residue was purified by flash column chromatography (eluent: ethyl acetate / hexane 30/70). The fractions of the product were collected, then the solvent was evaporated and the obtained residual oil was dried, providing 1.6 g of the intermediate (17). b) Preparation of the intermediary (18) A mixture of 4 '- (trifluoromethyl) - [1,1' -biphenyl] -2-carboxylic acid (0.0058 mol) in dichloromethane (40 ml) was stirred at 0 ° C and under nitrogen, then dichloride was added. of ethanedioyl (0.0087 mol), followed by dimethylformamide (2 drops). The resulting mixture was heated at 15 ° C for 1 hour and then at 30-35 ° C for 1 hour. The solvent was evaporated and the yellow solid obtained was dissolved in dichloromethane. This solution was added to a solution of the intermediate (17) (0.0058 moles) and triethylamine (0.0087). moles) in dichloromethane under nitrogen, and then the reaction mixture was stirred for 16 hours at room temperature. The mixture was diluted with ethyl acetate (100 ml) and washed with 1 N HCl (50 ml), with a saturated solution of NaHCO3 (50 ml) and with brine (50 ml). The organic layer was dried and the solvent was evaporated. The oil obtained was further purified by flash column chromatography (eluent: ethyl acetate / hexane 30/70). The product fractions were collected and the solvent was evaporated, providing 1.6 g of the intermediate (18). - c) Preparation of the intermediary (19) The reaction was carried out under nitrogen: the intermediate (18) (0.0029 mol) was dissolved in ethanol (20 ml) at 20 ° C, and then a mixture of NaOH (0.0087 mol) in water (20 ml) was added. The resulting emulsion was stirred for 16 hours at 20 ° C and for 1 hour at 60 ° C. The reaction mixture was neutralized with 2N HCl and a suspension formed. The ethanol was evaporated, then the aqueous concentrate was cooled to 0 ° C and the resulting solids were filtered. Dichloromethane was added to the filtrate obtained previously, and then the emulsion was separated in its layers. Finally, the solvent was evaporated, providing 1 g of the intermediate (19).

EXAMPLE A.7 a) Preparation of the intermediary (20) A mixture of ethyl ether hydrochloride 4-piperidineacetic acid (0.025 mol), 5-bromo-2-nitro-pyridine (0.03 mol) and potassium carbonate (0.06 mol) in dimethylformamide (100 ml), was heated for two days at 60 ° C and then the solvent was evaporated under reduced pressure. The obtained residue was stirred in water and filtered. The filter residue was taken up in dichloromethane (100 ml), dried and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate / hexane 1/5, 1/3). The fractions of the product were collected and the solvent was evaporated, providing 3.3 g of the intermediate (20). b) Preparation of the intermediary (21) A mixture of intermediate (20) (0.01 mol) in ethanol (100 ml) was subjected to hydrogenation overnight in an autoclave (30 bar = 3,106 Pa) at 30 ° C with palladium on carbon (10%, 0.5 g) as a catalyst After uptake of hydrogen (3 equivalents), the reaction mixture was filtered and the filtrate was evaporated, yielding 2.8 g of the intermediate (21). c) Preparation of the intermediary (22) Reaction at 0 ° C and under nitrogen: ethanediyl dichloride (0.01 mole) and dimethyl formamide (2 drops) were added to a part of the acid 6-methyl-4 '- (trifluoromethyl) - [1,1' -biphenyl] - 2-carboxylic acid (0.2 g) in dichloromethane (100 ml), and then 6-methyl-4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (1.9 g) was added in portions. ) remaining (no acid present when the reaction mixture was taken in methanol for TLC analyzes). Mix of reaction was stirred for 2 hours at 0 ° C, and the solvent was removed by evaporation. The residue was taken up in dichloromethane (25 ml), and the mixture was added dropwise to a stirred solution of intermediate (21) (0.0075 ml) and triethylamine (0.75 g) in dichloromethane (25 ml). After stirring overnight, the reaction mixture was washed with water, dried and the solvent was evaporated. The residue was purified by flash column chromatography (eluent: ethyl acetate / hexane 1/3). The product fractions were collected and the solvent was evaporated, providing 1.5 g of the intermediate (22). d) Preparation of the intermediary (23) A mixture of NaOH (0.008 mol) in water (20 ml) was added to a mixture of intermediate (22) (0.003 mol) in ethanol (20 ml), and then the reaction mixture was stirred for 2 hours at 50 ° C. C. After cooling, the mixture was acidified with concentrated HCl, filtered and washed with water. The filter residue was taken up in diethyl ether, and dried and the solvent was evaporated, yielding 1 g of the intermediate (23).

EXAMPLE A.8 Preparation of the intermediary (24) Water (28 ml) and lithium hydroxide (0.7 g) were added to a solution of compound (46) (0.013 mol) in THF (84 ml), and the reaction mixture was stirred at room temperature until the reaction was complete. . The mixture was filtered and then most of the dried filtrate residue was taken in a small amount of water. The resulting mixture was washed with dichloromethane and the aqueous layer was carefully acidified to a pH of 7. The resulting precipitate was filtered and dried in a desiccator, yielding 6.9 g of the intermediate (24) (pp. 170-172 ° C).

EXAMPLE A.9 a) Preparation of the intermediary (25) A mixture of intermediate (14) (0.008 mol), aqueous formaldehyde solution (37%, 0.01 mol) and platinum on carbon (5%, 0.1 g) in ethyl acetate (100 ml), dried under hydrogen for 2 hours and then an additional portion of aqueous formaldehyde solution (37%, 0.01 mol) was added. The reaction mixture was stirred for 24 hours and then heated overnight at 40 ° C. The filtrate was evaporated and the residue obtained was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 1/1). The product fractions were collected and the solvent was evaporated, yielding 1.7 g of the intermediate (25). b) Preparation of the intermediary (26) Reaction at 0 ° C and under nitrogen: 0.18 g of 6-methyl-4 '- (trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid were stirred in dichloromethane (50 ml) with ethanediyl dichloride (0.008 g) moles), and then the mixture was started with dimethylformamide (1 drop). The remaining 6-methyl-4-trifluoromethyl) - [1,1'-biphenyl] -2-carboxylic acid (1.62 g) was added in portions, and the resulting mixture was stirred for 2 hours. The dichloromethane was evaporated under reduced pressure to provide the Residue (I). A mixture of the intermediary (25) (0.0065 moles) and triethylamine in dichloromethane (50 ml), cooled under nitrogen at 0 ° C, and a solution of Residue (I) in dichloromethane (20 ml) was added dropwise. The reaction mixture was stirred for 3 hours at room temperature and diluted with water. The organic layer was separated, washed with water, dried and the solvent was evaporated. The obtained residue was purified by flash column chromatography (eluent: ethyl acetate / hexane 1/3). The product fractions were collected and the solvent was evaporated, providing 1.2 g of the intermediate (26). c) Preparation of the intermediary (27) The intermediate (26) (0.0022 mol) was added to a solution of sodium hydroxide (0.0066 mol) in water (16 ml) and ethanol (30 ml) and then the reaction mixture was stirred for 18 hours at 30 ° C. . The solvent was evaporated under reduced pressure and the residue obtained was acidified with 4N HCl. Finally, the solvent was evaporated, providing 1.2 g of the intermediate (27).

EXAMPLE A.10 a) Preparation of the intermediary (28) A mixture of intermediate (4) (0.0019 moles) and potassium carbonate (0.0053 moles) in dimethylformamide (30 ml) was heated for 30 minutes at 45 ° C, then bromoacetic acid phenylmethyl ester (0.0029 moles) was added. and the reaction mixture was heated for 3 hours at 45 ° C. The mixture was poured into water (75 ml) and dichloromethane (75 ml) and stirred, then the dichloromethane layer was separated and concentrated to give 0.9 g of the intermediate (28). b) Preparation of the intermediary (29) A solution of intermediate (28) (0.0014 mol) in ethyl acetate (40 ml) and ethanol (40 ml) was subjected to hydrogenation at room temperature. atmospheric and at room temperature for 16 hours with palladium on carbon (10%, 0.100 g) as a catalyst. After uptake of hydrogen (1 equivalent), the reaction mixture was filtered over celite, and the filtrate was evaporated, yielding 0.600 g of the intermediate (29).

B. Preparation of the final compounds EXAMPLE B.1 The intermediate (2) (0.0001 moles), was dissolved in dichloromethane (2 ml) and PS-DIEA (0.03 g) was added. The resulting suspension was stirred overnight at room temperature and filtered. PS-DCC (0.08 g) was added to the filtrate from the previous step and 2- (ethoxycarbonyl) piperidine (0.0001 mol) dissolved in dimethylphomamide (2 ml) was added. The reaction mixture was stirred for 20 hours at room temperature and filtered. The filtrate was evaporated and purified by reverse phase HPLC to give 0.001 g of compound (1).

EXAMPLE B.2 N '- (ethylcarbonimidoyl) -N, N-dimethyl-1,3-propanediamine (0.0015 mol) monohydrochloride was added to a mixture of intermediate (8) (0.001 mol), 1-hydroxy-1 H-benzotriazole (0.0015 moles), 4-methylmorpholine (0.004 mole) and D-alanine ethyl ester hydrochloride (0.001 mole) in dichloromethane (50 ml), and the reaction mixture was stirred overnight under nitrogen. The mixture was washed with 1N HCl (20 ml), with saturated NaHCO3 solution (20 ml) and with brine, then dried and filtered. The solvent was evaporated under reduced pressure and the obtained residue was stirred in hexane to provide 0.470 g of the compound (38) (mp 213-215 ° C).

EXAMPLE B.3 Intermediate (4) (0.002 moles), dimethylformamide were stirred (50 ml) and N-ethyl-N- (1-methylethyl) -2-propanamine (0.5 ml) until the solution was completed, then 1- [bis (dimethylamino) methylene] -1 H- was added. benzotriazolium, hexafluorophosphate (1-), 3-oxide (0.0033 mol), and the mixture was stirred for 15 minutes. L-glutamic acid diethyl ester hydrochloride (0.003 mole) was added and the reaction mixture was stirred overnight. The mixture was poured into water and extracted with ethyl acetate (< 30 ° C). The organic layer was evaporated and the residue obtained was triturated under diisopropyl ether with 3 drops of 2-propanol. The resulting precipitate was filtered and purified by reverse phase silica column chromatography (eluent: dichloromethane). The product fractions were collected and the solvent was evaporated, yielding 0.6 g of the compound (52).

Compounds (2) to (34) were prepared by reacting intermediate (1) with one of the following reagents: 2- (R) -piperidinecarboxylic acid methyl ester hydrochloride, 2- (S) methyl ester hydrochloride -piperidinecarboxylic acid, 3- (ethoxycarbonyl) piperidine, (S) -3-piperidinecarboxylic acid ethyl ester, (R) -3-piperidinecarboxylic acid ethyl ester, ethyl D-proline hydrochloride, ethyl ester hydrochloride 4-trans-hydroxy-L-proline, methyl ester hydrochloride of 4-trans-hydroxy-L-proline, methyl ether hydrochloride of 4-cis-hydroxy-L-proline, methyl ester hydrochloride (± ) -alanine, (S) -alaninate ethyl hydrochloride, (R) -alaninate ethyl hydrochloride, (±) -valine methyl ester hydrochloride, (S) -valine ethyl ester hydrochloride, (R) -valine ethyl ester hydrochloride, (R) -phenylglycine ethyl ester hydrochloride, (S) -phenylglycine ethyl ester hydrochloride, hydrochloride of methyl ester of (±) -phenylalanine, ethyl ester of (S) -phenylalanine, ethyl ester of (R) -phenylalanine, hydrochloride of 3-aminopropionic acid ethyl ester, N-methyl-licinate hydrochloride of ethyl, diethyl L-glutamate hydrochloride, (S) -2-amino-4 - [[(1,1-dimethyl-ethoxy) carbonyl] amino] -butanoic acid methyl ester hydrochloride, methyl ester hydrochloride N5 - [(1,1-dimethyl-ethoxy) carbonyl] -L-omitin, N6 - [(1,1-dimethyl-ethoxy) carbonyl] -L-lysine methyl ester hydrochloride, ethyl ester hydrochloride alanine, (S) -leucine ethyl ester hydrochloride, tryptophan ethyl ester hydrochloride, S-methionine ethyl ester hydrochloride, ester hydrochloride (S) -tyrosine ethyl ester, (S) -proline ethyl ester hydrochloride or 3-amino-3-benzo [1,3-dioxol-5-yl-propionic acid ethyl ester hydrochloride]. Table F-1 lists the compounds that were prepared according to one of the above Examples.

TABLE F-1 omitted (S) Compound Number 10; Example B.1; Compound Number 38; Example B.2; (S) (R) p. F. 213-215 ° C; [a] 20D = + 13 ° (c = 0.5% weight / volume in ethanol) Compound Number 11; Example B.1; Compound Number 39; Example B.2; (S) (S) p. F. 210-212 ° C; [a] 20D = -18 ° (c = 0.5% weight / volume in ethanol) Compound Number 12; Example B.1; Compound Number 40; Example B.2; (R) (R) p. F. 200-202 ° C; [a] 20D = + 27 ° (c = 0.5% weight / volume in ethanol) Compound Number 13; Example B.1; Compound Number 41; Example B.2; (R) (S) p. F. 203-205 ° C; [a] 20D = -21 ° (c = 0.5% weight / volume in ethanol) Compound identification Compounds (8) to (34) were identified by LC / MS using a gradient elution system in reverse phase HPLC. The compounds were identified by their specific retention time and their MH + peak of the protonated molecular ion. The HPLC gradient was supplied by a Waters Alliance HT 2790 system with a column heater set at 40 ° C. The column flow was divided into a detector of the Waters 996 photodiode array (PDA) and a Waters Micromass ZQ mass spectrometer with an electro-ionization ionization source operated in the positive and negative ionization mode. Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml / minute. Three mobile phases were used (mobile phase A: 95% 25 mM ammonium acetate + 5% acetonitrile, mobile phase B: acetonitrile, mobile phase C: methanol), to run a gradient condition of 100% from A to 50 % B and 50% C in 10 minutes, 100% B in 1 minute, 100% B for 3 minutes and rebalance with 100% A for 2.5 minutes. An injection volume of 10 μL was used. Mass spectra were acquired by scanning from 100 to 1000 in 1 second, using a residence time of 0.1 seconds. The capillary needle voltage was 3 kV, and the source temperature was maintained at 140 ° C. Nitrogen was used as the nebulizer gas. The cone voltage was 10 V for the positive ionization mode and 20 V for the mode of negative ionization. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

TABLE F-2 Retention time (TR in minutes) and molecular weight as MH + PHARMACOLOGICAL EXAMPLES C.1. Quantification of ApoB secretion HepG2 cells were cultured in 24-well plates in MEM Rega 3, containing 10% fetal calf serum. At 70% confluence, the medium was loaded and the second compound or carrier (DMSO, 0.4% final concentration) was added. After 24 hours of incubation, the medium was transferred to Eppendorf tubes and removed by centrifugation. A sheep antibody directed against apoB was added to the supernatant and the mixture was kept at 8 ° C for 24 hours. Next, the rabbit anti-rave antibody was added and the immune complex allowed to precipitate for 24 hours at 8 ° C. The immunoprecipitate was granulated by centrifugation for 25 minutes at 1320 g and washed twice with a buffer containing 40 mM Mops, 40 mM NaH2PO4, 100 mM NaF, 0.2 mM DTT, 5 mM EDTA, 5 mM EGTA, Triton-X-100 at 1%, 0.5% sodium deoxycholate (DOC), 0.1% SDS, 0.2 μM leupeptin and 0.2 μM PMSF. The radioactivity in the granule was quantified by liquid scintillation counting. The resulting Cl50 values are listed in Table C.1. When the calculated Cl50 was less than 6, not enough data points were available at the concentrations tested to calculate a CI5o- value.

TABLE C.1 Values of pCI50 (= -log of the Clgg value) C.2. MTP assay MTP activity was measured using an assay similar to one described by J. R. Wetterau and D. B. Zilversmit in Chemistry and Physics of Lipids, 38, 205-222 (1985). To prepare the donor and recipient vesicles, the appropriate lipids in chloroform were placed in a glass test tube, and dried under a stream of N2. A shock absorber that contains 15 mM Tris HCl pH 7.5, 1 mM EDTA, 40 mM NaCl, 0.02% NaN3 (assay buffer), added to the dried lipid. The mixture was vortexed briefly, and the lipids were then allowed to hydrate for 20 minutes on ice. The vesicles were then prepared by sonication of the bath (Benson 2200) at room temperature for a maximum of 15 minutes. Butylated hydroxytoluene was included in all preparations of the vesicles at a concentration of 0.1%. The mixture of the lipid transfer assay containing the donor vesicles (40 nmol phosphatidylcholine, 7.5% in mol of cardiolipin and 0.25% in mol of glycerol tri [1-14C] -oleate), receptor vesicles (240 nmol phosphatidylcholine) and mg of BSA in a total volume of 675 μl in a 1.5 ml microcentrifuge tube. The test compounds were added dissolved in DMSO (0.13% final concentration). After 5 minutes of preincubation at 37 ° C, the reaction was initiated by the addition of MTP in 100 μl of dialysis buffer. The reaction was stopped by the addition of 400 μl of DEAE-cellulose 52 pre-equilibrated in 15 mM Tris-HCl, pH 7.5, 1 M EDTA, 0.02% NaN3 (1: 1, volume / volume). The mixture was stirred for 4 minutes and centrifuged for 2 minutes at a maximum speed in an Eppendorf centrifuge (4 ° C) to pellet the donor vesicles bound to DEAE-52. An aliquot of supernatant containing the receptor liposomes was counted and [14 C] counts were used to calculate the percent triglyceride transfer for donor vesicles to recipients. The percent of triglyceride transfer from donor vesicles to recipients measured, results in a "% C" value (% control) of 100%, when the test compound does not inhibit MTP activity, and a lower% C value when the test compound inhibits MTP activity. The resulting IC50 values are listed in Table C.2. When the calculated Cl50 was less than 7, not enough data points were available at the concentrations tested to calculate an IC50 value.

TABLE C.2 Values of pCI50 (= -log of the value of Clsn)

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R 1 is hydrogen, C 1-4 alkyl, halo or polyhaloalkyl of C -? - 4; R 2 is hydrogen, C 1-4 alkyl, halo or polyhaloalkyl of C -? _; R3 is hydrogen or C-) alkyl; R 4 is hydrogen, C 1-4 alkyl, or halo; n is an integer of 0 or 1; X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon; or X1 is carbon and X2 is nitrogen; X3 is carbon or nitrogen; Y represents O or NR6, wherein R6 is hydrogen or C-? -4 alkyl; R5 represents a radical of formula wherein, m is an integer of 0, 1 or 2; Z is O or NH; R7 is hydrogen; C? -6 alkyl; C? -6 alkyl substituted with hydroxy, amino, mono or di (C-? -) alkyl amino, C1- alkyloxycarbonyl, aminocarbonyl, aryl or heteroaryl; C 1-4 alkyl-O-C 1 - alkyl; C 1-4 alkyl-S-C 4 alkyl; or aryl; R8 is hydrogen or alkyl

R9 is hydrogen, C? -4 alkyl, aryl1, or C? -alkyl substituted with aryl1; or when Y represents NR 6, the radicals R 5 and R 6 can be taken together with the nitrogen to which they are attached to form a pyrrolidinyl substituted with C 1 alkyloxycarbonyl, and optionally further substituted with hydroxy; or piperidinyl substituted with C1- alkyloxycarbonyl; aryl is phenyl; phenyl substituted with one, two or three substituents, each independently selected from C 1-4 alkyl, C 1-4 alkyloxy, halo, hydroxy, nitro, cyano, C 1-4 alkyloxycarbonyl, trifluoromethyl or trifluoromethoxy; or benzo [1,3] dioxolyl; aryl1 is phenyl; phenyl substituted with one, two or three substituents, each independently selected from C 1-4 alkyl, C 1-4 alkyloxy, halo, hydroxy, nitro, cyano, C 1- alkyloxycarbonyl, trifluoromethyl or trifluoromethoxy; and the heteroaryl is imidazolyl, thiazolyl, indolyl or pyridinyl. 2. The compound according to claim 1, further characterized in that X1, X2 and X3 are carbon.

3. - The compound according to claim 1, further characterized in that R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6, wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1), wherein m is the integer 0.

4. The compound according to claim 1, further characterized in that R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6, wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1), wherein m is the integer 1.

5. The compound according to claim 1, further characterized in that R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6, wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-2), wherein m is the integer 1.

6. The compound according to claim 1, further characterized in that R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 and R5 and R6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl substituted with C-- 4 alkyloxycarbonyl and optionally further substituted with hydroxy, or substituted piperidinyl with C1-alkyloxycarbonyl.

7. - A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any of claims 1 to 6.

8. A process for preparing a pharmaceutical composition according to claim 7, wherein an amount Therapeutically active compound of any one of claims 1 to 6 is intimately mixed with a pharmaceutically acceptable carrier.

9. The compound according to any of claims 1 to 6, further characterized in that it is used as a medicine.

10. A process for preparing a compound of formula (I), wherein a) an intermediate of formula (II), wherein R3, R4, R5, Y, n, X1, X2 and X3 are as defined in accordance with claim 1, is reacted with a biphenylcarboxylic acid or a halide having the formula (III), wherein R1 and R2 are as defined in the formula (I), and Q1 is selected from hydroxy and halo, in at least one reaction with a inert solvent and optionally, in the presence of a suitable base b) or, the compounds of formula (I) are each converted following the transformation reactions known in the art; or if desired; a compound of formula (I) is converted to an acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted to a free base form with an alkali; and, if desired, preparing the stereochemically isomeric forms thereof.